Publications by authors named "Esther Jimenez"

91 Publications

HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders.

Sci Rep 2021 Sep 8;11(1):17823. Epub 2021 Sep 8.

Department of Psychiatry & Center of Sleep Disorders, National Taiwan University Hospital, Taipei, Taiwan.

Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p < 1 × 10; FDR < 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common inflammatory/autoimmune processes, our findings strongly suggest that HLA-mediated low inflammatory background may contribute to the efficient response to Li in BD patients, while an inflammatory status overriding Li anti-inflammatory properties would favor a weak response.
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http://dx.doi.org/10.1038/s41598-021-97140-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426488PMC
September 2021

Bipolar symptoms, somatic burden, and functioning in older-age bipolar disorder: Analyses from the Global Aging & Geriatric Experiments in Bipolar Disorder Database project.

Bipolar Disord 2021 Jul 27. Epub 2021 Jul 27.

Department of Psychiatry, University of California San Diego, San Diego, CA, USA.

Objective: Literature on older-age bipolar disorder (OABD) is limited. This first-ever analysis of the Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE-BD) investigated associations among age, BD symptoms, comorbidity, and functioning.

Methods: This analysis used harmonized, baseline, cross-sectional data from 19 international studies (N = 1377). Standardized measures included the Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS), and Global Assessment of Functioning (GAF).

Results: Mean sample age was 60.8 years (standard deviation [SD] 12.2 years), 55% female, 72% BD I. Mood symptom severity was low: mean total YMRS score of 4.3 (SD 5.4) and moderate-to-severe depression in only 22%. Controlled for sample effects, both manic and depressive symptom severity appeared lower among older individuals (p's < 0.0001). The negative relationship between older age and symptom severity was similar across sexes, but was stronger among those with lower education levels. GAF was mildly impaired (mean =62.0, SD = 13.3) and somatic burden was high (mean =2.42, SD = 1.97). Comorbidity burden was not associated with GAF. However, higher depressive (p < 0.0001) and manic (p < 0.0001) symptoms were associated with lower GAF, most strongly among older individuals.

Conclusions: Findings suggest an attenuation of BD symptoms in OABD, despite extensive somatic burden. Depressive symptom severity was strongly associated with worse functioning in older individuals, underscoring the need for effective treatments of BD depression in older people. This international collaboration lays a path for the development of a better understanding of aging in BD.
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http://dx.doi.org/10.1111/bdi.13119DOI Listing
July 2021

Age- and gender-related differences in brain tissue microstructure revealed by multi-component T relaxometry.

Neurobiol Aging 2021 10 10;106:68-79. Epub 2021 Jun 10.

FIDMAG Germanes Hospitalàries Research Foundation, Sant Boi de Llobregat, Barcelona, Spain; Mental Health Research Networking Center (CIBERSAM), Madrid, Spain.

In spite of extensive work, inconsistent findings and lack of specificity in most neuroimaging techniques used to examine age- and gender-related patterns in brain tissue microstructure indicate the need for additional research. Here, we performed the largest Multi-component T relaxometry cross-sectional study to date in healthy adults (N = 145, 18-60 years). Five quantitative microstructure parameters derived from various segments of the estimated T spectra were evaluated, allowing a more specific interpretation of results in terms of tissue microstructure. We found similar age-related myelin water fraction (MWF) patterns in men and women but we also observed differential male related results including increased MWF content in a few white matter tracts, a faster decline with age of the intra- and extra-cellular water fraction and its T relaxation time (i.e. steeper age related negative slopes) and a faster increase in the free and quasi-free water fraction, spanning the whole grey matter. Such results point to a sexual dimorphism in brain tissue microstructure and suggest a lesser vulnerability to age-related changes in women.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.06.002DOI Listing
October 2021

Peer Mentoring as a Tool for Developing Soft Skills in Clinical Practice: A 3-Year Study.

Dent J (Basel) 2021 May 17;9(5). Epub 2021 May 17.

Dentistry Department, Faculty of Dentistry, Universitat Internacional de Catalunya, 08195 Sant Cugat del Vallés, Spain.

Education currently focuses on improving academic knowledge and clinical skills, but it is also important for students to develop personal and interpersonal skills from the start of their clinical practice. The aim was to evaluate the effect of peer mentoring in third-year students and to gauge the evolution of non-technical skills (NTS) acquisition up to the fifth year. The study groups were selected between September 2015 and May 2018, based on the NTS training they had or had not received: (1) fifth-year students with no training (G1); (2) third-year students mentored in NTS (G2a); and (3) a small group of fifth-year students who became mentors (G2b). A total of 276 students who took part in this study were assessed using a 114-item self-evaluation questionnaire. Data were collected from seven surveys conducted between September 2015 and May 2018, and statistical analysis was performed using one-way ANOVA and Fisher's post-hoc test. G2a improved their non-technical skill acquisition over three years of clinical training up to their fifth year. This group and G2b showed statistically significant differences compared to non-mentored students (G1). Peer mentoring at the beginning of clinical practice is a valid option for training students in non-technical skills.
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http://dx.doi.org/10.3390/dj9050057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156670PMC
May 2021

methylation is associated with bipolar disorder and the isoform expression and methylation of myelin genes.

Epigenomics 2021 Jun 4;13(11):845-858. Epub 2021 May 4.

Hospital Universitari Institut Pere Mata, Ctra. de l'Institut Pere Mata, s/n. 43206, Reus, Catalonia, Spain.

To investigate  methylation in the brains of bipolar disorder (BD) patients and its association with mRNA levels and comethylation with myelin genes. Genome-wide profiling of DNA methylation (Infinium MethylationEPIC BeadChip) corrected for glial composition and gene expression analysis in the occipital cortices of individuals with BD (n = 15) and healthy controls (n = 15) were conducted. 5-methylcytosine levels were increased and directly associated with b mRNA expression in the brains of BD patients. We also observed that was comethylated with a group of myelin genes. is hypermethylated in BD brain tissue and is associated with isoform expression. Additionally, comethylation with myelin genes supports the role of this receptor in myelination.
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http://dx.doi.org/10.2217/epi-2021-0006DOI Listing
June 2021

Comparison of Two Approaches for the Metataxonomic Analysis of the Human Milk Microbiome.

Front Cell Infect Microbiol 2021 25;11:622550. Epub 2021 Mar 25.

Department of Nutrition and Food Science, Complutense University of Madrid, Madrid, Spain.

Recent work has demonstrated the existence of large inter-individual and inter-population variability in the microbiota of human milk from healthy women living across variable geographical and socio-cultural settings. However, no studies have evaluated the impact that variable sequencing approaches targeting different 16S rRNA variable regions may have on the human milk microbiota profiling results. This hampers our ability to make meaningful comparisons across studies. In this context, the main purpose of the present study was to re-process and re-sequence the microbiome in a large set of human milk samples (n = 412) collected from healthy women living at diverse international sites (Spain, Sweden, Peru, United States, Ethiopia, Gambia, Ghana and Kenya), by targeting a different 16S rRNA variable region and reaching a larger sequencing depth. Despite some differences between the results obtained from both sequencing approaches were notable (especially regarding alpha and beta diversities and Proteobacteria representation), results indicate that both sequencing approaches revealed a relatively consistent microbiota configurations in the studied cohorts. Our data expand upon the milk microbiota results we previously reported from the INSPIRE cohort and provide, for the first time across globally diverse populations, evidence of the impact that different DNA processing and sequencing approaches have on the microbiota profiles obtained for human milk samples. Overall, our results corroborate some similarities regarding the microbial communities previously reported for the INSPIRE cohort, but some differences were also detected. Understanding the impact of different sequencing approaches on human milk microbiota profiles is essential to enable meaningful comparisons across studies.

Clinical Trial Registration: www.clinicaltrials.gov, identifier NCT02670278.
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http://dx.doi.org/10.3389/fcimb.2021.622550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027255PMC
July 2021

COVID-19 and older adults with bipolar disorder: Problems and solutions.

Bipolar Disord 2021 06 12;23(4):420-422. Epub 2021 Mar 12.

GGZ inGeest, Department of Psychiatry, Amsterdam UMC, location VU Medical Center, Amsterdam Neuroscience, Amsterdam Public Health Research Institute, Amsterdam, the Netherlands.

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http://dx.doi.org/10.1111/bdi.13069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014237PMC
June 2021

COVID-19 and older adults with bipolar disorder: Problems and solutions.

Bipolar Disord 2021 06 12;23(4):420-422. Epub 2021 Mar 12.

GGZ inGeest, Department of Psychiatry, Amsterdam UMC, location VU Medical Center, Amsterdam Neuroscience, Amsterdam Public Health Research Institute, Amsterdam, the Netherlands.

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http://dx.doi.org/10.1111/bdi.13069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014237PMC
June 2021

Prediction of lithium response using genomic data.

Sci Rep 2021 01 13;11(1):1155. Epub 2021 Jan 13.

Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.

Predicting lithium response prior to treatment could both expedite therapy and avoid exposure to side effects. Since lithium responsiveness may be heritable, its predictability based on genomic data is of interest. We thus evaluate the degree to which lithium response can be predicted with a machine learning (ML) approach using genomic data. Using the largest existing genomic dataset in the lithium response literature (n = 2210 across 14 international sites; 29% responders), we evaluated the degree to which lithium response could be predicted based on 47,465 genotyped single nucleotide polymorphisms using a supervised ML approach. Under appropriate cross-validation procedures, lithium response could be predicted to above-chance levels in two constituent sites (Halifax, Cohen's kappa 0.15, 95% confidence interval, CI [0.07, 0.24]; and Würzburg, kappa 0.2 [0.1, 0.3]). Variants with shared importance in these models showed over-representation of postsynaptic membrane related genes. Lithium response was not predictable in the pooled dataset (kappa 0.02 [- 0.01, 0.04]), although non-trivial performance was achieved within a restricted dataset including only those patients followed prospectively (kappa 0.09 [0.04, 0.14]). Genomic classification of lithium response remains a promising but difficult task. Classification performance could potentially be improved by further harmonization of data collection procedures.
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http://dx.doi.org/10.1038/s41598-020-80814-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806976PMC
January 2021

Multivariate Brain Functional Connectivity Through Regularized Estimators.

Front Neurosci 2020 8;14:569540. Epub 2020 Dec 8.

Campbell Family Mental Health Research Institute, Toronto, ON, Canada.

Functional connectivity analyses are typically based on matrices containing bivariate measures of covariability, such as correlations. Although this has been a fruitful approach, it may not be the optimal strategy to fully explore the complex associations underlying brain activity. Here, we propose extending connectivity to multivariate functions relating to the temporal dynamics of a region with the rest of the brain. The main technical challenges of such an approach are multidimensionality and its associated risk of overfitting or even the non-uniqueness of model solutions. To minimize these risks, and as an alternative to the more common dimensionality reduction methods, we propose using two regularized multivariate connectivity models. On the one hand, simple linear functions of all brain nodes were fitted with ridge regression. On the other hand, a more flexible approach to avoid linearity and additivity assumptions was implemented through random forest regression. Similarities and differences between both methods and with simple averages of bivariate correlations (i.e., weighted global brain connectivity) were evaluated on a resting state sample of = 173 healthy subjects. Results revealed distinct connectivity patterns from the two proposed methods, which were especially relevant in the age-related analyses where both ridge and random forest regressions showed significant patterns of age-related disconnection, almost completely absent from the much less sensitive global brain connectivity maps. On the other hand, the greater flexibility provided by the random forest algorithm allowed detecting sex-specific differences. The generic framework of multivariate connectivity implemented here may be easily extended to other types of regularized models.
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http://dx.doi.org/10.3389/fnins.2020.569540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753183PMC
December 2020

A prospective longitudinal study searching for predictors of response to group psychoeducation in bipolar disorder.

J Affect Disord 2020 09 28;274:1113-1121. Epub 2020 Feb 28.

Mental Health Research Group, IMIM-Parc de Salut Mar, CIBERSAM, Auotonomous University of Barcelona (Department of Clinical and Health Psychology), Office 202, PRBB Building, Charles Darwin Sq. (SN) 08003, Barcelona, Catalonia, Spain. Electronic address:

Background: The efficacy of adjunctive group psychoeducation in bipolar disorder has been proven although treatment response differ among individuals. The aim of this study was to characterize responders and non-responders to group psychoeducation in order to identify baseline variables that could predict treatment response.

Methods: The sample was composed of 103 medicated euthymic patients with bipolar disorder referred to 21 sessions of group psychoeducation (6 months). Sociodemographic and clinical variables, temperament, circadian rhythms, BDNF, cognitive and psychosocial functioning were collected. At the 18-month endpoint, the patients were split in two groups on the basis of having suffered any recurrence. Significant group differences were included in a logistic regression analysis.

Results: Ninety patients out of 103 engaged in group psychoeducation, 47 of whom (52.2%) responded to psychoeducation and 43 (47.8%) did not. Recurrences occurred more often in the follow-up, the most common being depression. Responders and non-responders differed in gender, age at diagnosis, latency of diagnosis, temperament, attention composite score and BDNF. Lower age at diagnosis of bipolar disorder, lower cyclothimic temperament scores and being male -which was associated with bipolar type I and a trend to more previous manic episodes- were significantly related to a better response to psychoeducation in the regression analysis.

Limitations: No control group.

Conclusions: This study identifies age at diagnosis as a significant modifiable risk factor of treatment response, highlighting the need for early identification of bipolar disorder. Existing programs should be adjusted to the characteristics of specific subpopulations in the framework of a personalized approach.
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http://dx.doi.org/10.1016/j.jad.2020.02.047DOI Listing
September 2020

Effects of an integrative approach to bipolar disorders combining psychoeducation, mindfulness-based cognitive therapy and functional remediation: Study protocol for a randomized controlled trial.

Rev Psiquiatr Salud Ment (Engl Ed) 2020 Jul - Sep;13(3):165-173. Epub 2020 Jul 7.

Barcelona Bipolar Disorders and Depressive Unit, Institute of Neurosciences, University of Barcelona, IDIBAPS, CIBERSAM, Hospital Clínic of Barcelona, Villarroel, 170, 08036 Barcelona, Catalonia, Spain.

Introduction: Bipolar disorder is related to a high level of personal, familial, social and economic burden. There is a need for feasible adjunctive psychological interventions easy to implement in clinical practice in order to enhance aspects that medication alone cannot achieve. This study aims to evaluate the impact of a 12-session adjunctive integrative program designed for patients with bipolar disorder.

Methods: This is a single-blind prospective, randomized controlled trial involving a total of 132 outpatients with bipolar disorder who will be recruited from the Hospital Clinic of Barcelona. All participants will be randomly assigned to two arms. All the patients will receive treatment as usual (TAU) but in addition the experimental group will receive an integrative approach consisting of 12-sessions of 90min each in which contents of psychoeducation for patients have been combined with a session for family members, and complemented with aspects related to health promotion, mindfulness training, and strategies for cognitive and functional enhancement. The whole sample will be assessed at baseline, after completion (3-months) and at 12 months from baseline regarding demographic and clinical variables, psychosocial and cognitive functioning, wellbeing and quality of life. The primary outcome measure will be improvement in psychosocial functioning.

Conclusions: If the integrative approach is effective, it would allow clinicians to cover different areas that may be affected by bipolar disorder, by means of a brief intervention that can therefore be easily generalized to clinical practice.

Trial Registration: NCT04031560. Date registered July 24, 2019.
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http://dx.doi.org/10.1016/j.rpsm.2020.05.005DOI Listing
July 2020

Maternal and Perinatal Factors Associated with the Human Milk Microbiome.

Curr Dev Nutr 2020 Apr 9;4(4):nzaa027. Epub 2020 Mar 9.

Margaret Ritchie School of Family and Consumer Sciences, University of Idaho, Moscow, ID, USA.

Microbes are present in human milk regardless of the mother's health. The origins of the milk microbiota likely include the mother's skin, infant's mouth, and transfer from the maternal gastrointestinal (GI) tract. Prominent bacterial taxa in human milk are and , but many other genera are also found including anaerobic , , and . The milk microbiome is highly variable and potentially influenced by geographic location, delivery mode, time postpartum, feeding mode, social networks, environment, maternal diet, and milk composition. Mastitis alters the milk microbiome, and the intake of Lactobacilli has shown potential for mastitis treatment and prevention. Although milk and infant fecal microbiomes are different, their variations appear to be related - suggesting that milk is an important contributor of early GI colonization. Nonetheless, nothing is known regarding whether the milk microbiome influences infant health. Further research and clinical interventions are needed to determine if changes in the microbiomes of human milk and infant formula/food impact health.
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http://dx.doi.org/10.1093/cdn/nzaa027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7127925PMC
April 2020

Association of polygenic score for major depression with response to lithium in patients with bipolar disorder.

Mol Psychiatry 2021 Jun 16;26(6):2457-2470. Epub 2020 Mar 16.

Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.

Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLiGen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18-2.01) and European sample: OR = 1.75 (95% CI: 1.30-2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61-4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.
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http://dx.doi.org/10.1038/s41380-020-0689-5DOI Listing
June 2021

Conscious sedation in Spanish dental schools: Current situation.

Clin Exp Dent Res 2019 08 9;5(4):356-364. Epub 2019 May 9.

Education School International University of Catalonia (Universidad Internacional de Catalunya) Barcelona Spain.

The current Spanish curricula for degrees in dentistry include conscious sedation (CS) as a basic training competency. However, is the CS training delivered by Spanish dental schools a consensus-based educational framework enabling students to use this anesthetic technique after graduation? To answer this research question, a study was designed aiming to identify the strategies used to teach this competency in Spanish dental schools and the characteristics of teaching. The authors reviewed legislation concerning officially established requirements for a degree in dentistry as well as curricula currently taught in Spain. Our analysis identified clear discrepancies among the schools of dentistry studied. The only overlap was observed in reference to the level of proficiency imparted, which prevents Spanish dentistry students from using this anesthetic technique after graduation. Specific features of the normative framework and of the Spanish legislative system underlying the design of the present curricula of degrees in dentistry would explain the discrepancies in CS competencies taught at our schools of dentistry. Almost 10 years since its implementation and in light of the new demands of the complex society in which we live, Spanish universities must unify their educational criteria regarding CS training to ensure the appropriate qualification of our new dentists in this technique.
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http://dx.doi.org/10.1002/cre2.190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6704054PMC
August 2019

colonization in preterm neonates during their neonatal intensive care unit stay.

Antimicrob Resist Infect Control 2019 9;8:135. Epub 2019 Aug 9.

1Department of Nutrition and Food Science, Complutense University of Madrid, Avda. Puerta de Hierro, s/n, 28040 Madrid, Spain.

Background: Nosocomial sepsis is the main problem that preterms have to face during their stay at neonatal intensive care units (NICU). is an emerging cause of preterm sepsis but its epidemiology is still largely unknown. Consequently, the aims of this study were to know the rate of preterms colonized by during their stay at the NICU and the characteristics and evolution of the population, including the susceptibility to clinically relevant antibiotics.

Methods: Twenty-six preterm infants born with a gestational age ≤ 32 weeks and/or weigh ≤1500 g were included in the study. Samples of meconium and feces ( = 92) were collected during their first month of life of the infants, together with feeding samples after their pass through enteral feeding tubes ( = 37). Samples were inoculated on MacConkey agar plates. The isolates identified as were genotyped using RAPD and PFGE; and antibiotics susceptibility was performed in a Vitek 2 system.

Results: A total of 179  isolates were obtained from the samples. PFGE profiling and cluster analysis allowed the classification of the isolates into 7 different clones. PFGE patterns 1 and 3 were the dominant strains in the fecal samples colonizing 31 and 35% of the infants, respectively. Those isolates causing bacteremia in two infants clustered in PFGE pattern 3.

Conclusion: is a bacterial species closely associated to the NICU environment. It can be frequently isolated from preterm's feces although only some genetic lineages seem to be associated to sepsis. Enteral feeding tubes act as important reservoirs to keep the population in the NICU.

Trial Registration: The local ethic committee approved this trial with the reference 09/157.
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http://dx.doi.org/10.1186/s13756-019-0584-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688303PMC
June 2020

Lifetime Psychotic Symptoms, Subthreshold Depression and Cognitive Impairment as Barriers to Functional Recovery in Patients with Bipolar Disorder.

J Clin Med 2019 Jul 18;8(7). Epub 2019 Jul 18.

Barcelona Bipolar Disorders and Depressive Unit, Hospital Clinic, Institute of Neurosciences, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, 08036 Catalonia, Spain.

(1) Background: bipolar disorder (BD) is a chronic disease that often leads to functional impairment. The objective of this study is to elucidate which variables are associated with better functional outcomes in a sample of euthymic patients with BD. (2) Methods: patients were recruited at the Hospital Clinic of Barcelona and they underwent a clinical interview, a functional assessment, and a comprehensive neuropsychological evaluation. After that, patients were divided into two groups according to the Functioning Assessment Short Test total score: functionally remitted vs. functionally impaired. Following this, a multivariate logistic regression was run in order to identify clinical, demographic and cognitive factors associated with functional remission. (3) Results: a total of 420 euthymic patients with BD were assessed for this study, distributed as follows: functionally remitted ( = 221) and functionally impaired ( = 199). Finally, the multivariate logistic regression revealed that only five variables significantly contributed to the model, including: lifetime history of psychotic symptoms (the variable that contributed the most to the model), followed by the Hamilton Depression total score, and cognitive performance (executive functions and verbal memory). (4) Conclusions: treatments to ensure a good functional outcome in BD should specially prevent psychosis, target subthreshold depressive symptoms and enhance cognition, more specifically executive functions and verbal memory.
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http://dx.doi.org/10.3390/jcm8071046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679346PMC
July 2019

Improving Functioning, Quality of Life, and Well-being in Patients With Bipolar Disorder.

Int J Neuropsychopharmacol 2019 08;22(8):467-477

Bipolar and Depressive Disorders Unit, Institute of Neurosciences, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain.

People with bipolar disorder frequently experience persistent residual symptoms, problems in psychosocial functioning, cognitive impairment, and poor quality of life. In the last decade, the treatment target in clinical and research settings has focused not only on clinical remission, but also on functional recovery and, more lately, in personal recovery, taking into account patients' well-being and quality of life. Hence, the trend in psychiatry and psychology is to treat bipolar disorder in an integrative and holistic manner. This literature review offers an overview regarding psychosocial functioning in bipolar disorder. First, a brief summary is provided regarding the definition of psychosocial functioning and the tools to measure it. Then, the most reported variables influencing the functional outcome in patients with bipolar disorder are listed. Thereafter, we include a section discussing therapies with proven efficacy at enhancing functional outcomes. Other possible therapies that could be useful to prevent functional decline and improve functioning are presented in another section. Finally, in the last part of this review, different interventions directed to improve patients' well-being, quality of life, and personal recovery are briefly described.
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http://dx.doi.org/10.1093/ijnp/pyz018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6672628PMC
August 2019

Functional remediation improves bipolar disorder functioning with no effects on brain-derived neurotrophic factor levels.

Eur Neuropsychopharmacol 2019 06 7;29(6):701-710. Epub 2019 May 7.

Barcelona Bipolar and Depressive Disorders Program, Institute of Neurosciences, University of Barcelona, IDIBAPS, CIBERSAM, Hospital Clinic of Barcelona, Catalonia, Spain.

The main aim of this study is to evaluate the impact of functional remediation (FR) in serum brain derived neurotrophic factor (BDNF) levels in euthymic adult patients with Bipolar Disorder (BD). A total of 128 participants were recruited at the Hospital Clinic of Barcelona. They were assessed at baseline and at the end of follow-up by the means of Hamilton Depression Scale (HAM-D), Young Mania Rating Scale (YMRS) and Functioning Assessment Short Test (FAST), as well as a clinical structured interview to collect clinical and demographic variables of interest. Blood samples were also collected to assess BDNF levels. After baseline assessment, patients received FR, Psychoeducation or treatment as usual (TAU). One hundred and two out of 126 participants finished the study distributed as follows: FR group (n = 39); Psychoeducation group (n = 47) and TAU group (n = 16). Longitudinal repeated-measures analyses addressing the treatment effect on BDNF levels showed non-significant differences between the three groups (Pillai's trace = 0.06; F= 0.28; p = 0.75), suggesting no interaction between treatment allocation and time on BDNF levels. The results of this study suggest that FR has no effect on peripheral BDNF levels in euthymic patients with BD, despite the improvement in psychosocial functioning.
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http://dx.doi.org/10.1016/j.euroneuro.2019.04.002DOI Listing
June 2019

What's Normal? Microbiomes in Human Milk and Infant Feces Are Related to Each Other but Vary Geographically: The INSPIRE Study.

Front Nutr 2019 17;6:45. Epub 2019 Apr 17.

Margaret Ritchie School of Family and Consumer Sciences, University of Idaho, Moscow, ID, United States.

Microbial communities in human milk and those in feces from breastfed infants vary within and across populations. However, few researchers have conducted cross-cultural comparisons between populations, and little is known about whether certain "core" taxa occur normally within or between populations and whether variation in milk microbiome is related to variation in infant fecal microbiome. The purpose of this study was to describe microbiomes of milk produced by relatively healthy women living at diverse international sites and compare these to the fecal microbiomes of their relatively healthy infants. We analyzed milk ( = 394) and infant feces ( = 377) collected from mother/infant dyads living in 11 international sites (2 each in Ethiopia, The Gambia, and the US; 1 each in Ghana, Kenya, Peru, Spain, and Sweden). The V1-V3 region of the bacterial 16S rRNA gene was sequenced to characterize and compare microbial communities within and among cohorts. Core genera in feces were , and , and in milk were and , although substantial variability existed within and across cohorts. For instance, relative abundance of was highest in feces from rural Ethiopia and The Gambia, and lowest in feces from Peru, Spain, Sweden, and the US; was relatively more abundant in milk produced by women in rural Ethiopia than all other cohorts. Bacterial diversity also varied among cohorts. For example, Shannon diversity was higher in feces from Kenya than Ghana and US-California, and higher in rural Ethiopian than Ghana, Peru, Spain, Sweden, and US-California. There were limited associations between individual genera in milk and feces, but community-level analyses suggest strong, positive associations between the complex communities in these sample types. Our data provide additional evidence of within- and among-population differences in milk and infant fecal bacterial community membership and diversity and support for a relationship between the bacterial communities in milk and those of the recipient infant's feces. Additional research is needed to understand environmental, behavioral, and genetic factors driving this variation and association, as well as its significance for acute and chronic maternal and infant health.
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http://dx.doi.org/10.3389/fnut.2019.00045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6479015PMC
April 2019

Cognitive Reserve Assessment Scale in Health (CRASH): Its Validity and Reliability.

J Clin Med 2019 Apr 28;8(5). Epub 2019 Apr 28.

Barcelona Clinic Schizophrenia Unit, Hospital Clinic of Barcelona, Neuroscience Institute, 08036 Barcelona, Spain.

(1) Background: The cognitive reserve (CR) concept has not been precisely defined in severe mental disorders and has been estimated using heterogeneous methods. This study aims to investigate and develop the psychometric properties of the Cognitive Reserve Assessment Scale in Health (CRASH), an instrument designed to measure CR in people with severe mental illness; (2) Methods: 100 patients with severe mental illness (non-affective psychoses and affective disorders) and 66 healthy controls were included. The internal consistency and convergent validity of CRASH were assessed. Spearman's correlations coefficients were also performed to examine the relationship between CRASH and neuropsychological tests, psychosocial functioning, and clinical course; (3) Results: The internal consistency was high (Cronbach's alpha coefficient = 0.903). The CRASH global score had a large positive correlation with the Cognitive reserve questionnaire total score ( = 0.838, < 0.001), demonstrating good convergent validity. The correlation coefficients between the CRASH total scores and clinical, functional, and neuropsychological performance were different between groups. In order to provide clinical interpretation, severity classification based on diagnosis (non-affective psychotic disorders, affective disorders, and healthy controls) have been created; (4) Conclusions: CRASH is the first CR measure developed specifically for patients with severe mental illness, facilitating reliable and valid measurement of this construct. The scale may aid in the stratification of patients and the implementation of personalized interventions.
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http://dx.doi.org/10.3390/jcm8050586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572583PMC
April 2019

Spanish validation of the Barcelona TEMPS-A questionnaire in patients with bipolar disorder and general population.

J Affect Disord 2019 Apr 12;249:199-207. Epub 2019 Feb 12.

Bipolar and Depression Disorders Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain. Electronic address:

Background: The Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego (TEMPS-A) is a self-administered questionnaire intended to assess five affective temperaments: depressive, cyclothymic, hyperthymic, irritable and anxious. Our objective was to examine the psychometric properties of the TEMPS-A using a sample comprised by patients with bipolar disorder (BD) and healthy controls (HC) and to determine cut-off scores for each temperament.

Methods: Five hundred and ninety-eight individuals (327 BD and 271 HC) completed the TEMPS-A. Cronbach's alpha was used to examine internal consistency reliability. Test-retest reliability and association between different temperamental scales were assessed using Spearman correlation. To confirm factor structure a confirmatory factor analysis (CFA) was carried out. Cut-off scores indicating the presence of dominant temperament were also calculated.

Results: Internal consistency was optimal for all temperament subscales (α: 0.682- 0.893). The questionnaire demonstrated good test-retest reliability (ρ: 0.594-0.754). The strongest positive associations were found between cyclothymic and anxious and between depressive and anxious temperaments. Hyperthymic and depressive as well as hyperthymic and anxious temperaments showed a strong negative correlation.

Limitations: The HC sample was not matched with the BD group. There were some sociodemographic and clinical differences between groups that may impact on the obtained results. A portion of patients with BD was recruited from tertiary centers.

Conclusions: The Spanish version of the Barcelona TEMPS-A questionnaire presents a good internal consistency and their results are stable in clinical population. The performance of the Barcelona TEMPS-A is as good as the original scale.
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http://dx.doi.org/10.1016/j.jad.2019.02.037DOI Listing
April 2019

Prevention of Recurrent Acute Otitis Media in Children Through the Use of PS7, a Target-Specific Probiotic Strain.

Nutrients 2019 Feb 12;11(2). Epub 2019 Feb 12.

Department of Nutrition and Food Science, Complutense University of Madrid, 28040 Madrid, Spain.

Acute otitis media (AOM) is one of the most common bacterial infections in children. Empiric antibiotherapy leads to increasing antimicrobial resistance rates among otopathogens and may impair the correct development of the microbiota in early life. In this context, probiotics seem to be an attractive approach for preventing recurrent AOM (rAOM) through the restoration of the middle ear and nasopharyngeal microbiota. The aim of this study was the selection of a probiotic strain ( PS7), specifically tailored for its antagonism against otopathogens. Since PS7 was safe and displayed a strong antimicrobial activity against otopathogens, its efficacy in preventing rAOM was assessed in a trial involving 61 children suffering from rAOM. Children consumed daily ~1 × 10⁸ CFU of PS7, and the number of AOM episodes were registered and compared with that observed in the previous 6 and 12 months. The microbiota of samples collected from the external auditory canal samples was quantitatively and qualitatively assessed. The number of AOM episodes during the intervention period decreased significantly (84%) when compared to that reported during the 6 months period before the probiotic intervention. In conclusion, PS7 is a promising strain for the prevention of rAOM in infants and children.
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http://dx.doi.org/10.3390/nu11020376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413216PMC
February 2019

Cognitive Remediation Interventions in Schizoaffective Disorder: A Systematic Review.

Front Psychiatry 2018 4;9:470. Epub 2018 Oct 4.

Barcelona Bipolar Disorders Program, Institute of Neurosciences, IDIBAPS, CIBERSAM, Hospital Clinic, University of Barcelona, Barcelona, Spain.

Patients with schizoaffective disorder (SAD) suffer from cognitive impairment, which negatively influences their functionality. Cognitive remediation (CR) interventions have been shown to be effective in patients with schizophrenia (SZ) and bipolar disorder (BD), but evidence in SAD is limited so far. The aim of this study is to systematically review the published data on CR interventions, either in neurocognition or social cognition, in patients with SAD. We conducted a comprehensive, computerized literature search using terms related to CR interventions in psychotic and affective disorders, and particularly in SAD. Pubmed, Embase, and Web of Knowledge databases were used up to February 28th, 2018 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The search returned 2672 articles of which four were finally selected meeting the inclusion criteria. Cognitive Enhancement Therapy, computerized Cognitive Remediation Therapy and Cognitive Training showed positive results in subsamples of patients with SAD regarding neurocognition and functioning in comparable terms to patients with schizophrenia as well as in a greater extent in quality of life. Benefits in social cognition were also described when Social Cognition Interaction Training was considered in patients with SAD. CR interventions seem to improve neurocognition and social cognition in patients with SAD as well as functioning and quality of life. However, further randomized controlled trials on CR interventions with an optimized design focusing on selected sample of patients with SAD are imperative.
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http://dx.doi.org/10.3389/fpsyt.2018.00470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180287PMC
October 2018

An Exploratory Search for Potential Molecular Targets Responsive to the Probiotic PS2 in Women With Mastitis: Gene Expression Profiling vs. Interindividual Variability.

Front Microbiol 2018 13;9:2166. Epub 2018 Sep 13.

Research Group on Quality, Safety and Bioactivity of Plant Foods, Department of Food Science and Technology, Centro de Edafología y Biología Aplicada del Segura-Consejo Superior de Investigaciones Científicas, Murcia, Spain.

Probiotics constitute an attractive alternative in the battle against microbial infections. Oral administration of certain strains of lactobacilli isolated from human milk has resulted in an effective reduction of the bacterial load as well as an improvement of the mastitis-associated symptoms. Nevertheless, little is yet known about the potential molecular mechanisms and specific targets implicated in these effects. Transcriptomic profiling has been used to search for disease-associated and therapy-responsive molecules in different disorders and experimental models. We have applied for the first time a gene expression-based molecular approach to explore for potential targets responsive to intervention with a probiotic in: (i) breast milk somatic cells ( = 17) and (ii) blood leukocytes ( = 19). Women with mastitis ingested a new strain of lactobacilli, PS2 (3 × capsules per day, each capsule contained ~9.5 log10 CFU) for 21 days. We applied Affymetrix microarrays and Taqman one-step quantitative reverse transcription PCR (RT-qPCR) to analyze and compare gene expression changes between samples pre- and post-treatment. Our results substantiate the involvement of inflammatory and cell-growth related pathways and genes in the breast milk somatic cells following the intake of PS2. Individual analyses of selected genes: (1) supported the upregulation of and and the downregulation of and in the somatic cells of the patients as potential targets responsive to the probiotic, (2) detected a lack of a relationship between the gene expression responses in the two types of cells, and (3) evidenced a substantial interindividual variability in the gene expression changes in both types of cells. Our study provides an insight into the essentiality of incorporating the study of tissue-specific interindividual molecular responsivity into future clinical intervention trials to further understand the complexity of human gene expression responses to therapy and the potentiality of selecting appropriate responsive targets.
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http://dx.doi.org/10.3389/fmicb.2018.02166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6146105PMC
September 2018

Investigating polygenic burden in age at disease onset in bipolar disorder: Findings from an international multicentric study.

Bipolar Disord 2019 02 28;21(1):68-75. Epub 2018 Jun 28.

Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany.

Objectives: Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early-onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD- and schizophrenia (SCZ)-associated risk variants is associated with an earlier AAO in BD patients.

Methods: A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn-Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18 years] vs adulthood [>18 years]) or considered as a continuous measure. The associations between BD- and SCZ-PRSs and AAO were evaluated with regression models.

Results: BD- and SCZ-PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment.

Conclusions: The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype.
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http://dx.doi.org/10.1111/bdi.12659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585855PMC
February 2019

Analysis of the Influence of microRNAs in Lithium Response in Bipolar Disorder.

Front Psychiatry 2018 31;9:207. Epub 2018 May 31.

Mood Disorders Unit, HUG - Geneva University Hospitals, Geneva, Switzerland.

Bipolar disorder (BD) is a common, highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. Lithium is the best-established long-term treatment for BD, even though individual response is highly variable. Evidence suggests that some of this variability has a genetic basis. This is supported by the largest genome-wide association study (GWAS) of lithium response to date conducted by the International Consortium on Lithium Genetics (ConLiGen). Recently, we performed the first genome-wide analysis of the involvement of miRNAs in BD and identified nine BD-associated miRNAs. However, it is unknown whether these miRNAs are also associated with lithium response in BD. In the present study, we therefore tested whether common variants at these nine candidate miRNAs contribute to the variance in lithium response in BD. Furthermore, we systematically analyzed whether any other miRNA in the genome is implicated in the response to lithium. For this purpose, we performed gene-based tests for all known miRNA coding genes in the ConLiGen GWAS dataset ( = 2,563 patients) using a set-based testing approach adapted from the versatile gene-based test for GWAS (VEGAS2). In the candidate approach, showed a nominally significant association with lithium response, providing some evidence for involvement in both development and treatment of BD. In the genome-wide miRNA analysis, 71 miRNAs showed nominally significant associations with the dichotomous phenotype and 106 with the continuous trait for treatment response. A total of 15 miRNAs revealed nominal significance in both phenotypes with showing the strongest association with the continuous trait ( = 9.80E-04) and with the dichotomous phenotype ( = 5.79E-04). No association between miRNAs and treatment response to lithium in BD in either of the tested conditions withstood multiple testing correction. Given the limited power of our study, the investigation of miRNAs in larger GWAS samples of BD and lithium response is warranted.
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http://dx.doi.org/10.3389/fpsyt.2018.00207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5991073PMC
May 2018

Association between genetic variation in the myo-inositol monophosphatase 2 (IMPA2) gene and age at onset of bipolar disorder.

J Affect Disord 2018 05 13;232:229-236. Epub 2018 Feb 13.

Bipolar Disorders Unit, Hospital Clinic, Institute of Neurosciences, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain. Electronic address:

Introduction: The age at onset of bipolar disorder (BD) has significant implications for severity, duration of affective episodes, response to treatment, and psychiatric comorbidities. It has been suggested that early-onset BD (EO-BD) could represent a clinically distinct subtype with probable genetic risk factors different from those of late-onset BD (LO-BD). To date, several genes have been associated with BD risk but few studies have investigated the genetic differences between EO-BD and LO-BD. The aim of this study was to evaluate if variants of the gene coding for myo-inositol monophosphatase (IMPA2) are linked to age at onset of BD.

Method: 235 bipolar patients were recruited and assessed. The final sample consisting of 192 euthymic individuals, was compared according to the age at onset. Polymorphisms were genotyped in the IMPA2 gene (rs669838, rs1020294, rs1250171, and rs630110). Early-onset was defined by the appearance of a first affective episode before the age of 18.

Results: The analyses showed that in the genotype distribution rs1020294 (p = .01) and rs1250171 (p = .01) were associated with the age at onset. The significant effect remained only in the rs1020294 SNP in which G carriers were more likely to debut later compared to patients presenting the AA genotype (p = .002; OR = 9.57, CI95%[2.37-38.64]). The results also showed that EO-BD tended to experience more alcohol misuse (p = .003; OR = .197, CI95%[.07-.58]) compared to LO-BD.

Conclusions: Our results provide evidence for genetic differences between EO-BD and LO-BD at the IMPA2 gene as well as clinical differences between subgroups with therapeutic implications.
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http://dx.doi.org/10.1016/j.jad.2018.02.002DOI Listing
May 2018

Physiological Translocation of Lactic Acid Bacteria during Pregnancy Contributes to the Composition of the Milk Microbiota in Mice.

Nutrients 2017 Dec 23;10(1). Epub 2017 Dec 23.

Department of Nutrition, Food Science and Food Technology, Complutense University of Madrid, 28040 Madrid, Spain.

The human milk microbiota is a complex and diverse ecosystem that seems to play a relevant role in the mother-to-infant transmission of microorganisms during early life. Bacteria present in human milk may arise from different sources, and recent studies suggest that at least some of them may be originally present in the maternal digestive tract and may reach the mammary gland through an endogenous route during pregnancy and lactation. The objective of this work was to elucidate whether some lactic acid bacteria are able to translocate and colonize the mammary gland and milk. For this purpose, two lactic acid bacteria strains ( MG1614 and PS2) were transformed with a plasmid containing the genes; subsequently, the transformed strains were orally administered to pregnant mice. The murine model allowed the visualization, isolation, and Polymerase Chain Reaction (PCR)-detection of the transformed bacteria in different body locations, including mammary tissue and milk, reinforcing the hypothesis that physiological translocation of maternal bacteria during pregnancy and lactation may contribute to the composition of the mammary and milk microbiota.
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http://dx.doi.org/10.3390/nu10010014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5793242PMC
December 2017
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