scholarly journals Can the Imbalance Between Neurotrophic and Apoptotic Proteins be the "Beware the Ides of March" for Unaffected Relatives of Schizophrenia Patients?

2021 ◽  
Author(s):  
Umit Haluk Yesilkaya ◽  
Sakir Gica ◽  
Pelin Ozkara Menekseoglu ◽  
Busra Guney Tasdemir ◽  
Zeynep Cirakli ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Healthy Control Group ◽  
First Episode ◽  
Control Group ◽  
Episode Psychosis ◽  
Healthy Siblings ◽  
Healthy Control ◽  
Drug Naïve ◽  
Apoptotic Proteins ◽  
Synaptic Pruning

Abstract Schizophrenia (SZ) is a mental disorder with a strong genetic basis as well as epigenetic aspects. Siblings of patients with SZ can share certain endophenotypes with the patients, suggesting that the siblings may be important for distinguishing between trait and state markers. In the current study, we aimed to characterize the balance between pro-BDNF/mature BDNF and its receptors p75NTR/TrkB, which is tpa-BDNF pathways proteins and thought to play a role in synaptic pruning as a possible endophenotype of schizophrenia. Forty drug-naïve patients with first-episode psychosis (FEP) matched for age, gender and level of education, 40 unaffected siblings (UAS) of patients with FEP and 67 healthy controls (HC) were included in the study. Blood samples were collected from all participants to determine BDNF, pro-BDNF, TrkB and p75NTR, PAI1, tPA, ACTH and cortisol levels. We showed that levels of proteins of the tPA-BDNF pathway, pro-BDNF/m-BDNF and p75NTR/TrkB ratios could successfully differentiateFEP and their siblings from the HCs by using ROC analysis. Plasma levels of m-BDNF were found to be the lowest in the healthy siblings and highest in the healthy control group with statistically significant differences between all 3 groups. The plasma levels of pro-BDNF in the healthy control group were similar to the FEP patients, the same in the healthy siblings of the FEP patients. Our data Support the hypothesis that imbalance between neurotrophic and apoptotic proteins might occur in SZ, and this imbalance could be an endophenotype of the disease.

scholarly journals Is the Association Between TNF-α-308 A Allele and DMT1 Independent of HLA-DRB1, DQB1 Alleles?

2006 ◽  
Vol 2006 ◽  
pp. 1-7 ◽  
Author(s):  
Grazyna Deja ◽  
Przemyslawa Jarosz-Chobot ◽  
Joanna Polanska ◽  
Urszula Siekiera ◽  
Ewa Malecka-Tendera
Keyword(s):  
Risk Factors ◽  
Linkage Disequilibrium ◽  
Genetic Susceptibility ◽  
Genetic Risk ◽  
Healthy Control Group ◽  
Control Group ◽  
Tnf Α ◽  
Healthy Siblings ◽  
Diabetic Children ◽  
Healthy Control

The aim of the study was to assess chosen factors of genetic susceptibility to DMT1: DRB1, DQB1, and TNF-αpolymorphisms-308 (G/A) in children with DMT1 and their up-to-now healthy siblings. Then we tested whether the association between TNF-αgenes and DMT1 is independent of HLA. 87 diabetic children, their 78 siblings, and 85 persons from healthy control group were followed up. The highest risk of DMT1 was connected with alleles: DRB1*0401 (OR = 3.39; CI: 1.55–7.41), DRB1*0301 (OR = 2.72; CI: 1.48–5.01), DQB1*0201 (OR = 4.04; CI: 2.17–7.52), DQB1*0302 (OR = 5.08; CI: 2.54–10.14), and TNF-α-308 A allele (OR = 2.59; CI: 1.23–5.44). Moreover linkage disequilibrium for TNF-α-308 A allele with DRB1*0301 and DQB1*0201 was observed in both diabetic children and their siblings. Diabetic children and their siblings present similar genetic risk factors for DMT1. The association between TNF-α-308 A allele and DMT1 is dependent of HLA-DRB1 and DQB1 alleles.

scholarly journals First-Episode Psychotic Patients Showed Longitudinal Brain Changes Using fMRI With an Emotional Auditory Paradigm

2020 ◽  
Vol 11 ◽  
Author(s):  
Carlos González-Vivas ◽  
Gracián García-Martí ◽  
Pau Soldevila-Matías ◽  
Roberto Sanz-Requena ◽  
Eduardo J. Aguilar ◽  
...  
Keyword(s):  
Word Processing ◽  
Block Design ◽  
First Episode ◽  
Control Group ◽  
Activation Patterns ◽  
Individual Level ◽  
Episode Psychosis ◽  
Great Heterogeneity ◽  
Healthy Control

Most previous longitudinal studies of functional magnetic resonance imaging (fMRI) in first-episode psychosis (FEP) using cognitive paradigm task found an increased activation after antipsychotic medications. We designed an emotional auditory paradigm to explore brain activation during emotional and nonemotional word processing. This study aimed to analyze if longitudinal changes in brain fMRI BOLD activation is present in patients vs. healthy controls. A group of FEP patients (n = 34) received clinical assessment and had a fMRI scan at baseline and follow-up (average, 25-month interval). During the fMRI scan, both emotional and nonemotional words were presented as a block design. Results were compared with a pair of healthy control group (n = 13). Patients showed a decreased activation at follow-up fMRI in amygdala (F = 4.69; p = 0.04) and hippocampus (F = 5.03; p = 0.03) compared with controls. Middle frontal gyrus was the only area that showed a substantial increased activation in patients (F = 4.53; p = 0.04). A great heterogeneity in individual activation patterns was also found. These results support the relevance of the type of paradigm in neuroimaging for psychosis. This is, as far as we know, the first longitudinal study with an emotional auditory paradigm in FEP. Our results suggested that the amygdala and hippocampus play a key role in psychotic disease. More studies are needed to understand the heterogeneity of response at individual level.

Effects of Low-Dose Risperidone and Low-Dose Zuclopenthixol on Cognitive Functions in First-Episode Drug-Naïve Schizophrenic Patients

CNS Spectrums ◽  
2004 ◽  
Vol 9 (5) ◽  
pp. 364-374 ◽  
Author(s):  
Birgitte Fagerlund ◽  
Torben Mackeprang ◽  
Anders Gade ◽  
Ralf Hemmingsen ◽  
Birte Y. Glenthøj
Keyword(s):  
Cognitive Deficits ◽  
Cognitive Functions ◽  
Low Dose ◽  
First Episode ◽  
Control Group ◽  
Anticholinergic Medication ◽  
Extrapyramidal Side Effects ◽  
Schizophrenic Patients ◽  
Healthy Control ◽  
Drug Naïve

AbstractBackground: Studies on the effects of antipsychotics on cognitive deficits in schizophrenia mostly suggest a superior effect of atypical over typical compounds, although findings are inconsistent and effect sizes small. Several methodological issues, such as heterogenous patient samples, incomparable drug doses, effects of prior medication, construct validity, and retest effects on neuropsychological tasks, confound most results and the comparability between studies. Consequently, the conclusion concerning effects of antipsychotics on cognition is still equivocal.Objective: The present randomized clinical trial examined the effects on cognition of comparatively low doses of a typical antipsychotic (zuclopenthixol) and an atypical antipsychotic (risperidone) in a homogenous group of drug-naïve first-episode schizophrenic patients in a longitudinal setting.Methods: First-episode schizophrenic patients who had never previously been exposed to antipsychotic treatment (N-25) were randomly allocated to treatment with flexible doses of zuclopenthixol or risperidone in an open-label design. Cognitive functions were examined both when patients were drug-naïve, and after 13 weeks of treatment. A comprehensive neuropsychological battery was used in order to optimize construct validity, and principal components of cognitive functions were extrapolated in order to reduce type I errors. A healthy control group was tested at baseline and after 13 weeks, in order to examine retest effects. The cognitive domains studied were executive functions, selective attention, and reaction time.Results: The patients showed considerable cognitive deficits when drug-naïve. There were few differential effects of risperidone and zuclopenthixol on cognitive deficits, except for a differential significance, respectively, tendency towards improved reaction and movement times in the risperidone group, and a lack of such in the zuclopenthixol group. These differences were no longer significant after covarying for extrapyramidal side effects and anticholinergic medication that were more prevalent in the zuclopenthixol group and the increases after medication were comparable with retest effects in controls.Conclusion: The study underscores the importance of examining impact of factors, such as clinical improvement, extrapyramidal side effects, anticholinergic medication and retest effects in longitudinal efficacy studies. This study does not support efficacy of either risperidone or zuclopenthixol on cognitive functions in drug-naïve schizophrenia patients after 3 months of medication, because neither could be distinguished from retest effects of the healthy control group.

Childhood psychopathological antecedents in early onset schizophrenia

2005 ◽  
Vol 20 (4) ◽  
pp. 309-314 ◽  
Author(s):  
F. Muratori ◽  
F. Salvadori ◽  
G. D’Arcangelo ◽  
V. Viglione ◽  
L Picchi
Keyword(s):  
Early Onset ◽  
Attention Problems ◽  
First Episode ◽  
Control Group ◽  
Early Onset Schizophrenia ◽  
School Problems ◽  
Social Competencies ◽  
Episode Psychosis ◽  
Healthy Control ◽  
Premorbid State

AbstractObjectiveTo describe the premorbid state of early onset schizophrenia (EOS).MethodsTwenty-three adolescents with EOS were compared to a healthy control group (CG) and to a group of anorexic patients (AG). The premorbid state was studied through the CBCL and the data obtained were analyzed using ANOVA’s and t-test.ResultsDuring the premorbid period EOS showed significantly higher scores on all scales, relative to the CG, and only on some scales (social, thought and attention problems, and school competencies) relative to the AG.ConclusionsChildren who develop first episode psychosis during adolescence differ from children with normal development. The premorbid internalizing state is common to AG but social competencies and school problems are the most affected areas in EOS when compared to the AG. It is hypothesized that both EOS and AG can be considered as the expression of a previous vulnerability.

Vitamin D Treatment in Patients with Hashimoto’s Thyroiditis may Decrease the Development of Hypothyroidism

2016 ◽  
Vol 86 (1-2) ◽  
pp. 9-17 ◽  
Author(s):  
Bekir Ucan ◽  
Mustafa Sahin ◽  
Muyesser Sayki Arslan ◽  
Nujen Colak Bozkurt ◽  
Muhammed Kizilgul ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Deficiency ◽  
Hashimoto’S Thyroiditis ◽  
Healthy Control Group ◽  
Hashimoto's Thyroiditis ◽  
Control Group ◽  
Endocrine Society ◽  
Thyroid Autoantibody ◽  
Healthy Control ◽  
The Mean

Abstract.The relationship between Hashimoto’s thyroiditis and vitamin D has been demonstrated in several studies. The aim of the present study was to evaluate vitamin D concentrations in patients with Hashimoto’s thyroiditis, the effect of vitamin D therapy on the course of disease, and to determine changes in thyroid autoantibody status and cardiovascular risk after vitamin D therapy. We included 75 patients with Hashimoto’s thyroiditis and 43 healthy individuals. Vitamin D deficiency is defined as a 25-hydroxy vitamin D (25(OH)D3) concentration less than 20ng/mL. Vitamin D deficient patients were given 50.000 units of 25(OH)D3 weekly for eight weeks in accordance with the Endocrine Society guidelines. All evaluations were repeated after 2 months of treatment. Patients with Hashimoto’s thyroiditis had significantly lower vitamin D concentrations compared with the controls (9.37±0.69 ng/mL vs 11.95±1.01 ng/mL, p < 0.05, respectively). Thyroid autoantibodies were significantly decreased by vitamin D replacement treatment in patients with euthyroid Hashimoto’s thyroiditis. Also, HDL cholesterol concentrations improved in the euthyroid Hashimoto group after treatment. The mean free thyroxine (fT4) concentrations were 0.89±0.02 ng/dL in patients with Hashimoto’s thyroiditis and 1.07±0.03 ng/dL in the healthy control group (p < 0.001). The mean thyroid volumes were 7.71±0.44 mL in patients with Hashimoto’s thyroiditis and 5.46±0.63 mL in the healthy control group (p < 0.01). Vitamin D deficiency is frequent in Hashimoto’s thyroiditis and treatment of patients with this condition with Vitamin D may slow down the course of development of hypothyroidism and also decrease cardiovascular risks in these patients. Vitamin D measurement and replacement may be critical in these patients.

Brief psycho-education for caregivers of persons with first episode psychosis

2018 ◽  
Vol 9 (01) ◽  
Author(s):  
Praful Prabhuappa Kapse ◽  
Manisha Kiran
Keyword(s):  
First Episode Psychosis ◽  
First Episode ◽  
Control Group ◽  
Episode Psychosis ◽  
Study Results ◽  
Before And After ◽  
Quasi Experimental ◽  
Expressed Emotions ◽  
Experimental Group ◽  
Group Family

Caring for the persons with first episode psychosis is challenging and demanding. It may lead to the increased burden, expressed emotions among the caregivers. The numerous studies have shown that high burden and negative expressed emotions among caregivers can lead to early relapse in the patients with first episode psychosis. To evaluate the effects of the brief psychoeducation on the caregivers burden and expressed emotions. A quasi experimental - before and after with control group research design was adopted for the study. A total of 60 caregivers have participated in the study, of which 30 caregivers in experimental group and 30 caregivers in the control group. Family Burden Interview Schedule (Pai and Kapoor, 1981) and Attitude Questionnaire (Sethi et al., 1981) was used to assess caregiver's burden and expressed emotions. At end of the psychoeducation intervention, burden among caregivers and negative expressed emotions of the caregivers have significantly reduced. The positive expressed emotions have been increased. Study results demonstrates the importance of psychoeducation intervention in reducing the burden and negative expressed emotions.

Plasma-Free Amino Acid Profiling of Nasal Polyposis Patients

2020 ◽  
Vol 22 (9) ◽  
pp. 657-662 ◽  
Author(s):  
Mustafa Celik ◽  
Alper Şen ◽  
İsmail Koyuncu ◽  
Ataman Gönel
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Free Amino Acid ◽  
Free Amino ◽  
Nasal Polyposis ◽  
Amino Acid Profile ◽  
Healthy Control Group ◽  
Control Group ◽  
Healthy Control ◽  
History Of

Aim and Objective:: To determine the mechanisms present in the etiopathogenesis of nasal polyposis. It is not clear whether amino acids contribute in a causal way to the development of the disease. Therefore, the aim of this study was to determine the plasma-free amino acid profile in patients with nasal polyposis and to compare the results with a healthy control group. Materials and Methods:: This was a prospective controlled study that took place in the Otolaryngology Department at the Harran University Faculty of Medicine between April 2017 and April 2018. Plasmafree amino acid profile levels were studied in serum samples taken from a patient group and a healthy control group. Patients who were diagnosed with bilateral diffuse nasal polyposis and were scheduled for surgical interventions were included in this study. Individuals whose age, gender, and body mass index values were compatible with that of the patient group and who did not have any health problems were included in the control group. All the participants whose levels of plasma-free amino acid were thought to be affected by one or more of the following factors were excluded from the study: smoking and alcohol use, allergic rhinitis presence, the presence of acute or chronic sinusitis, a history of endoscopic sinus surgery, unilateral nasal masses, a history of chronic drug use, systemic or topical steroid use in the last three months for any reason, and liver, kidney, hematological, cardiovascular, metabolic, neurological, or psychiatric disorders or malignancies. Results: In patients with nasal polyposis, 3-methyl histidine (3-MHIS: nasal polyposis group (ng) = 3.22 (1.92 – 6.07); control group (cg) = 1.21 (0.77 – 1.68); p = 0.001); arginine (arg: ng = 98.95 (70.81 – 117.75); cg = 75.10 (54.49 – 79.88); p = 0.005); asparagine (asn: ng = 79.84 (57.50 – 101.44); cg = 60.66 (46.39 – 74.62); p = 0.021); citrulline (cit: ng = 51.83 (43.81 – 59.78); cg = 38.33 (27.81 – 53.73); p = 0.038); cystine (cys: ng = 4.29 (2.43 – 6.66); cg = 2.41 (1.51 – 4.16); p = 0.019); glutamic acid (glu: ng = 234.86 (128.75 – 286.66); cg = 152.37 (122.51 – 188.34); p = 0.045); histidine (his: ng = 94.19 (79.34 – 113.99); cg = 74.80 (62.76 – 98.91); p = 0.018); lysine (lys: ng = 297.22 (206.55 – 371.25); cg = 179.50 (151.58 – 238.02); p = 0.001); ornithine (ng = 160.62 (128.36 – 189.32); cg = 115.91 (97.03 – 159.91); p = 0.019); serine (ser: ng = 195.15 (151.58 – 253.07); cg = 83.07 (67.44 – 92.44); p = 0.001); taurine (tau: ng = 74.69 (47.00 – 112.13); cg = 53.14 (33.57 – 67.31); p = 0.006); tryptophan (trp: ng = 52.31 (33.81 – 80.11); cg = 34.44 (25.94 – 43.07); p = 0.005), homocitrulline (ng = 1.75 (1.27 – 2.59); cg = 0.00 (0.00 – 0.53); p = 0.001); norvaline (ng = 6.90 (5.61 – 9.18); cg = 4.93 (3.74 – 7.13); p = 0.021); argininosuccinic acid (ng = 14.33 (10.06 – 25.65); cg = 12.22 (5.77 – 16.87) p = 0.046); and plasma concentrations were significantly higher than in the healthy control group (p <0.05). However, the gamma-aminobutyric acid (gaba: ng = 0.16 (0.10 – 0.24); cg = 0.21 (0.19 – 0.29); p = 0.010) plasma concentration was significantly lower in the nasal polyposis group than in the healthy control group. Conclusion: In this study, plasma levels of 15 free amino acids were significantly higher in the nasal polyposis group than in the healthy control group. A plasma level of 1 free amino acid was found to be significantly lower in the nasal polyposis group compared to the healthy control group. Therefore, it is important to determine the possibility of using the information obtained to prevent the recurrence of the condition and to develop effective treatment strategies. This study may be a milestone for studies of this subject. However, this study needs to be confirmed by further studies conducted in a larger series.

scholarly journals Correlation analysis of epicardial adipose tissue thickness, C-reactive protein, interleukin-6, visfatin, juxtaposed with another zinc finger protein 1, and type 2 diabetic macroangiopathy

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Yuan-Yuan Gong ◽  
Hai-Ying Peng
Keyword(s):  
Correlation Analysis ◽  
Zinc Finger Protein ◽  
Pearson Correlation ◽  
Statistical Significance ◽  
Healthy Control Group ◽  
Control Group ◽  
Diabetes Group ◽  
Reactive Protein ◽  
Healthy Control

Abstract Background To investigate the correlation between the thickness of epicardial adipose tissue (EAT), C-reactive protein (CRP), interleukin (IL) -6, visfatin, juxtaposed with another zinc finger protein 1 (JAZF1) and type 2 diabetic mellitus (T2DM) macroangiopathy. Methods The study enrolled 82 patients with T2DM with macroangiopathy (the Complication Group), and 85 patients with T2DM (the Diabetes Group) who were admitted to Shandong Provincial Third Hospital from February 2018 to February 2020. In addition, 90 healthy people who underwent physical examination at the same hospital during the same period were enrolled (the Healthy Control Group). Age, gender, height, weight, waist circumference (WC), hip circumference (HC), diabetic course and therapeutic drugs, waist hip ratio (WHR), and body mass index (BMI) were recorded and calculated. Results The baseline characteristics of the three groups were comparable, and the diabetic course of the Complication Group and the Diabetes Group was not significantly different (P > 0.05). The WHR of the Complication Group was higher than that of the Diabetes Group and the Healthy Control Group, with statistical significance (P < 0.05). The FPG, 2hPG, HbA1C, CRP, IL-6, Visfatin, JAZF1, HOMA-IR, EAT thickness, and baPWV of the Complication Group were all higher than those of the Diabetes Group and the Healthy Control Group (P < 0.05, respectively). The JAZF1 and FIns of the Complication Group and Diabetes Group were lower than those of the Healthy Control Group, and JAZF1 of the Complication Group was lower than the Diabetes Group with statistical significance (P<0.05, respectively). Pearson correlation analysis showed that the EAT thickness was positively correlated with CRP, IL-6, visfatin, and JAZF1 (r = 0.387, 0.451, 0.283, 0.301, respectively, all P<0.001). Pearson correlation analysis showed that baPWV was positively correlated with EAT thickness, CRP, IL-6, visfatin, and JAZF1 (r = 0.293, 0.382, 0.473, 0.286, respectively, all P < 0.001). Multivariate stepwise regression analysis showed that FPG, 2hPG, HbA1C, CRP, IL-6, visfatin, JAZF1, and EAT thickness were independent risk factors that affected T2DM macroangiopathy. Conclusions Clinical monitoring and treatment of T2DM macroangiopathy can use CRP, IL-6, Visfatin, JAZF1, and EAT thickness as new targets to delay the progression of the disease. Further research on the relationship between the above factors and the pathogenesis of T2DM macroangiopathy may be helpful provide new treatment strategies.

scholarly journals Implementation of NAVIGATE Coordinated Specialty Care for First Episode Psychosis: the Michigan Experience

CNS Spectrums ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 177-178
Author(s):  
Eric D. Achtyes ◽  
Kari Kempema ◽  
Zhehui Luo ◽  
Katharine N. Thakkar ◽  
Catherine Adams ◽  
...  
Keyword(s):  
Mental Health ◽  
Clinical Symptoms ◽  
The United States ◽  
First Episode Psychosis ◽  
Specialty Care ◽  
First Episode ◽  
Control Group ◽  
Evidence Based ◽  
Block Grant ◽  
Episode Psychosis

AbstractStudy ObjectivesCoordinated specialty care (CSC) is widely accepted as an evidence-based treatment for first episode psychosis (FEP). The NAVIGATE intervention from the Recovery After an Initial Schizophrenia Episode Early Treatment Program (RAISE-ETP) study is a CSC intervention which offers a suite of evidence-based treatments shown to improve engagement and clinical outcomes, especially in those with shorter duration of untreated psychosis (DUP). Coincident with the publication of this study, legislation was passed by the United States Congress in 2014–15 to fund CSC for FEP via a Substance Abuse and Mental Health Services Administration (SAMHSA) block grant set-aside for each state. In Michigan (MI) the management of this grant was delegated to Network180, the community mental health authority in Kent County, with the goal of making CSC more widely available to the 10 million people in MI. Limited research describes the outcomes of implementation of CSC into community practices with no published accounts evaluating the use of the NAVIGATE intervention in a naturalistic setting. We describe the outcomes of NAVIGATE implementation in the state of MI.MethodsIn 2014, 3 centers in MI were selected and trained to provide NAVIGATE CSC for FEP. In 2016 a 4th center was added, and 2 existing centers were expanded to provide additional access to NAVIGATE. Inclusion: age 18–31, served in 1 of 4 FEP centers in MI. Data collection began in 2015 for basic demographics, global illness (CGI q3 mo), hospital/ED use and work/school (SURF q3 mo) and was expanded in 2016 to include further demographics, diagnosis, DUP, vital signs; and in 2018 for clinical symptoms with the modified Colorado Symptom Inventory (mCSI q6 mo), reported via an online portal. This analysis used data until 12/31/19. Mixed effects models adjusted by age, sex and race were used to account for correlated data within patients.ResultsN=283 had useable demographic information and were included in the analysis. Age at enrollment was 21.6 ± 3.0 yrs; 74.2% male; 53.4% Caucasian, 34.6% African American; 12.9 ± 1.7 yrs of education (N=195). 18 mo retention was 67% with no difference by sex or race. CGI scores decreased 20% from baseline (BL) to 18 mo (BL=3.5, N=134; 15–18 mo=2.8, N=60). Service utilization via the SURF was measured at BL (N=172) and 18 mo (N=72): psychiatric hospitalizations occurred in 37% at BL and 6% at 18 mo (p<0.01); ER visits occurred in 40% at BL and 13% at 18 mo (p<0.01). 44% were working or in school at BL and 68% at 18 mo (p<0.01). 21% were on antipsychotics (AP) at BL (N=178) and 85% at 18 mo (N=13) with 8% and 54% on long acting injectable-AP at BL and 18 mo, respectively. Limitations include missing data and lack of a control group.ConclusionThe implementation of the NAVIGATE CSC program for FEP in MI resulted in meaningful clinical improvement for enrollees. Further support could make this evidence-based intervention available to more people with FEP.FundingSupported by funds from the SAMHSA Medicaid State Block Grant set-aside awarded to Network180 (Achtyes, Kempema). The funders had no role in the design of the study, the analysis or the decision to publish the results.

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