Evolving AIDS- and non-AIDS Mortality and Predictors in the PISCIS Cohort of People Living With HIV in Catalonia and the Balearic Islands (Spain), 1998-2020.

Background: Effective antiretroviral therapy (ART) has substantially reduced acquired immunodeficiency syndrome (AIDS)-related deaths, shifting the focus to non-AIDS conditions in people living with human immunodeficiency virus (HIV) (PLWH). We examined mortality trends and predictors of AIDS- and non-AIDS mortality in the Population HIV Cohort from Catalonia and Balearic Islands (PISCIS) cohort of PLWH from 1998 to 2020. Methods: We used a modified Coding Causes of Death in HIV protocol, which has been widely adopted by various HIV cohorts to classify mortality causes. We applied standardized mortality rates (SMR) to compare with the general population and used competing risks models to determine AIDS-related and non-AIDS-related mortality predictors. Results: Among 30 394 PLWH (81.5% male, median age at death 47.3), crude mortality was 14.2 per 1000 person-years. All-cause standardized mortality rates dropped from 9.6 (95% confidence interval [CI], 8.45-10.90) in 1998 through 2003 to 3.33 (95% CI, 3.14-3.53) in 2015 through 2020, P for trend = .0001. Major causes were AIDS, non-AIDS cancers, cardiovascular disease, AIDS-defining cancers, viral hepatitis, and nonhepatitis liver disease. Predictors for AIDS-related mortality included being aged ≥40 years, not being a man who have sex with men, history of AIDS-defining illnesses, CD4 < 200 cells/µL, ≥2 comorbidities, and nonreceipt of ART. Non-AIDS mortality increased with age, injection drug use, heterosexual men, socioeconomic deprivation, CD4 200 to 349 cells/µL, nonreceipt of ART, and comorbidities, but migrants had lower risk (adjusted hazard risk, 0.69 [95% CI, .57-.83]). Conclusions: Mortality rates among PLWH have significantly decreased over the past 2 decades, with a notable shift toward non-AIDS-related causes. Continuous monitoring and effective management of these non-AIDS conditions are essential to enhance overall health outcomes.

Characterization of a selective, iron-chelating antifungal compound that disrupts fungal metabolism and synergizes with fluconazole.

Fungal infections are a growing global health concern due to the limited number of available antifungal therapies as well as the emergence of fungi that are resistant to first-line antimicrobials, particularly azoles and echinocandins. Development of novel, selective antifungal therapies is challenging due to similarities between fungal and mammalian cells. An attractive source of potential antifungal treatments is provided by ecological niches co-inhabited by bacteria, fungi, and multicellular organisms, where complex relationships between multiple organisms have resulted in evolution of a wide variety of selective antimicrobials. Here, we characterized several analogs of one such natural compound, collismycin A. We show that NR-6226C has antifungal activity against several pathogenic Candida species, including C. albicans and C. glabrata, whereas it only has little toxicity against mammalian cells. Mechanistically, NR-6226C selectively chelates iron, which is a limiting factor for pathogenic fungi during infection. As a result, NR-6226C treatment causes severe mitochondrial dysfunction, leading to formation of reactive oxygen species, metabolic reprogramming, and a severe reduction in ATP levels. Using an in vivo model for fungal infections, we show that NR-6226C significantly increases survival of Candida-infected Galleria mellonella larvae. Finally, our data indicate that NR-6226C synergizes strongly with fluconazole in inhibition of C. albicans. Taken together, NR-6226C is a promising antifungal compound that acts by chelating iron and disrupting mitochondrial functions.IMPORTANCEDrug-resistant fungal infections are an emerging global threat, and pan-resistance to current antifungal therapies is an increasing problem. Clearly, there is a need for new antifungal drugs. In this study, we characterized a novel antifungal agent, the collismycin analog NR-6226C. NR-6226C has a favorable toxicity profile for human cells, which is essential for further clinical development. We unraveled the mechanism of action of NR-6226C and found that it disrupts iron homeostasis and thereby depletes fungal cells of energy. Importantly, NR-6226C strongly potentiates the antifungal activity of fluconazole, thereby providing inroads for combination therapy that may reduce or prevent azole resistance. Thus, NR-6226C is a promising compound for further development into antifungal treatment.

Neoadjuvant chemotherapy with dose-dense MVAC in muscle-invasive bladder cancer: a tertiary center experience.

PURPOSE: Neoadjuvant chemotherapy in muscle-invasive bladder cancer (MIBC) patients has proven beneficial in overall survival. However, the optimal regimen is still a matter of debate. MATERIALS AND METHODS: In this retrospective analysis, we evaluate the results obtained in 42 patients treated in our center with 4 cycles of neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) followed by radical cystectomy from August 2015 to October 2020. All patients had cT2 or higher non-metastatic MIBC. Clinical and pathological outcomes are reported. RESULTS: Of the 42 patients, 90.5% were men (n = 38) and the mean age was 65 years. All of them had ECOG 0-1 at diagnosis and most tumors had an initial clinical stage T2N0 (76%). Thirty-six patients (85.7%) completed 4 cycles of neoadjuvant treatment, and 21.4% required a dose reduction. The most frequent adverse event (AE) was grade 1-2 asthenia (81%), while neutropenia was the most frequent grade 3 or higher AE (38%). Complete pathological response (ypT0, ypN0) was achieved in 50% of patients (n = 21), and down-staging was observed in 57.1% (n = 24). Only one patient presented radiological progressive disease during neoadjuvant treatment (2.4%), and after a mean follow-up time of 31.5 months, 33.3% of patients experienced disease recurrence. CONCLUSIONS: Neoadjuvant chemotherapy with 4 cycles of dd-MVAC is an effective regimen with high rates of pathological complete responses and down-staging along with an acceptable toxicity profile. DD-MVAC should be considered as an alternative to cisplatin and gemcitabine in patients with good clinical performance status.

Iron drives anabolic metabolism through active histone demethylation and mTORC1.

All eukaryotic cells require a minimal iron threshold to sustain anabolic metabolism. However, the mechanisms by which cells sense iron to regulate anabolic processes are unclear. Here we report a previously undescribed eukaryotic pathway for iron sensing in which molecular iron is required to sustain active histone demethylation and maintain the expression of critical components of the pro-anabolic mTORC1 pathway. Specifically, we identify the iron-binding histone-demethylase KDM3B as an intrinsic iron sensor that regulates mTORC1 activity by demethylating H3K9me2 at enhancers of a high-affinity leucine transporter, LAT3, and RPTOR. By directly suppressing leucine availability and RAPTOR levels, iron deficiency supersedes other nutrient inputs into mTORC1. This process occurs in vivo and is not an indirect effect by canonical iron-utilizing pathways. Because ancestral eukaryotes share homologues of KDMs and mTORC1 core components, this pathway probably pre-dated the emergence of the other kingdom-specific nutrient sensors for mTORC1.

Single-nucleotide polymorphism associations with efficacy and toxicity in metastatic castration-resistant prostate cancer treated with cabazitaxel.

Background: The aim of this study was to evaluate the impact of certain single-nucleotide polymorphisms (SNPs) in cabazitaxel activity and toxicity in patients with metastatic castration-resistant prostate cancer (mCRPC). Patients & methods: 56 SNPs in five genes (CYP3A4, CYP3A5, ABCB1, TUBB1 and CYP2C8) were genotyped in 67 mCRPC patients and their correlation with outcomes analyzed. Results:TUBB1-rs151352 (hazard ratio: 0.52) and CYP2C8-rs1341164 (hazard ratio: 0.53) were associated with better overall survival, and CYP2C8-rs1058932 with biochemical progression (odds ratio: 6.60) in multivariate analysis. ABCB1-rs17327624 correlated with severe toxicity ≥grade 3 (odds ratio: 8.56) and CYP2C8-rs11572093 with asthenia (odds ratio: 8.12). Conclusion: Genetic variants in mCRPC patients could explain different outcomes with cabazitaxel. Nonetheless, the small sample size and the high number of SNPs analyzed mean that the results are only hypothesis-generating and require further validation.

Determinants of carbon load in airway macrophages in pregnant women.

The airway macrophages carbon loading (AMCL) has been suggested to be a biomarker of the long-term exposure to air pollution; however, to date no study has characterized AMCL for the pregnancy period. Therefore, this study aimed to assess the determinants of AMCL during pregnancy in Iran, a middle-income country. This study was based on a sample of 234 pregnant women with term and normal vaginal delivery who were residing in Sabzevar, Iran (2019). We characterized 35 potential determinants of personal exposure to air pollution for each participant, including six personal, nine indoor, and 20 home-outdoor factors. We applied Deletion/Substitution/Addition algorithm to identify the most relevant determinants that could predict AMCL levels. The median (IQR) of AMCL level was 0.12 (0.30) µm2 with a successful sputum induction in 82.9% (194) of participants. Ambient residential PM2.5 levels were positively associated with higher AMCL levels. On the other hand, increased residential distance to the traffic lights, squares and ring-roads, the duration of opening window per day, and opening window during cooking were inversely associated with AMCL levels. Our findings provide novel insights on the different personal, indoor, and outdoor determinants of personal exposure to air pollution during pregnancy in a middle-income country.

Iron Regulatory Mechanisms in Saccharomyces cerevisiae.

Iron is an essential micronutrient for all eukaryotic organisms because it participates as a redox cofactor in many cellular processes. However, excess iron can damage cells since it promotes the generation of reactive oxygen species. The budding yeast Saccharomyces cerevisiae has been used as a model organism to study the adaptation of eukaryotic cells to changes in iron availability. Upon iron deficiency, yeast utilizes two transcription factors, Aft1 and Aft2, to activate the expression of a set of genes known as the iron regulon, which are implicated in iron uptake, recycling and mobilization. Moreover, Aft1 and Aft2 activate the expression of Cth2, an mRNA-binding protein that limits the expression of genes encoding for iron-containing proteins or that participate in iron-using processes. Cth2 contributes to prioritize iron utilization in particular pathways over other highly iron-consuming and non-essential processes including mitochondrial respiration. Recent studies have revealed that iron deficiency also alters many other metabolic routes including amino acid and lipid synthesis, the mitochondrial retrograde response, transcription, translation and deoxyribonucleotide synthesis; and activates the DNA damage and general stress responses. At high iron levels, the yeast Yap5, Msn2, and Msn4 transcription factors activate the expression of a vacuolar iron importer called Ccc1, which is the most important high-iron protecting factor devoted to detoxify excess cytosolic iron that is stored into the vacuole for its mobilization upon scarcity. The complete sequencing and annotation of many yeast genomes is starting to unveil the diversity and evolution of the iron homeostasis network in this species.

The yeast Aft1 transcription factor activates ribonucleotide reductase catalytic subunit RNR1 in response to iron deficiency.

Eukaryotic ribonucleotide reductases are iron-dependent enzymes that catalyze the rate-limiting step in the de novo synthesis of deoxyribonucleotides. Multiple mechanisms regulate the activity of ribonucleotide reductases in response to genotoxic stresses and iron deficiency. Upon iron starvation, the Saccharomyces cerevisiae Aft1 transcription factor specifically binds to iron-responsive cis elements within the promoter of a group of genes, known as the iron regulon, activating their transcription. Members of the iron regulon participate in iron acquisition, mobilization and recycling, and trigger a genome-wide metabolic remodeling of iron-dependent pathways. Here, we describe a mechanism that optimizes the activity of yeast ribonucleotide reductase when iron is scarce. We demonstrate that Aft1 and the DNA-binding protein Ixr1 enhance the expression of the gene encoding for its catalytic subunit, RNR1, in response to iron limitation, leading to an increase in both mRNA and protein levels. By mutagenesis of the Aft1-binding sites within RNR1 promoter, we conclude that RNR1 activation by iron depletion is important for Rnr1 protein and deoxyribonucleotide synthesis. Remarkably, Aft1 also activates the expression of IXR1 upon iron scarcity through an iron-responsive element located within its promoter. These results provide a novel mechanism for the direct activation of ribonucleotide reductase function by the iron-regulated Aft1 transcription factor.

Global translational repression induced by iron deficiency in yeast depends on the Gcn2/eIF2α pathway.

Iron is an essential element for all eukaryotic organisms because it participates as a redox active cofactor in a wide range of biological processes, including protein synthesis. Translation is probably the most energy consuming process in cells. Therefore, one of the initial responses of eukaryotic cells to stress or nutrient limitation is the arrest of mRNA translation. In first instance, the budding yeast Saccharomyces cerevisiae responds to iron deficiency by activating iron acquisition and remodeling cellular metabolism in order to prioritize essential over non-essential iron-dependent processes. We have determined that, despite a global decrease in transcription, mRNA translation is actively maintained during a short-term exposure to iron scarcity. However, a more severe iron deficiency condition induces a global repression of translation. Our results indicate that the Gcn2-eIF2α pathway limits general translation at its initiation step during iron deficiency. This bulk translational inhibition depends on the uncharged tRNA sensing Gcn1-Gcn20 complex. The involvement of the Gcn2-eIF2α pathway in the response to iron deficiency highlights its central role in the eukaryotic response to stress or nutritional deprivation, which is conserved from yeast to mammals.

A genome-wide transcriptional study reveals that iron deficiency inhibits the yeast TORC1 pathway.

Iron is an essential micronutrient that participates as a cofactor in a broad range of metabolic processes including mitochondrial respiration, DNA replication, protein translation and lipid biosynthesis. Adaptation to iron deficiency requires the global reorganization of cellular metabolism directed to optimize iron utilization. The budding yeast Saccharomyces cerevisiae has been widely used to characterize the responses of eukaryotic microorganisms to iron depletion. In this report, we used a genomic approach to investigate the contribution of transcription rates to the modulation of mRNA levels during adaptation of yeast cells to iron starvation. We reveal that a decrease in the activity of all RNA polymerases contributes to the down-regulation of many mRNAs, tRNAs and rRNAs. Opposite to the general expression pattern, many genes including components of the iron deficiency response, the mitochondrial retrograde pathway and the general stress response display a remarkable increase in both transcription rates and mRNA levels upon iron limitation, whereas genes encoding ribosomal proteins or implicated in ribosome biogenesis exhibit a pronounced fall. This expression profile is consistent with an activation of the environmental stress response. The phosphorylation stage of multiple regulatory factors strongly suggests that the conserved nutrient signaling pathway TORC1 is inhibited during the progress of iron deficiency. These results suggest an intricate crosstalk between iron metabolism and the TORC1 pathway that should be considered in many disorders.

Dissecting mRNA decay and translation inhibition during iron deficiency.

Iron participates as a vital cofactor in multiple metabolic pathways. Despite its abundance, iron bioavailability is highly restricted in aerobic and alkaline environments. Therefore, living organisms have evolved multiple adaptive mechanisms to respond to iron scarcity. These strategies include a global remodeling of iron metabolism directed to optimize iron utilization. In the baker's yeast Saccharomyces cerevisiae, this metabolic reorganization is accomplished to a large extent by an mRNA-binding protein called Cth2. Yeast Cth2 belongs to a conserved family of tandem zinc finger containing proteins that specifically bind to transcripts with AU-rich elements and promote their turnover. A recent study has revealed that Cth2 also inhibits the translation of its target mRNAs (Ramos-Alonso et al., PLoS Genet 14:e1007476, https://doi.org/10.1371/journal.pgen.1007476 , 2018). Interestingly, the mammalian Cth2 ortholog known as tristetraprolin (aka TTP/TIS11/ZFP36), which is also implicated in controlling iron metabolism, promotes the decay and prevents the translation of its regulated transcripts. These observations open the possibility to study the relative contribution of altering mRNA stability and translation to the physiological adaptation to iron deficiency, the function played by the different domains within the mRNA-binding protein, and the potential factors implicated in coordinating both post-transcriptional events.

Molecular strategies to increase yeast iron accumulation and resistance.

All eukaryotic organisms rely on iron as an essential micronutrient for life because it participates as a redox-active cofactor in multiple biological processes. However, excess iron can generate reactive oxygen species that damage cellular macromolecules. The low solubility of ferric iron under physiological conditions increases the prevalence of iron deficiency anemia. A common strategy to treat iron deficiency consists of dietary iron supplementation. The baker's yeast Saccharomyces cerevisiae is used as a model eukaryotic organism, but also as a feed supplement. In response to iron deficiency, the yeast Aft1 transcription factor activates cellular iron acquisition. However, when constitutively active, Aft1 inhibits growth probably due to iron toxicity. In this report, we have studied the consequences of using hyperactive AFT1 alleles, including AFT1-1UP, to increase yeast iron accumulation. We first characterized the iron sensitivity of cells expressing different constitutively active AFT1 alleles. We rescued the high iron sensitivity conferred by the AFT1 alleles by deleting the sphingolipid signaling kinase YPK1. We observed that the deletion of YPK1 exerts different effects on iron accumulation depending on the AFT1 allele and the environmental iron. Moreover, we determined that the impairment of the high-affinity iron transport system partially rescues the high iron toxicity of AFT1-1UP-expressing cells. Finally, we observed that AFT1-1UP inhibits oxygen consumption through activation of the RNA-binding protein Cth2. Deletion of CTH2 partially rescues the AFT1-1UP negative respiratory effect. Collectively, these results contribute to understand how the Aft1 transcription factor functions and the multiple consequences derived from its constitutive activation.

Yeast Cth2 protein represses the translation of ARE-containing mRNAs in response to iron deficiency.

In response to iron deficiency, the budding yeast Saccharomyces cerevisiae undergoes a metabolic remodeling in order to optimize iron utilization. The tandem zinc finger (TZF)-containing protein Cth2 plays a critical role in this adaptation by binding and promoting the degradation of multiple mRNAs that contain AU-rich elements (AREs). Here, we demonstrate that Cth2 also functions as a translational repressor of its target mRNAs. By complementary approaches, we demonstrate that Cth2 protein inhibits the translation of SDH4, which encodes a subunit of succinate dehydrogenase, and CTH2 mRNAs in response to iron depletion. Both the AREs within SDH4 and CTH2 transcripts, and the Cth2 TZF are essential for translational repression. We show that the role played by Cth2 as a negative translational regulator extends to other mRNA targets such as WTM1, CCP1 and HEM15. A structure-function analysis of Cth2 protein suggests that the Cth2 amino-terminal domain (NTD) is important for both mRNA turnover and translation inhibition, while its carboxy-terminal domain (CTD) only participates in the regulation of translation, but is dispensable for mRNA degradation. Finally, we demonstrate that the Cth2 CTD is physiologically relevant for adaptation to iron deficiency.

mRNA-binding protein tristetraprolin is essential for cardiac response to iron deficiency by regulating mitochondrial function.

Cells respond to iron deficiency by activating iron-regulatory proteins to increase cellular iron uptake and availability. However, it is not clear how cells adapt to conditions when cellular iron uptake does not fully match iron demand. Here, we show that the mRNA-binding protein tristetraprolin (TTP) is induced by iron deficiency and degrades mRNAs of mitochondrial Fe/S-cluster-containing proteins, specifically Ndufs1 in complex I and Uqcrfs1 in complex III, to match the decrease in Fe/S-cluster availability. In the absence of TTP, Uqcrfs1 levels are not decreased in iron deficiency, resulting in nonfunctional complex III, electron leakage, and oxidative damage. Mice with deletion of Ttp display cardiac dysfunction with iron deficiency, demonstrating that TTP is necessary for maintaining cardiac function in the setting of low cellular iron. Altogether, our results describe a pathway that is activated in iron deficiency to regulate mitochondrial function to match the availability of Fe/S clusters.

The elemental role of iron in DNA synthesis and repair.

Iron is an essential redox element that functions as a cofactor in many metabolic pathways. Critical enzymes in DNA metabolism, including multiple DNA repair enzymes (helicases, nucleases, glycosylases, demethylases) and ribonucleotide reductase, use iron as an indispensable cofactor to function. Recent striking results have revealed that the catalytic subunit of DNA polymerases also contains conserved cysteine-rich motifs that bind iron-sulfur (Fe/S) clusters that are essential for the formation of stable and active complexes. In line with this, mitochondrial and cytoplasmic defects in Fe/S cluster biogenesis and insertion into the nuclear iron-requiring enzymes involved in DNA synthesis and repair lead to DNA damage and genome instability. Recent studies have shown that yeast cells possess multi-layered mechanisms that regulate the ribonucleotide reductase function in response to fluctuations in iron bioavailability to maintain optimal deoxyribonucleotide concentrations. Finally, a fascinating DNA charge transport model indicates how the redox active Fe/S centers present in DNA repair machinery components are critical for detecting and repairing DNA mismatches along the genome by long-range charge transfers through double-stranded DNA. These unexpected connections between iron and DNA replication and repair have to be considered to properly understand cancer, aging and other DNA-related diseases.

Duodenal diverticular bleeding: an endoscopic challenge.

Duodenal diverticula are an uncommon cause of upper gastrointestinal bleeding. Until recently, it was primarily managed with surgery, but advances in the field of endoscopy have made management increasingly less invasive. We report a case of duodenal diverticular bleeding that was endoscopically managed, and review the literature about the various endoscopic therapies thus far described.

Rendimiento del score PIM 2 en una Unidad de Cuidados Intensivos Pediátricos / PIM 2 score yield in a Pediatric Intensive Care Unit

Objetivo: evaluar el rendimiento del score de predicción de mortalidad PIM 2 en una población de pacientes pediátricos críticos. Materiales y métodos: se realizó un estudio prospectivo, entre el 01 de enero y el 31 de diciembre de 2013. Se incluyeron todos los pacientes con una edad comprendida entre 29 días y 14 años que ingresaron a la Unidad de Cuidados Intensivos Pediátricos (CIP) de la Asociación Española. Fueron excluidos aquellos pacientes que fallecieron antes de las 12 horas, los que ingresaron para monitorización u observación luego de procedimientos endoscópicos o quirúrgicos menores o para realización de vías y los neonatos. Para evaluar el rendimiento del score PIM 2 se analizó tanto su calibración, como su discriminación, mediante la aplicación del test de bondad de ajuste de Hosmer-Lemeshow y la construcción de la curva ROC y el cálculo del área bajo la curva. Resultados: se incluyeron 184 pacientes para el análisis. La tasa de mortalidad de esta población fue de 5,4% (IC95% 1,88-8,98). La media de internación fue de 8,3 días (rango 12 horas a 27 días) y en el caso de los fallecidos fue de 11.3 días (rango 1-20). La aplicación del test de Hosmer-Lemeshow arrojó un valor de Chi cuadrado de 5,37 (p=0,71). El área bajo la curva ROC fue de 0,90. Para un punto de corte de 0,5 el rendimiento de la prueba evidenció una validez global del 96,7% (IC 95% entre 93,77-99,57), un valor predictivo positivo del 100% (87,50-100) y un valor predictivo negativo de 96,67% (93,77-99,57). La sensibilidad para este corte fue del 40% (4,64-75,36) y una especificidad del 100% (99,71-100). Conclusiones: el score PIM 2 ha presentado en la población estudiada una adecuada calibración y discriminación global. Por tanto, su utilidad como instrumento para medición y evaluación de la calidad asistencial permanece vigente. Pese a ello, su aplicabilidad práctica fue limitada en pacientes asignados a deciles de riesgo “bajo” en donde el score presentó problemas de discriminación y una alta tasa de falsos negativos.

Objective: to assess the PIM 2 score yield for the prediction of mortality in a population of critical pediatric patients. Methods: a prospective study was conducted, from January 1 to December 31, 2013. All patients who were between 29 days and 14 years old and were admitted to the Pediatric Intensive Care Unit at Asociación Española were included in the study. Those patients who died before 12 hours, those who were admitted for monitorization or observation after minor endoscopic or surgical procedures, or for the placement of catheters and neonates were excluded from the study. To assess yield of the PIM 2 score both its calibration and its discrimination, by means of a Hosmer-Lemeshow test for goodness of fit and the construction of the ROC curve and the area under the curve were analysed. Results: 184 patients were included for the analysis. The mortality rate of this populaiton was 5.4% (CI 98% 1.88-8.98). Average hospitalization was 8.3 days (range 12 hours to 27 days) and in the case of the patients who died, it was 11.3 days (range 1-20). Application of the Hosmer-Lemeshow test resulted in a Chi square test value of 5.37 (p=0.71). The area under the ROC curve was 0.90. For a 0.5 cut off point the yield of the test evidenced a global validity of 96.7 (CI 95% between 93.77- 99.57), a positive predictive value of 100% (87.5-100) and a negative prediciton value of 96.67% (93.77-99.57). Sensitivity for this cut off point was 40% (4.64-75.36) and a specificity of 100% (99.71-100). Conclusions: the PIM 2 score has evidenced, in the studied population and adequate global calibration and discrimination. Therefore, its usefulness as a tool for measuring and assessing assistance quality is still valid. However, its practical applicability was limited in patients allocated to “low”risk deciles, where the score presented discrimination problems and a high rate of false negatives.

Relationship between chronic pathologies of the supraspinatus tendon and the long head of the biceps tendon: systematic review.

BACKGROUND: Chronic supraspinatus tendinopathy is a common clinical problem that causes functional and labor disabilities in the population. It is the most frequent cause of shoulder pain. This pathology may be frequently associated to the affectation of the long head of biceps tendon (LHBT), the main stabilizer of the glenohumeral joint together with the supraspinatus. The main aim of this work is to study the prevalence of lesions in LHBT associated to the chronic pathology of the supraspinatus tendon. METHODS: A systematic review was carried out between May to July 2013 in the electronic databases: CINAHL, WOK, Medline, Scopus, PEDro, IME (CSIC) and Dialnet. The keywords used were: 1) in English: chronic, supraspinatus "long head of the biceps tendon", biceps, rotator cuff, tendinosis, tendinopathy, evaluation, examination; 2) in Spanish: supraespinoso, biceps, tendinopatía. Inclusion criteria of the articles included subjects with a previously diagnosed chronic pathology of rotator cuff (RC) without previous surgery or any other pathologies of the shoulder complex. The total number of articles included in the study were five. RESULTS: The results show an epidemiological relationship between both tendons. The age of the subjects included in the review was between 35 and 80 years, and some of the studies seem to indicate that the tendinopathy is more frequent in men than in women. The sample size of the studies varies according to the design, the highest being composed of 229 subjects, and the minimum of 28. Not all the articles selected specify the diagnostic testing, though the ones most normally used are arthroscopy, ultrasound, magnetic resonance imaging and assessment tests. The percentage of associated lesions of LHBT and supraspinatus tendon is between 78.5% and 22%, with a major prevalence in the studies with a smaller sample. CONCLUSIONS: The review of literature corroborates an association between the chronic pathology of the supraspinatus tendon and LHBT due to the epidemiological data. In addition, some authors confirm the existence of an anatomical and functional relationship between LHBT and the supraspinatus tendon, the latter being part of the LHBT pulley.

Evaluación de capacidades básicas para cumplir el Reglamento Sanitario Internacional en puntos de entrada de Uruguay / Assessment of core capacities for enforcement of the International Health Regulations at points of entry in Uruguay

OBJETIVO: Describir las características y resultados de la evaluación de capacidades básicas para cumplir el Reglamento Sanitario Internacional (RSI) en puntos de entrada de Uruguay, mediante la aplicación simultánea de los instrumentos de la Organización Mundial de la Salud (OMS) y el MERCOSUR, así como también las fortalezas y debilidades identificadas en ambos al ser aplicados en el terreno. MÉTODOS: Se realizó un estudio descriptivo y transversal mediante la aplicación de los instrumentos OMS y MERCOSUR de evaluación de capacidades básicas para el RSI. Se seleccionaron dos puntos de entrada (PDE 1 y 2) escogidos como muestra de conveniencia por presentar el mayor volumen de tráfico de pasajeros y bienes del país. Ambos instrumentos fueron caracterizados individual y cualitativamente en términos de fortalezas y debilidades. RESULTADOS: El valor promedio de implementación de capacidades básicas fue de 69 por ciento (OMS) y 67,4 por ciento (MERCOSUR) para el PDE 1 y de 68 por ciento (OMS) y 63,9 por ciento (MERCOSUR) para el PDE 2; se registró una diferencia promedio entre instrumentos de 1,6 por ciento para el PDE 1 y 4,1 por ciento para el PDE 2. Ambos instrumentos examinaron factores no mensurables, sujetos al juicio del evaluador, sin utilizar definiciones operacionales de las variables relevadas. CONCLUSIONES: La aplicación simultánea de los instrumentos de la OMS y del MERCOSUR arrojó niveles de implementación semejantes en los dos puntos de entrada evaluados. Estos procesos de evaluación se verían enriquecidos por el intercambio de las fortalezas y la mejora de las debilidades observadas en ambos instrumentos y registradas en el presente trabajo.

OBJECTIVE: To describe the characteristics and results of the assessment of core capacities for enforcement of the International Health Regulations (IHR) at points of entry in Uruguay through simultaneous application of the World Health Organization (WHO) and MERCOSUR instruments, and indicate the strengths and weaknesses identified in both instruments when applied in the field. METHODS: A descriptive cross-sectional study was conducted through the application of the WHO and MERCOSUR instruments to assess core capacities for the enforcement of the IHR. Two points of entry (POE 1 and 2) were selected as a convenience sample because they had the highest volume of passenger and goods traffic in the country. Both instruments were characterized individually and qualitatively in terms of strengths and weaknesses. RESULTS: The average values for the implementation of core capacities were 69 percent (WHO) and 67.4 percent (MERCOSUR) for POE 1 and 68 percent (WHO) and 63.9 percent (MERCO-SUR) for POE 2. The average differences recorded between the instruments were 1.6 percent for POE 1 and 4.1 percent for POE 2. Both instruments examined nonmeasurable factors that are subject to the evaluator's judgment, without using operational definitions of the relevant variables. CONCLUSIONS: Simultaneous application of the WHO and MERCOSUR instruments yielded similar levels of implementation at the two points of entry assessed. The assessment processes of the two instruments would be enhanced by capitalizing on each other's strengths and addressing the weaknesses observed and recorded in this study.