The impact of patient support programs in Europe: a systematic literature review

Background and Objective : Patient support programs aim to provide solutions beyond the medication itself, by enhancing treatment adherence, improving clinical outcomes, elevating patient experience, and/or increasing quality of life. As patient support programs increasingly play an important role in assisting patients, numerous observational studies and pragmatic trials designed to evaluate their impact on healthcare have been conducted in recent years. This review aims to characterize these studies. Methods : A systematic literature review, supplemented by a broad search of gray literature, was conducted following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and Cochrane recommendations. Observational studies and pragmatic trials conducted in Europe to evaluate the impact of patient support programs, published in English or Spanish between 17/03/2010 and 17/03/2020, were reviewed. Two patient support program definitions were applied starting with Ganguli et al.’s broad approach, followed by the European Medicines Agency definition, narrowed to Marketing Authorization Holders organized systems and their medicines. The quality of publications was assessed using the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) statement 22-item checklist. Results : Of the 49 identified studies following the Ganguli et al. definition, 20 studies met the European Medicines Agency definition and were reviewed. Patient support program impact was evaluated based on a wide range of methodologies: 70% assessed patient support program-related patient-reported outcomes, 55% reported clinical outcomes, and 25% reported economic impacts on health resources. Only 45% conducted a comparative analysis. Overall, 75% of the studies achieved their proposed objectives. Conclusions : The heterogeneity of the observational studies reviewed reflects the complexity of patient support programs that are built ad hoc for specific diseases, treatments, and patients. Results suggest that patient support programs play a key role in promoting treatment effectiveness, clinical outcomes, and satisfaction. However, there is a need for standardizing the definition of patient support programs and the methods to evaluate their impact

Mycobacterial aminoglycoside acetyltransferases: a little of drug resistance, and a lot of other roles

Aminoglycoside acetyltransferases are important determinants of resistance to aminoglycoside antibiotics in most bacterial genera. In mycobacteria, however, aminoglycoside acetyltransferases contribute only partially to aminoglycoside susceptibility since they are related with low level resistance to these antibiotics (while high level aminoglycoside resistance is due to mutations in the ribosome). Instead, aminoglycoside acetyltransferases contribute to other bacterial functions, and this can explain its widespread presence along species of genus Mycobacterium. This review is focused on two mycobacterial aminoglycoside acetyltransferase enzymes. First, the aminoglycoside 2'-N-acetyltransferase [AAC(2')], which was identified as a determinant of weak aminoglycoside resistance in M. fortuitum, and later found to be widespread in most mycobacterial species; AAC(2') enzymes have been associated with resistance to cell wall degradative enzymes, and bactericidal mode of action of aminoglycosides. Second, the Eis aminoglycoside acetyltransferase, which was identified originally as a virulence determinant in M. tuberculosis (enhanced intracellular survival); Eis protein in fact controls production of pro-inflammatory cytokines and other pathways. The relation of Eis with aminoglycoside susceptibility was found after the years, and reaches clinical significance only in M. tuberculosis isolates resistant to the second-line drug kanamycin. Given the role of AAC(2') and Eis proteins in mycobacterial biology, inhibitory molecules have been identified, more abundantly in case of Eis. In conclusion, AAC(2') and Eis have evolved from a marginal role as potential drug resistance mechanisms into a promising future as drug targets

Mycobacterial Aminoglycoside Acetyltransferases: A Little of Drug Resistance, and a Lot of Other Roles

Aminoglycoside acetyltransferases are important determinants of resistance to aminoglycoside antibiotics in most bacterial genera. In mycobacteria, however, aminoglycoside acetyltransferases contribute only partially to aminoglycoside susceptibility since they are related with low level resistance to these antibiotics (while high level aminoglycoside resistance is due to mutations in the ribosome). Instead, aminoglycoside acetyltransferases contribute to other bacterial functions, and this can explain its widespread presence along species of genus Mycobacterium. This review is focused on two mycobacterial aminoglycoside acetyltransferase enzymes. First, the aminoglycoside 2′-N-acetyltransferase [AAC(2′)], which was identified as a determinant of weak aminoglycoside resistance in M. fortuitum, and later found to be widespread in most mycobacterial species; AAC(2′) enzymes have been associated with resistance to cell wall degradative enzymes, and bactericidal mode of action of aminoglycosides. Second, the Eis aminoglycoside acetyltransferase, which was identified originally as a virulence determinant in M. tuberculosis (enhanced intracellular survival); Eis protein in fact controls production of pro-inflammatory cytokines and other pathways. The relation of Eis with aminoglycoside susceptibility was found after the years, and reaches clinical significance only in M. tuberculosis isolates resistant to the second-line drug kanamycin. Given the role of AAC(2′) and Eis proteins in mycobacterial biology, inhibitory molecules have been identified, more abundantly in case of Eis. In conclusion, AAC(2′) and Eis have evolved from a marginal role as potential drug resistance mechanisms into a promising future as drug targets

TFAP2E Methylation and Expression Status Does Not Predict Response to 5-FU-based Chemotherapy in Colorectal Cancer

Purpose: A recent study reported that 5-fluorouracil (5-FU)- based chemotherapy is less effective in treating patients with advanced colorectal cancer demonstrating hypermethylation of the TFAP2E gene. The aim of our study was to confirm and validate these findings in large, uniformly treated, wellcharacterized patient cohorts. Experimental Design: Two cohorts of 783 patients with colorectal cancer: 532 from a population-based, multicenter cohort (EPICOLON I) and 251 patients from a clinic-based trial were used to study the effectiveness of TFAP2E methylation and expression as a predictor of response of colorectal cancer patients to 5-FU–based chemotherapy. DNA methylation status of the TFAP2E gene in patients with colorectal cancer was assessed by quantitative bisulfite pyrosequencing analysis. IHC analysis of the TFAP2E protein expression was also performed. Results: Correlation between TFAP2E methylation status and IHC staining was performed in 607 colorectal cancer samples. Among 357 hypermethylated tumors, only 141 (39.6%) exhibited loss of protein expression. Survival was not affected by TFAP2E hypermethylation in stage IV patients [HR, 1.21; 95% confidence interval (CI), 0.79–1.87; log-rank P¼ 0.6]. In stage II– III cases, disease-free survival was not influenced by TFAP2E hypermethylation status in 5-FU–treated (HR, 0.91; 95% CI, 0.52–1.59; log-rank P ¼ 0.9) as well as in nontreated patients (HR, 0.88; 95% CI, 0.5–1.54; log-rank P ¼ 0.7). Conclusions: TFAP2E hypermethylation does not correlate with loss of its protein expression. Our large, systematic, and comprehensive study indicates that TFAP2E methylation and expression may not play a major role in predicting response to 5- FU–based chemotherapy in patients with colorectal cancer

Prevalence of Lynch Syndrome among Patients with Newly Diagnosed Endometrial Cancers

Background: Lynch syndrome (LS) is a hereditary condition that increases the risk for endometrial and other cancers. The identification of endometrial cancer (EC) patients with LS has the potential to influence life-saving interventions. We aimed to study the prevalence of LS among EC patients in our population. Methods: Universal screening for LS was applied for a consecutive series EC. Tumor testing using microsatellite instability (MSI), immunohistochemistry (IHC) for mismatch-repair (MMR) protein expression and MLH1-methylation analysis, when required, was used to select LS-suspicious cases. Sequencing of corresponding MMR genes was performed. Results: One hundred and seventy-three EC (average age, 63 years) were screened. Sixty-one patients (35%) had abnormal IHC or MSI results. After MLH1 methylation analysis, 27 cases were considered suspicious of LS. From these, 22 were contacted and referred for genetic counseling. Nineteen pursued genetic testing and eight were diagnosed of LS. Mutations were more frequent in younger patients (<50 yrs). Three cases had either intact IHC or MSS and reinforce the need of implement the EC screening with both techniques. Conclusion: The prevalence of LS among EC patients was 4.6% (8/173); with a predictive frequency of 6.6% in the Spanish population. Universal screening of EC for LS is recommended.This study was supported by Conselleria Sanidad Comunidad Valenciana, Spain (AP/177/10) (http://www.san.gva.es/); Biomedical Research Foundations of the Alicante University Hospital (PI14/2006 and NI02/2011) (http://www.dep19.san.gva.es/); and the Elche University Hospital, Spain (FIBElx-CO11/03) (http://www.dep20.san.gva.es/)

Mapas de actividades comunitarias y activos para la salud: ¿Cómo trabajar con ellos?

El modelo de activos para la salud tiene relaciones íntimas con el paradigma de la Promoción de la Salud, de modelos de Desarrollo Comunitario o de la Teoría Salutogénica de Antonovsky, siendo su punto de partida la Salud Positiva de una comunidad y de las personas que la integran

Age and date for early arrival of the Acheulian in Europe (Barranc de la Boella, la Canonja, Spain)

The first arrivals of hominin populations into Eurasia during the Early Pleistocene are currently considered to have occurred as short and poorly dated biological dispersions. Questions as to the tempo and mode of these early prehistoric settlements have given rise to debates concerning the taxonomic significance of the lithic assemblages, as trace fossils, and the geographical distribution of the technological traditions found in the Lower Palaeolithic record. Here, we report on the Barranc de la Boella site which has yielded a lithic assemblage dating to ,1 million years ago that includes large cutting tools (LCT). We argue that distinct technological traditions coexisted in the Iberian archaeological repertoires of the late Early Pleistocene age in a similar way to the earliest sub-Saharan African artefact assemblages. These differences between stone tool assemblages may be attributed to the different chronologies of hominin dispersal events. The archaeological record of Barranc de la Boella completes the geographical distribution of LCT assemblages across southern Eurasia during the EMPT (Early-Middle Pleistocene Transition, circa 942 to 641 kyr). Up to now, chronology of the earliest European LCT assemblages is based on the abundant Palaeolithic record found in terrace river sequences which have been dated to the end of the EMPT and later. However, the findings at Barranc de la Boella suggest that early LCT lithic assemblages appeared in the SW of Europe during earlier hominin dispersal episodes before the definitive colonization of temperate Eurasia took place.The research at Barranc de la Boella has been carried out with the financial support of the Spanish Ministerio de Economı´a y Competitividad (CGL2012- 36682; CGL2012-38358, CGL2012-38434-C03-03 and CGL2010-15326; MICINN project HAR2009-7223/HIST), Generalitat de Catalunya, AGAUR agence (projects 2014SGR-901; 2014SGR-899; 2009SGR-324, 2009PBR-0033 and 2009SGR-188) and Junta de Castilla y Leo´n BU1004A09. Financial support for Barranc de la Boella field work and archaeological excavations is provided by the Ajuntament de la Canonja and Departament de Cultura (Servei d’Arqueologia i Paleontologia) de la Generalitat de Catalunya. A. Carrancho’s research was funded by the International Excellence Programme, Reinforcement subprogramme of the Spanish Ministry of Education. I. Lozano-Ferna´ndez acknowledges the pre-doctoral grant from the Fundacio´n Atapuerca. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Risk of Cancer in Cases of Suspected Lynch Syndrome Without Germline Mutation

Background & Aims: Colorectal cancers (CRCs) with microsatellite instability (MSI) and a mismatch repair (MMR) immunohistochemical deficit without hypermethylation of the MLH1 promoter are likely to be caused by Lynch syndrome. Some patients with these cancers have not been found to have pathogenic germline mutations and are considered to have Lynch-like syndrome (LLS). The aim of this study was to determine the risk of cancer in families of patients with LLS. Methods: We studied a population-based cohort of 1705 consecutive patients, performing MSI tests and immunohistochemical analyses of MMR proteins. Patients were diagnosed with Lynch syndrome when they were found to have pathogenic germline mutations. Patients with MSI and loss of MSH2 and/or MSH6 expression, isolated loss of PMS2 or loss of MLH1 without MLH1 promoter hypermethylation, and no pathogenic mutation were considered to have LLS. The clinical characteristics of patients and the age- and sex-adjusted standardized incidence ratios (SIRs) of cancer in families were compared between groups. Results: The incidence of CRC was significantly lower in families of patients with LLS than in families with confirmed cases of Lynch syndrome (SIR for Lynch syndrome, 6.04; 95% confidence interval [CI], 3.58–9.54; SIR for LLS, 2.12; 95% CI, 1.16–3.56; P < .001). However, the incidence of CRC was higher in families of patients with LLS than in families with sporadic CRC (SIR for sporadic CRC, 0.48; 95% CI, 0.27–0.79; P < .001). Conclusions: The risk of cancer in families with LLS is lower that of families with Lynch syndrome but higher than that of families with sporadic CRC. These results confirm the need for special screening and surveillance strategies for these patients and their relatives.This work was supported by grants from Instituto de Salud Carlos III (PI-080726, INT-09/208, and PI11/026030), the Fondo de Investigación Sanitaria/FEDER (PS09/02368, 10/00384, 10/00918, 11/00219, and 11/00681), Fundació Olga Torres (CRP) and FP7 CHIBCHA Consortium (SCB and ACar), the Ministerio de Economía y Competitividad (SAF2010-19273), and Agència de Gestió d’Ajuts Universitaris i de Recerca (2009 SGR 849). SCB is supported by a contract from the Fondo de Investigación Sanitaria (CP03-0070). CIBERER and CIBERehd are funded by the Instituto de Salud Carlos III

Land- and water-based exercise intervention in women with fibromyalgia: the al-andalus physical activity randomised controlled trial

Background The al-Andalus physical activity intervention study is a randomised control trial to investigate the effectiveness of a land- and water-based exercise intervention for reducing the overall impact of fibromyalgia (primary outcome), and for improving tenderness and pain-related measures, body composition, functional capacity, physical activity and sedentary behaviour, fatigue, sleep quality, health-related quality of life, and cognitive function (secondary outcomes) in women with fibromyalgia. Methods/Design One hundred eighty women with fibromyalgia (age range: 35-65 years) will be recruited from local associations of fibromyalgia patients in Andalucía (Southern Spain). Patients will be randomly assigned to a usual care (control) group (n = 60), a water-based exercise intervention group (n = 60) or a land-based exercise intervention group (n = 60). Participants in the usual care group will receive general physical activity guidelines and participants allocated in the intervention groups will attend three non-consecutive training sessions (60 min each) per week during 24 weeks. Both exercise interventions will consist of aerobic, muscular strength and flexibility exercises. We will also study the effect of a detraining period (i.e., 12 weeks with no exercise intervention) on the studied variables. Discussion Our study attempts to reduce the impact of fibromyalgia and improve patients' health status by implementing two types of exercise interventions. Results from this study will help to assess the efficacy of exercise interventions for the treatment of fibromyalgia. If the interventions would be effective, this study will provide low-cost and feasible alternatives for health professionals in the management of fibromyalgia. Results from the al-Andalus physical activity intervention will help to better understand the potential of regular physical activity for improving the well-being of women with fibromyalgia.This study was supported by the Consejeria de Turismo, Comercio y Deporte (CTCD-201000019242-TRA), the Spanish Ministry of Science and Innovation (I + D + I DEP2010-15639, grants: BES-2009-013442, BES-2011-047133, RYC-2010-05957, RYC-2011-09011), the Swedish Heart-Lung Foundation (20090635), the Spanish Ministry of Education (AP-2009-3173), Granada Research of Excelence Initiative on Biohealth (GREIB), Campus BioTic, University of Granada, Spain and European University of Madrid. Escuela de Estudios Universitarios Real Madrid. 2010/04RM

Novel genes and sex differences in COVID-19 severity

[EN] Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10−8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10−22 and P = 8.1 × 10−12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10−8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10−8) and ARHGAP33 (P = 1.3 × 10−8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10−8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.S