Immunomodulatory Therapy Does Not Increase the Risk of Cancer in Persons With Inflammatory Bowel Disease and a History of Extracolonic Cancers.

OBJECTIVES: Immunosuppressant therapies (IMTs; thiopurines, anti-tumor necrosis factor agents) may influence the immunologic control of cancer and might facilitate the spread and recurrence of cancer. This study assesses the impact of the use of IMTs on the development of incident cancers (recurrent or new) in patients with inflammatory bowel disease (IBD) and a history of malignancy. METHODS: Patients with IBD included in the ENEIDA registry with a history of cancer without being exposed to IMTs were identified and retrospectively reviewed and compared regarding further treatment with IMTs or not by means of a log-rank test. RESULTS: Overall, 520 patients with previous extracolonic cancer naive to IMTs before the diagnosis of cancer were identified. Of these, 146 were subsequently treated with IMTs (exposed), whereas 374 were not (nonexposed). The proportion of patients with incident cancers was similar in both exposed (16%) and nonexposed (18%) patients (P = 0.53); however, there was more than a 10-year difference in the age at index cancer between these 2 groups. Cancer-free survival was 99%, 98%, and 97% at 1, 2, and 5 years in exposed patients, and 97%, 96%, and 92% at 1, 2, and 5 years in non-exposed patients, respectively (P = 0.03). No differences in incident cancer rates were observed between exposed and nonexposed patients when including only those who were exposed within the first 5 years after cancer diagnosis. DISCUSSION: In patients with IBD and a history of cancer not related to immunosuppression, the use of IMTs is not associated with an increased risk of new or recurrent cancers even when IMTs are started early after cancer diagnosis.

Wine aromatic compound production and fermentative behaviour within different non-Saccharomyces species and clones.

AIMS: Twenty-five enological yeasts belonging to nine different species (Candida zeylanoides, Cryptococcus uzbekistanensis, Debaryomyces hansenii, Lachancea thermotolerans, Metschnikowia pulcherrima, Torulaspora delbrueckii, Williopsis pratensis, Zygosaccharomyces bailii and Saccharomyces cerevisiae) were screened for aroma formation and fermentative behaviour as part of a non-Saccharomyces yeast selection programme. METHODS AND RESULTS: Pure cultures were inoculated in pasteurized grape juice in order to perform alcoholic fermentations. Some non-Saccharomyces species did not ferment, others did not get established and none of them completed alcoholic fermentations. The physico-chemical parameters of the wines and the abundance of aromatic compounds at the end of alcoholic fermentation highlighted the notable differences in the aroma-forming ability and fermentative behaviour of the different non-Saccharomyces species, but not within clones. CONCLUSIONS: Lower diversity was detected within non-Saccharomyces species than that reported in S. cerevisiae with regard to enological behaviour and aromatic profiles. Metschnikowia pulcherrima and L. thermotolerans are the two species with higher possibilities to become an inoculum. SIGNIFICANCE AND IMPACT OF THE STUDY: Few significant differences were found within clones of the same species, but very important parameters in wine quality, such as volatile acidity, ethyl acetate and acetoin, which would justify selection programmes within those species. The results also demonstrated that T. delbrueckii and L. thermotolerans are two close species in their aromatic profiles.

Genetic and phenotypic intraspecific variability of non-Saccharomyces yeasts populations from La Rioja winegrowing region (Spain).

AIMS: To determine the intraspecific genetic diversity within five non-Saccharomyces yeast species and the diversity in phenotypic characteristic related to their technological properties. METHODS AND RESULTS: Seventy-one non-Saccharomyces yeasts isolated from different fermentations and facilities of the DOCa Rioja (Spain) belonging to five different wine species (Torulaspora delbrueckii, Lachancea thermotolerans, Metschnikowia pulcherrima, Zygosaccharomyces bailii and Williopsis pratensis) were subjected to clonal characterization by RAPD-PCR, which evidenced wide diversity between them. They were also submitted to a screening for some oenological traits related to the improvement of the aroma of the wine and yeast development in musts. Strains within the same species showed different enzyme activities, tolerated different levels of SO2 and possessed different killer phenotypes. These characteristics made them adjust better or worse to specific vinification processes or wine quality criteria. CONCLUSIONS: A significant genetic and phenotypic variation within the non-Saccharomyces species studied was found, which makes necessary to carry out a selection process in each one. SIGNIFICANCE AND IMPACT OF THE STUDY: Williopsis pratensis, a species that has not been thoroughly explored, may deserve further consideration for oenological applications. Due to the wide range of variation within species, the strains adaptation to the SO2 levels in musts has to be taken into account in selection processes.

Latrepirdine stimulates autophagy and reduces accumulation of α-synuclein in cells and in mouse brain.

Latrepirdine (Dimebon; dimebolin) is a neuroactive compound that was associated with enhanced cognition, neuroprotection and neurogenesis in laboratory animals, and has entered phase II clinical trials for both Alzheimer's disease and Huntington's disease (HD). Based on recent indications that latrepirdine protects cells against cytotoxicity associated with expression of aggregatable neurodegeneration-related proteins, including Aß42 and γ-synuclein, we sought to determine whether latrepirdine offers protection to Saccharomyces cerevisiae. We utilized separate and parallel expression in yeast of several neurodegeneration-related proteins, including α-synuclein (α-syn), the amyotrophic lateral sclerosis-associated genes TDP43 and FUS, and the HD-associated protein huntingtin with a 103 copy-polyglutamine expansion (HTT gene; htt-103Q). Latrepirdine effects on α-syn clearance and toxicity were also measured following treatment of SH-SY5Y cells or chronic treatment of wild-type mice. Latrepirdine only protected yeast against the cytotoxicity associated with α-syn, and this appeared to occur via induction of autophagy. We further report that latrepirdine stimulated the degradation of α-syn in differentiated SH-SY5Y neurons, and in mouse brain following chronic administration, in parallel with elevation of the levels of markers of autophagic activity. Ongoing experiments will determine the utility of latrepirdine to abrogate α-syn accumulation in transgenic mouse models of α-syn neuropathology. We propose that latrepirdine may represent a novel scaffold for discovery of robust pro-autophagic/anti-neurodegeneration compounds, which might yield clinical benefit for synucleinopathies including Parkinson's disease, Lewy body dementia, rapid eye movement (REM) sleep disorder and/or multiple system atrophy, following optimization of its pro-autophagic and pro-neurogenic activities.

Latrepirdine improves cognition and arrests progression of neuropathology in an Alzheimer's mouse model.

Latrepirdine (Dimebon) is a pro-neurogenic, antihistaminic compound that has yielded mixed results in clinical trials of mild to moderate Alzheimer's disease, with a dramatically positive outcome in a Russian clinical trial that was unconfirmed in a replication trial in the United States. We sought to determine whether latrepirdine (LAT)-stimulated amyloid precursor protein (APP) catabolism is at least partially attributable to regulation of macroautophagy, a highly conserved protein catabolism pathway that is known to be impaired in brains of patients with Alzheimer's disease (AD). We utilized several mammalian cellular models to determine whether LAT regulates mammalian target of rapamycin (mTOR) and Atg5-dependent autophagy. Male TgCRND8 mice were chronically administered LAT prior to behavior analysis in the cued and contextual fear conditioning paradigm, as well as immunohistological and biochemical analysis of AD-related neuropathology. Treatment of cultured mammalian cells with LAT led to enhanced mTOR- and Atg5-dependent autophagy. Latrepirdine treatment of TgCRND8 transgenic mice was associated with improved learning behavior and with a reduction in accumulation of Aß42 and α-synuclein. We conclude that LAT possesses pro-autophagic properties in addition to the previously reported pro-neurogenic properties, both of which are potentially relevant to the treatment and/or prevention of neurodegenerative diseases. We suggest that elucidation of the molecular mechanism(s) underlying LAT effects on neurogenesis, autophagy and behavior might warranty the further study of LAT as a potentially viable lead compound that might yield more consistent clinical benefit following the optimization of its pro-neurogenic, pro-autophagic and/or pro-cognitive activities.

Update of the PANCCO clinical practice guidelines for the treatment of ulcerative colitis in the adult population.

Ulcerative colitis (US) is a chronic disease of unknown etiology. It is incurable and its clinical course is intermittent, characterized by periods of remission and relapse. The prevalence and incidence of the disease has been increasing worldwide. The update presented herein includes the participation of healthcare professionals, decision-makers, and a representative of the patients, all of whom declared their conflicts of interest. Answerable clinical questions were formulated, and the outcomes were graded. The information search was conducted on the Medline/PubMed, Embase, Epistemonikos, and LILACS databases, and covered grey literature sources, as well. The search was updated on November 30, 2020, with no restrictions regarding date or language. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) classification system was implemented to establish the strength of the recommendation and quality of evidence. A formal consensus was developed, based on the RAND/UCLA methodology and the document was peer reviewed. The short version of the Clinical Practice Guidelines for the Treatment of Ulcerative Colitis in the Adult Population is presented herein, together with the supporting evidence and respective recommendations. In mild-to-moderate UC, budesonide MMX is an option when treatment with 5-ASA fails, and before using systemic steroids. In moderate-to-severe UC, infliximab, adalimumab, vedolizumab, ustekinumab, and tofacitinib can be used as first-line therapy. If there is anti-TNF therapy failure, ustekinumab and tofacitinib provide the best results. In patients with antibiotic-refractory pouchitis, anti-TNFs are the treatment of choice.

[Electronic prescription: differences between autonomous communities affecting access to treatment and the quality of pharmaceutical care].

BACKGROUND: The electronic prescription systems implemented in the different autonomous communities in Spain show differences. This study aims to describe how these differences affect access to treatments and pharmaceutical care, and what specific characteristics facilitate them. METHODS: A survey was designed to evaluate the electronic prescription systems. This survey was carried out at the Drug Information Centers of the Official Pharmacists' Colleges of all the Spanish autonomous communities during February and March 2020. RESULTS: In all autonomous communities there were some limitations regarding the temporary availability of the treatment, and incidents regarding the way of accessing the electronic prescription were recorded only in only five communities. In no community are pharmacies able to solve availability problems in special circumstances, nor is there any effective system for communicating with the doctor or recording patient data. Only some communities organize certain replacements to adapt the prescription to the patient's requirements. CONCLUSIONS: The current electronic prescription system could be optimized to avoid inequalities between autonomous communities and improve the quality of care received by patients, facilitating access to treatments, and avoiding the need to travel and delays. Access on presenting the health card, adaptation of time limitations to avoid blockages, dispensing medicines in special circumstances justified and registered by the pharmacist, as well as enabling efficient pharmacist-doctor communication, are general measures that avoid inequalities and facilitate access to treatments and pharmaceutical care.

Treatment of ankyloglossia with dental laser in paediatric patients: Scoping review and a case report.

AIM: The two aims of this article were to conduct a scoping review of current knowledge regarding laser treatment of ankyloglossia in children and to report a case of a male paediatric patient with ankyloglossia treated with laser surgery. METHODS: A comprehensive literature search was carried out on the following electronic databases: PubMed; Embase; Google Scholar; The Cochrane Library, and Dentistry and Oral Science Source (EBSCO). RESULTS: The initial search identified 278 references. After the process of title/abstract screening, 61 articles received a full-text reading; finally, 17 articles were selected. According to this scoping literature review, lingual frenulectomy managed with laser surgery provides a more efficient and comfortable treatment for both the paediatric patient and the dentist compared with conventional scalpel/blades/suturing techniques. Nevertheless, further high-quality studies on the clinical efficacy of laser devices for lingual frenulectomy in paediatric populations are required. CONCLUSION: Early diagnosis and treatment of ankyloglossia are fundamental for the adequate functional oral development of paediatric patients. Laser surgery for lingual frenulectomy provides a more efficient and comfortable treatment for both the child and the paediatric dentist compared to traditional scalpel/blade methods.

Balance of corneal horizontal coma by internal optics in eyes with intraocular artificial lenses: evidence of a passive mechanism.

It is well known that the aberrations of the cornea are partially compensated by the aberrations of the internal optics of the eye (primarily the crystalline lens) in young subjects. This effect has been found not only for the spherical aberration, but also for horizontal coma. It has been debated whether the compensation of horizontal coma is the result of passive mechanism [Artal, P., Benito, A., & Tabernero, J. (2006). The human eye is an example of robust optical design. Journal of Vision, 6 (1), 1-7] or through an active developmental feedback process [Kelly, J. E., Mihashi, T., & Howland, H. C. (2004). Compensation of corneal horizontal/vertical astigmatism, lateral coma, and spherical aberration by internal optics of the eye. Journal of Vision, 4 (4), 262-271]. In this study we investigate the active or passive nature of the horizontal coma compensation using eyes with artificial lenses, where no active developmental process can be present. We measured total and corneal aberrations, and lens tilt and decentration in a group of 38 eyes implanted with two types of intraocular lenses designed to compensate the corneal spherical aberration of the average population. We found that spherical aberration was compensated by 66%, and horizontal coma by 87% on average. The spherical aberration is not compensated at an individual level, but horizontal coma is compensated individually (coefficients of correlation corneal/internal aberration: -0.946, p<0.0001). The fact that corneal (but not total) horizontal coma is highly correlated with angle lamda (computed from the shift of the 1st Purkinje image from the pupil center, for foveal fixation) indicates that the compensation arises primarily from the geometrical configuration of the eye (which generates horizontal coma of opposite signs in the cornea and internal optics). The amount and direction of tilts and misalignments of the lens are comparable to those found in young eyes, and on average tend to compensate (rather than increase) horizontal coma. Computer simulations using customized model eyes and different designs of intraocular lenses show that, while not all designs produce a compensation of horizontal coma, a wide range of aspheric biconvex designs may produce comparable compensation to that found in young eyes with crystalline lenses, over a relatively large field of view. These findings suggest that the lens shape, gradient index or foveal location do not need to be fine-tuned to achieve a compensation of horizontal coma. Our results cannot exclude a fine-tuning for the orientation of the crystalline lens, since cataract surgery seems to preserve the position of the capsule.

Real-time deformable models of non-linear tissues by model reduction techniques.

In this paper we introduce a new technique for the real-time simulation of non-linear tissue behavior based on a model reduction technique known as proper orthogonal (POD) or Karhunen-Loève decompositions. The technique is based upon the construction of a complete model (using finite element modelling or other numerical technique, for instance, but possibly from experimental data) and the extraction and storage of the relevant information in order to construct a model with very few degrees of freedom, but that takes into account the highly non-linear response of most living tissues. We present its application to the simulation of palpation a human cornea and study the limitations and future needs of the proposed technique.

Haptic simulation of tissue tearing during surgery.

We present a method for the real-time, interactive simulation of tissue tearing during laparoscopic surgery. The method is designed to work at haptic feedback rates (ie, around 1 kHz). Tissue tearing is simulated under the general framework of continuum damage mechanics. The problem is stated as a general, multidimensional parametric problem, which is solved by means of proper generalized decomposition methods. One of the main novelties is the reduction of history-dependent problems, such as damage mechanics, by resorting to an approach in which a reduced-order field of initial damage values is considered as a parameter of the formulation. We focus on the laparoscopic cholecystectomy procedure as a general example of the performance of the method.

An index with improved diagnostic accuracy for the diagnosis of Crohn's disease derived from the Lennard-Jones criteria.

BACKGROUND: The Lennard-Jones criteria are considered the gold standard for diagnosing Crohn's disease (CD) and include the items granuloma, macroscopic discontinuity, transmural inflammation, fibrosis, lymphoid aggregates and discontinuous inflammation on histology. The criteria have never been subjected to a formal validation process. AIM: To develop a validated and improved diagnostic index based on the items of Lennard-Jones criteria. METHODS: Included were 328 adult patients with long-standing CD (median disease duration 10 years) from three centres and classified as 'established', 'probable' or 'non-CD' by Lennard-Jones criteria at time of diagnosis. Controls were patients with ulcerative colitis (n = 170). The performance of each of the six diagnostic items of Lennard-Jones criteria was modelled by logistic regression and a new index based on stepwise backward selection and cut-offs was developed. The diagnostic value of the new index was analysed by comparing sensitivity, specificity and accuracy vs. Lennard-Jones criteria. RESULTS: By Lennard-Jones criteria 49% (n = 162) of CD patients would have been diagnosed as 'non-CD' at time of diagnosis (sensitivity/specificity/accuracy, 'established' CD: 0.34/0.99/0.67; 'probable' CD: 0.51/0.95/0.73). A new index was derived from granuloma, fibrosis, transmural inflammation and macroscopic discontinuity, but excluded lymphoid aggregates and discontinuous inflammation on histology. Our index provided improved diagnostic accuracy for 'established' and 'probable' CD (sensitivity/specificity/accuracy, 'established' CD: 0.45/1/0.72; 'probable' CD: 0.8/0.85/0.82), including the subgroup isolated colonic CD ('probable' CD, new index: 0.73/0.85/0.79; Lennard-Jones criteria: 0.43/0.95/0.69). CONCLUSION: We developed an index based on items of Lennard-Jones criteria providing improved diagnostic accuracy for the differential diagnosis between CD and UC.

Primer consenso cubano sobre el uso de terapia convencional y biológica en pacientes con artritis reumatoide / First Cuban consensus on the use of conventional and biological therapy in patients with rheumatoid arthritis

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Introduction: The development of recommendations for the treatment of rheumatoid arthritis (RA) in the Cuban context may be one of the ways to achieve better control of this disease. Objective: To reach a consensus and update relevant aspects of conventional and biological RA modifier therapy in Cuba. Methods: 18 specialists from 8 Cuban provinces, experts in RA care, were summoned, according to the years of dedication to the specialty, the conferences on this topic and their publications. The first meeting took place in March 2016 in the provincial hospital of Villa Clara, Cuba, with the participation of all the experts. A review of the literature on conventional and biological therapy previously collected by the participants was developed, and two teams were formed: the first would address everything related to conventional therapy in RA (HRCT) and the other, biological therapy in RA (TBAR). Three questionnaires related to the use of corticosteroids, HRCT and TBAR, were prepared, answered by the participants via email. In a second meeting, held in October 2016 in Havana, the analysis of all the responses provided was carried out. Questions with a response of 90% or more votes were considered as recommendations. Results: The questionnaires were answered by 95% of the participants. 9 recommendations and 1 algorithm were established. The recommendations are as follows: methotrexate is the drug of choice in the treatment of RA after diagnosis; The administration of another conventional drug (DMARDc) (azathioprine, salazosulfapyridine, antimalarials and leflunomide) is recommended in patients with a diagnosis of active RA in whom methotrexate is contraindicated or there is a failure in response - consider the administration of low doses of prednisone or equivalent (<7.5 mg/d) associated with DMARDc in patients with active moderate to severe RA, for the shortest possible time; perform serological control including tests for hepatitis B and C viruses and screening for HIV in all patients diagnosed with RA before starting treatment with DMARDc and biologics; in patients in remission or, at least, with a DAS-28 below 3.2, consideration should be given to withdrawing one of the DMARDs or reducing, to the minimum possible expression, the dose of both disease modifiers; if methotrexate fails, tocilizumab in combination with methotrexate or as monotherapy will be indicated. Conclusions: Aspects related to conventional therapy with methotrexate, azathioprine, salazosulfapyridine, antimalarials and leflunomide were agreed. The value of early diagnosis and immediate initiation of DMARDc therapy and the use of glucocorticoids was analyzed. Treatment with tocilizumab, the only biological available in Cuba against RA, will be administered when there is a failure in the response to conventional therapy and combinations between these drugs. It is recommended to hold educational conferences through the mass media aimed at patientshttp(AU)

Changes on grape phenolic composition induced by grapevine foliar applications of phenylalanine and urea.

Grapevines may require the input of nitrogen to grow and to guarantee an appropriate grape composition. Recently there has been a growing interest in foliar fertilization, which entails a fast and efficient assimilation of the products. The aim of this work was to study the influence of foliar applications of phenylalanine and urea, at two different doses, on grape anthocyanins, flavonols, flavan-3-ols, phenolic acids, and stilbenes. All treatments were applied at veraison and one week later at doses of 0.9 and 1.5 kg N/ha. The results showed that the synthesis of phenolic compounds was favoured by foliar applications of phenylalanine and urea. The application of the lowest dose of urea was the most effective treatment, increasing the content of several anthocyanins and flavonols. Moreover, none of the foliar treatments worsened the grape phenolic composition. In conclusion, foliar application of phenylalanine and especially urea, could be an interesting management tool for improving grape quality and their health-promoting properties.

Contrast sensitivity after posterior chamber phakic intraocular lens implantation for high myopia.

PURPOSE: To evaluate contrast sensitivity after posterior chamber phakic intraocular lens (PIOL) implantation for the correction of high myopia. METHODS: Twenty eyes of ten patients had a posterior chamber phakic intraocular lens (Staar ICL) implanted to correct high myopia. Mean preoperative myopia was -14.10+/-2.70 D. Follow-up was 24 months for all patients. Contrast sensitivity was tested with best spectacle-corrected visual acuity preoperatively and 3, 6, 12, 18, and 24 months postoperatively. RESULTS: Contrast sensitivity increased after surgery in all spatial frequencies. Normal values were achieved for low and intermediate spatial frequencies (3 and 6 c/deg). However, in spite of the improvement, values were still below normal for high spatial frequencies (12 and 18 c/deg). When the first postoperative examination was not considered, there were no statistically significant differences in contrast sensitivity values at different postoperative periods. CONCLUSION: Contrast sensitivity increased after posterior chamber phakic intraocular lens implantation (Staar ICL) in all spatial frequencies when compared to preoperative contrast sensitivity (best spectacle-corrected).

Photorefractive keratectomy for myopic astigmatism using the emphasis erodible mask. Spanish User Group.

Photorefractive keratectomy (PRK) using the Summit emphasis erodible mask was performed on 229 eyes with myopic astigmatism. To analyze the efficacy and safety of the method, we evaluated the following: spectacle corrected visual acuity and refractive error as parameters of efficacy; corneal clarity, decentration of the ablation zone and complications as parameters of safety. Despite the short follow up (the longest was 12 months) our results show that the emphasis erodible mask appears to be an effective surgical method for correcting myopic astigmatism. However, we found a great number of complications and subjective symptoms that worsened the visual outcome. We conclude that the emphasis erodible mask has satisfactory efficacy but unsatisfactory safety.