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UNIVERSIDADE FEDERAL DE GOIÁS
HOSPITAL DAS CLÍNICAS PROGRAMA DE RESIDÊNCIA MULTIPROFISSIONAL EM ÁREA DA SAÚDE
ÁREA DE TERAPIA INTENSIVA
TATYANNE LETÍCIA NOGUEIRA GOMES
BAIXA VITAMINA D NA ADMISSÃO NA UTI ESTÁ ASSOCIADA A CÂNCER, INFECÇÕES, INSUFICIÊNCIA RESPIRATÓRIA AGUDA E INSUFICIÊNCIA
HEPÁTICA
Goiânia 2018
TERMO DE CIÊNCIA E DE AUTORIZAÇÃO PARA DISPONIBILIZAR O ARTIGO
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1. Identificação do Artigo
Autor (a)
principal:
Tatyanne Letícia Nogueira Gomes
Co-autores
Renata Costa Fernandes; Liana Lima Vieira; Raquel Machado Schincaglia; João
Felipe Mota; Marciano de Souza Nóbrega; Claude Pichard; Gustavo Duarte
Pimentel.
E-mail: [email protected]
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Título: Baixa vitamina D na admissão na UTI está associada a câncer, infecções,
insuficiência respiratória aguda e insuficiência hepática
Palavras-chave: Vitamina D; Unidade de Terapia Intensiva; Resultados clínicos. Título em outra língua: Low vitamin D at ICU admission is associated with cancer,
infections, acute respiratory insufficiency and liver failure
Palavras-chave em outra língua: Vitamin D; Intensive Care Unit; Clinical outcome.
Área de concentração: Terapia Intensiva
Data defesa: (20/02/2018)
Programa de Pós-Graduação: Residência Multiprofissional em Saúde
Orientador (a): Gustavo Duarte Pimentel
E-mail: [email protected]
Co-orientador (a): Renata Costa Fernandes
E-mail: [email protected]
Enviado para a Revista: Clinical Nutrition ESPEN
2. Informações de acesso ao documento:
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envio do(s) arquivo(s) em formato digital PDF ou DOC do ARTIGO.
Data: 20 / 03 / 2018
Assinatura do (s) autor (es):
___________________________________________________________________
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ii
TATYANNE LETÍCIA NOGUEIRA GOMES
BAIXA VITAMINA D NA ADMISSÃO NA UTI ESTÁ ASSOCIADA A
CÂNCER, INFECÇÕES, INSUFICIÊNCIA RESPIRATÓRIA AGUDA E
INSUFICIÊNCIA HEPÁTICA
Artigo apresentado ao Programa de Residência Multiprofissional em Saúde, do Hospital das Clínicas, da Universidade Federal de Goiás, como requisito parcial para obtenção do Título de Residente Multiprofissional em Saúde.
Orientador: Dr. Gustavo Duarte Pimentel Co-orientador: Esp.Renata Costa Fernandes
Goiânia 2018
iii
iv
Programa de Residência Multiprofissional em Saúde, do Hospital das Clínicas, da Universidade Federal de Goiás
BANCA EXAMINADORA
Residente: Tatyanne Letícia Nogueira Gomes
Orientador(a): Dr. Gustavo Duarte Pimentel
Co-Orientador(a): Esp. Renata Costa Fernandes
Membros:
1. Dr. João Felipe Mota
2. Ms. Liana Lima Vieira
3. Dr. Gustavo Duarte Pimentel (Orientador)
Data: 20/02/2018
v
Dedico este trabalho à minha família e a meu noivo.
vi
AGRADECIMENTOS
À Deus e a Nossa Senhora, que me guiaram e me fizeram acreditar que posso vencer
todos os obstáculos que aparecem em meu caminho.
À minha mãe Raquel e a meus avós Maria Barbára e Jerônimo Luiz que sempre
acreditaram na minha capacidade e sempre se esforçaram para que eu pudesse
alcançar todos os meus sonhos.
Ao meu noivo Wildiner por expressar seu amor ao me dar apoio e segurança em todos
os momentos, pelo companheirismo e por sempre acreditar no meu potencial.
Ao meu orientador Prof. Dr. Gustavo Duarte Pimentel pelo auxílio prestado durante
esses anos de estudo e por acreditar no meu potencial.
À minha coorientadora Renata Costa Fernandes por todo apoio e suporte que recebi
nos momentos que mais precisei.
As minhas amigas nutricionistas Tatiane Fagundes e Isabel Reis por estarem sempre
presentes e me auxiliarem neste projeto.
À nutricionista Liana, por todo incentivo e suporte durante o período de estudo.
A chefe do Laborátorio de análises Clínicas do Hospital das Clinicas Tatiane Luiza pelo
apoio e confiança na pesquisa.
Ao chefe das Unidades de Terapia Intensiva do Hospital das Clínicas Dr. Marciano
Nobrega, pela confiança e apoio para o desenvolvimento desse estudo.
A toda equipe de biomédicos do Hospital das Clínicas pela ajuda nas análises e apoio
no estudo, em especial ao seu Inácio, Thais, Wildo, Lara, Sanayara, Romário e Carlos.
A toda equipe da Unidade de Terapia Intensiva clínica do Hospital das Clínicas, em
especial as Doutoras Dimitra, Suelene, Simone e Nádia.
7
SUMÁRIO
ARTIGO......................................................................................................... 9
Abstract......................................................................................................... 10
Introduction................................................................................................... 11
Methods......................................................................................................... 13
Results............................................................................................................ 15
Discussion........................................................................................................ 17
Conclusion ………………………………………………………………………… 19
Acknowledgements.......................................................................................... 19
Declaration of Conflict of Interest................................................................ 19
Funding........................................................................................................... 20
References................................................................................................... 21
ANEXOS....................................................................................................... 35
8
TABELAS, FIGURAS E ANEXOS
Figura 1. Flow chart of study............................................................................. 26
Figura 2. Distributions of serum 25(OH)D concentrations................................ 27
Tabela 1. Sociodemographic and clinical data of patients at ICU (n = 71)…….. 28
Tabela 2. Association of serum of the 25(OH)D concentrations at ICU
admission with with prognostic indicators, blood high-sensitive C-reactive
protein (hs-CRP) concentrations, mechanical ventilation duration, and
mortality..............................................................................................................
31
Tabela 3. Association of serum 25(OH)D concentrations with clinical
conditions and comorbidities at ICU admission................................................
33
Tabela 4. Association of serum 25-hydroxy-vitamin D concentrations with
clinical complications in next 28 days at ICU admission…………………………
34
ANEXO 1 – PARECER DO COMITE DE ÉTICA............................................... 35
ANEXO 2 – INSTRUÇÕES AOS AUTORES CLINICAL NUTRITION
ESPEN.................................................................................................................
38
9
ARTIGO 1
Low vitamin D at ICU admission is associated with cancer, infections, acute 2
respiratory insufficiency and liver failure 3
4
Short title: Vitamin D at ICU admission and clinical outcome 5
6
Tatyanne L N Gomes2, Renata C Fernandes
2, Liana L Vieira
2, Raquel M Schincaglia
1, 7
João F Mota1, Marciano S Nóbrega
2, Claude Pichard
3, Gustavo D Pimentel
1* 8
9
1. Clinical and Sports Nutrition Research Laboratory (Labince), Nutrition Faculty 10
(FANUT) – Federal University of Goias (UFG), Goiânia, GO, Brazil. 11
2. Clinical Hospital, Empresa Brasileira de Serviços Hospitalares (EBSERH) – Federal 12
University of Goias (UFG), Goiânia, GO, Brazil. 13
3.Clinical Nutrition, Geneva University Hospital, Geneva, Switzerland. 14
15
Abbreviations: ICU: Intensive Care Unit; APACHE II: Acute Physiology and Chronic 16
Health Evaluation II; SOFA: Sequential Organ Failure Assessment; 25(OH) D: 25-17
Hidroxi vitamin D; hs-CRP: High-sensitive C Reative Protein; MV: Mechanic 18
ventilation; NUTRIC score: NUTrition Risk in the Critically Ill. 19
20
Corresponding author: 21
Gustavo Duarte Pimentel, Gabinete 10, Faculdade de Nutrição (FANUT) – Universidade 22
Federal de Goiás (UFG), Rua 227, Quadra 68 s/n°, Setor Leste Universitário, CEP: 23
74605-080, Goiânia – GO. Brasil. Email: [email protected] 24
25
26
27
28
29
30
31
10
Abstract 32
Background: Vitamin D deficiency may be associated with comorbidities and poorer 33
prognosis. However, this association in Intensive Care Units (ICU) patients is not fully 34
elucidated. 35
Aim: To investigate whether the serum concentrations of the 25-hydroxyvitamin D 36
(25(OH)vitamin D) within the first 48 hours at ICU admission are associated with 37
prognostic indicators (APACHE II, SOFA score, Charlson comorbidity index), clinical 38
complications, serum C-reactive protein concentrations, mechanical ventilation duration, 39
and mortality. 40
Methods: Seventy-one patients admitted at ICU and with concentrations of 41
25(OH)vitamin D in the first 48 hours were analyzed. To evaluate the prognostic factors 42
at ICU, the APACHE II, SOFA score, Charlson comorbidity index questionnaires and 43
mechanical ventilation time, CRP and mortality were used. 44
Results: The mean concentration of 25(OH)vitamin D was 17.7 ± 8.27 (range 3.5-37.5) 45
ng/mL and 91.6% presented deficiency at admission. Although no associations were 46
found between serum 25(OH)vitamin D concentrations with mechanical ventilation 47
time, CRP, mortality, and APACHE II and SOFA severity scores, we found associations 48
with the Charlson comorbidity index when adjusted by age (Model 1: OR=1.64; 95%, 49
1.14-2.34) and by age, sex and body mass index (BMI) (Model 2: OR=1.59; 95%, 1.10-50
2.34). In addition, among the comorbidities present, 25(OH)vitamin D concentrations 51
were inversely associated with cancer (Crude model OR= 3.42; 95%, 1.21-9.64) and 52
liver disease (Crude model OR= 9.64; 95%, 2.28-40.60). 53
Conclusion: We found a strong association of 25(OH)vitamin D concentrations with the 54
prognostic indicator (CCI) and clinical complications (acute respiratory insufficiency, 55
acute liver failure and infections), but no associations with prognostic indicators 56
APACHE II and SOFA score, CRP, MV duration and mortality. The main comorbidities 57
associated with low 25(OH)vitamin D were cancer and liver disease, suggesting that 58
determination of 25(OH)vitamin D is relevant during the ICU stay. 59
60
Keywords: Vitamin D; Intensive Care Unit; Clinical outcome. 61
62
63
11
Introduction 64
The 25-hydroxyvitamin D (25(OH)vitamin D) is synthesized by the skin from 7-65
dehydrocholesterol in response to sun exposure [1], et can also be obtained by feeding 66
[2]. Both dietary and endogenous vitamin D concentrations are considered biologically 67
inactive. To become active, vitamin D undergoes hydroxylation, initially in the liver by 68
25-hydroxylase, forming the 25(OH)vitamin D and subsequently 25(OH)vitamin D 69
undergoes further hydroxylation by 1 alpha-hydroxylase in the kidney and forms 1.25-70
dihydroxyvitamin D, active form of the vitamin D [3,4]. Despite its role in calcium 71
metabolism, phosphorus and regulation of bone growth, vitamin D plays pleiotropic 72
action [4–7]. Vitamin D has an anti-inflammatory action by attenuating the expression of 73
inflammatory biomarkers [8,9]. Thus, serum of 25(OH)vitamin D concentrations are 74
inversely associated with inflammatory markers such as CRP. Vitamin D concentrations 75
decrease during acute diseases, such as in ICU patients, or in case of chronic 76
comorbidities, such as liver disease and cancer [10]. 77
The prevalence of vitamin D deficiency in ICU patients occurs in 26 to 74% [11–13]. A 78
prospective study admitted to a surgical ICU showed that low of 25(OH)vitamin D 79
concentrations <12ng/mL were associated with a higher mortality [13]. Likewise, 80
inadequate vitamin D (<30ng/mL) concentrations in ICU patients may be associated 81
with increased risk of clinical complications such as infections, organ failure evaluated 82
by the Sequential Organ Failure Assessment (SOFA) score [14,15], length of ICU stay 83
[11,16], time of mechanical ventilation (MV) [7] and mortality [2,11,13]. In addition to 84
traditional severity indicators, such as the SOFA score and Acute Physiology and 85
Chronic Health Evaluation II (APACHE) II, the Charlson Comorbidity Index (CCI has 86
also been used as a prognostic indicator in ICU patients [17–19]. In a cohort study in 87
310 ICU patients, vitamin D paired with CCI questionnaire was better associated with 88
mortality than when CCI was used alone, showing the benefit of the evaluation of 89
vitamin D on disease prognosis [18]. 90
Although some studies have shown the association of vitamin D concentrations with the 91
clinical outcome of ICU patients [7,13,16,20–28], some studies did not find association 92
of vitamin D with prognostic indicators such as SOFA, APACHE II, mortality and 93
comorbidities [20,29–31]. Therefore, we formed the hypothesis that low 25(OH)vitamin 94
12
D concentrations in ICU patients is associated with a higher inflammatory state, duration 95
of mechanical ventilation and a greater number of comorbidities. 96
97
This study aims at investigating whether 25(OH)vitamin D concentrations obtained 98
within the first 48 hours of ICU admission are associated with prognostic indicators 99
(APACHE II, SOFA score, Charlson comorbidity index), clinical complications, higher 100
CRP concentrations, duration of MV, and mortality in ICU patients.101
13
Methods 102
103
Design of study and recruitment: A cross-sectional study carried out at the Clinical ICU 104
at University Hospital between May and November 2017. The study was approved by 105
the Research Ethics Committee at Clinical Hospital, UFG-EBSERH under protocol 106
number 2.024.798.T 107
he determination of the sample size was based on the equation proposed by Lwanga & 108
Lemeshow (1991)[32]. Using a significance level of 5% and statistical power of 80%, 109
considering that 37% of critically ill patients with vitamin D deficiency use mechanical 110
ventilation and present a relative risk of 2, the minimum sample size determined were 71 111
patients. 112
We included ICU patients older than 18 years who had serum 25(OH)vitamin D 113
determination made within 48 hours of ICU admission. Exclusion criteria were as 114
follows: previous use of vitamin D supplements [33]; pregnancy; parenteral nutrition or 115
palliative care .In total, 91 patients were admitted. Of this total, 13 patients were 116
excluded due to the unavailability of 25(OH)vitamin D levels, five because they were on 117
parenteral nutrition and two because of pregnancy (Figure 1). 118
119
Data collection: Data were collected in medical records and included: age; sex; 120
comorbidities; breed; admission category (medical or surgical); days of ICU stay; body 121
mass index (BMI), which was calculated by the weight ratio (kg) by the square of the 122
height (m) NUTrition Risk in the Critically Ill (NUTRIC score) which is a score that 123
assesses the nutritional risk of critically ill patients and identifies those who require more 124
intensive nutritional therapy [34]; CCI, method that evaluates the risk of mortality based 125
on present comorbidities and age of the patient [17]; APACHE II, an instrument that 126
evaluates the risk of mortality based on routine physiological measurements, age and 127
previous health status [35]; SOFA score which evaluates the evolution of organ failure 128
[36]; use of MV at admission; days in MV; time of fasting after admission (in hours) and 129
clinical complications within 28 days in ICU [37,38] and comorbidities, such as acute 130
renal failure, acute liver failure, infections, sepsis, cardiorespiratory arrest, and acute 131
pulmonary insufficiency. 132
14
133
Laboratory: Blood samples were obtained within the first 48 hours at ICU admission. 134
The 25(OH)vitamin D concentration was measured by an immunoassay and the high 135
sensitivity CRP concentration was quantified by immunoturbidimetry. 136
137
Statistical analyses: The descriptive statistical analysis was performed with a cutoff of 138
12 ng/mL, according to Moraes et al., 2015 [13]. The continuous data were presented in 139
mean and standard deviation and the categorical in absolute (n) and relative (%) data. 140
Comparisons of the characteristics of the sample were made using unpaired t-Student´s 141
test in the presence of normality of the data and U-Mann-Whitney´s test in the absence 142
of this. The Chi-square test and Fisher's exact test were made to test the homogeneity 143
and possible differences of the groups in relation to the proportions (%). 144
When considering the outcomes for MV, CRP, SOFA score, APACHE, CCI and clinical 145
outcomes (death or discharge during the ICU stay), logistic regression was performed to 146
verify the association of these variables with serum vitamin concentrations D. In 147
addition, a new logistic regression was performed to evaluate the association between 148
comorbidities present at admission with low serum vitamin D concentrations. For this, 149
binary models (crude) were constructed and adjusted for age (model 1) and age, sex and 150
BMI (model 2). The results are presented in odds ratio (OR) and confidence interval. For 151
all analyzes, p<0.05 was considered significant. Analyzes were performed using 152
STATA® (version 14.0) and MedCalc® softwares.153
15
Results 154
The mean of serum 25(OH)vitamin D concentrations patients at admission was 17.7 ± 155
8.27 (range 3.5-37.5) ng/mL, being that only six patients (8.4%) had vitamin D as 156
sufficient (≥30 ng/mL) and 91.6% presented deficiency. Figure 2 shows the blood 157
25(OH)D concentrations distribution among patients. 158
The mean age was 53 ± 18 y old. The majority of patients were of clinical admission 159
63.38% and female sex 57.74% (p=0.003) (Table 1). Regarding severity scores, mean of 160
the APACHE II was 21.37 ± 9.6 points, SOFA score 6.7 ± 4.3 points and CCI 3.87 ± 2.3 161
points. The mean BMI was 23.43 ± 6.1 kg/m² and the NUTRIC score 4.83 ± 2.2 points. 162
Regarding to CRP, the mean value found was 33.1 ± 15.29 mg/dL (data not shown). 163
Table 1 presents the demographic factors, clinical and comorbidities indicators at 164
admission, and clinical complications of patients during the first 28 days at ICU 165
admission. The patients were dichotomized according to serum of 25(OH)vitamin D 166
concentrations from a previous Brazilian study [13]. Those with values lower than 167
12ng/mL had a higher frequency of comorbidities, such as cancer (p=0.017) and liver 168
disease (p=0.001). In addition, those with low of 25(OH)vitamin D concentrations also 169
had more clinical complications, such as acute respiratory failure (p=0.003), acute liver 170
failure (p=0.002), and infections (p=0.034). However, there was no difference between 171
the groups in terms of admission categories, fasting hours, clinical outcomes (death or 172
discharge), mechanical ventilation days and ICU stay (Table 1). 173
Although there was no association of serum 25(OH)vitamin D concentrations of 174
admission with of hs-CRP concentrations, SOFA score, APACHE II, duration of MV 175
and clinical outcomes, we found association with CCI when adjusted for age (Model 1) 176
(OR= 1.64, 95%, 1.14-2.34) and by age, sex and BMI (Model 2) (OR= 1.59, 95%, 1.10-177
2.34). We identified a higher CCI score when vitamin D concentrations were below 12 178
ng/mL, that is, worse was the Charlson comorbidities indicator (Table 2). 179
Next, we performed a new logistic regression analysis to identify which comorbidities 180
were associated with the low serum 25(OH)vitamin D concentrations at admission 181
(Table 3). We found that low serum of 25(OH)vitamin D concentrations are inversely 182
associated with cancer (Crude, OR= 3.42, 95%, 1.21-9.64) and liver disease (Crude, 183
16
OR= 9.64, 95%, 2.28-40.60). In addition, this association remained even after adjusting 184
for age, sex and BMI (see Table 3, Models 1 and 2) (Table 3). 185
In table 4, we demonstrated that serum 25(OH)vitamin D concentrations also were 186
positively associated with clinical complications in next 28 at ICU admission, acute 187
respiratory insufficiency and acute liver failure, (Crude, OR= 13.20, 95%, 1.63-106.45) 188
and (Crude, OR= 7.88, 95%, 2.29-27.12), respectively, as well as adjusted by age (M1) 189
and age, sex and BMI (M2). Additionally, a positive association was found with 190
infections (Crude, OR= 4.01, 95%, 1.18-13.59) and (M1, OR= 4.00, 95%, 1.17-13.64), 191
but not when adjusted by sex, age and BMI (M2). 192
193
17
Discussion 194
This observational study shows that patients with 25(OH)vitamin D concentrations 195
below 12 ng/mL at ICU admission were associated with a higher number of 196
comorbidities when assessed by CCI. In addition, low of 25(OH)D concentrations are 197
strongly associated with cancer and liver disease. This study is one of the few studies 198
carried out in Brazil and the first one performed in the Midwest region that evaluated the 199
serum of 25(OH)vitamin D concentrations in ICU patients. 200
Although evidence suggests that CCI is not as effective as the other severity scores when 201
compared to APACHE II and SOFA in predicting ICU mortality, this index is a tool 202
with good accuracy to identify severity and risk of mortality in ICU, once considers the 203
pre-existing co-morbidities [19,39,40]. In addition, studies with ICU patients suggest 204
that, in addition to comorbidities, the inadequacy of serum 25(OH)vitamin D 205
concentrations may be of great influence on ICU patient severity, increasing the risk of 206
clinical complications and mortality [13,33,41,42]. 207
Although serum 25(OH)vitamin D concentrations are influenced by insufficient sun 208
exposure, skin pigmentation, dietary intake, and liver disease [43], it is still unclear 209
whether serum vitamin D deficiency influences the development of comorbidities. 210
However, recent studies have shown that serum of 25(OH)vitamin D concentrations may 211
be used as a biological marker of health worsening [10,43]. In our study, was found that 212
25(OH)vitamin D concentrations at admission were associated with the presence of 213
comorbidities such as cancer (Crude, OR= 3.42, 95%, 1.21-9.64) and liver disease 214
(Crude: OR= 9.64, 95%, 2.28-40.60), as well as acute liver failure. 215
Due to its pleiotropic action, vitamin D acts in several cellular pathways that regulate 216
processes such as proliferation, differentiation, angiogenesis, metastasis, and apoptosis, 217
and thus playing an important role in carcinogenesis inhibition [27]. Among the actions 218
involved in the inhibition of carcinogenesis are increased expression of proteins such as 219
p21, BCL-2 associated protein X (BAX) and cell adhesion proteins; and also the 220
reduction of the expression of matrix metallopeptidase 9 (MMP9), plasminogen 221
activating factor, and vascular endothelial growth factor (VEGF) [44]. In a cohort study, 222
Giovannucci et al 2006 [45] found that patients with low serum of 25(OH)vitamin D 223
18
concentrations had a higher incidence of cancer of the digestive tract and higher risk of 224
mortality. 225
Vitamin D deficiency can occur in case of liver failure, reduced concentrations may also 226
contribute to liver damages [43,46]. Vitamin D deficiency may lead to increased hepatic 227
injury by increasing inflammatory processes and developing liver fibrosis [47]. 228
Although studies show an association between low vitamin D levels with inflammation 229
[39,48], in the present study, no association was found between serum CRP and 230
25(OH)vitamin D concentrations at ICU admission. 231
Although some studies show that there are associations between 25(OH)vitamin D 232
concentrations with severity scores such as SOFA and APACHE II [3,14], the present 233
study and others [20,29], did not find any association between the severity scores 234
APACHE II and SOFA with 25(OH)vitamin D concentrations, which suggests that 235
further clarification are needed. 236
Similar to our findings, Atalan et al. 2017 [29] that evaluated the 25(OH)vitamin D 237
concentrations at ICU admission of 491 patients, also found no association between the 238
APACHE II score and a number of organ dysfunction with vitamin D. In another study, 239
conducted by Long-Xiang et al. 2013 [20], patients in the ICU with a diagnosis of sepsis 240
and controls were also evaluated, and no associations between APACHE II and SOFA 241
severity scores with 25(OH)vitamin D concentrations were found. Regarding the clinical 242
outcomes, studies have shown that reduced 25(OH)vitamin D concentrations may 243
predict a higher mortality risk in ICU patients, likely due to a higher inflammatory state 244
and risk of infections [2,22,49]. Likewise, our study found a higher frequency of 245
infectious complications in patients with 25(OH)vitamin D concentrations below 12 246
ng/mL (Crude: 4.01, 95%, 1.18-13.59) (Table 4), but without association with mortality. 247
Another factor related to the worse prognosis in ICU patients is the prolonged time on 248
MV. 249
Vitamin D deficiency may influence the increased risk of chest fractures, decreased lung 250
capacity, increased risk of infections, elevated inflammatory status, and increased risk of 251
pulmonary parenchymal degradation [50] which reduces breath capacity. Likewise, in a 252
cohort study performed with 210 critical patients from a surgical ICU who were using 253
MV at admission, the authors observed that serum 25(OH)vitamin D concentrations 254
19
were inversely associated with MV duration [7]. In our study, we found no association 255
between MV duration and 25(OH)vitamin D concentrations, but with acute respiratory 256
insufficiency, which is a clinical complication that may impact on MV. 257
A limitation of the present study was that the serum 25(OH)vitamin D concentrations 258
were only measured at ICU admission, which limits the identification of whether the 259
ICU duration would reduce 25(OH)vitamin D concentrations and how would be the 260
clinical evolution of the patients with low concentrations. Moreover, in our study it was 261
not possible to collect data on dietary intake due to the lack of data recorded in medical 262
and nutritionist’s records. In addition, we did not measure the renal megalin expression, 263
which could have influenced the endocytosis of 25(OH)vitamin D filtered from the 264
glomerular ultrafiltrate and thus reduced 25(OH)vitamin D concentrations[51]. Although 265
we evaluated the MV duration, data were not recorded in hours, thus a patient with a 266
minimum of 12 hours was considered one day on MV. 267
268
Conclusion 269
We found a strong association of 25(OH)vitamin D concentrations with the prognostic 270
indicator (CCI) and clinical complications (acute respiratory insufficiency, acute liver 271
failure and infections), but no associations with prognostic indicators APACHE II and 272
SOFA score, CRP, MV duration and mortality. In addition, the main comorbidities 273
associated with low 25(OH)vitamin D were cancer and liver disease, suggesting that 274
determination of 25(OH)vitamin D is relevant during the ICU stay. 275
276
Acknowledgements 277
We thank Tatiane Luiza da Costa for enabling the data collection from the biochemical 278
exams. 279
280
Declaration of Conflict of Interest 281
The authors declare no conflicts of interest. TLNG, RCF, LLV, and GDP participated in 282
the conception and design of study; GDP, TLNG and RMS performed the statistical 283
analyses; TLNG collected data. TLNG, RCF, CP and GDP drafted the manuscript. JFM, 284
20
MSN and CP interpreted and discussed the data. All authors participated in the 285
interpretation of data, review and final approval of the manuscript. 286
287
Funding 288
This study was supported by internal funding of the Clinical and Sports Nutrition 289
Research Laboratory. 290
291
21
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458
459
460
Figure 1. Flow chart of the study.461
27
462
463
464
465
Figure 2. Distribution of serum 25-hydroxy-vitamin D concentrations. 466
467
468
469
28
Table 1. Sociodemographic and clinical data of patients at ICU admission (n = 71). 470
Variables
<12 ng/mL
n=23
≥12 ng/mL
n=48
p value
25-hydroxi-vitamin D (ng/mL) 1
9.22 ± 2.22 21.85 ± 6.85 <0.001
Age (years)1 49.91 ± 18.13 55.35 ± 18.32 0.182
Sex2, n (%) 0.003
Female 19 (82.60) 22 (45.83)
Male 4 (17.40) 26 (54.17)
SOFA score3 7.73 ± 5.25 6.28 ± 3.71 0.209
APACHE II1,4
23.17 ± 10.93 20.49 ± 895 0.311
Charlson Comorbidity Index5 4.57 ± 2.71 3.54 ± 2.10 0.086
NUTRIC score5 5.10 ± 2.41 4.70 ± 2.20 0.521
NUTRIC score5, n (%) 0.845
Low risk (1-4) 10 (47.61) 18 (45)
High risk (>4) 11 (52.39) 22 (55)
Body weight (kg)1 58.71 ± 15.30 63.26 ± 16.12 0.171
Height (m) 1.61 ± 0.08 1.63 ± 0.10 0.248
BMI (kg/m²)1 22.85 ± 6.06 23.71 ± 6.17 0.539
Hs-C reative protein (mg/dL)1,6
18.83 ± 14.05 16.39 ± 15.76 0.387
Admission category, n (%) 0.454
Surgery 7 (30.43) 19 (39.58)
Clinical 16 (69.57) 29 (60.42)
Comorbidities, n (%)
29
Cancer 14 (60.86) 15 (31.25) 0.017
Renal disease2 4 (17.39) 15 (31.25) 0.172
Diabetes2 5 (21.73) 8 (16.67) 0.744
Liver disease2 9 (39.13) 3 (6.25) 0.001
COPD2 5 (21.73) 5 (10.41) 0.275
Clinical complications, n (%)
Cardiorespiratory arrest 11 (47.82) 14 (29.16) 0.123
Acute respiratory insufficiency2 22 (95.65) 30 (62.50) 0.003
Acute renal failure 13 (56.52) 22 (45.83) 0.399
Acute liver failure2 11 (47.82) 5 (10.41) 0.002
Infections2 19 (82.60) 26 (54.16) 0.034
Sepsis 17 (73.91) 24 (50.00) 0.056
Mechanic ventilation, n (%) 0.179
No 11 (47.82) 31 (64.58)
Yes 12 (52.18) 17 (35.42)
Fasting from admission (hours)1 34.43 ± 47.91 14.50 ± 21.43 0.177
Mechanic ventilation duration (days)1 3.87 ± 6.46 2.71 ± 5.31 0.196
Time at ICU (days)1 7.04 ± 6.84 5.40 ± 5.95 0.351
Mortality, n (%) 0.084
Alive 12 (52.18) 35 (72.91)
Died 11 (47.82) 13 (27.08)
APACHE: Acute physiology and chronic health disease classification system; BMI: 471
Body mass index; COPD: Chronic obstructive pulmonary disease; NUTRIC score: 472
NUTrition risk in the critically Ill; SOFA: Sepsis-related organ failure assessment; Data 473
30
are presented as mean ± standard deviation for continuous variables and absolute values 474
(n) and percentage (%). P-value: means comparison by unpaired t-Student test for 475
continuous variables (1U-Mann-Whitney test); or comparison of proportions by chi-476
square test (2Fisher exact test).
3 n=62;
4 n=70;
5 n=61;
6 n=66. 477
478
479
480
481
482
483
484
485
486
487
488
489
490
491
492
493
494
495
496
497
498
499
500
501
502
503
31
Table 2. Association of serum of the 25-hydroxy-vitamin D concentrations with clinical 504
outcomes at ICU admission. 505
Variables OR (95 % CI) 25(OH)D
(continuous variables) p value
C-Reative protein
Crude
Model 1
Model 2
1.01 (0.97-1.04)
1.01 (0.98-1.04)
1.02 (0.98-1.06)
0.530
0.422
0.167
Mechanical ventilation duration
Crude
Model 1
Model 2
1.03 (0.95-1.12)
1.03 (0.95-1.12)
1.06 (0.96-1.12)
0.425
0.421
0.208
SOFA score
Crude
Model 1
Model 2
1.08 (0.95-1.22)
1.08 (0.95-1.22)
1.10 (0.96-1.26)
0.208
0.204
0.143
APACHE II
Crude
Model 1
Model 2
1.02 (0.97-1.08)
1.03 (0.98-1.09)
1.03 (0.97-1.09)
0.274
0.177
0.238
Charlson Comorbidity Index (CCI)
Crude
Model 1
Model 2
1.20 (0.97-1.50)
1.64 (1.14-2.34)
1.59 (1.10-2.34)
0.091
0.006
0.001
Mortality
Crude
Model 1
Model 2
2.46 (0.87-6.95)
2.73 (0.93-7.95)
2.08 (0.66-6.59)
0.087
0.065
0.210
Time at ICU
Crude
Model 1
1.04 (0.96-1.12)
1.04 (0.96-1.12)
0.303
0.307
32
Model 2 1.05 (0.96-1.15) 0.225
APACHE: Acute physiology and chronic health disease classification system; SOFA: 506
Sepsis-related organ failure assessment. OR: odds ratio; Model 1: adjusted by age. 507
Model 2: adjusted by age, sex, and body mass index. P-value: means differences in 508
variables. 509
510
511
33
Table 3. Association of serum 25-hydroxy-vitamin D concentrations with clinical 512
conditions and comorbidities at ICU admission. 513
Variables
OR (95 % CI)
25-hydroxy-vitamin D
(continuous variables)
p value
Cancer
Crude
Model 1
Model 2
3.42 (1.21-9.64)
3.64 (1.26-10.51)
4.15 (1.24-13.94)
0.017
0.016
0.021
Acute renal failure
Crude
Model 1
Model 2
0.46 (0.13-1.59)
0.50 (0.14-1.79)
0.66 (0.17-2.54)
0.223
0.292
0.546
Diabetes mellitus
Crude
Model 1
Model 2
1.38 (0.39-4.83)
1.47 (0.41-5.20)
1.47 (0.37-5.83)
0.606
0.548
0.581
Liver diseases
Crude
Model 1
Model 2
9.64 (2.28-40.60)
10.36 (2.38-45.11)
17.26 (2.75-108.18)
0.0008
0.001
0.0001
COPD
Crude
Model 1
Model 2
2.38 (0.61-9.27)
2.37 (0.60-9.35)
3.65 (0.77-17.19)
0.208
0.214
0.101
COPD: Chronic obstructive pulmonary disease; OR: odds ratio; Model 1: adjusted by 514
age. Model 2: adjusted by age, sex and body mass index. P-value: means differences in 515
variables. 516
517
34
Table 4. Association of serum 25-hydroxy-vitamin D concentrations with clinical 518
complications in next 28 days at ICU admission. 519
Variables
OR (95 % CI)
25-hydroxy-vitamin D
(continuous variables)
p value
Acute respiratory insufficiency
Crude
Model 1
Model 2
13.20 (1.63-106.45)
12.30 (1.50-100.40)
12.53 (1.44-108.79)
0.015
0.019
0.021
Acute liver failure
Crude
Model 1
Model 2
7.88 (2.29-27.12)
7.53 (2.17-26.11)
6.87 (1.75-26.95)
0.001
0.001
0.005
Infections
Crude
Model 1
Model 2
4.01 (1.18-13.59)
4.00 (1.17-13.64)
3.57 (0.99-12.88)
0.025
0.026
0.051
Sepsis
Crude
Model 1
Model 2
2.83 (0.95-8.42)
2.84 (0.94-8.53)
2.53 (0.79-8.03)
0.060
0.062
0.114
OR: odds ratio; Model 1: adjusted by age. Model 2: adjusted by age, sex and body mass 520
index. P-value: means differences in variables. 521
522
523
35
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is linked to the original contribution via electronic indexing and becomes part of the formal published
record.
Research/publication misconduct is a serious breach of ethics. Such misconduct includes:
i) Redundant or duplicate publication by same author(s),
ii) Publication in another source by the same author(s) without acknowledgement or permission from the
publisher, or
iii) Plagiarism or self-plagiarism (publication of material without acknowledging original author source).
iv) Fabrication of data, not substantiable via review of research records.
Should such publications occur, editorial action would be taken. In certain cases, secondary publication is
justifiable and even beneficial; however, such circumstances should be prospectively discussed with and
agreed upon by the Editor-In-Chief.
Nutrition will not accept a submission of work previously reported in large part in a published article
(duplicate) or that is contained in another paper submitted or accepted for publication in Nutrition or
elsewhere.
Declaration of interest
All authors must disclose any financial and personal relationships with other people or organizations that
could inappropriately influence (bias) their work. Examples of potential conflicts of interest include
employment, consultancies, stock ownership, honoraria, paid expert testimony, patent
applications/registrations, and grants or other funding. Authors must disclose any interests in two places:
1. A summary declaration of interest statement in the title page file (if double-blind) or the manuscript file
(if single-blind). If there are no interests to declare then please state this: 'Declarations of interest: none'.
This summary statement will be ultimately published if the article is accepted. 2. Detailed disclosures as
part of a separate Declaration of Interest form, which forms part of the journal's official records. It is
41
important for potential interests to be declared in both places and that the information matches. More
information.
Submission declaration and verification
Submission of an article implies that the work described has not been published previously (except in the
form of an abstract, a published lecture or academic thesis, see 'Multiple, redundant or concurrent
publication' for more information), that it is not under consideration for publication elsewhere, that its
publication is approved by all authors and tacitly or explicitly by the responsible authorities where the
work was carried out, and that, if accepted, it will not be published elsewhere in the same form, in English
or in any other language, including electronically without the written consent of the copyright-holder. To
verify originality, your article may be checked by the originality detection service Crossref Similarity
Check.
Authorship
Corresponding Author: One author is designated the corresponding author (not necessarily the senior
author) who will be approached to clarify any issues, such as those pertaining to materials and methods, or
technical comments. If Nutritionreceives feedback from its readers concerning the published paper,the
corresponding author will be contacted. It is this author's responsibility to inform all coauthors of such
matters to ensure they are dealt with promptly.
The corresponding author must affirm in the cover letter at the time of submission that:
1. None of the material in the manuscript is included in another manuscript, has been published
previously, or is currently under consideration for publication elsewhere. This includes symposia
proceedings, transactions, books, articles published by invitation, and preliminary publications of any kind
except an abstract of less than 250 words. If there is any question concerning potential overlap, the related
material must be included for evaluation.
2. Ethical guidelines were followed by the investigator in performing studies on humans or animals and
should be described in the paper. The approval of the institutional review board of either animal or human
ethics committee must be cited in the Methods.
3. Each author must have participated sufficiently in the work to take public responsibility for the content
of the paper and must approve of the final version of the manuscript. Authorship should be based on
substantive contributions to each of the following: conception and design of the study; generation,
collection, assembly, analysis and/or interpretation of data; and drafting or revision of the manuscript;
approval of the final version of the manuscript. Authors are required to include a statement in the
Acknowledgements to specify the actual contribution of each coauthor under the above headings.
4. If requested, the authors will provide the data or will cooperate fully in obtaining and providing the data
on which the manuscript is based for examination by the editors or their assignees
Changes to Authorship
This policy concerns the addition, deletion, or rearrangement of author names in the authorship of
accepted manuscripts:
Changes to author names after acceptance are strongly discouraged and can be accepted only in
compelling circumstances.
Before the accepted manuscript is published in an online issue Requests to add or remove an author, or to
rearrange the author names, must be sent to the Journal Manager from the corresponding author of the
accepted manuscript and must include: (a) the reason the name should be added or removed, or the author
names rearranged and (b) written confirmation (e-mail, fax, letter) from all authors that they agree with the
addition, removal or rearrangement. In the case of addition or removal of authors, this includes
confirmation from the author being added or removed. Requests that are not sent by the corresponding
author will be forwarded by the Journal Manager to the corresponding author, who must follow the
procedure as described above. Note that: (1) Journal Managers will inform the Journal Editors of any such
requests and (2) publication of the accepted manuscript in an online issue is suspended until authorship
has been agreed.
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After the accepted manuscript is published in an online issue: Any requests to add, delete, or rearrange
author names in an article published in an online issue will follow the same policies as noted above and
result in a corrigendum.
Reporting clinical trials
Randomized controlled trials should be presented according to the CONSORT guidelines. At manuscript
submission, authors must provide the CONSORT checklist accompanied by a flow diagram that illustrates
the progress of patients through the trial, including recruitment, enrollment, randomization, withdrawal
and completion, and a detailed description of the randomization procedure. The CONSORT checklist and
template flow diagram are available online.
Copyright
Upon acceptance of an article, authors will be asked to complete a 'Journal Publishing Agreement'
(see more information on this). An e-mail will be sent to the corresponding author confirming receipt of
the manuscript together with a 'Journal Publishing Agreement' form or a link to the online version of this
agreement.
Subscribers may reproduce tables of contents or prepare lists of articles including abstracts for internal
circulation within their institutions. Permission of the Publisher is required for resale or distribution
outside the institution and for all other derivative works, including compilations and translations. If
excerpts from other copyrighted works are included, the author(s) must obtain written permission from the
copyright owners and credit the source(s) in the article. Elsevier has preprinted forms for use by authors in
these cases.
For gold open access articles: Upon acceptance of an article, authors will be asked to complete an
'Exclusive License Agreement' (more information). Permitted third party reuse of gold open access articles
is determined by the author's choice of user license.
Author rights As an author you (or your employer or institution) have certain rights to reuse your work. More
information.
Elsevier supports responsible sharing
Find out how you can share your research published in Elsevier journals.
Role of the funding source
You are requested to identify who provided financial support for the conduct of the research and/or
preparation of the article and to briefly describe the role of the sponsor(s), if any, in study design; in the
collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the
article for publication. If the funding source(s) had no such involvement then this should be stated.
Funding body agreements and policies
Elsevier has established a number of agreements with funding bodies which allow authors to comply with
their funder's open access policies. Some funding bodies will reimburse the author for the gold open
access publication fee. Details of existing agreements are available online.
After acceptance, open access papers will be published under a noncommercial license. For authors
requiring a commercial CC BY license, you can apply after your manuscript is accepted for publication.
Open access
This journal offers authors a choice in publishing their research:
Subscription • Articles are made available to subscribers as well as developing countries and patient groups through
our universal access programs.
• No open access publication fee payable by authors.
• The Author is entitled to post the accepted manuscript in their institution's repository and make this
public after an embargo period (known as green Open Access). The published journal article cannot be
shared publicly, for example on ResearchGate or Academia.edu, to ensure the sustainability of peer-
reviewed research in journal publications. The embargo period for this journal can be found below.
Gold open access
• Articles are freely available to both subscribers and the wider public with permitted reuse.
• A gold open access publication fee is payable by authors or on their behalf, e.g. by their research funder
or institution.
43
Regardless of how you choose to publish your article, the journal will apply the same peer review criteria
and acceptance standards.
For gold open access articles, permitted third party (re)use is defined by the following Creative Commons
user licenses:
Creative Commons Attribution-NonCommercial-NoDerivs (CC BY-NC-ND)
For non-commercial purposes, lets others distribute and copy the article, and to include in a collective
work (such as an anthology), as long as they credit the author(s) and provided they do not alter or modify
the article.
The gold open access publication fee for this journal is USD 2500, excluding taxes. Learn more about
Elsevier's pricing policy: https://www.elsevier.com/openaccesspricing.
Green open access
Authors can share their research in a variety of different ways and Elsevier has a number of green open
access options available. We recommend authors see our green open access page for further information.
Authors can also self-archive their manuscripts immediately and enable public access from their
institution's repository after an embargo period. This is the version that has been accepted for publication
and which typically includes author-incorporated changes suggested during submission, peer review and
in editor-author communications. Embargo period: For subscription articles, an appropriate amount of
time is needed for journals to deliver value to subscribing customers before an article becomes freely
available to the public. This is the embargo period and it begins from the date the article is formally
published online in its final and fully citable form. Find out more.
This journal has an embargo period of 12 months.
Elsevier Researcher Academy
Researcher Academy is a free e-learning platform designed to support early and mid-career researchers
throughout their research journey. The "Learn" environment at Researcher Academy offers several
interactive modules, webinars, downloadable guides and resources to guide you through the process of
writing for research and going through peer review. Feel free to use these free resources to improve your
submission and navigate the publication process with ease.
Language (usage and editing services)
Please write your text in good English (American or British usage is accepted, but not a mixture of these).
Authors who feel their English language manuscript may require editing to eliminate possible grammatical
or spelling errors and to conform to correct scientific English may wish to use the English Language
Editing service available from Elsevier's WebShop.
Submission
Our online submission system guides you stepwise through the process of entering your article details and
uploading your files. The system converts your article files to a single PDF file used in the peer-review
process. Editable files (e.g., Word, LaTeX) are required to typeset your article for final publication. All
correspondence, including notification of the Editor's decision and requests for revision, is sent by e-mail.
Submit your article
All new manuscripts must be submitted through Nutrition's online submission and review Web
site https://www.evise.com/profile/#/NUT/login
Referees
Please submit the names and institutional e-mail addresses of several potential referees. For more details,
visit our Support site. Note that the editor retains the sole right to decide whether or not the suggested
reviewers are used.
NEW SUBMISSIONS
Submission to this journal proceeds totally online and you will be guided stepwise through the creation
and uploading of your files. The system automatically converts your files to a single PDF file, which is
used in the peer-review process.
As part of the Your Paper Your Way service, you may choose to submit your manuscript as a single file to
44
be used in the refereeing process. This can be a PDF file or a Word document, in any format or lay-out
that can be used by referees to evaluate your manuscript. It should contain high enough quality figures for
refereeing. If you prefer to do so, you may still provide all or some of the source files at the initial
submission. Please note that individual figure files larger than 10 MB must be uploaded separately.
Authors please note: We please ask you to use line numbering throughout the manuscript text, to facilitate
clear and rapid peer review
References
There are no strict requirements on reference formatting at submission. References can be in any style or
format as long as the style is consistent. Where applicable, author(s) name(s), journal title/book title,
chapter title/article title, year of publication, volume number/book chapter and the pagination must be
present. Use of DOI is highly encouraged. The reference style used by the journal will be applied to the
accepted article by Elsevier at the proof stage. Note that missing data will be highlighted at proof stage for
the author to correct.
Formatting requirements
There are no strict formatting requirements but all manuscripts must contain the essential elements needed
to convey your manuscript, for example Abstract, Keywords, Introduction, Materials and Methods,
Results, Conclusions, Artwork and Tables with Captions.
If your article includes any Videos and/or other Supplementary material, this should be included in your
initial submission for peer review purposes.
Divide the article into clearly defined sections.
Figures and tables embedded in text
Please ensure the figures and the tables included in the single file are placed next to the relevant text in the
manuscript, rather than at the bottom or the top of the file. The corresponding caption should be placed
directly below the figure or table.
Peer review
This journal operates a double blind review process. All contributions will be initially assessed by the
editor for suitability for the journal. Papers deemed suitable are then typically sent to a minimum of two
independent expert reviewers to assess the scientific quality of the paper. The Editor is responsible for the
final decision regarding acceptance or rejection of articles. The Editor's decision is final. More
information on types of peer review.
REVISED SUBMISSIONS Use of word processing software
Regardless of the file format of the original submission, at revision you must provide us with an editable
file of the entire article. Keep the layout of the text as simple as possible. Most formatting codes will be
removed and replaced on processing the article. The electronic text should be prepared in a way very
similar to that of conventional manuscripts (see also the Guide to Publishing with Elsevier). See also the
section on Electronic artwork.
To avoid unnecessary errors you are strongly advised to use the 'spell-check' and 'grammar-check'
functions of your word processor.
Article structure Subdivision - unnumbered sections
Divide your article into clearly defined sections. Each subsection is given a brief heading. Each heading
should appear on its own separate line. Subsections should be used as much as possible when cross-
referencing text: refer to the subsection by heading as opposed to simply 'the text'.
Introduction
State the objectives of the work and provide an adequate background, avoiding a detailed literature survey
or a summary of the results.
Material and methods
Provide sufficient details to allow the work to be reproduced by an independent researcher. Methods that
are already published should be summarized, and indicated by a reference. If quoting directly from a
previously published method, use quotation marks and also cite the source. Any modifications to existing
methods should also be described.
Theory/calculation
A Theory section should extend, not repeat, the background to the article already dealt with in the
45
Introduction and lay the foundation for further work. In contrast, a Calculation section represents a
practical development from a theoretical basis.
Results
Results should be clear and concise.
Discussion
This should explore the significance of the results of the work, not repeat them. A combined Results and
Discussion section is often appropriate. Avoid extensive citations and discussion of published literature.
Conclusions
The main conclusions of the study may be presented in a short Conclusions section, which may stand
alone or form a subsection of a Discussion or Results and Discussion section.
Appendices
If there is more than one appendix, they should be identified as A, B, etc. Formulae and equations in
appendices should be given separate numbering: Eq. (A.1), Eq. (A.2), etc.; in a subsequent appendix, Eq.
(B.1) and so on. Similarly for tables and figures: Table A.1; Fig. A.1, etc.
This should include 1) title of paper (use no abbreviations, limit: 120 characters with spaces), 2)
running head of fewer than 55 characters with spaces, 3) full names of all authors with highest academic
degree(s); 4) affiliations of all authors; 4) role of each author in the work (see Authorship); 5) a word
count for the entire manuscript (including figures and tables), and the number of figures and tables, 4) the
complete mailing address (including telephone, fax, and e-mail address of the corresponding author for e-
mailing of proofs and reprint requests).
Abstracts should be no more than 250 words. The structured abstract for an original investigation should
be organized as follows:
Objective: The abstract should begin with a clear statement of the precise objective or question addressed
in the paper. If a hypothesis was tested, it should be stated.
Research Methods & Procedures: The basic design of the study and its duration should be described. The
methods used should be stated, the statistical data/methods provided and referenced.
Results: The main results of the study should be given in narrative form. Measurements or other
information that may require explanation should be defined. Levels of statistical significance should be
indicated, including other factors crucial to the outcome of the study.
Conclusion(s): State only conclusions that are directly supported by the evidence and the implications of
the findings.
Graphical abstract
Although a graphical abstract is optional, its use is encouraged as it draws more attention to the online
article. The graphical abstract should summarize the contents of the article in a concise, pictorial form
designed to capture the attention of a wide readership. Graphical abstracts should be submitted as a
separate file in the online submission system. Image size: Please provide an image with a minimum of 531
× 1328 pixels (h × w) or proportionally more. The image should be readable at a size of 5 × 13 cm using a
regular screen resolution of 96 dpi. Preferred file types: TIFF, EPS, PDF or MS Office files. You can
view Example Graphical Abstracts on our information site.
Authors can make use of Elsevier's Illustration Services to ensure the best presentation of their images and
in accordance with all technical requirements.
Highlights
Highlights are mandatory for this journal. They consist of a short collection of bullet points that convey
the core findings of the article and should be submitted in a separate editable file in the online submission
system. Please use 'Highlights' in the file name and include 3 to 5 bullet points (maximum 85 characters,
including spaces, per bullet point). You can view example Highlights on our information site.
Keywords
5—7 key words or phrases should be provided which should be selected from the body of the text and not
duplicate title words.
Abbreviations
Define abbreviations that are not standard in this field in a footnote to be placed on the first page of the
article. Such abbreviations that are unavoidable in the abstract must be defined at their first mention there,
as well as in the footnote. Ensure consistency of abbreviations throughout the article.
46
Acknowledgments
Collate acknowledgements in a separate section at the end of the article before the references and do not,
therefore, include them on the title page, as a footnote to the title or otherwise. List here those individuals
who provided help during the research (e.g., providing language help, writing assistance or proof reading
the article, etc.).
Formatting of funding sources
List funding sources in this standard way to facilitate compliance to funder's requirements:
Funding: This work was supported by the National Institutes of Health [grant numbers xxxx, yyyy]; the
Bill & Melinda Gates Foundation, Seattle, WA [grant number zzzz]; and the United States Institutes of
Peace [grant number aaaa].
It is not necessary to include detailed descriptions on the program or type of grants and awards. When
funding is from a block grant or other resources available to a university, college, or other research
institution, submit the name of the institute or organization that provided the funding.
If no funding has been provided for the research, please include the following sentence:
This research did not receive any specific grant from funding agencies in the public, commercial, or not-
for-profit sectors.
Units
Follow internationally accepted rules and conventions: use the international system of units (SI). If other
units are mentioned, please give their equivalent in SI.
Math formulae
Please submit math equations as editable text and not as images. Present simple formulae in line with
normal text where possible and use the solidus (/) instead of a horizontal line for small fractional terms,
e.g., X/Y. In principle, variables are to be presented in italics. Powers of e are often more conveniently
denoted by exp. Number consecutively any equations that have to be displayed separately from the text (if
referred to explicitly in the text).
Footnotes
Footnotes should be used sparingly. Number them consecutively throughout the article. Many word
processors build footnotes into the text, and this feature may be used. Should this not be the case, indicate
the position of footnotes in the text and present the footnotes themselves separately at the end of the
article.
Artwork Electronic artwork
General points
• Make sure you use uniform lettering and sizing of your original artwork.
• referred fonts: Arial (or Helvetica), Times New Roman (or Times), Symbol, Courier.
• Number the illustrations according to their sequence in the text.
• Use a logical naming convention for your artwork files.
• Indicate per figure if it is a single, 1.5 or 2-column fitting image.
• For Word submissions only, you may still provide figures and their captions, and tables within a single
file at the revision stage.
• lease note that individual figure files larger than 10 MB must be provided in separate source files.
A detailed guide on electronic artwork is available.
You are urged to visit this site; some excerpts from the detailed information are given here.
Formats
Regardless of the application used, when your electronic artwork is finalized, please 'save as' or convert
the images to one of the following formats (note the resolution requirements for line drawings, halftones,
and line/halftone combinations given below):
EPS (or PDF): Vector drawings. Embed the font or save the text as 'graphics'.
TIFF (or JPG): Color or grayscale photographs (halftones): always use a minimum of 300 dpi.
TIFF (or JPG): Bitmapped line drawings: use a minimum of 1000 dpi.
TIFF (or JPG): Combinations bitmapped line/half-tone (color or grayscale): a minimum of 500 dpi is
required.
47
Please do not:
• Supply files that are optimized for screen use (e.g., GIF, BM , ICT, W G); the resolution is too low.
• Supply files that are too low in resolution.
• Submit graphics that are disproportionately large for the content.
Color artwork
Please make sure that artwork files are in an acceptable format (TIFF (or JPEG), EPS (or PDF), or MS
Office files) and with the correct resolution. If, together with your accepted article, you submit usable
color figures then Elsevier will ensure, at no additional charge, that these figures will appear in color
online (e.g., ScienceDirect and other sites) regardless of whether or not these illustrations are reproduced
in color in the printed version. For color reproduction in print, you will receive information regarding
the costs from Elsevier after receipt of your accepted article. Please indicate your preference for color:
in print or online only. Further information on the preparation of electronic artwork.
Illustration services
Elsevier's WebShop offers Illustration Services to authors preparing to submit a manuscript but concerned
about the quality of the images accompanying their article. Elsevier's expert illustrators can produce
scientific, technical and medical-style images, as well as a full range of charts, tables and graphs. Image
'polishing' is also available, where our illustrators take your image(s) and improve them to a professional
standard. Please visit the website to find out more.
Figure captions
Ensure that each illustration has a caption. A caption should comprise a brief title (not on the figure itself)
and a description of the illustration. Keep text in the illustrations themselves to a minimum but explain all
symbols and abbreviations used.
Tables
Please submit tables as editable text and not as images. Tables can be placed either next to the relevant
text in the article, or on separate page(s) at the end. Number tables consecutively in accordance with their
appearance in the text and place any table notes below the table body. Be sparing in the use of tables and
ensure that the data presented in them do not duplicate results described elsewhere in the article. Please
avoid using vertical rules and shading in table cells.
References Citation in text
Please ensure that every reference cited in the text is also present in the reference list (and vice versa). Any
references cited in the abstract must be given in full. Unpublished results and personal communications
are not recommended in the reference list, but may be mentioned in the text. If these references are
included in the reference list they should follow the standard reference style of the journal and should
include a substitution of the publication date with either 'Unpublished results' or 'Personal communication'.
Citation of a reference as 'in press' implies that the item has been accepted for publication.
Reference links
Increased discoverability of research and high quality peer review are ensured by online links to the
sources cited. In order to allow us to create links to abstracting and indexing services, such as Scopus,
CrossRef and PubMed, please ensure that data provided in the references are correct. Please note that
incorrect surnames, journal/book titles, publication year and pagination may prevent link creation. When
copying references, please be careful as they may already contain errors. Use of the DOI is encouraged.
A DOI can be used to cite and link to electronic articles where an article is in-press and full citation details
are not yet known, but the article is available online. A DOI is guaranteed never to change, so you can use
it as a permanent link to any electronic article. An example of a citation using DOI for an article not yet in
an issue is: VanDecar J.C., Russo R.M., James D.E., Ambeh W.B., Franke M. (2003). Aseismic
continuation of the Lesser Antilles slab beneath northeastern Venezuela. Journal of Geophysical Research,
https://doi.org/10.1029/2001JB000884. Please note the format of such citations should be in the same style
as all other references in the paper.
Web references
As a minimum, the full URL should be given and the date when the reference was last accessed. Any
further information, if known (DOI, author names, dates, reference to a source publication, etc.), should
also be given. Web references can be listed separately (e.g., after the reference list) under a different
heading if desired, or can be included in the reference list.
48
Data references
This journal encourages you to cite underlying or relevant datasets in your manuscript by citing them in
your text and including a data reference in your Reference List. Data references should include the
following elements: author name(s), dataset title, data repository, version (where available), year, and
global persistent identifier. Add [dataset] immediately before the reference so we can properly identify it
as a data reference. The [dataset] identifier will not appear in your published article.
References in a special issue
Please ensure that the words 'this issue' are added to any references in the list (and any citations in the text)
to other articles in the same Special Issue.
Reference management software
Most Elsevier journals have their reference template available in many of the most popular reference
management software products. These include all products that support Citation Style Language styles,
such as Mendeley and Zotero, as well as EndNote. Using the word processor plug-ins from these products,
authors only need to select the appropriate journal template when preparing their article, after which
citations and bibliographies will be automatically formatted in the journal's style. If no template is yet
available for this journal, please follow the format of the sample references and citations as shown in this
Guide.
Users of Mendeley Desktop can easily install the reference style for this journal by clicking the following
link:
http://open.mendeley.com/use-citation-style/nutrition
When preparing your manuscript, you will then be able to select this style using the Mendeley plug-ins for
Microsoft Word or LibreOffice.
Reference formatting
There are no strict requirements on reference formatting at submission. References can be in any style or
format as long as the style is consistent. Where applicable, author(s) name(s), journal title/book title,
chapter title/article title, year of publication, volume number/book chapter and the pagination must be
present. Use of DOI is highly encouraged. The reference style used by the journal will be applied to the
accepted article by Elsevier at the proof stage. Note that missing data will be highlighted at proof stage for
the author to correct. If you do wish to format the references yourself they should be arranged according to
the following examples:
Reference style
Text: Indicate references by number(s) in square brackets in line with the text. The actual authors can be
referred to, but the reference number(s) must always be given.
List: Number the references (numbers in square brackets) in the list in the order in which they appear in
the text.
Examples:
Reference to a journal publication:
[1] Van der Geer J, Hanraads JAJ, Lupton RA. The art of writing a scientific article. J Sci Commun
2010;163:51–9.
Reference to a book:
[2] Strunk Jr W, White EB. The elements of style. 4th ed. New York: Longman; 2000.
Reference to a chapter in an edited book:
[3] Mettam GR, Adams LB. How to prepare an electronic version of your article. In: Jones BS, Smith RZ,
editors. Introduction to the electronic age, New York: E-Publishing Inc; 2009, p. 281–304.
Reference to a website:
[4] Cancer Research UK. Cancer statistics reports for the UK,
http://www.cancerresearchuk.org/aboutcancer/statistics/cancerstatsreport/; 2003 [accessed 13 March
2003].
Reference to a dataset:
[dataset] [5] Oguro M, Imahiro S, Saito S, Nakashizuka T. Mortality data for Japanese oak wilt disease
and surrounding forest compositions, Mendeley Data, v1; 2015. https://doi.org/10.17632/xwj98nb39r.1.
Note shortened form for last page number. e.g., 51–9, and that for more than 6 authors the first 6 should be
listed followed by 'et al.' For further details you are referred to 'Uniform Requirements for Manuscripts
submitted to Biomedical Journals' (J Am Med Assoc 1997;277:927–34) (see also Samples of Formatted
References).
49
Journal abbreviations source
Journal names should be abbreviated according to the List of Title Word Abbreviations.
Video
Elsevier accepts video material and animation sequences to support and enhance your scientific research.
Authors who have video or animation files that they wish to submit with their article are strongly
encouraged to include links to these within the body of the article. This can be done in the same way as a
figure or table by referring to the video or animation content and noting in the body text where it should be
placed. All submitted files should be properly labeled so that they directly relate to the video file's content.
. In order to ensure that your video or animation material is directly usable, please provide the file in one
of our recommended file formats with a preferred maximum size of 150 MB per file, 1 GB in total. Video
and animation files supplied will be published online in the electronic version of your article in Elsevier
Web products, including ScienceDirect. Please supply 'stills' with your files: you can choose any frame
from the video or animation or make a separate image. These will be used instead of standard icons and
will personalize the link to your video data. For more detailed instructions please visit our video
instruction pages. Note: since video and animation cannot be embedded in the print version of the journal,
please provide text for both the electronic and the print version for the portions of the article that refer to
this content.
AudioSlides
The journal encourages authors to create an AudioSlides presentation with their published article.
AudioSlides are brief, webinar-style presentations that are shown next to the online article on
ScienceDirect. This gives authors the opportunity to summarize their research in their own words and to
help readers understand what the paper is about. More information and examples are available. Authors of
this journal will automatically receive an invitation e-mail to create an AudioSlides presentation after
acceptance of their paper.
Data visualization
Include interactive data visualizations in your publication and let your readers interact and engage more
closely with your research. Follow the instructions hereto find out about available data visualization
options and how to include them with your article.
Supplementary material
Supplementary material such as applications, images and sound clips, can be published with your article to
enhance it. Submitted supplementary items are published exactly as they are received (Excel or
PowerPoint files will appear as such online). Please submit your material together with the article and
supply a concise, descriptive caption for each supplementary file. If you wish to make changes to
supplementary material during any stage of the process, please make sure to provide an updated file. Do
not annotate any corrections on a previous version. Please switch off the 'Track Changes' option in
Microsoft Office files as these will appear in the published version.
Research data
This journal encourages and enables you to share data that supports your research publication where
appropriate, and enables you to interlink the data with your published articles. Research data refers to the
results of observations or experimentation that validate research findings. To facilitate reproducibility and
data reuse, this journal also encourages you to share your software, code, models, algorithms, protocols,
methods and other useful materials related to the project.
Below are a number of ways in which you can associate data with your article or make a statement about
the availability of your data when submitting your manuscript. If you are sharing data in one of these
ways, you are encouraged to cite the data in your manuscript and reference list. Please refer to the
"References" section for more information about data citation. For more information on depositing,
sharing and using research data and other relevant research materials, visit the research data page.
Data linking
If you have made your research data available in a data repository, you can link your article directly to the
dataset. Elsevier collaborates with a number of repositories to link articles on ScienceDirect with relevant
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repositories, giving readers access to underlying data that gives them a better understanding of the
research described.
There are different ways to link your datasets to your article. When available, you can directly link your
dataset to your article by providing the relevant information in the submission system. For more
information, visit the database linking page.
For supported data repositories a repository banner will automatically appear next to your published article
on ScienceDirect.
In addition, you can link to relevant data or entities through identifiers within the text of your manuscript,
using the following format: Database: xxxx (e.g., TAIR: AT1G01020; CCDC: 734053; PDB: 1XFN).
Mendeley Data
This journal supports Mendeley Data, enabling you to deposit any research data (including raw and
processed data, video, code, software, algorithms, protocols, and methods) associated with your
manuscript in a free-to-use, open access repository. Before submitting your article, you can deposit the
relevant datasets to Mendeley Data. Please include the DOI of the deposited dataset(s) in your main
manuscript file. The datasets will be listed and directly accessible to readers next to your published article
online.
For more information, visit the Mendeley Data for journals page.
Data in Brief
You have the option of converting any or all parts of your supplementary or additional raw data into one
or multiple data articles, a new kind of article that houses and describes your data. Data articles ensure that
your data is actively reviewed, curated, formatted, indexed, given a DOI and publicly available to all upon
publication. You are encouraged to submit your article for Data in Brief as an additional item directly
alongside the revised version of your manuscript. If your research article is accepted, your data article will
automatically be transferred over to Data in Brief where it will be editorially reviewed and published in
the open access data journal, Data in Brief. Please note an open access fee of 500 USD is payable for
publication in Data in Brief. Full details can be found on the Data in Brief website. Please use this
template to write your Data in Brief.
Data statement
To foster transparency, we encourage you to state the availability of your data in your submission. This
may be a requirement of your funding body or institution. If your data is unavailable to access or
unsuitable to post, you will have the opportunity to indicate why during the submission process, for
example by stating that the research data is confidential. The statement will appear with your published
article on ScienceDirect. For more information, visit the Data Statement page.
Online proof correction
Corresponding authors will receive an e-mail with a link to our online proofing system, allowing
annotation and correction of proofs online. The environment is similar to MS Word: in addition to editing
text, you can also comment on figures/tables and answer questions from the Copy Editor. Web-based
proofing provides a faster and less error-prone process by allowing you to directly type your corrections,
eliminating the potential introduction of errors.
If preferred, you can still choose to annotate and upload your edits on the PDF version. All instructions for
proofing will be given in the e-mail we send to authors, including alternative methods to the online version
and PDF.
We will do everything possible to get your article published quickly and accurately. Please use this proof
only for checking the typesetting, editing, completeness and correctness of the text, tables and figures.
Significant changes to the article as accepted for publication will only be considered at this stage with
permission from the Editor. It is important to ensure that all corrections are sent back to us in one
communication. Please check carefully before replying, as inclusion of any subsequent corrections cannot
be guaranteed. Proofreading is solely your responsibility.
Offprints
The corresponding author will, at no cost, receive a customized Share Linkproviding 50 days free access
to the final published version of the article on ScienceDirect. The Share Link can be used for sharing the
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article via any communication channel, including email and social media. For an extra charge, paper
offprints can be ordered via the offprint order form which is sent once the article is accepted for
publication. Both corresponding and co-authors may order offprints at any time via Elsevier's Webshop.
Corresponding authors who have published their article gold open access do not receive a Share Link as
their final published version of the article is available open access on ScienceDirect and can be shared
through the article DOI link.
Visit the Elsevier Support Center to find the answers you need. Here you will find everything from
Frequently Asked Questions to ways to get in touch.
You can also check the status of your submitted article or find out when your accepted article will be
published.
