The importance of routine genetic testing in pediatric epilepsy surgery.

Genetic variants in relevant genes coexisting with MRI lesions in children with drug-resistant epilepsy (DRE) can negatively influence epilepsy surgery outcomes. Still, presurgical evaluation does not include genetic diagnostics routinely. Here, we report our presurgical evaluation algorithm that includes routine genetic testing. We analyzed retrospectively the data of 68 children with DRE operated at a mean age of 7.8 years (IQR: 8.1 years) at our center. In 49 children, genetic test results were available. We identified 21 gene variants (ACMG III: n = 7, ACMG IV: n = 2, ACMG V: n = 12) in 19 patients (45.2%) in the genes TSC1, TSC2, MECP2, DEPDC5, HUWE1, GRIN1, ASH1I, TRIO, KIF5C, CDON, ANKD11, TGFBR2, ATN1, COL4A1, JAK2, KCNQ2, ATP1A2, and GLI3 by whole-exome sequencing as well as deletions and duplications by array CGH in six patients. While the results did not change the surgery indication, they supported counseling with respect to postoperative chance of seizure freedom and weaning of antiseizure medication (ASM). The presence of genetic findings leads to the postoperative retention of at least one ASM. In our cohort, the International League against Epilepsy (ILAE) seizure outcome did not differ between patients with and without abnormal genetic findings. However, in the 7/68 patients with an unsatisfactory ILAE seizure outcome IV or V 12 months postsurgery, 2 had an abnormal or suspicious genetic finding as a putative explanation for persisting seizures postsurgery, and 3 had received palliative surgery including one TSC patient. This study highlights the importance of genetic testing in children with DRE to address putative underlying germline variants as genetic epilepsy causes or predisposing factors that guide patient and/or parent counseling on a case-by-case with respect to their individual chance of postoperative seizure freedom and ASM weaning. PLAIN LANGUAGE SUMMARY: Genetic variants in children with drug-resistant epilepsy (DRE) can negatively influence epilepsy surgery outcomes. However, presurgical evaluation does not include genetic diagnostics routinely. This retrospective study analyzed the genetic testing results of the 68 pediatric patients who received epilepsy surgery in our center. We identified 21 gene variants by whole-exome sequencing as well as deletions and duplications by array CGH in 6 patients. These results highlight the importance of genetic testing in children with DRE to guide patient and/or parent counseling on a case-by-case with respect to their individual chance of postoperative seizure freedom and ASM weaning.

Epidemiological study of vaccination against SARS-CoV-2 and its impact on COVID-19 progression in a cohort of patients in gran Canaria.

Objectives. We analyzed the impact of age, sex, vaccination against COVID-19, immunosuppressive treatment, and comorbidities on patients' risk of requiring hospital admission or of death. Methods. Population-based observational retrospective study conducted on a cohort of 19,850 patients aged 12 years or more, who were diagnosed with COVID-19 between June 1st and December 31st, 2021, in the island of Gran Canaria. Results. Hypertension (18.5%), asthma (12.8%) and diabetes (7.2%) were the most frequent comorbidities; 147 patients died (0.7%). The combination of advanced age, male sex, cancer, coronary heart disease, immunosuppressive treatment, hospital admission, admission to the intensive care unit, mechanical ventilation and lack of complete COVID-19 vaccination or booster dose was strongly predictive of mortality (p < 0.05); 831 patients required hospital admission and it was more frequent in men, older age groups, and patients with cancer, diabetes, arterial hypertension, chronic obstructive pulmonary disease, congestive heart failure or immunosuppressive treatment. The COVID-19 vaccine booster dose was associated with a lower risk of death ([OR] 0.11, 95% CI 0.06-0.21, p < 0.05) or hospital admission ([OR] 0.36, 95% CI 0.29-0.46, p < 0.05). Conclusions. Cancer, coronary heart disease, and immunosuppressive treatment were associated with increased COVID-19 mortality. More complete vaccination was associated with lower risk of hospital admission or death. Three doses of the SARS-CoV-2 vaccine were highly associated with the prevention of death and hospital admission in all age groups. These findings suggest that COVID-19 vaccination can help bring the pandemic under control.

Objetivos. Analizamos el impacto de la edad, el sexo, la vacunación frente a la COVID-19, el tratamiento inmunosupresor y las comorbilidades en el riesgo de los pacientes de precisar ingreso hospitalario o de fallecer.Métodos. Estudio retrospectivo observacional de base poblacional realizado sobre una cohorte de 19.850 pacientes de 12 años o más, que fueron diagnosticados de COVID-19 entre el 1 de junio y el 31 de diciembre de 2021, en la isla de Gran Canaria.Resultados. La hipertensión arterial (18,5%), el asma (12,8%) y la diabetes (7,2%) fueron las comorbilidades más frecuentes; Fallecieron 147 pacientes (0,7%). La combinación de edad avanzada, sexo masculino, cáncer, cardiopatía coronaria, tratamiento inmunosupresor, ingreso hospitalario, ingreso en unidad de cuidados intensivos, ventilación mecánica y la falta de vacunación completa contra el COVID-19 o dosis de refuerzo fue fuertemente predictiva de mortalidad (p < 0,05); 831 pacientes requirieron ingreso hospitalario y fue más frecuente en hombres, grupos de mayor edad y pacientes con cáncer, diabetes, hipertensión arterial, enfermedad pulmonar obstructiva crónica, insuficiencia cardiaca congestiva o tratamiento inmunosupresor. La dosis de refuerzo contra la vacuna del COVID-19 se asoció con un menor riesgo de muerte ([OR] 0.11, IC 95% 0.06­0.21, p < 0,05) o ingreso hospitalario ([OR] 0.36, IC 95% 0.29­0.46; p < 0,05).Conclusiones. El cáncer, la enfermedad coronaria y el tratamiento inmunosupresor se asociaron con una mayor mortalidad por COVID-19. Una vacunación más completa se asoció con un menor riesgo de hospitalización o muerte. Tres dosis de la vacuna contra el SARS-CoV-2 se asociaron a una mayor prevención de la muerte y el ingreso hospitalario relacionados con la COVID-19 en todos los grupos de edad. Estos hallazgos sugieren que la vacunación contra el COVID-19 puede ayudar a controlar la pandemia.

Caracterización de los sistemas productores de conejos en el municipio Ciego de Ávila, Cuba / Characterization of rabbit production systems in the Ciego de Ávila municipality, Cuba

Resumen La crianza de conejos contribuye a la obtención de proteína animal, así como de ingresos por la venta de dicha especie. La descripción y caracterización de los sistemas de producción de estos animales arrojan información valiosa para el diseño de planes de intervención y mejoras. El objetivo del presente trabajo fue determinar las principales variables que influyen en la heterogeneidad de los sistemas productores de conejos en el municipio Ciego de Ávila, Cuba. La muestra estuvo formada por 49 fincas. Se obtuvo la información cuantitativa de indicadores productivos, reproductivos y sociales, a través de un análisis de factores, usando componentes principales (CP). Se calcularon las puntuaciones factoriales de cada caso, en cada CP, y los estadísticos descriptivos de los indicadores medidos. En las condiciones del territorio estudiado, la eficiencia estuvo determinada por 6 CP que explicaron el 77.6 % de la varianza: 1) tamaño del rebaño y áreas de forrajes; 2) comportamiento reproductivo; 3) edad del productor y manejo reproductivo; 4) mortalidad; 5) edad al destete y sacrificio y 6) número de montas para gestar las conejas. La caracterización a partir del uso de CP, y el índice factorial de cada caso de estudio en cada CP, sirve de base para interpretar la gran heterogeneidad existente en los indicadores estudiados, así como su similitud, y contribuye a definir relaciones y comportamientos en la caracterización de fincas cunícolas en esta región, lo que permitirá implementar planes de mejora productiva.

Abstract The breeding of rabbits contributes to obtaining animal protein and generating income from the sale of this species. The description and characterization of the production systems of these animals provide valuable information for the design of intervention and improvement plans. The aim of this study was to determine the main variables that influence the heterogeneity of the rabbit production systems in the Ciego de Ávila municipality, Cuba. The sample consisted of 49 farms. Quantitative data on productive, reproductive and social indicators were obtained through factor analysis using principal components (PC). The factor scores of each case were calculated, in each PC, and descriptive statistics of the indicators measured. In the conditions of the studied territory, the efficiency was determined by 6 PC that explained 77.6 % of the variance: 1) size of the herd and forage areas; 2) reproductive behavior; 3) age of the producer and reproductive management; 4) mortality; 5) age at weaning and age at slaughter and 6) number of mounts to gestate the breeders. The characterization from the use of PC, and the factor index for each case study in each PC, serve as the basis for interpreting the great existing heterogeneity in the indicators studied, as well as their similarity. It also contributes to defining relationships and behaviors in the characterization of rabbit farms in this region, which will allow the implementation of productive improvement plans.

Comparative analysis of the anthelmintic efficacy of European heather extracts on Teladorsagia circumcincta and Trichostrongylus colubriformis egg hatching and larval motility.

BACKGROUND: Gastrointestinal nematode (GIN) control is traditionally achieved with the use of anthelmintic drugs, however due to regulations in organic farming and the rise in anthelmintic resistance, alternatives are sought after. A promising alternative is the use of bioactive plant feeding due to the presence of plant secondary metabolites (PSMs) such as proanthocyanidins (PAs). This study focussed on the perennial shrub heather (Ericaceae family), a plant rich in PAs, highly abundant across Europe and with previously demonstrated anthelmintic potential. METHODS: In vitro assays were used to investigate heather's anthelmintic efficacy against egg hatching and larval motility. Heather samples were collected from five European countries across two seasons, and extracts were tested against two GIN species: Teladorsagia circumcincta and Trichostrongylus colubriformis. Polyphenol group-specific ultraperformance liquid chromatography-tandem mass spectrometry analysis was performed to identify relevant polyphenol subgroups present, including the PA concentration and size and ratio of the subunits. Partial least squares analysis was performed to associate efficacy with variation in PSM composition. RESULTS: Heather extracts reduced egg hatching of both GIN species in a dose-dependent manner by up to 100%, while three extracts at the highest concentration (10 mg/ml) reduced larval motility to levels that were not significantly different from dead larvae controls. PAs, particularly the procyanidin type, and flavonol derivatives were associated with anthelmintic activity, and the particular subgroup of polyphenols associated with the efficacy was dependent on the GIN species and life stage. CONCLUSIONS: Our results provide in vitro evidence that heather, a widely available plant often managed as a weed in grazing systems, has anthelmintic properties attributed to various groups of PSMs and could contribute to sustainable GIN control in ruminant production systems across Europe.

Assessment of SARS-CoV-2 Infection According to Previous Metabolic Status and Its Association with Mortality and Post-Acute COVID-19.

Background. SARS-CoV-2 infection was analyzed according to previous metabolic status and its association with mortality and post-acute COVID-19. Methods. A population-based observational retrospective study was conducted on a cohort of 110,726 patients aged 12 years or more who were diagnosed with COVID-19 infection between June 1st, 2021, and 28 February 2022 on the island of Gran Canaria, Spain. Results. In the 347 patients who died, the combination of advanced age, male sex, cancer, immunosuppressive therapy, coronary heart disease, elevated total cholesterol and reduced high-density lipoprotein cholesterol (HDL-C) was strongly predictive of mortality (p < 0.05). In the 555 patients who developed post-acute COVID-19, the persistence of symptoms was most frequent in women, older subjects and patients with obstructive sleep apnea syndrome, asthma, elevated fasting glucose levels or elevated total cholesterol (p < 0.05). A complete vaccination schedule was associated with lower mortality (incidence rate ratio (IRR) 0.5, 95%CI 0.39−0.64; p < 0.05) and post-acute COVID-19 (IRR 0.37, 95%CI 0.31−0.44; p < 0.05). Conclusions. Elevated HDL-C and elevated total cholesterol were significantly associated with COVID-19 mortality. Elevated fasting glucose levels and elevated total cholesterol were risk factors for the development of post-acute COVID-19.

Spanish Validation of the COMM Scale to Assess the Misuse of Prescription Opioids in Patients with Chronic Noncancer Pain.

The Current Opioid Misuse Measure (COMM) is a questionnaire used to identify and monitor chronic pain patients on opioid therapy who may be misusing their prescription opioids. The aim of the present study was to adapt the questionnaire for its use in Spanish-speaking populations. A total of 171 individuals (131 women and 40 men) with nononcological chronic pain participated in this cross-sectional study. The most frequent pain diagnoses in the sample were fibromyalgia, herniated disc, and rheumatoid arthritis. Systematic sampling was used. All individuals were interviewed at their clinic between March 2018 and February 2020. The dimensionality of the COMM-SV items was evaluated using an optimal implementation of parallel analysis (PA) and an exploratory factor analysis. Internal consistency, test-retest reliability, and criterion and convergent validity were calculated. The COMM-SV comprises five factors: problematic interpersonal behaviour, searching for more medication than prescribed, medication misuse and self-injurious thoughts, emergency use, and memory and attention problems. It has good reliability and adequate test-retest stability. The results support its criterion and convergent validity. Given the increasing use and abuse of opioids, a valid and reliable instrument is needed in Spanish settings to identify patients with chronic pain who present aberrant behaviour related to the use of these medications. The COMM-SV enables Spanish clinicians to do that.

GLI3 variants causing isolated polysyndactyly are not restricted to the protein's C-terminal third.

Loss of function variants of GLI3 are associated with a variety of forms of polysyndactyly: Pallister-Hall syndrome (PHS), Greig-Cephalopolysyndactyly syndrome (GCPS), and isolated polysyndactyly (IPD). Variants affecting the N-terminal and C-terminal thirds of the GLI3 protein have been associated with GCPS, those within the central third with PHS. Cases of IPD have been attributed to variants affecting the C-terminal third of the GLI3 protein. In this study, we further investigate these genotype-phenotype correlations. Sequencing of GLI3 was performed in patients with clinical findings suggestive of a GLI3-associated syndrome. Additionally, we searched the literature for reported cases of either manifestation with mutations in the GLI3 gene. Here, we report 48 novel cases from 16 families with polysyndactyly in whom we found causative variants in GLI3 and a review on 314 previously reported GLI3 variants. No differences in location of variants causing either GCPS or IPD were found. Review of published data confirmed the association of PHS and variants affecting the GLI3 protein's central third. We conclude that the observed manifestations of GLI3 variants as GCPS or IPD display different phenotypic severities of the same disorder and propose a binary division of GLI3-associated disorders in either PHS or GCPS/polysyndactyly.

Anticholinergic Exposure in Elderly Complex Chronic Patients: A Cross-Sectional Study.

BACKGROUND: Elderly patients with multiple chronic conditions are closely linked to polymedication, a condition that is also highly associated with the presence of adverse effects, such as those observed by anticholinergic activity. Anticholinergic burden is defined in a very variable way and is described inconsistently using different scores and providing different interpretations of the risk of suffering from anticholinergic adverse effects. OBJECTIVE: The objective is to analyse the anticholinergic risk exposure in elderly complex chronic patients. METHODS: A observational multicentre study was performed for a cohort of complex chronic patients over 65 years who received treatment with at least one drug with anticholinergic activity. Anticholinergic exposure was assessed using ten scales included in the Anticholinergic Burden Calculator. RESULTS: 473 patients were recruited, being 67.7% with excessive polypharmacy. 80 was the total number of anticholinergic drugs with any scale, with a median of 2 drugs with anticholinergic activity per patient (IQR=2). Three scales evaluated more than 70% of the patients (Chew: 79.1%; Drug Burden Index (DBI): 77.8%; Anticholinergic Cognitive Burden (ACB): 75.9%). The percentage of different drugs with anticholinergic properties evaluated ranged from 13.8% (Anticholinergic Burden Classification (ABC)) to 57.5% (DBI) and anticholinergic drugs prescriptions oscillated from 14% (Anticholinergic Risk Scale (ARS)) to 53.3% (DBI). 71.1% of patients were at risk (moderate and high risk) according to DBI vs. 9.7% by ARS at the opposite side. Important differences of anticholinergic risk in patients with excessive polypharmacy were in ACB, ABC and DBI scales. CONCLUSION: This study has highlighted clear differences between the scales used. DBI seems to be the scale that identifies a higher number of elderly chronic complex patients at risk of developing anticholinergic adverse effects.

Selection criteria for early breast cancer patients in the DBCG proton trial - The randomised phase III trial strategy.

BACKGROUND AND PURPOSE: Adjuvant radiotherapy of internal mammary nodes (IMN) improves survival in high-risk early breast cancer patients but inevitably leads to more dose to heart and lung. Target coverage is often compromised to meet heart/lung dose constraints. We estimate heart and lung dose when target coverage is not compromised in consecutive patients. These estimates are used to guide the choice of selection criteria for the randomised Danish Breast Cancer Group (DBCG) Proton Trial. MATERIALS AND METHODS: 179 breast cancer patients already treated with loco-regional IMN radiotherapy from 18 European departments were included. If the clinically delivered treatment plan did not comply with defined target coverage requirements, the plan was modified retrospectively until sufficient coverage was reached. The choice of selection criteria was based on the estimated number of eligible patients for different heart and lung dose thresholds in combination with proton therapy capacity limitations and dose-response relationships for heart and lung. RESULTS: Median mean heart dose was 3.0 Gy (range, 1.1-8.2 Gy) for left-sided and 1.4 Gy (0.4-11.5 Gy) for right-sided treatment plans. Median V17Gy/V20Gy (hypofractionated/normofractionated plans) for ipsilateral lung was 31% (9-57%). The DBCG Radiotherapy Committee chose mean heart dose ≥ 4 Gy and/or lung V17Gy/V20Gy ≥ 37% as thresholds for inclusion in the randomised trial. Using these thresholds, we estimate that 22% of patients requiring loco-regional IMN radiotherapy will be eligible for the trial. CONCLUSION: The patient selection criteria for the DBCG Proton Trial are mean heart dose ≥ 4 Gy and/or lung V17Gy/V20Gy ≥ 37%.

Stereotactic Radiotherapy for Hepatocellular Carcinoma, Radiosensitization Strategies and Radiation-Immunotherapy Combination.

Stereotactic body radiotherapy (SBRT) is an emerging ablative modality for hepatocellular carcinoma (HCC). Most patients with HCC have advanced disease at the time of diagnosis, and therefore, are not candidates for definitive-intent therapies such as resection or transplantation. For this reason, various alternative local and regional therapies have been used to prevent disease progression, palliate symptoms, and delay liver failure. Stereotactic body radiation therapy is a non-invasive technique of delivering ablative doses of radiation to tumors while sparing normal or non-tumor hepatic tissue. Incorporation of SBRT in multidisciplinary HCC management is gradual, initially applied when other liver-directed therapies have failed or are contraindicated, and tried in combination with other locoregional or systemic therapies for more unfavorable conditions by more experienced teams. In order to improve SBRT therapeutic ratio, there has been much interest in augmenting the effect of radiation on tumors by combining it with chemotherapy, molecularly targeted therapeutics, nanoparticles, and immunotherapy. This review aims to synthesize available evidence to evaluate the clinical feasibility and efficacy of SBRT for HCC, and to explore novel radio-potentiation concepts by combining SBRT with novel therapeutics. It is expected that those approaches would result in improved therapeutic outcomes, even though many questions remain with regard to the optimal way to assemble treatments. Further trials are needed to evaluate and consolidate these promising therapies for HCC.

Simultaneous diagnosis of liver PEComa in a family with known Li-Fraumeni syndrome: a case report.

BACKGROUND: Li-Fraumeni syndrome (LFS) is an autosomal dominant hereditary disease. It is associated with the loss of function of the p53 protein and an increased risk of malignant tumor development at early age. The most frequently detected tumors include breast cancer, sarcomas, leukemia, brain tumors, and adrenocortical carcinomas. While sarcomas account for only 1% of solid tumors, they are more frequently detected in these families. CASE PRESENTATION: We report a simultaneous diagnosis of hepatic perivascular epithelioid cell tumor (PEComa), a very rare subtype of sarcoma, in two siblings with a LFS. CONCLUSIONS: The simultaneous diagnosis of PEComa in two siblings presented in this case allowed us to review the frequency of PEComa in this genetic syndrome previously reported, which was very little. Despite its rarity, PEComa must be considered in the differential diagnosis of new-onset liver lesions in patients who were previously diagnosed with LFS.

Depletion of Blautia Species in the Microbiota of Obese Children Relates to Intestinal Inflammation and Metabolic Phenotype Worsening.

Cross-sectional studies conducted with obese and control subjects have suggested associations between gut microbiota alterations and obesity, but the links with specific disease phenotypes and proofs of causality are still scarce. The present study aimed to profile the gut microbiota of lean and obese children with and without insulin resistance to characterize associations with specific obesity-related complications and understand the role played in metabolic inflammation. Through massive sequencing of 16S rRNA gene amplicons and data analysis using a novel permutation approach, we have detected decreased incidence of Blautia species, especially Blautia luti and B. wexlerae, in the gut microbiota of obese children, which was even more pronounced in cases with both obesity and insulin resistance. There was also a parallel increase in proinflammatory cytokines and chemokines (gamma interferon [IFN-γ], tumor necrosis factor alpha [TNF-α], and monocyte chemoattractant protein 1 [MCP-1]) in feces of obese children compared to those of lean ones. B. luti and B. wexlerae were also shown to exert an anti-inflammatory effect in peripheral blood mononuclear cell cultures in vitro, compared to non-obesity-associated species. We suggest that the depletion of B. luti and B. wexlerae species in the gut ecosystem may occur in cases of obesity and contribute to metabolic inflammation leading to insulin resistance.IMPORTANCE Child obesity constitutes a risk factor for developing insulin resistance which, if sustained, could lead to more severe conditions like type 2 diabetes (T2D) in adulthood. Our study identified previously unknown species whose depletion (Blautia luti and Blautia wexlerae) is associated with insulin resistance in obese individuals. Our results also indicate that these bacterial species might help to reduce inflammation causally linked to obesity-related complications. Childhood is considered a window of opportunity to tackle obesity. These new findings provide, therefore, valuable information for the future design of microbiota-based strategies for the early prevention of obesity-related complications.

Anesthesia in Combination with Propofol Increases Disease-Free Survival in Bladder Cancer Patients Who Undergo Radical Tumor Cystectomy as Compared to Inhalational Anesthetics and Opiate-Based Analgesia.

BACKGROUND: The effect of anesthetic techniques on cancer recurrence has been the subject of intensive research in the past years, as it affects a large proportion of the population. The use of opioids and halogenated agents in cancer patients during the perioperative period may be related to higher rates of cancer recurrence and reduced disease-free survival. METHODS: This was a prospective study. The sample was composed of 100 patients who underwent a radical cystectomy for infiltrating bladder cancer in a reference center. We compared disease-free survival associated with combined anesthesia versus opiate-based analgesia. The relationship between the administered hypnotic and disease-free survival was also investigated. RESULTS: The median disease-free survival of the patients who received combined anesthesia was 585 (240-1,005) days versus 210 (90-645) days in the other group. A significant difference was observed between the two groups (p = 0.01). Combined analysis of all groups revealed significant differences in disease-free survival between patients who received combined anesthesia with propofol (510 [315-1,545] disease-free days) and those who received sevoflurane and opioids (150 [90-450] disease-free days) (p = 0.02). CONCLUSIONS: Anesthesia may play a crucial role in tumor relapse, as it is administered at the moment of the greatest risk of dissemination: surgical handling of the tumor. Opioids and volatile agents have been related to an increased risk for cancer recurrence. We compared the use of propofol + local anesthesia versus sevoflurane + opioids and also found that disease-free survival was longer among patients who received propofol + local anesthesia. Disease-free survival increases with the use of propofol in combination with epidural anesthesia in patients who undergo surgery for infiltrating bladder cancer.

Outpatient management of incidental pulmonary embolism in cancer patient.

PURPOSE: Incidentally discovered pulmonary embolism is a prevalent clinical problem for cancer patients and contributes significantly to the burden of cancer-associated thrombosis. The aim of this study was to explore if outpatient management of incidental pulmonary embolism (iPE) in cancer patients is effective and can be conducted safely. METHODS/PATIENTS: We performed a prospective observational cohort study in a single Spanish tertiary hospital. Patients diagnosed with iPE and active cancer were enrolled. Between May 2016 and May 2017, 25 consecutive patients were included in the study. RESULTS: All patients were assessed in the emergency room (ER) and started treatment with low-molecular weight heparins (LMWH) being discharged in the following 24 h. Congestive heart failure and right ventricular dysfunction were ruled out, and none of them presented massive PE, active bleeding or any disease-related reason that required hospitalization. The 90-day follow-up visit showed no venous thromboembolism (VTE) recurrence and the major bleeding rate was 4%. Mortality rate at 30 and 90 days was 0%. CONCLUSIONS: Outpatient management for iPE in cancer patients appears to be feasible and safe in selected cancer patients.

Antibiotics for trachoma.

BACKGROUND: Trachoma is the world's leading infectious cause of blindness. In 1996, WHO launched the Alliance for the Global Elimination of Trachoma by the year 2020, based on the 'SAFE' strategy (surgery, antibiotics, facial cleanliness, and environmental improvement). OBJECTIVES: To assess the evidence supporting the antibiotic arm of the SAFE strategy by assessing the effects of antibiotics on both active trachoma (primary objective), Chlamydia trachomatis infection of the conjunctiva, antibiotic resistance, and adverse effects (secondary objectives). SEARCH METHODS: We searched relevant electronic databases and trials registers. The date of the last search was 4 January 2019. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that satisfied either of two criteria: (a) trials in which topical or oral administration of an antibiotic was compared to placebo or no treatment in people or communities with trachoma, (b) trials in which a topical antibiotic was compared with an oral antibiotic in people or communities with trachoma. We also included studies addressing different dosing strategies in the population.  DATA COLLECTION AND ANALYSIS: We used standard methods expected by Cochrane. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We identified 14 studies where individuals with trachoma were randomised and 12 cluster-randomised studies. Any antibiotic versus control (individuals)Nine studies (1961 participants) randomised individuals with trachoma to antibiotic or control (no treatment or placebo). All of these studies enrolled children and young people with active trachoma. The antibiotics used in these studies included topical (oxy)tetracycline (5 studies), doxycycline (2 studies), and sulfonamides (4 studies). Four studies had more than two study arms. In general these studies were poorly reported, and it was difficult to judge risk of bias.These studies provided low-certainty evidence that people with active trachoma treated with antibiotics experienced a reduction in active trachoma at three months (risk ratio (RR) 0.78, 95% confidence interval (CI) 0.69 to 0.89; 1961 people; 9 RCTs; I2 = 73%) and 12 months (RR 0.74, 95% CI 0.55 to 1.00; 1035 people; 4 RCTs; I2 = 90%). Low-certainty evidence was available for ocular infection at three months (RR 0.81, 95% CI 0.63 to 1.04; 297 people; 4 RCTs; I2 = 0%) and 12 months (RR 0.25, 95% CI 0.08 to 0.78; 129 people; 1 RCT). None of these studies assessed antimicrobial resistance. In those studies that reported harms, no serious adverse effects were reported (low-certainty evidence).Oral versus topical antibiotics (individuals)Eight studies (1583 participants) compared oral and topical antibiotics. Only one study included people older than 21 years of age. Oral antibiotics included azithromycin (5 studies), sulfonamides (2 studies), and doxycycline (1 study). Topical antibiotics included (oxy)tetracycline (6 studies), azithromycin (1 study), and sulfonamide (1 study). These studies were poorly reported, and it was difficult to judge risk of bias.There was low-certainty evidence of little or no difference in effect between oral and topical antibiotics on active trachoma at three months (RR 0.97, 95% CI 0.81 to 1.16; 953 people; 6 RCTs; I2 = 63%) and 12 months (RR 0.93, 95% CI 0.75 to 1.15; 886 people; 5 RCTs; I2 = 56%). There was very low-certainty evidence for ocular infection at three or 12 months. Antimicrobial resistance was not assessed. In those studies that reported adverse effects, no serious adverse effects were reported; one study reported abdominal pain with azithromycin; one study reported a couple of cases of nausea with azithromycin; and one study reported three cases of reaction to sulfonamides (low-certainty evidence).Oral azithromycin versus control (communities)Four cluster-randomised studies compared antibiotic with no or delayed treatment. Data were available on active trachoma at 12 months from two studies but could not be pooled because of reporting differences. One study at low risk of bias found a reduced prevalence of active trachoma 12 months after a single dose of azithromycin in communities with a high prevalence of infection (RR 0.58, 95% CI 0.52 to 0.65; 1247 people). The other, lower quality, study in low-prevalence communities reported similar median prevalences of infection at 12 months: 9.3% in communities treated with azithromycin and 8.2% in untreated communities. We judged this moderate-certainty evidence for a reduction in active trachoma with treatment, downgrading one level for inconsistency between the two studies. Two studies reported ocular infection at 12 months and data could be pooled. There was a reduction in ocular infection (RR 0.36, 0.31 to 0.43; 2139 people) 12 months after mass treatment with a single dose compared with no treatment (moderate-certainty evidence). There was high-certainty evidence of an increased risk of resistance of Streptococcus pneumoniae, Staphylococcus aureus, and Escherichia coli to azithromycin, tetracycline, and clindamycin in communities treated with azithromycin, with approximately 5-fold risk ratios at 12 months. The evidence did not support increased resistance to penicillin or trimethoprim-sulfamethoxazole. None of the studies measured resistance to C trachomatis. No serious adverse events were reported. The main adverse effect noted for azithromycin (˜10%) was abdominal pain, vomiting, and nausea.Oral azithromycin versus topical tetracycline (communities)Three cluster-randomised studies compared oral azithromycin with topical tetracycline. The evidence was inconsistent for active trachoma and ocular infection at three and 12 months (low-certainty evidence) and was not pooled due to considerable heterogeneity. Antimicrobial resistance and adverse effects were not reported.Different dosing strategiesSix studies compared different strategies for dosing. There were: mass treatment at different dosing intervals; applying cessation or stopping rules to mass treatment; strategies to increase mass treatment coverage. There was no strong evidence to support any variation in the recommended annual mass treatment. AUTHORS' CONCLUSIONS: Antibiotic treatment may reduce the risk of active trachoma and ocular infection in people infected with C trachomatis, compared to no treatment/placebo, but the size of the treatment effect in individuals is uncertain. Mass antibiotic treatment with single dose oral azithromycin reduces the prevalence of active trachoma and ocular infection in communities. There is no strong evidence to support any variation in the recommended periodicity of annual mass treatment. There is evidence of an increased risk of antibiotic resistance at 12 months in communities treated with antibiotics.

Management of myelodysplastic syndromes after failure of response to hypomethylating agents.

Hypomethylating agents (HMAs) are the standard of care for patients with myelodysplastic syndrome (MDS). However, only around 50% of patients respond to these agents, and responses tend to be transient, with loss of response frequently happening within 2 years and being associated with very poor prognosis and limited therapeutic options. Identification of patients who will respond to HMAs is challenging. Mechanisms underlying resistance to HMAs are not clear yet. Recently, absence of response has been associated with increased cell-cycle quiescence among the hematopoietic progenitor cells. There are no standard-of-care options for patients after HMA failure. However, the increasing knowledge of MDS pathogenesis has led to the development of new potential therapies, including HMAs with longer half-life and exposure, inhibition of the antiapoptotic BCL2 protein with venetoclax or inhibition of immune-checkpoint regulatory proteins such as PD-1 or CTLA-4, innate immunity and targeting of CD33/CD3 with multiple monoclonal antibodies. In addition, multiple targeted agents are opening opportunities to treat subgroups of patients whose disease harbors mutations in TP53, IDH, FLT3, and genes involved in splicing machinery. Newer formulations of intensive chemotherapy and its different combinations may be considered a valid option in selected patients after HMA failure. Finally, decision making at the time of failure of response to HMAs should be personalized, taking into account that allogenic stem-cell transplantation remains the only therapeutic approach with curative potential in these patients. In the current review, we will focus on all the above aspects.

Chronic pain, posttraumatic stress disorder, and opioid intake: A systematic review.

BACKGROUND: The literature suggests that there is a high degree of co-occurrence between chronic pain and posttraumatic stress disorder (PTSD). An association has been found between PTSD and substance abuse. PTSD is a severe disorder that should be taken into account when opioids are prescribed. It has been found that the prevalence of opioid use disorder (OUD) in chronic pain patients is higher among those with PTSD than those without this disorder. AIM: To perform a systematic review on the association between PTSD, chronic non-cancer pain (CNCP), and opioid intake (i.e., prescription, misuse, and abuse). METHODS: We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The Patient, Intervention, Comparator, and Outcomes (PICOS) criteria were formulated a priori in the protocol of the systematic review. A search was conducted of the PROSPERO database. In March 2019, searches were also conducted of 5 other databases: PubMed, MEDLINE, PsycINFO, Web of Science, and PILOTS. The Scottish Intercollegiate Guidelines Network checklist for cohort studies was used to assess the selected studies for their methodological quality and risk of bias. Each study was evaluated according to its internal validity, participant sampling, confounding variables, and the statistical analysis. RESULTS: A total of 151 potentially eligible studies were identified of which 17 were retained for analysis. Only 10 met the selection criteria. All the studies were published between 2008 and 2018 and were conducted in the United States. The eligible studies included a total of 1622785 unique participants. Of these, 196516 had comorbid CNCP and PTSD and were consuming opiates. The participants had a cross-study mean age of 35.2 years. The majority of participants were men (81.6%). The most common chronic pain condition was musculoskeletal pain: back pain (47.14% across studies; range: 16%-60.6%), arthritis and joint pain (31.1%; range: 18%-67.5%), and neck pain (28.7%; range: 3.6%-63%). In total, 42.4% of the participants across studies had a diagnosis of PTSD (range: 4.7%-95%). In relation to opioid intake, we identified 2 different outcomes: opioid prescription and OUD. All the studies reported evidence of a greater prevalence of PTSD in CNCP patients who were receiving prescribed opioids and that PTSD was associated with OUD in CNCP patients. CONCLUSION: Opioid analgesic prescription as the treatment of choice for CNCP patients should include screening for baseline PTSD to ensure that these drugs are safely consumed.

A meta-analysis of airborne asbestos fiber concentrations from work with or around asbestos-containing floor tile.

In this meta-analysis, exposures to airborne asbestos during work with or around floor tiles were characterized according to several variables: study, sample type, activity, and task. Personal breathing zone, bystander, and area sample exposure concentrations were differentiated and compared against current occupational exposure limits to asbestos. In total, 22 studies, including 804 personal, 57 bystander, and 295 area samples, were included in the analysis. The arithmetic mean airborne fiber concentrations were 0.05, 0.02, and 0.01 f/cm3 for personal, bystander, and area samples, respectively. Arithmetic mean time-weighted-average fiber concentrations over an 8-h working day were 0.02 and 0.01 f/cm3 for personal and bystander samples, respectively. Phase contrast microscopy (PCM) personal airborne fiber concentrations were highest for maintenance activities, followed by removal and installation. Tasks that involved buffing or burnishing, scoring or snapping, and scraping or lifting had the highest personal PCM concentrations, while stripping floor tile and removing it with chemical solvent had the lowest concentrations. Exposures associated with handling asbestos floor tiles, under working conditions normally encountered, do not generally produce airborne concentrations at levels that exceed the current OSHA PEL nor do they appear to approach the threshold cumulative asbestos dose concentrations that have been previously associated with an increased risk of asbestos-related disease.

Coordination capacity of cytosine, adenine and derivatives towards open-paddlewheel diruthenium compounds.

[Ru2Cl2(DPhF)3] (DPhF = diphenylformamidinate) links preferentially to the junctions of RNA (ribonucleic acid) structures, although the bonding mode is not known. In order to clarify this question the reactions between [Ru2Cl2(DPhF)3] and cytosine (Hcyto), cytidine (Hcyti), cytidine 2',3'-cyclic monophosphate sodium salt (NacCMP), adenine (Hade), adenosine (Haden) and adenosine 3',5'-cyclic monophosphate (HcAMP) have been carried out. In the resultant complexes, cyto (cytosinate), cyti (cytidinate), cCMP (cytidine 2',3'-cyclic monophosphate monoanion), ade (adeninate), aden (adenosinate) and cAMP (deprotonated adenosine 3',5'-cyclic monophosphate) are bonded to the diruthenium unit as N,N'-bridging ligands, as confirmed by the solution of the crystal structures of [RuCl(DPhF)3(cyto)] and [RuCl(DPhF)3(ade)] by X-ray diffraction. The axial positions of the diruthenium species are still available for additional interactions with other residues that could explain its preference towards RNA junctions.