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Market signals such as: (1) the limited number of biosimilars in the development pipeline, (2) the focus of biosimilar development on high-profit therapeutic areas only, and (3) the increase in the number of biosimilar discontinuations and withdrawals, are indicative of sustainability threats facing biosimilar markets in Europe. Two prominent factors that undermine sustainability are: competing interests between the various stakeholders and a preferential focus on short-term gains, disregarding future sustainability threats, hence the need for effective policies that create sustainable competition in biologic markets. Thus far, measures implemented to foster biosimilar adoption have not been necessarily complied with and have had mixed success. Further, these policies have not consistently led to improving access to affordable biologics. In this commentary, we aim to raise awareness of vulnerabilities of biosimilar markets and of difficulties relating to reaching an agreement on policy solutions with a long-term vision. We propose to build on knowledge from collective action theory to advance in reconciling stakeholder interests. This first-of-its-kind approach can inform long-term solutions for biosimilar markets. [ABSTRACT FROM AUTHOR]

A systematic literature review undertaken by the ISPOR Biosimilar Special Interest Group highlighted that limited guidance exists on how to assess biosimilars value and on appropriate economic evaluation techniques. This study described current health technology assessment (HTA) agency approaches for biosimilar value assessment. Semi-structured interviews (n = 16) were carried out with HTA experts in Africa, America, Asia, Australia, and Europe to investigate current HTA practices for biosimilars. Data categorization was based on a thematic analysis approach. Findings from the qualitative data analysis were interpreted in view of relevant published literature. Our research suggests that in systems in which frameworks for biosimilar regulatory approval are well established, HTA agencies can accept the regulators' comparability exercise, and reimbursement decisions can generally be based on price comparisons. This approach is accepted in practice and allows streamlining of biosimilars value assessment. Nevertheless, conducting HTAs for biosimilars can be relevant when (1) the originator is not reimbursed, (2) the biosimilar marketing authorization holder seeks reimbursement for indications/populations, pharmaceutical forms, methods and routes of administration that differ with respect to the originator, and (3) a price premium is sought for a biosimilar based on an added-value claim. Further, HTA agencies' role conducting class-review updates following biosimilar availability can support greater patients' access to biologics. Internationally, there are differences in how national competent authorities on pricing and reimbursement of pharmaceuticals perceive HTA's role for biosimilars. Therefore, HTA agencies are encouraged to issue clear guidance on when and how to conduct HTAs for biosimilars, and on which economic techniques to apply. • National competent authorities on pricing and reimbursement of pharmaceuticals perceive health technology assessment (HTA)'s role for biosimilars differently. Limited guidance exists on assessing biosimilars value and addressing limitations of current value assessment frameworks. • This article addresses knowledge gaps on HTA agency approaches for biosimilar value assessment. • Our study indicates that biosimilar reimbursement decisions do not need to be systematically informed by HTAs. Nevertheless, conducting HTAs can be occasionally relevant. For example, when: (1) the originator is not reimbursed, (2) biosimilar manufacturers seek reimbursement for indications/populations, pharmaceutical forms, methods and routes of administration that differ with respect to the originator, and (3) price premiums are sought for biosimilars based on added-value claims. [ABSTRACT FROM AUTHOR]

This study aims to provide an overview of the gaps and challenges in the value assessment of biosimilars and to identify potential approaches to address them. A multidisciplinary, international team of biosimilar experts identified gaps and challenges. A systematic review was conducted of the peer-reviewed literature in PubMed, EMBASE, Web of Science Core Collection, EBSCOhost Business Source Complete; and of the gray literature. Preliminary results were presented at ISPOR conferences and this article benefited from 2 review rounds among ISPOR Biosimilar Special Interest Group members. Given that a biosimilar is highly similar to its reference biologic, health technology assessment agencies should accept the comparability exercise approved by regulatory authorities and, thus, conduct a price comparison when biosimilar reimbursement is requested for the same indication as the reference biologic. If the reference biologic is not reimbursed or is not the standard of care, a full economic evaluation of the biosimilar versus a relevant comparator needs to be conducted. To date, little consideration has been given to specific challenges, such as how biosimilar value assessment can account for the nocebo effect, potential differences between biologic-naive and biologic-experienced patients, the availability of intravenous and subcutaneous administration forms or different administration devices for the same active compound, value-added services, and the contribution of biosimilars for generating health gain at the population level. There is a need to gather further insights in the methodology of value assessment for biosimilars, and health technology assessment agencies need to develop more elaborate guidance on biosimilar value assessment in specific circumstances. • There is debate about the methodology of value assessment for biosimilars, and the practices of health technology assessment agencies can vary. • This article discusses and proposes approaches to address multiple challenges in biosimilar value assessment. • In light of the comparability exercise approved by regulatory authorities, a price comparison is appropriate when biosimilar reimbursement is requested for the same indication as the reference biologic. A full economic evaluation needs to be conducted in other specific circumstances. [ABSTRACT FROM AUTHOR]

In the rapidly evolving domain of machine learning, the ability to adapt to unforeseen circumstances and novel data types is of paramount importance. The deployment of Artificial Intelligence is progressively aimed at more realistic and open scenarios where data, tasks, and conditions are variable and not fully predetermined, and therefore where a closed set assumption cannot be hold. In such evolving environments, machine learning is asked to be autonomous, continuous, and adaptive, requiring effective management of uncertainty and the unknown to fulfill expectations. In response, there is a vigorous effort to develop a new generation of models, which are characterized by enhanced autonomy and a broad capacity to generalize, enabling them to perform effectively across a wide range of tasks. The field of machine learning in open set environments poses many challenges and also brings together different paradigms, some traditional but others emerging, where the overlapping and confusion between them makes it difficult to distinguish them or give them the necessary relevance. This work delves into the frontiers of methodologies that thrive in these open set environments, by identifying common practices, limitations, and connections between the paradigms Open-Ended Learning, Open-World Learning, Open Set Recognition, and other related areas such as Continual Learning, Out-of-Distribution detection, Novelty Detection, and Active Learning. We seek to easy the understanding of these fields and their common roots, uncover open problems and suggest several research directions that may motivate and articulate future efforts towards more robust and autonomous systems. • Motivation and significance of managing unknown knowledge in machine learning. • Concepts, definition, and methodological approaches of Open Set Recognition. • Common grounds and distinctions of Open Set Recognition and its related areas. • A prospect of existing problems and future research lines for Open Set Recognition. [ABSTRACT FROM AUTHOR]

Background: To encourage the rational prescribing of biologics, payers across Europe have experimented with the implementation of benefit-sharing programs. Benefit-sharing programs are incentive programs that promote the use of 'best-value' off-patent biologics and biosimilars by driving changes in prescribing practices. The aim of these programs is to generate savings that can be shared among stakeholders involved (e.g. health authorities/payers, health care professionals, hospital managers/administration) and are generally used to improve the quality of health care and to increase patients' access to innovative services and medicines. However, the scarcity of information concerning the design, implementation and outcomes of benefit-sharing programs limits the transfer of knowledge to institutions aiming to adopt these types of incentive schemes in the future. Objective: The aim of our study was to map benefit-sharing experiences across Europe, to compare their design and implementation characteristics and to assess the impact of the different benefit-sharing strategies on the use of 'best-value' biologics. Method: Our approach was based on a literature review and on semi-structured interviews with payers/insurers, regulators, health care professionals and industry representatives. Results: Our analysis revealed variable design characteristics for benefit-sharing programs, depending on the organization of the health care system, the specific timeframe, the care setting and the policy environment. All these aspects can influence the robustness of benefit-sharing initiatives and their potential to stay in effect over time. We also noted a generalized lack of transparency regarding the distribution of savings and how they are reinvested. This lack of transparency has raised questions on how to optimally implement benefit-sharing in the future. Conclusions: To realize the full potential of benefit-sharing programs, we identify the importance of (i) setting up and timely monitoring success indicators for these programs; (ii) including quality of care and access to care parameters as success indicators; (iii) establishing clear pathways for the transparent redistribution/reinvestment of savings and (iv) transparently communicating with patients about the outcomes of benefit-sharing programs. [ABSTRACT FROM AUTHOR]

This article analyzes current theoretical discourses within the Neolithic and Chalcolithic research of Southwestern Asia, which is still dominated by interpretations that assume a progression of increased hierarchization. Whether explicitly or implicitly, social evolutionary thinking still pervades our scholarship, and prevents innovative theory-building. This entails an inability to break with heuristics of 'origins' inherited from the past (e.g. "from the origins of domestication to the origins of civilization"), even though old and new discoveries, when integrated, are already pointing towards alternative research pathways. Sedentism, domestication, and urbanism were all complex, protracted, non-linear processes. Yet, the visualization of an 'Uruk phenomenon' expanding over large areas of Mesopotamia during the 4th millennium BC, ridden with problematic inconsistencies, still heralds the triumphal rise of civilization. Instead of relying on obsolete political and economic theories, or fake economy/ritual dichotomies, the investigation of social intelligence and the articulation of the biosocial in the landscape and within the prehistoric community should be a priority. The 'agency' of 'elites' is merely an interpretive deus ex machina helping scholars deal with the many difficulties and uncertainties of their research. [ABSTRACT FROM AUTHOR]

Introduction: Introduction: disease-related malnutrition (DRM) affects more than 30 million people in Europe, representing about 170 billion euros each year. Despite the growing consensus for the diagnosis of DRM, it is still necessary to implement multidisciplinary and coordinated protocols for a comprehensive approach to DRM in hospitals. Objetive: to study the proportion of patients affected by DRM upon admission, as well as the duration and the cost of their stay in a general hospital. Methods: an observational cross-sectional study with a sample size of 203 subjects. From June to December 2018, a nutritional screening was carried out according to the Nutritional Risk Screening 2002 (NRS-2002); diagnoses were made according to the Global Leadership Initiative on Malnutrition (GLIM) criteria, length of stay was recorded, and the cost of stay was estimated for all patients admitted to Internal Medicine who met the selection criteria. Results: the proportion of people at risk of DRM was 28 % (57/203; 95 % CI: 22 % to 34 %). The proportion of patients diagnosed with DRM was 19 % (36/192; 95 % CI: 13 % to 24 %). Patients classified with risk or diagnosis of DRM upon admission had a longer stay than those with normal nutrition by 3 days (p < 0.01), and a higher cost by €1,803.66 (p < 0.01). Conclusions: a comprehensive, multidisciplinary approach to DRM coordinated from Primary Care to hospitals is necessary, especially in women aged ≥ 70 years with pulmonary disease. [ABSTRACT FROM AUTHOR]

Background: In the context of biosimilar use and switching, a patient's negative perception of a biosimilar might trigger a nocebo effect, where negative expectations unrelated to its pharmacologic action may lead to worsened symptoms, resulting in less perceived therapeutic benefit or worsened adverse events. Considering the crucial role biosimilars have in reducing health care costs and expanding access to safe biologics globally, it is essential to develop and implement effective strategies to mitigate the possible occurrence of such nocebo effects. Objective: The aim of this systematic literature review was two-fold: (i) to review strategies that have been applied and/or tested for minimising the nocebo effect in clinical practice, within and outside the context of biosimilar switching, and (ii) to propose recommendations on useful mitigation strategies to minimise the occurrence of the nocebo effect in the context of biosimilar switching. Methods: Biomedical databases PubMed and Embase were screened up until the end of April 2023 with a search string consisting of the following search terms "nocebo", "biosimilar", "mitigation", "strategy", and "prevention" and related synonyms. The search strategy was supplemented by snowballing of the included studies. The quality of the studies was assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Systematic Reviews and Research Syntheses, the Scale for the Assessment of Narrative Review Articles, and the Mixed Methods Appraisal Tool. Results: Of the 1617 identified and screened records, 60 met the inclusion criteria. Among these, 10 (17%) were conducted within the context of biosimilar switching, 7 of which specifically tested strategies to mitigate the nocebo effect. Among the remaining 50 studies conducted outside the biosimilar switching context, 46 tested mitigation strategies. Across the included studies, 13 distinct mitigation strategies were identified, which can be employed within the context of biosimilar switching: (i) open non-verbal communication, (ii) positive framing, (iii) empathic communication, (iv) validating communication, (v) shared decision making, (vi) self-affirmation, (vii) education of patients and health care professionals about the nocebo effect, (viii) education of patients and health care professionals about biosimilars, (ix) soft-skills training for health care professionals, (x) personalised information, (xi) supporting information, (xii) multidisciplinary approach, (xiii) organisation of the switch. Conclusion: This review has identified a set of strategies that have been tested to mitigate the nocebo effect, which can be applied by health care professionals in the context of biosimilar switching with the aim of mitigating the occurrence of a nocebo effect. We recommend implementing a combination of mitigation strategies for patients and health care professionals to utilise before, during, and after a switch. It should be noted that given the limited number of studies specifically testing nocebo mitigation strategies within the biosimilar switching context to date, it is not yet possible to draw definite conclusions about the effect size of each mitigation strategy individually or in combination. [ABSTRACT FROM AUTHOR]

Amphiphilic nonionic ligands, synthesized with a fixed hydrophobic moiety formed by a thiolated alkyl chain and an aromatic ring, and with a hydrophilic tail composed of a variable number of oxyethylene units, were used to functionalize spherical gold nanoparticles (AuNPs) in water. Steady-state and time-resolved fluorescence measurements of the AuNPs in the presence of α-cyclodextrin (α-CD) revealed the formation of supramolecular complexes between the ligand and macrocycle at the surface of the nanocrystals. The addition of α-CD induced the formation of inclusion complexes with a high apparent binding constant that decreased with the increasing oxyethylene chain length. The formation of polyrotaxanes at the surface of AuNPs, in which many α-CDs are trapped as hosts on the long and linear ligands, was demonstrated by the formation of large and homogeneous arrays of self-assembled AuNPs with hexagonal close packing, where the interparticle distance increased with the length of the oxyethylene chain. The estimated number of α-CDs per polyrotaxane suggests a high rigidization of the ligand upon complexation, allowing for nearly perfect control of the interparticle distance in the arrays. This degree of supramolecular control was extended to arrays formed by AuNPs stabilized with polyethylene glycol and even to binary arrays. Electromagnetic simulations showed that the enhancement and distribution of the electric field can be finely controlled in these plasmonic arrays. [ABSTRACT FROM AUTHOR]

Objective. To study the effectiveness and safety in a real-life setting of budesonide/formoterol (Symbicort) Maintenance And Reliever Therapy® (Symbicort SMART®), a simplified management approach with one inhaler, compared with conventional best practice (CBP) with multiple inhalers in patients with persistent asthma. Design. Open-label randomized controlled parallel-group trial, 6-month treatment. Participants. A total of 654 adult patients, with persistent asthma receiving treatment with inhaled corticosteroids (ICS), either alone or in conjunction with long-acting β2-agonist. Main outcome measures. Time to first severe asthma exacerbation and number of severe asthma exacerbations. Results. No difference between groups was seen in time to first severe exacerbation ( p = .2974). Exacerbation rates were low in both groups. A total of 22 patients in the Symbicort SMART group experienced a total of 24 severe asthma exacerbations, and 31 patients in the CBP group experienced a total of 34 severe asthma exacerbations (annual rate 0.16 vs. 0.22, p = .2869). The mean daily dose of ICS expressed in beclomethasone dipropionate equivalent was significantly lower in the Symbicort SMART group (including as-needed use) versus the CBP group (799 μg vs.1184 μg; p < .001). Mean scores in Asthma Control Questionnaire, five-question version, improved significantly in the SMART group compared with the CBP group (p = .0292). Symbicort SMART and CBP were equally well tolerated. The mean drug cost per patient per 6 months was lower for the patients in the SMART group compared with patients receiving CBP (€295.32 vs. €387.98, p < .0001). Conclusions. A simplified regimen using budesonide/formoterol maintenance and reliever therapy (Symbicort SMART) was at least as effective at improving clinical control compared with CBP with a significantly lower ICS dose and lower drug costs. [ABSTRACT FROM AUTHOR]

Introduction. Control is a priority treatment objective in asthma, and classification based on control is recommended in the follow-up of asthmatic patients. Different factors affect this control, and there are several regional differences, both in terms of prevalence and in terms of management and degree of control. Objective. To evaluate the factors associated with control of severe asthma in routine clinical practice. Material and Methods. This was a prospective, cross-sectional, observational study of patients with severe asthma who were receiving treatment with a fixed combination of a corticosteroid (at least 800 μg/day of budesonide or equivalent) and an inhaled β2-adrenergic agonist in respiratory medicine and allergology clinics throughout Spain. The authors collected demographic and socioeconomic data, as well as clinical data on asthma. The patients also completed a self-administered validated questionnaire—the Asthma Control Questionnaire (ACQ)—about the control of their asthma. Results. The authors included 1471 patients, of whom 1224 (83%) were valid for the final analysis. Women accounted for 61%. Mean age was 51 ± 16 years. The mean number of exacerbations during the previous year was 2.0 ± 2.0. The global score on the ACQ was 1.8 ± 1.1 (0 = no symptoms; 6 = maximum number of symptoms). Only 20.4% of patients were well controlled (ACQ < 0.75), and 55.7% of patients were poorly controlled (ACQ > 1.5). The multivariate analysis revealed that the variable with the greatest effect on control of asthma was the number of exacerbations during the previous year: when the number of exacerbations increased from 0 to 1 or more, the ACQ score increased by 0.56 points. Employed patients had a mean of 0.23 points less (better control) than unemployed and retired patients. Control of asthma was also significantly affected by adherence to treatment, patient knowledge of the disease, body mass index, gender, and number of visits to a physician in the previous 3 months. Conclusions. Many patients with severe asthma have poor control of their disease. The number of exacerbations is the variable with the greatest effect on control of asthma. Knowledge of the disease and adherence to treatment are associated with better control. [ABSTRACT FROM AUTHOR]

Efficient electron delocalization by aromatic homoconjugated 7,7-diphenylnorbornane (DPN) in alternated homoconjugated-conjugated block copolymers and reference compounds is revealed by photophysical and electrochemical measurements. The synthesis of the polymers was achieved by Suzuki polycondensation reaction. Effective electron delocalization by DPN is demonstrated by the significant red shifts observed in the absorption and emission spectra and the variation of the energy band gap of the polymers and monomeric model compounds in comparison to a series of oligophenylenes used as references (p-quaterphenyl, p-terphenyl, and biphenyl). The electron delocalization is also clearly demonstrated by the lower oxidation potential measured for homoconjugated model compound in comparison to p-terphenyl. The results show that the electron delocalization caused by two homoconjugated aryl rings is comparable to the effect produced by one conjugated aryl ring. [ABSTRACT FROM AUTHOR]

Introduction. The main objective of asthma treatment is tailored control for each patient. However, despite the excellent therapeutic arsenal currently available, many patients remain unable to achieve adequate control of this disease. Objective. The main objective this study was to evaluate the degree of control and the determinants of asthma in patients with persistent asthma in Spain in usual clinical practice. Materials and Methods. This was a cross-sectional epidemiological study. The patients enrolled were 18 years of age or over, with a 6-month history of diagnosed persistent asthma, who were followed up by primary care physicians in Spain between the months of June and December 2006. Demographic and socioeconomic data were collected, as were anthropometric data and different clinical variables. The control of asthma was evaluated using the Asthma Control Questionnaire (ACQ). Results. The study included 6,824 patients, of whom 306 were excluded; therefore the final number of patients analyzed was 6,518 (95.5%). According to severity, 41.4% of patients had mild persistent asthma, 51.2% had moderate persistent asthma, and the remainder severe persistent asthma. The mean score in the ACQ was 1.4 ± 1.0, distributed as follows: in 28.4% of cases, the score was below 0.75; in 31.6%, it was between 0.75 and 1.5; and in 39.7% it was above 1.5. Multiple regression analysis showed that the factor that most affected the degree of control of the disease was classification by severity. Other associated factors were sex, race, body mass index, smoking, level of education, habitual activity, years since diagnosis of asthma, number of exacerbations and admissions to hospital during the last year, and basic treatment of the disease. Conclusions. The number of patients with poorly controlled persistent asthma in Spain is high (71.6%). There are demographic, socioeconomic, anthropometric, and clinical variables that affect the level of control of this disease. [ABSTRACT FROM AUTHOR]

Abstract: To evaluate the success of almost 20 years of pollution abatement in the Bilbao estuary watershed in northern Spain, we analyzed temporal trends in pollution discharges and water quality from 1993 to 2003. Over that period a great portion of the raw wastewater discharge was intercepted and treated, leading to a significant reduction in the pollution load to the estuary (51.8% in biochemical oxygen demand, 70.9% in ammonia nitrogen and 81.9% in faecal coliforms). Temporal trends of mean annual levels of water quality variables showed statistically significant increases in dissolved oxygen saturation (between 2.04 and 4.11%/year) and decreases in ammonia nitrogen (between −4.15 and −175.75μMNH3/year) and faecal coliforms concentrations (from 2.55×105 to 2.13×104 CFU/100ml). The improvement of the Bilbao estuary water quality reported in this paper is primarily attributed to the pollution abatement measures accomplished by the local water authority. Finally, as a result of these pollution control efforts, European bathing water quality standards were met at local beaches. [Copyright &y& Elsevier]

Background: Resveratrol is a polyphenol with important antiinflammatory and antioxidant properties. We investigated the effect of resveratrol on alcohol-induced mortality and liver lesions in mice. Methods: Mice were randomly distributed into four groups (control, resveratrol-treated control, alcohol and resveratrol-treated alcohol). Chronic alcohol intoxication was induced by progressively administering alcohol in drinking water up to 40% v/v. The mice administered resveratrol received 10 mg/ml in drinking water. The animals had free access to standard diet. Blood levels were determined for transaminases, IL-1 and TNF-á. A histological evaluation was made of liver damage, and survival among the animals was recorded. Results: Transaminase concentration was significantly higher in the alcohol group than in the rest of the groups (p < 0.05). IL-1 levels were significantly reduced in the alcohol plus resveratrol group compared with the alcohol group (p < 0.05). TNF-á was not detected in any group. Histologically, the liver lesions were more severe in the alcohol group, though no significant differences between groups were observed. Mortality in the alcohol group was 78% in the seventh week, versus 22% in the alcohol plus resveratrol group (p < 0.001). All mice in the alcohol group died before the ninth week. Conclusion: The results obtained suggest that resveratrol reduces mortality and liver damage in mice. [ABSTRACT FROM AUTHOR]

Examines the chemical properties of the prepared diphenylmethane derivatives. Measurement of the 2-fluoroaryl-norbornane bond by the DNMR; Description of the electrostatic interactions; Details on the preparation of the diphenylmethane.

Liver-associated lymphocytes (LAL) from human liver are phenotypically and functionally different from peripheral blood lymphocytes (PBL). Phenotypically, they are mainly represented by the CD3+/-CD56+ phenotype and functionally they spontaneously possess lymphokine-activated killer (LAK) activity. In this study we evaluated the expression of cell-adhesion molecules (CAM) which could be involved in LAL contacts with other sinusoidal cells and/or be responsible for the LAK activity. The LAL population was isolated by sinusoidal high-pressure lavage from partial hepatectomies obtained from patients operated on for benign liver disease (n=6). Surface expression of the β22 integrin chains (CD18, CD11a, CD11b, CD11c), as well as that of members of the immunoglobulin superfamily (CD2, CD54, CD56, CD58), were analysed by one or two-colour flow cytometry. Quantitative and qualitative differences were observed in the expression of CAM between LAL and PBL. LAL were characterized by an increase in the percentages of CD11b+, CD54+, CD56+ and CD58+ cells and a decrease in the percentage of CD2+ cells compared to PBL. Fluorescence intensity values for CD2 and CD56 were higher in LAL than in PBL. Moreover, CD11a/CD18 cells presented a bimodal distribution (dim and bright) in both PBL and LAL; whereas these two subpopulations were equally represented in PBL, the number of bright cells was significantly greater (>80%) in LAL. The increase in CAM expression (percentage of positive cells and intensity of fluorescence) on LAL combined with their increase in natural killer (NK) and LAK activities already reported, support the idea that, at least some, LAL might be, compared to PBL, in an activated state in vivo. [ABSTRACT FROM AUTHOR]

Drug budget and prescription control measures are implemented regionally in Germany, meaning that the uptake of pharmaceuticals, including biosimilars, can vary by region. We examine regional market dynamics of tumor necrosis factor alpha (TNFα) inhibitor originators and biosimilars in Germany and studied the influence of biosimilar policies on these dynamics. This study is based on: (1) a literature review in which German biosimilar policies are identified, (2) the analysis of dispensing data (2010–2018) for the class of TNFα inhibitors, and (3) ten semi-structured interviews investigating prescribers' and insurers' views on factors potentially influencing biosimilar uptake. The analysis of biosimilar market shares of infliximab and etanercept revealed wide variations across the 17 German Regional Associations of Statutory Health Insurance Accredited Physicians (PA regions). Quantitative analyses indicated that biosimilar market shares for infliximab and etanercept were significantly lower in former East Germany when compared to former West Germany regions. Through qualitative interview analyses, this study showed that the use of infliximab and etanercept biosimilars across Germany is primarily influenced by (1) the regional-level implementation of biosimilar quotas and the presence of monitoring/sanctioning mechanisms to ensure adherence to these quotas, (2) the different insurer-manufacturer discount contracts, and (3) gainsharing arrangements established at the insurer-prescriber level. [ABSTRACT FROM AUTHOR]

Background/Objectives: The objective of this meta-analysis was to determine the impact of bariatric surgery on phase angle (PhA) and other bioimpedance measures among adults with obesity, comparing the effects of Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). Methods: A systematic review and meta-analysis were conducted following PRISMA guidelines, including studies up to May 2024 from MEDLINE, Scopus, Cochrane Library, and Web of Science. Eligible studies assessed PhA changes pre- and post-bariatric surgery in adults with BMI ≥ 30 kg/m2. Data on PhA, fat mass (FM), fat-free mass (FFM), body cell mass (BCM), weight, and BMI were extracted and analyzed. Results: Thirteen studies with a total of 1124 patients were included. Significant PhA reductions were observed at 6 months post-surgery (effect size: −1.00; 95% CI: −1.11 to −0.89; p < 0.001), with a more substantial reduction in RYGB patients compared to SG. FM and FFM decreased significantly at 12 months (FM: −27.58; 95% CI: −32.58 to −22.57; p < 0.001; FFM: −10.51; 95% CI: −12.81 to −8.94; p < 0.001). Weight and BMI showed marked reductions at 6 months (Weight: −31.42 kg; 95% CI: −37.28 to −25.26; p < 0.001; BMI: −11.39; 95% CI: −12.60 to −10.18; p < 0.001), with sustained decreases at 12 and 24 months. Conclusions: Bariatric surgery significantly reduces PhA, FM, FFM, weight, and BMI, with initial greater impacts observed in RYGB compared to SG. PhA shows potential as a marker for monitoring post-surgical recovery and nutritional status. Further long-term studies and standardized measurement protocols are recommended to optimize patient management. [ABSTRACT FROM AUTHOR]

Background: Erectile dysfunction (ED) can stem from various organic and functional causes but is often linked to vascular health and cardiovascular disease. Limited data exist on how cardiovascular disease markers correlate with objective ED tests like the Nocturnal Penile Tumescence and Rigidity (NPTR) test and Penile Color Doppler Ultrasound (PCDU). Methods: A prospective observational study was performed, and 58 men with ED were assessed using the International Index of Erectile Function-15 (IIEF-15), NPTR test, and PCDU. Peripheral vascular health was evaluated through carotid intima-media thickness (cIMT) and brachial flow-mediated dilation (FMD). Results: Out of the participants, 44 had normal NPTR results, while 14 had abnormal results. The group with abnormal NPTR results was significantly older and had higher rates of hypertension and diabetes. Although the IIEF-15 scores were similar between the two groups, those with abnormal NPTR results had a lower peak systolic velocity (PSV) and a higher prevalence of impaired PSV. Correlations between the IIEF, NPTR, PCDU, and peripheral vascular markers lost significance after the age adjustment. Conclusions: This study suggests that abnormal NPTR results, combined with cardiovascular risk factors, may signal vascular ED and generalized vasculopathy, highlighting the need for cardiovascular assessment. An accurate ED diagnosis should integrate clinical evaluation with multiple tests while considering aging as a key risk factor. [ABSTRACT FROM AUTHOR]

Several models, theoretical levels and computational methods, all based on the canonical variational transition state approximation, have been used to predict both the experimental activation energies (Δ Eexp≠) and the experimental activation free energies (Δ Gexp≠) for the hydrolysis of aryldiazonium ions. It is demonstrated that the computation of activation energies (Δ E≠), instead of activation free energies (Δ G≠), agrees better with the corresponding experimental data, showing that the employed computational methods do not afford reliable entropic contributions to the free energy barriers in the case of the studied reaction. However, the most fitted computations of Δ E≠ were not able to clearly differentiate between the mechanisms proposed for this interesting reaction (SN1, SN2 and water cluster). In contrast, the use of the Marcus theory (hyperbolic-cosine equation) instead of the canonical variational transition state theory leads to excellent agreement between the in-water-computed activation energies (Δ EwM≠) and the corresponding Δ Eexp≠ values for the SN2 mechanism, but far beyond the limit of error for the SN1 process. The validity of the Marcus theory for the studied SN1 and SN2 reactions is ensured by the fact that both reactions can be described as SET processes. On the other hand, apparently compelling evidence against the SN2 mechanism, such as 13C KIEs and experimental observation of N2 scrambling, are also discussed and alternative explanations are proposed. [ABSTRACT FROM AUTHOR]

Brachydactyly (BD) refers to the shortening of the hands, feet or both. There are different types of BD; among them, type E (BDE) is a rare type that can present as an isolated feature or as part of more complex syndromes, such as: pseudohypoparathyroidism (PHP), hypertension with BD or Bilginturan BD (HTNB), BD with mental retardation (BDMR) or BDE with short stature, PTHLH type. Each syndrome has characteristic patterns of skeletal involvement. However, brachydactyly is not a constant feature and shows a high degree of phenotypic variability. In addition, there are other syndromes that can be misdiagnosed as brachydactyly type E, some of which will also be discussed. The objective of this review is to describe some of the syndromes in which BDE is present, focusing on clinical, biochemical and genetic characteristics as features of differential diagnoses, with the aim of establishing an algorithm for their differential diagnosis. As in our experience many of these patients are recruited at Endocrinology and/or Pediatric Endocrinology Services due to their short stature, we have focused the algorithm in those steps that could mainly help these professionals. [ABSTRACT FROM AUTHOR]

Selection of reservoir location, the floodable basin forest handling, and the design of dam structures devoted to water supply (e.g. water outlets) constitute relevant features which strongly determine water quality and frequently demand management strategies to be adopted. Although these crucial aspects should be carefully examined during dam design before construction, currently the development of ad hoc limnological studies tailoring dam location and dam structures to the water quality characteristics expected in the future reservoir is not typical practice. In this study, we use numerical simulation to assist on the design of a new dam project in Spain with the aim of maximizing the quality of the water supplied by the future reservoir. First, we ran a well-known coupled hydrodynamic and biogeochemical dynamic numerical model (DYRESM–CAEDYM) to simulate the potential development of anoxic layers in the future reservoir. Then, we generated several scenarios corresponding to different potential hydraulic conditions and outlet configurations. Second, we built a simplified numerical model to simulate the development of the hypolimnetic oxygen content during the maturation stage after the first reservoir filling, taking into consideration the degradation of the terrestrial organic matter flooded and the adoption of different forest handling scenarios. Results are discussed in terms of reservoir design and water quality management. The combination of hypolimnetic withdrawal from two deep outlets and the removal of all the valuable terrestrial vegetal biomass before flooding resulted in the best water quality scenario. [Copyright &y& Elsevier]

The activation energy in the gas phase (ΔE) and the free energy of activation (ΔG) in water solution for the hydrolysis of the monohydrates of methyl chloride (Me Cl), tert-butyl chloride (t-BuCl), and 1-adamantyl chloride (AdC1) have been computed with the B3LYP/631-G(d) method and the polarizable continuum (PCM) solvation model. There is a fair agreement between the ΔG values computed by us and the experimental data. The mechanistic implications of our computations are in severe contradiction with conventional representations. Thus, the computed nucleophilic solvent assistance (NSA) for the backside attack of a water molecule in the hydrolysis of MeCl is slightly lower than the corresponding NSA for t-BuCl. Hence, the hydrolysis of both MeCl and t-BuCl takes place mainly according to the classical SN2 mechanism. The most relevant difference is that ΔG for the frontside attack of water to t-BuCl is disfavored only by ca. 2 kcal/mol with regard to the backside attack but by ca. 23 kcal/mol in the case of MeCl. The higher solvolysis rate in water of t-BuCl in relation to AdCl is not due to steric factors affecting the specific solvation of the corresponding transition states, but to differential bulk solvent effects, which are accounted for by the PCM model. [ABSTRACT FROM AUTHOR]

Examines the effect of methyl group on bridgehead cations. Stability of the cations in the gas phase; Solvolysis of cubyl triflate; Structure of the carbocation.

Pratylenchus thornei-chickpea interactions were investigated under controlled and fluctuating environmental conditions in the growth chamber, greenhouse and shadehouse. Under controlled conditions. P. thornei infected chickpea tines 12071/10054 and P 2245 and cukivars Andoum 1, JG 62 and UC27. Line P2245 and cv. JG 62 were the most susceptible genotypes on the basis of root damage and nematode reproduction, but nematode infection did not significantly reduce root and shoot weights. Cultivars Andoum 1 and UC 27 and line 12071/10054 showed the least root damage and nematode reproduction. Inoculation of cv. Andoum 1 with 2500,5000 or 10000 nematodes per plant in pots did not affect shoot weight. regardless of the conditions of water stress of the plants. However, root weight was significantly reduced by nematode infection in plants grown under water stress and fluctuating temperature conditions in the greenhouse. but was not affected by any other treatment. The nematode reproduction index was not affected by soil water content under shadehouse conditions, but was greater on plants watered to soil water-holding capacity than in water-stressed plants under greenhouse conditions. For both environments, the nematode reproduction index decreased when inoculum density was greater than 5000 nematodes per plant. [ABSTRACT FROM AUTHOR]

The design of nanovectors able to overcome biological barriers is one of the main challenges in biomedicine. Gemini cationic lipids are considered potential candidates for gene therapy due to their high biocompatibility and capacity to condense nucleic acids safely in the form of lipoplexes. However, this approach presents difficulties regarding genetic unpacking and, therefore, control over this process becomes crucial to ensure successful transfection. In this work, gemini cationic lipoplexes were prepared in the presence of plasmonic gold nanostars (AuNSs) to afford a nanovector that efficiently releases plasmid DNA (pDNA) upon irradiation with near-infrared femtosecond laser pulses. A critical AuNSs concentration of 50 pM and optimized laser power density of 400 mW led to successful pDNA release, whose efficiency could be further improved by increasing the irradiation time. Agarose gel electrophoresis was used to confirm pDNA release. UV-Vis-NIR spectroscopy and transmission electron microscopy studies were performed to monitor changes in the morphology of the AuNSs and lipoplexes after irradiation. From a physicochemical point of view, this study demonstrates that the use of AuNSs combined with gemini cationic lipoplexes allows control over pDNA release under ultrafast laser irradiation. [ABSTRACT FROM AUTHOR]

Background: Pathogenic variants in the spastic paraplegia type 7 gene cause a complicated hereditary spastic paraplegia phenotype associated with classical features of mitochondrial diseases, including ataxia, progressive external ophthalmoplegia, and deletions of mitochondrial DNA.Objectives: To better characterize spastic paraplegia type 7 disease with a clinical, genetic, and functional analysis of a Spanish cohort of spastic paraplegia type 7 patients.Methods: Genetic analysis was performed in patients suspecting hereditary spastic paraplegia and in 1 patient with parkinsonism and Pisa syndrome, through next-generation sequencing, whole-exome sequencing, targeted Sanger sequencing, and multiplex ligation-dependent probe analysis, and blood mitochondrial DNA levels determined by quantitative polymerase chain reaction.Results: Thirty-five patients were found to carry homozygous or compound heterozygous pathogenic variants in the spastic paraplegia type 7 gene. Mean age at onset was 40 years (range, 12-63); 63% of spastic paraplegia type 7 patients were male, and three-quarters of all patients had at least one allele with the c.1529C>T (p.Ala510Val) mutation. Eighty percent of the cohort showed a complicated phenotype, combining ataxia and progressive external ophthalmoplegia (65% and 26%, respectively). Parkinsonism was observed in 21% of cases. Analysis of blood mitochondrial DNA indicated that both patients and carriers of spastic paraplegia type 7 pathogenic variants had markedly lower levels of mitochondrial DNA than control subjects (228 per haploid nuclear DNA vs. 176 vs. 573, respectively; P < 0.001).Conclusions: Parkinsonism is a frequent finding in spastic paraplegia type 7 patients. Spastic paraplegia type 7 pathogenic variants impair mitochondrial DNA homeostasis irrespective of the number of mutant alleles, type of variant, and patient or carrier status. Thus, spastic paraplegia type 7 supports mitochondrial DNA maintenance, and variants in the gene may cause parkinsonism owing to mitochondrial DNA abnormalities. Moreover, mitochondrial DNA blood analysis could be a useful biomarker to detect at risk families. © 2019 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Genomic technologies such as next-generation sequencing (NGS) are revolutionizing molecular diagnostics and clinical medicine. However, these approaches have proven inefficient at identifying pathogenic repeat expansions. Here, we apply a collection of bioinformatics tools that can be utilized to identify either known or novel expanded repeat sequences in NGS data. We performed genetic studies of a cohort of 35 individuals from 22 families with a clinical diagnosis of cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Analysis of whole-genome sequence (WGS) data with five independent algorithms identified a recessively inherited intronic repeat expansion [(AAGGG) exp ] in the gene encoding Replication Factor C1 (RFC1). This motif, not reported in the reference sequence, localized to an Alu element and replaced the reference (AAAAG) 11 short tandem repeat. Genetic analyses confirmed the pathogenic expansion in 18 of 22 CANVAS-affected families and identified a core ancestral haplotype, estimated to have arisen in Europe more than twenty-five thousand years ago. WGS of the four RFC1 -negative CANVAS-affected families identified plausible variants in three, with genomic re-diagnosis of SCA3, spastic ataxia of the Charlevoix-Saguenay type, and SCA45. This study identified the genetic basis of CANVAS and demonstrated that these improved bioinformatics tools increase the diagnostic utility of WGS to determine the genetic basis of a heterogeneous group of clinically overlapping neurogenetic disorders. [ABSTRACT FROM AUTHOR]

Huntington’s disease (HD) age of onset (AO) is mainly determined by the length of the CAG repeat expansion in the huntingtin gene. The remaining AO variability has been attributed to other little-known factors. A factor that has been associated with other neurodegenerative diseases is arterial hypertension (AHT). The aim of this study is to evaluate the contribution of AHT to the AO of HD. We used data from a cohort of 630 European HD patients with adult onset collected by the REGISTRY project of the European Huntington’s Disease Network. Multiple linear regression and ANOVA, controlling for the CAG repeat number of the expanded allele (CAGexp) of each patient, were performed to assess the association between the AHT condition and the AO of the motor symptoms (mAO). The results showed a significant association between AHT and mAO, especially when we only considered the patients diagnosed with AHT prior to manifesting any HD signs (pre-HD AHT). Remarkably, despite the low number of cases, those patients developed motor symptoms 5–8 years later than normotensive patients in the most frequent CAGexp range (40–44). AHT is an age-related condition and consequently, the age of the patient at the time of data collection could be a confounder variable. However, given that most pre-HD AHT patients included in our study had started treatment with antihypertensive drugs prior to the onset of HD, and that antihypertensive drugs have been suggested to confer a neuroprotective effect in other neurodegenerative diseases, raises the interest in elucidating the impact of AHT and/or AHT treatment in HD age of onset in further studies. A confirmation of our results in a larger sample set would open the possibility to significantly improve HD management. [ABSTRACT FROM AUTHOR]

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disorder characterized by insensitivity to noxious stimuli and variable intellectual disability (ID) due to mutations in the NTRK1 gene encoding the NGF receptor TrkA. To get an insight in the effect of NTRK1 mutations in the cognitive phenotype we biochemically characterized three TrkA mutations identified in children diagnosed of CIPA with variable ID. These mutations are located in different domains of the protein; L213P in the extracellular domain, Δ736 in the kinase domain, and C300stop in the extracellular domain, a new mutation causing CIPA diagnosed in a Spanish teenager. We found that TrkA mutations induce misfolding, retention in the endoplasmic reticulum (ER), and aggregation in a mutation-dependent manner. The distinct mutations are degraded with a different kinetics by different ER quality control mechanisms; although C300stop is rapidly disposed by autophagy, Δ736 degradation is sensitive to the proteasome and to autophagy inhibitors, and L213P is a long-lived protein refractory to degradation. In addition L213P enhances the formation of autophagic vesicles triggering an increase in the autophagic flux with deleterious consequences. Mouse cortical neurons expressing L213P showed the accumulation of LC3-GFP positive puncta and dystrophic neurites. Our data suggest that TrkA misfolding and aggregation induced by some CIPA mutations disrupt the autophagy homeostasis causing neurodegeneration. We propose that distinct disease-causing mutations of TrkA generate different levels of cell toxicity, which may provide an explanation of the variable intellectual disability observed in CIPA patients. [ABSTRACT FROM AUTHOR]

Previous work demonstrated that physiological, morphological, and gene expression changes as well as the time-dependent entry into the viable but not culturable (VBNC) state are used by Vibrio species to survive and cope with diverse stress conditions including seasonal temperature downshifts and starvation. To learn more about the nature and specific contribution of membrane proteins to cell adaptation and survival, we analyzed variations in the protein composition of cell envelope and related them to morphological and physiological changes that were taking place during the long-term permanence of Vibrio harveyi in seawater microcosm at 4 °C. We found that after 21 days of permanence, nearly all population (ca. 99 %) of V. harveyi acquired the VBNC phenotype. Although the size of V. harveyi cells gradually decreased during the incubation time, we found that this morphological change was not directly related to their entry into the VBNC state. Our proteomic study revealed that the level of membrane proteins playing key roles in cellular transport, maintenance of cell structure, and in bioenergetics processes remained unchanged along starvation at low temperature, thus suggesting that V. harveyi might need these proteins for the long-term survival and/or for the resuscitation process. On a contrary, the level of two proteins, elongation factor Tu (EF-TU) and bacterioferritin, greatly increased reaching the maximal values by the end of the incubation period. We further discuss the above data with respect to the putative roles likely exerted by membrane proteins during transition to and maintaining of the VBNC state. [ABSTRACT FROM AUTHOR]

Acinetobacter baumannii possesses a tremendous potential to thrive under hostile conditions. To learn more about its survival strategy and capacity to persist in the environment, we studied the effect of temperature, nutrient deprivation and dryness on the long-term survival of two A. baumannii strains (ATCC 19606 and a clinical isolate). Our results revealed that both strains show a great persistence under stress that appears to involve a bust-and-boom strategy. Bacterial survival was differentially affected by temperature and physical environment: Desiccation favored cell resistance to stress at 20 and 37 °C, while survival in aqueous environments was temperature dependent and led to changes in several cellular characteristics. In addition, we tested the ability of the A. baumannii ATCC 19606 strain to form biofilms by monitoring the expression of adhesion-/biofilm-related genes ( ompA, bfmR and csuAB). The observed downregulation of these genes suggests that the potential difficulties to adhere to solid surfaces and form biofilms likely limit the capacity of starved cells to spread and colonize abiotic surfaces. [ABSTRACT FROM AUTHOR]

A synthesized thiol-functionalized non-ionic surfactant based on the IGEPAL® (polyoxyethylene(5) nonyl phenyl ether) structure, has been used to replace citrate ions from the surface of gold nanoparticles with 13.5 nm diameters. Upon IGEPAL®-type stabilization in water, the nanoparticles were transferred to ethanol, where a layer of silica was efficiently grown on the nanocrystal surface through the conventional Stöber approach. This method allows fine control over the silica thickness, showing uniform and homogeneous core-shell nanoparticles. Additionally, the luminescent properties of the IGEPAL® surfactant allow the versatile preparation of robust fluorescent nanoparticles with multiplexing potential as simultaneous plasmonic and fluorescence probes. [ABSTRACT FROM AUTHOR]

Owing to their ubiquitous presence and ability to act as primary or opportunistic pathogens, Vibrio species greatly contribute to the diversity and evolution of marine ecosystems. This study was aimed at unveiling the cellular strategies enabling the marine gammaproteobacterium Vibrio harveyi to adapt and persist in natural aquatic systems. We found that, although V. harveyi incubation in seawater microcosm at 20 °C for 2 weeks did not change cell viability and culturability, it led to a progressive reduction in the average cell size. Microarray analysis revealed that this morphological change was accompanied by a profound decrease in gene expression affecting the central carbon metabolism, major biosynthetic pathways, and energy production. In contrast, V. harveyi elevated expression of genes closely linked to the composition and function of cell envelope. In addition to triggering lipid degradation via the β-oxidation pathway and apparently promoting the use of endogenous fatty acids as a major energy and carbon source, V. harveyi upregulated genes involved in ancillary mechanisms important for sustaining iron homeostasis, cell resistance to the toxic effect of reactive oxygen species, and recycling of amino acids. The above adaptation mechanisms and morphological changes appear to represent the major hallmarks of the initial V. harveyi response to starvation. [ABSTRACT FROM AUTHOR]

Age of onset (AO) of Huntington disease (HD) is mainly determined by the length of the CAG repeat expansion (CAGexp) in exon 1 of the HTT gene. Additional genetic variation has been suggested to contribute to AO, although the mechanism by which it could affect AO is presently unknown. The aim of this study is to explore the contribution of candidate genetic factors to HD AO in order to gain insight into the pathogenic mechanisms underlying this disorder. For that purpose, two AO definitions were used: the earliest age with unequivocal signs of HD (earliest AO or eAO), and the first motor symptoms age (motor AO or mAO). Multiple linear regression analyses were performed between genetic variation within 20 candidate genes and eAO or mAO, using DNA and clinical information of 253 HD patients from REGISTRY project. Gene expression analyses were carried out by RT-qPCR with an independent sample of 35 HD patients from Basque Country Hospitals. We found suggestive association signals between HD eAO and/or mAO and genetic variation within the E2F2, ATF7IP, GRIN2A, GRIN2B, LINC01559, HIP1 and GRIK2 genes. Among them, the most significant was the association between eAO and rs2742976, mapping to the promoter region of E2F2 transcription factor. Furthermore, rs2742976 T allele patient carriers exhibited significantly lower lymphocyte E2F2 gene expression, suggesting a possible implication of E2F2-dependent transcriptional activity in HD pathogenesis. Thus, E2F2 emerges as a new potential HD AO modifier factor. [ABSTRACT FROM AUTHOR]

The use of a thiol-functionalized nonionic surfactant to stabilize spherical gold nanoparticles in water induces the spontaneous formation of polyrotaxanes at the nanoparticle surface in the presence of the macrocycle α-cyclodextrin. Whereas using an excess of surfactant an amorphous gold nanocomposite is obtained, under controlled drying conditions the self-assembly between the surface supramolecules provides large and homogenous supercrystals with hexagonal close packing of nanoparticles. Once formed, the self-assembled supercrystals can be fully redispersed in water. The reversibility of the crystallization process may offer an excellent reusable material to prepare gold nanoparticle inks and optical sensors with the potential to be recovered after use. [ABSTRACT FROM AUTHOR]

The use of a thiol-functionalized nonionic surfactant to stabilize spherical gold nanoparticles in water induces the spontaneous formation of polyrotaxanes at the nanoparticle surface in the presence of the macrocycle α-cyclodextrin. Whereas using an excess of surfactant an amorphous gold nanocomposite is obtained, under controlled drying conditions the self-assembly between the surface supramolecules provides large and homogenous supercrystals with hexagonal close packing of nanoparticles. Once formed, the self-assembled supercrystals can be fully redispersed in water. The reversibility of the crystallization process may offer an excellent reusable material to prepare gold nanoparticle inks and optical sensors with the potential to be recovered after use. [ABSTRACT FROM AUTHOR]

The life and survival of the marine bacterium Vibrio harveyi during its adaptation in natural aquatic systems is highly influenced by the availability of nutrients and temperature. To learn about adaptation strategies evolved by this bacterium to cope with drastic temperature downshifts and nutrients depletion, we have studied the phenotypical and gene expression changes occurring in V. harveyi during its adaptation to cold seawater. We found that incubation in cold seawater up to 12 h did not cause any significant morphological changes in V. harveyi and had no effect on the number of viable and culturable cells. Microarray analysis revealed that the V. harveyi response to cold seawater leads to up- and downregulation of numerous genes controlling the central carbon metabolism, nucleotide and amino acid biosynthesis as well as DNA repair. In addition, expression of some genes controlling biosynthesis of lipids, molecular transport, and energy production was altered to likely affect the composition and properties of the V. harveyi cell envelope, thus implying the putative role of this compartment in adaptation to stress. Here, we discuss these results with regard to the putative adaptive responses likely triggered by V. harveyi to cope with environmental challenges in natural aquatic systems. [ABSTRACT FROM AUTHOR]

CD6 has recently been identified and validated as risk gene for multiple sclerosis (MS), based on the association of a single nucleotide polymorphism (SNP), rs17824933, located in intron 1. CD6 is a cell surface scavenger receptor involved in T-cell activation and proliferation, as well as in thymocyte differentiation. In this study, we performed a haptag SNP screen of the CD6 gene locus using a total of thirteen tagging SNPs, of which three were non-synonymous SNPs, and replicated the recently reported GWAS SNP rs650258 in a Spanish-Basque collection of 814 controls and 823 cases. Validation of the six most strongly associated SNPs was performed in an independent collection of 2265 MS patients and 2600 healthy controls. We identified association of haplotypes composed of two non-synonymous SNPs [rs11230563 (R225W) and rs2074225 (A257V)] in the 2nd SRCR domain with susceptibility to MS (Pmax(T) permutation = 1×10−4). The effect of these haplotypes on CD6 surface expression and cytokine secretion was also tested. The analysis showed significantly different CD6 expression patterns in the distinct cell subsets, i.e. – CD4+ naïve cells, P = 0.0001; CD8+ naïve cells, P<0.0001; CD4+ and CD8+ central memory cells, P = 0.01 and 0.05, respectively; and natural killer T (NKT) cells, P = 0.02; with the protective haplotype (RA) showing higher expression of CD6. However, no significant changes were observed in natural killer (NK) cells, effector memory and terminally differentiated effector memory T cells. Our findings reveal that this new MS-associated CD6 risk haplotype significantly modifies expression of CD6 on CD4+ and CD8+ T cells. [ABSTRACT FROM AUTHOR]

Sánchez-Ferrero E, Coto E, Beetz C, Gámez J, Corao A, Díaz M, Esteban J, del Castillo E, Moris G, Infante J, Menéndez M, Pascual-Pascual SI, López de Munaín A, Garcia-Barcina MJ, Alvarez V on behalf of the Genetics of Spastic Paraplegia study group. SPG7 mutational screening in spastic paraplegia patients supports a dominant effect for some mutations and a pathogenic role for p.A510V. Mutations in the SPG7 gene were initially reported in patients with autosomal recessive hereditary spastic paraplegia (HSP). Recent works suggested a dominant effect for some SPG7 mutations. To characterize the SPG7 mutational spectrum in a large cohort of Spanish HSP patients, we sequenced the whole SPG7 gene in a total of 285 Spastic Paraplegia patients. Large gene rearrangements were also ascertained in some patients. We found a total of 14 SPG7 mutations (12 new) in 14 patients; 2 were large deletions. All the mutation carriers had an adult onset age but only five (35%) had a complicated phenotype. We identified a single mutation in 13 patients. Familial analysis suggested a dominant inheritance for one (p.Leu78*) of these mutations. Carriers of the rare p.A510V variant were significantly more frequent in patients vs healthy controls (3% vs 1%), suggesting a pathogenic role for this SPG7 variant. We reported a high frequency of patients with only one SPG7 mutation, and a putative pathogenic role for the p.A510V variant. [ABSTRACT FROM AUTHOR]

Brachydactyly (BD) refers to the shortening of the hands, feet or both. There are different types of BD; among them, type E (BDE) is a rare type that can present as an isolated feature or as part of more complex syndromes, such as: pseudohypopthyroidism (PHP), hypertension with BD or Bilginturan BD (HTNB), BD with mental retardation (BDMR) or BDE with short stature, PTHLH type. Each syndrome has characteristic patterns of skeletal involvement. However, brachydactyly is not a constant feature and shows a high degree of phenotypic variability. In addition, there are other syndromes that can be misdiagnosed as brachydactyly type E, some of which will also be discussed. The objective of this review is to describe some of the syndromes in which BDE is present, focusing on clinical, biochemical and genetic characteristics as features of differential diagnoses, with the aim of establishing an algorithm for their differential diagnosis. As in our experience many of these patients are recruited at Endocrinology and/or Pediatric Endocrinology Services due to their short stature, we have focused the algorithm in those steps that could mainly help these professionals. [ABSTRACT FROM AUTHOR]

A new molecular receptor ( 1) for ammonium recognition has been designed and constructed by using only carbon atoms. This molecular receptor can co-exist in two different isoenergetic conformations but, upon complexation, the conformers are no longer isoenergetic, and a basket-shaped conformation becomes clearly more stable. The pre-organised tetrahedral structure of this basket-shaped molecule favours the complexation of ammonium ions by NH⋅⋅⋅π interactions with the four phenyl groups of the host. A similar behaviour is not observed in a similar, but less pre-organised, reference molecule. ESI-MS competition experiments show that 1 is able to bind NH4+ over K+ selectively. This is the first example of a neutral molecular receptor that shows a remarkable NH4+/K+ selectivity. DFT-calculations provide insight into the nature of host-guest interactions of both 1⋅NH4+ and 1⋅K+ complexes as well as in the mechanism involved in multiple cation-π interactions and the influence of these interactions on the conformational stability and the selective binding of the host. [ABSTRACT FROM AUTHOR]

The article presents a study on the validation of the 10 genes which show evidence of association with multiple sclerosis (MS). The study used the iPLEX™ Sequenon to genotype eleven single nucleotide polymorphisms (SNPs) in Spanish patients. The results showed that the transmembrane protein 39A (TMEM39A), interleukin 12B (ILI2B), and Cbl proto-oncogene, E3 ubiquitin protein ligase B (CBLB) genes affect the MS susceptibility.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with presumed autoimmune origin, triggered by genetic and environmental risk factors. A recent genome-wide association study conducted on MS identified new biallelic markers outside the HLA (human leucocyte antigen) region involved in disease susceptibility: rs1109670 (DDEF2); rs1458175 (PDZRN4); rs1529316 and rs2049306 (CSMD1); rs16914086 (TBC1D2); rs1755289 (SH3GL2); rs1841770 (ZIC1); rs651477 (EN1); rs7607490 (TRIB2); rs397020 (C20orf46); rs908821 (SLC25A36); rs7672826 (MGC45800) and rs9523762 (GPC5). We aimed at replicating these top association signals in a Spanish cohort of 2863 MS patients and 2930 sex- and age-matched controls. Only rs9523762 mapping in the GPC5 gene was significantly associated (G allele, P=1.6 × 10−5; odds ratio (95% confidence interval)=1.23 (1.12-1.36)), supporting a role for this proteoglycan in MS predisposition. The independent replication of association signals to validate data generated by genome-wide association scans is a first step in the effort to improve patient care. [ABSTRACT FROM AUTHOR]