Adverse effects of sodium-glucose cotransporter-2 inhibitors in patients with heart failure: a systematic review and meta-analysis.

Sodium-glucose cotransoporter-2 inhibitors (SGLT-2Is) improve prognosis in heart failure (HF) patients both with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). However, these drugs can have some side effects. To estimate the relative risk of side effects in HF patients treated with SGLT-2Is irrespective from left ventricular EF and setting (chronic and non-chronic HF). Five randomized controlled trials (RCTs) enrolling patients with HFrEF, 4 RCTs enrolling non-chronic HF, and 3 RCTs enrolling HFpEF were included. Among side effects, urinary infection, genital infection, acute kidney injury, diabetic ketoacidosis, hypoglycemia, hyperkalemia, hypokalemia, bone fractures, and amputations were considered in the analysis. Overall, 24,055 patients were included in the analysis: 9020 (38%) patients with HFrEF, 12,562 (52%) with HFpEF, and 2473 (10%) with non-chronic HF. There were no differences between SGLT-2Is and placebo in the risk to develop diabetic ketoacidosis, hypoglycemia, hyperkalemia, hypokalemia, bone fractures, and amputations. HFrEF patients treated with SGLT-2Is had a significant reduction of acute kidney injury (RR = 0.54 (95% CI 0.33-0.87), p = 0.011), whereas no differences have been reported in the HFpEF group (RR = 0.94 (95% CI 0.83-1.07), p = 0.348) and non-chronic HF setting (RR = 0.79 (95% CI 0.55-1.15), p = 0.214). A higher risk to develop genital infection (overall 2.57 (95% CI 1.82-3.63), p < 0.001) was found among patients treated with SGLT-2Is irrespective from EF (HFrEF: RR = 1.96 (95% CI 1.17-3.29), p = 0.011; HFpEF: RR = 3.04 (95% CI 1.88-4.90), p < 0.001). The risk to develop urinary infections was increased among SGLT-2I users in the overall population (RR = 1.13 (95% CI 1.00-1.28), p = 0.046) and in the HFpEF setting (RR = 1.19 (95% CI 1.02-1.38), p = 0.029), whereas no differences have been reported in HFrEF (RR = 1.05 (95% CI 0.81-1.36), p = 0.725) and in non-chronic HF setting (RR = 1.04 (95% CI 0.75-1.46), p = 0.806). SGLT-2Is increase the risk of urinary and genital infections in HF patients. In HFpEF patients, the treatment increases the risk of urinary infections compared to placebo, whereas SGLT-2Is reduce the risk of acute kidney disease in patients with HFrEF.

Disease-free zones: bilateral recognition procedure in South America. / Zonas libres de enfermedades: proceso de reconocimiento bilateral en América del Sur.

According to the World Organisation for Animal Health (OIE), zoning is a risk management strategy for achieving the progressive control and eradication of animal diseases, and for providing guarantees for international trade. The implementation and effectiveness of zoning relies on the quality of Veterinary Services. Eradicating a disease and securing trading partners' recognition of this disease-free status demands resources, and promotes economic and fruitful development. It also guarantees the sanitary safety of trade, provided that OIE standards are applied and the World Trade Organization (WTO) Agreement on the Application of Sanitary and Phytosanitary Measures (SPS Agreement) is complied with. The OIE international standards and the SPS Agreement lay down provisions for the effective implementation of zoning and the recognition of disease-free zones. Although animal-disease-free statuses place such zones in a favourable position with regard to exporting their products to the international market, they can create internal restrictions between regions of the same country with differing statuses. As a general rule, each importing country implements its own evaluation procedure, independent of OIE official recognition. While this usually provides for information evaluation and an on-site inspection mission, there is no harmonisation between countries regarding the methodology or the information required for risk assessment. Recognition of a disease-free zone does not imply automatic permission to export any product from that zone. Firstly, it is necessary to request that the market be opened for each product in question, guaranteeing the conditions demanded by the target market (risk analysis and animal health certification). To benefit from external markets, there are ways of speeding up bilateral recognition of disease-free zones, such as bilateral veterinary agreements or free trade agreements that establish clear areas and procedures to be implemented by trading partner countries. The ongoing exchange of information among countries builds trust among their Veterinary Services and authorities, which leads to expedited recognition procedures. The work of the OIE (Pathway for the Evaluation of Performance of Veterinary Services [PVS Pathway], OIE Observatory) and the WTO Committee on Sanitary and Phytosanitary Measures (SPS Committee) (enforcement mechanisms) should be strengthened to assist countries in implementing zoning.

D'après l'Organisation mondiale de la santé animale (OIE), le « zonage ¼ est une stratégie de gestion du risque permettant d'avancer sur la voie du contrôle progressif des maladies animales et de leur éradication tout en fournissant des garanties dans le cadre des échanges internationaux. Sa mise en oeuvre et son efficacité sont tributaires de la qualité des Services vétérinaires. Si l'éradication réussie d'une maladie et la reconnaissance du statut indemne par les partenaires commerciaux mobilisent des ressources, elles constituent également une incitation majeure au développement productif et économique. En outre, elles garantissent la sécurité sanitaire des échanges internationaux, à condition d'appliquer les normes de l'OIE et de respecter les dispositions de l'Accord sur l'application des sanitaires et phytosanitaires (Accord SPS) de l'Organisation mondiale du commerce (OMC). L'OIE et l'Accord SPS établissent des dispositions pour la mise en oeuvre effective du « zonage ¼ et la reconnaissance des zones indemnes de maladies. Ce statut sanitaire place les zones qui en bénéficient en position favorable pour exporter leurs produits vers les marchés internationaux, mais il peut aussi entraîner des restrictions au niveau national par rapport aux zones du pays dotées d'un statut différent. Il est d'usage que chaque pays applique ses propres procédures indépendamment de la reconnaissance par l'OIE. Cela passe généralement par une évaluation de l'information fournie et par une mission d'inspection in situ, mais ni la méthodologie ni les informations requises pour mener à bien l'évaluation du risque n'ont fait l'objet d'une harmonisation de la part des pays. La reconnaissance d'une zone indemne ne vaut pas autorisation automatique d'exporter tout produit à partir de cette zone, car il faut encore, pour chaque produit, solliciter l'ouverture du marché et présenter des garanties démontrant que les conditions imposées par le marché de destination sont satisfaites (analyse du risque et certification sanitaire). Des méthodes existent pour bénéficier des marchés extérieurs en accélérant les reconnaissances bilatérales des zones indemnes de maladies ; il s'agit notamment des accords vétérinaires bilatéraux ou des accords de libre-échange, qui définissent clairement les cadres d'application et les procédures à mettre en place par les pays partenaires commerciaux. L'échange permanent d'informations entre les pays partenaires favorise la confiance entre leurs Services et Autorités vétérinaires respectifs, ce qui facilite d'autant ces procédures. Il convient de renforcer les travaux de l'OIE (Processus d'évaluation des performances des Services vétérinaires [Processus PVS], Observatoire des normes de l'OMC) et du Comité SPS de l'OMC (mécanismes d'évaluation de la conformité) afin d'aider les pays à mettre en oeuvre le « zonage ¼.

Según la Organización Mundial de Sanidad Animal (OIE), la «zonificación¼ es una estrategia de gestión del riesgo para avanzar en el control progresivo y la erradicación de enfermedades animales y para dar garantías al comercio internacional. Su implementación y eficacia dependen de la calidad de los Servicios Veterinarios. Erradicar una enfermedad y lograr el reconocimiento de tal situación por parte de socios comerciales implica recursos e incentiva el desarrollo productivo y económico. También garantiza la seguridad sanitaria del comercio siempre que se apliquen las normas de la OIE y se respete el Acuerdo sobre la Aplicación de Medidas Sanitarias y Fitosanitarias de la Organización Mundial del Comercio (OMC) (Acuerdo MSF). Las normas internacionales de la OIE y el Acuerdo MSF establecen disposiciones para una implementación efectiva de la «zonificación¼ y el reconocimiento de zonas libres de enfermedades. Este estatus sanitario posiciona favorablemente a dichas zonas para exportar sus productos al mercado internacional, pero puede generar restricciones internas respecto a regiones del mismo país con estatus diferentes. Lo habitual es que cada país aplique un proceso propio, independientemente del reconocimiento de la OIE. En general, contemplan una evaluación de la información y una misión de inspección in situ, pero no existe una armonización entre países ni respecto a la metodología ni respecto a la información requerida para la evaluación de riesgos. Este reconocimiento no implica el permiso automático para exportar cualquier producto desde esa zona, sino que se debe solicitar la apertura del mercado para cada producto en cuestión garantizando las condiciones exigidas por el mercado de destino (análisis del riesgo y certificación sanitaria). Para beneficiarse de los mercados externos, existen formas de agilizar los reconocimientos bilaterales de las zonas libres de enfermedades, como los acuerdos bilaterales veterinarios o los Acuerdos de Libre Comercio, mediante los cuales se establecen ámbitos y procedimientos claros a implementar por parte de los países socios comerciales. El intercambio de información permanente entre los países genera confianza entre sus Servicios y Autoridades Veterinarias, lo cual redunda en la agilización de estos procesos. Se debe reforzar el trabajo de la OIE (Proceso de Prestaciones de los Servicios Veterinarios [Proceso PVS], Observatorio de la OIE) y del Comité MSF de la OMC (mecanismos de observancia) para ayudar a los países a implementar la «zonificación¼.

Efficacy of self-administered complex decongestive therapy on breast cancer-related lymphedema: a single-blind randomized controlled trial.

PURPOSE: After surgery, breast cancer-related lymphedema (BCRL) is a frequent chronic condition. The complex decongestive therapy (CDT) delivered by physiotherapists at hospitals is the state-of-the-art treatment choice. As lymphedema requires continuous management, we designed a 1-month-long course to train women to professionally carry out a self-administered CDT (saCDT) and tested its efficacy while keeping the benefits of CDT. METHODS: Consecutive patients treated with CDT over a 1-year period at an Italian facility were randomly assigned to either experimental (EXP, saCDT course) or control (CTRL, usual care) group. Women were assessed before, at 1, and 6 months from enrolment. Pain assessed by the numerical pain rating scale (NPRS) was the primary outcome. Arm asymmetry assessed by the excess limb volume (ELV) was the secondary outcome. Outcome variations were compared to their MCID to classify women as improved, stable, or worsened. RESULTS: Forty-one women were included. The proportion of stable or improved women was significantly different between EXP and CTRL groups at 6 months after enrolment for both arm pain (p = 0.01) and asymmetry (p < 0.01). Noteworthy, only one EXP woman had worsened after 6 months. NPRS significantly decreased in the EXP group only, with a median variation of 2 points. Arm ELV significantly decreased with respect to the baseline value in the EXP group only, with a median reduction of 8%. CONCLUSIONS: Teaching saCDT to women with BCRL is effective in maintaining or improving the benefits of CDT and can be used as a self-care tool in the management of BCRL.

Evidence-Based Medicine and Clinical Practice: the first Italian attempt to define the appropriateness of rehabilitation admission criteria through the application of the Delphi method.

BACKGROUND: One of the consequences of today's global economic crisis is the need to control healthcare spending, in particular by improving the level of appropriateness. Thus, admission to rehabilitation has become an issue, especially as regards inappropriateness of resource allocation. The scientific literature suggests that more attention should be paid to the problem of clinical appropriateness in order to better identify the patients' actual needs. For the first time in Italy, this study aims at defining the appropriateness of intensive rehabilitation admission criteria through use of the Delphi method involving a panel of national experts. MATERIAL AND METHODS: A three-round Delphi survey was conducted according to international guidelines. Electronic questionnaires were individually sent via e-mail to ensure the participants' anonymity throughout the process. Questions were mostly based on rehabilitation literature. RESULTS: During the Delphi process, a total of 79 items were submitted to a heterogenous panel of rehabilitation experts who were asked to express their level of agreement to the item contents on a five-point Likert scale. At the end of the survey, a list of 19 appropriate criteria for admission to intensive rehabilitation facilities and 21 reasons for inappropriateness was drawn up. CONCLUSION: This study represents the first attempt in Italy to define shared and objective appropriateness criteria for admission to intensive rehabilitation. Out of the total number of experts invited to participate (31), only 16 completed the entire survey. This poor participation rate unfortunately demonstrates the lack of awareness among Italian rehabilitation professionals, which is a further sign of both the scarcity of scientific evidence in this area and the need to reach consensus on admission criteria.

[The importance of genetics in the study of hypertriglyceridemia]. / La importancia de la genética en el estudio de la hipertrigliceridemia.

Hypertriglyceridemia encompasses a set of lipid disorders common in clinical practice, generally defined as a fasting concentration above 150mg/dL. There are various classifications of the severity of hypertriglyceridaemia based on serum values, with levels generally considered moderate when below 500mg/dL and severe when above 1000mg/dL. Its importance lies in its association with other alterations in the lipid profile, contributing to increased cardiovascular risk and increased risk of acute pancreatitis, mainly with concentrations above 500mg/dL.

High evolutionary dynamism in 5S rDNA of fish: state of the art.

The 5S ribosomal DNA (rDNA) consists of one transcriptional unit of about 120 base pairs, which is separated from the next unit by a non-transcribed spacer (NTS). The coding sequence and the NTS together form a repeat unit which can be found in hundreds to thousands of copies tandemly repeated in the genomes. The NTS regions seem to be subject to rapid evolution. The first general model of evolution of these multigene families was referred to as divergent evolution, based on studies using hemoglobin and myoglobin as model systems. Later studies showed that nucleotide sequences of different multigene family members are more closely related within species than between species. This observation led to a new model of multigene family evolution, termed concerted evolution. Another model of evolution, named the birth-and-death model, has been found to be more suitable to explain the long-term evolution of these multigene families. According to this model, new genes originate by successive duplications, and these new genes are either maintained for a long time or are lost, or else degenerate into pseudogenes. In this review we describe different sources of variability in the 5S rDNA genes observed in several distinct fish species. This variability is mainly referred to NTSs and includes the presence of other multigene families (mainly LINEs, SINEs, non-LTR retrotransposons, and U snRNA families). Different types of microsatellites have also been found to contribute to the increase of variability in this region. Our recent results suggest that horizontal transfer contributes to the increase of diversity in the NTSs of some species. Variability in the 5S rDNA coding region affecting the stability of the structure, but without effects on the function of the 5S rRNA, is also described. Retrotransposons seem to be responsible for the high dynamism of 5S rDNA, while microsatellites acting as recombination hot spots could stabilize a wide variety of unusual DNA structures, affecting DNA replication and enhancing or decreasing promoter activity in gene expression. The relationship between the high variability found at molecular level and the low variability found at chromosomal level is also discussed.

Frequency of homozygous deletion at p16/CDKN2 in primary human tumours.

Many tumour types have been reported to have deletion of 9p21 (refs 1-6). A candidate target suppressor gene, p16 (p16INK4a/MTS-1/CDKN2), was recently identified within the commonly deleted region in tumour cell lines. An increasing and sometimes conflicting body of data has accumulated regarding the frequency of homozygous deletion and the importance of p16 in primary tumours. We tested 545 primary tumours by microsatellite analysis with existing and newly cloned markers around the p16 locus. We have now found that small homozygous deletions represent the predominant mechanism of inactivation at 9p21 in bladder tumours and are present in other tumour types, including breast and prostate cancer. Moreover, fine mapping of these deletions implicates a 170 kb minimal region that includes p16 and excludes p15.

[Monogenic form of secondary arterial hypertension]. / Forma monogénica de hipertensión arterial secundaria.

Multiple diagnostic entities are included among the causes of secondary arterial hypertension, so an appropriate screening is essential to diagnose potentially treatable pathologies. Genetic syndromes occupy a small percentage of these causes. The latter group includes Liddle syndrome, a rare genetic disease with autosomal dominant inheritance, caused by gain-of-function mutations in the genes that code for the epithelial sodium channel (ENaC), involved in sodium reabsorption in the distal renal tubules. The presence of a family history of arterial hypertension with onset at an early age and hypokalemia in some of them should lead to the suspicion of this genetic disorder, which must be confirmed with genetic tests. We describe a case, genetically confirmed, in which hypertension refractory to conventional treatment is the only manifestation of said syndrome, making diagnosis difficult and delayed until adulthood.

Arterial hypertension of infrequent cause.

Arterial hypertension is generally classified as primary or essential (90%), and secondary (10%). Infrequent causes of the latter include Cushing's syndrome, classified as ACTH-dependent and independent. A small percentage of ACTH-independent cases are due to ectopic ACTH secretion, generally due to neoplasia, and can present as arterial hypertension and hyperglycaemia that are refractory to pharmacological measures, metabolic alkalosis and hypokalaemia that are difficult to control, but which help guide the initial diagnosis. We present two clinical cases with a diagnosis of ectopic ACTH secretion secondary to small cell lung carcinoma, in which one of the debut manifestations was unknown, difficult to control arterial hypertension.