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Introduction | anxiety, infections, infectious disease, post-traumatic, infection, depression, post-traumatic stress | INFECTIOUS DISEASE, INFECTIONS, INFECTION | COVID-19 was identified as an infectious disease by the World Health Organization (WHO) on 11 February 2020.When examining the psychosocial impacts in a pandemic context, researchers experience key challenges not only with the choice of study design and measures but also in providing a multicultural perspective.To date, the majority of the literature examining the psychosocial impacts of COVID-19 is from studies conducted in China, Europe and the USA and a few multinational studies have been carried out among the general population. A multinational study that examined the psychosocial impacts of COVID-19 across several high-income countries (HICs) found generalised anxiety among 21.0% and major depression among 25.5% of their respondents.To address the issues identified above, we developed the 50-item COVID Psychosocial Impacts Scale (CPIS) to comprehensively assess the impacts of the pandemic including the adverse personal, social and economic consequences that followed. The construction of the scale was informed by our team’s experience assessing the psychosocial impacts of the Canterbury EarthquakesThe 50-item CPIS has been validated in a non-representative New Zealand sample at two-time points (2020, 2022) when the population exposure to COVID-19 community infections varied markedly.In addition to developing the CPIS, the research team took the opportunity to use resources that had already been deployed for the translation of the research instruments for the March 15th ProjectOur planned programme of work is to examine the 32-item CPIS and translated psychometric measures in the countries of interest. This protocol describes a cross-sectional observational study to assess the psychosocial impacts of the COVID-19 pandemic in seven LMICs (Indonesia, Iran, Iraq, Malaysia, Pakistan, Somalia and Turkey). It uses an online survey that includes the 32-item CPIS and standardised measures of psychological distress, post-traumatic stress, well-being and post-traumatic growth. Our findings will increase our understanding of the psychosocial impacts of the COVID-19 pandemic across several LMICs with differing rates of infection, morbidity and mortality. Findings will also provide psychometric evidence on the novel CPIS. As a result, our research will contribute to a growing body of mental health measures that can be used for cross-cultural comparison. | PMC10105919 |
Methods and analysis | PMC10105919 | |||
Study design | This is a cross-sectional observational study examining the psychosocial impacts of the COVID-19 pandemic being conducted in seven LMICs. | PMC10105919 | ||
Measures | The measures have all been translated into the appropriate language for the country in which they will be administered (see
| PMC10105919 | ||
Sociodemographic measures | Sociodemographic measures include age, gender, marital status, religion, ethnicity, self-reported English proficiency, highest level of education, occupation, study or work status and monthly income (in local currency). On the recommendation of the international collaborators, some of the demographic questions may vary to ensure contextual appropriateness. For example, in Turkey, students do not study part-time so that option was removed from the item. | PMC10105919 | ||
Prior trauma exposure | adversity, trauma | The exposure to previous trauma will also be sought to examine the effect of previous trauma on the psychosocial impacts of COVID-19. Participants will be asked to select as many as appropriate from a list of previous exposure to natural disasters, war or military conflict, childhood adversity, physical or sexual assault, and serious physical accident. | PMC10105919 | |
COVID Psychosocial Impacts Scale | ’ | This is a novel 32-item measure used to examine the psychosocial impacts of the COVID-19 pandemic. The scale asks participants if they have experienced stressors in response to COVID-19 and then to indicate the magnitude of stress on a 6-point scale scored from 0=‘no’, 1=‘yes, no stress at all’ to 5=‘yes, a lot of stress’. An overall pandemic-related stress score can be calculated ranging from 0 to 160. | PMC10105919 | |
Kessler-10 | This is a 10-item measure assessing symptoms of psychological distress in the previous 30 days. | PMC10105919 | ||
WHO Well-Being Index | This is a short 5-item measure assessing subjective psychological well-being in the previous 2 weeks. | PMC10105919 | ||
PTSD Checklist for DSM-5 | ’, PTSD, traumatic | EVENT | This is a 20-item measure assessing symptoms of PTSD in the past month anchored in response to COVID-19 as a potentially traumatic event. Each item is scored from 0=‘not at all’ to 4=‘extremely’; with a severity score range of 0–80. | PMC10105919 |
Post-traumatic Growth Inventory | trauma | This is a 21-item measure assessing change following exposure to trauma, | PMC10105919 | |
Participants | Adults (aged 18 years and over) who reside in Indonesia, Iran, Iraq, Malaysia, Pakistan, Somalia or Turkey will be recruited as participants. Anyone aged below 18 years and those not currently residing in the country of interest will be excluded from the study. | PMC10105919 | ||
Study status | RECRUITMENT | Different sites are at different stages of project implementation including ethical approval pending (Iran); ethical approval obtained and recruiting participants (Somalia) and participant recruitment completed (Indonesia, Iraq, Malaysia, Pakistan and Turkey). | PMC10105919 | |
Recruitment | RECRUITMENT | The mode of recruitment will vary between countries, but will generally involve the distribution of the survey link using a participant mailing list or social media list held by each international collaborator at the host site. The local researchers will be using sampling techniques that are appropriate within their cultures and contexts, which for the most part resemble snowball sampling techniques. | PMC10105919 | |
Procedure | RECRUITMENT | Participants receive a survey link via the recruitment method above. The online survey comprises a participant information sheet, consent form and questionnaires. If a subject consents, they are asked to complete the online survey (which includes the self-report measures described above) using the Qualtrics XM online survey platform. The survey takes approximately 15–20 min to complete and is provided in the appropriate language for the site. Information is provided about local supports that can be accessed if the self-report questions were to cause distress. | PMC10105919 | |
Patient and public involvement | The project has been designed with community and general public involvement. Feedback has also been taken on project design from academics and the general public in the countries of interest. | PMC10105919 | ||
Data management | To ensure the anonymity of the obtained dataset the following standard operating procedures are in place. Where applicable, only the international collaborators hold contact information for their participant pool. Each site has specific guidelines to preserve anonymity specified in their local ethics application. Following collection, data will be saved on the University of Otago, New Zealand Qualtrics platform using an auto-generated non-identifiable letter-number string. Importantly, the obtained data set will be completely anonymous as no identifiable information is obtained in the survey. | PMC10105919 | ||
Data analysis | Incomplete survey responses will be removed from the analyses. Statistical analyses will be carried out to examine the psychosocial impacts of the COVID-19 pandemic in different countries and provide psychometric evidence using SPSS V.28.0 | PMC10105919 | ||
Sample size estimation | As no prevalence of the psychosocial impacts of the COVID-19 pandemic in the general population of the countries of interest exists, no formal sample size calculations were conducted. The final target sample size of n=500 per country was pragmatically selected balancing the competing demands of maximising statistical power, expedited cost-effective data collection processes and international reach while simultaneously minimising institutional burden. | PMC10105919 | ||
Psychometric analyses | Reliability analyses will be carried out on each measure to determine the suitability of its use, employing item-total correlations and Cronbach’s α as a measure of internal homogeneity and consistency. The construct validity of CPIS with WHO-5 and K10 will be examined using a correlation matrix. | PMC10105919 | ||
Within-subjects analyses | post-traumatic, post-traumatic stress, trauma | Descriptive analysis will be carried out on sociodemographics (e.g., age, gender, ethnicity, religion, marital status, the highest level of education, work status, monthly household income, exposure to previous trauma) and study variables (well-being, psychological distress, post-traumatic stress, post-traumatic growth, pandemic-related stress from the CPIS) to inform site-specific sociodemographic profile and psychosocial outcomes. To explore the relationship between sociodemographic and study variables, follow-up analyses will be carried out using a linear mixed model (also known as multi-level modelling) to pool predictor variables. This will be carried out for each of the seven sites individually. | PMC10105919 | |
Between-subjects analyses | RESIDUAL | To look at empirical distributions across countries, graphing superimposed Cumulative Distribution Function (cdf) will be used. In addition, to understand the role of demographic and study variables, multi-level modelling will be carried out in which participants will be nested within their countries—which will be treated as random effects to investigate the association between probable distress and well-being indicators and sociodemographic and pandemic-related variables. This approach allows individual and country-level factors to be included. Residual diagnostics and model assumptions will also be checked. | PMC10105919 | |
Discussion | COVID-19-related stigmatisation, post-traumatic, post-traumatic stress | EVENTS, RECRUITMENT, DISORDERS | This is a cross-sectional observational research that examines the psychosocial impacts of the COVID-19 pandemic across seven LMICs using a novel CPIS and measures of well-being, psychological distress, post-traumatic stress and post-traumatic growth. Despite LMICs being significantly impacted by COVID-19, few studies have been published from these regions. This study will therefore provide findings to address this important gap in the literature. The multi-centre design of the study will allow comparisons between the empirical distributions across countries. Furthermore, by including individual and country-level factors, multi-level modelling will enable us to understand the role of demographic and study variables. The findings have the potential to contribute to the understanding of the psychosocial impacts of the COVID-19 pandemic in countries that have not been well studied and to allow cross-cultural, multi-site comparisons.Several multinational studies have been carried out examining the psychosocial impacts of COVID-19 among the general population using either standardised measures aloneAgainst this background, our study will comprehensively examine the psychosocial impacts of COVID-19 using standardised measures in combination with novel CPIS across seven LMICs examining both sociodemographics and study variables. Our study has the potential to make several contributions to the existing literature. The 32-item CPIS is a novel scale that comprehensively assesses the psychosocial impacts of the pandemic, with the scale design allowing assessment of both the number of exposures to specific pandemic-related life events and the associated level of stress related to each of these events. The psychosocial impacts of the pandemic-related life events will be examined cross-culturally in this study, which distinguishes it from the existing multinational studies that mainly focus on the prevalence of mental health disorders and do not examine the adverse personal, social and economic consequences that followed COVID-19 pandemic. Importantly, the multi-lingual nature of the study is an important contribution. An underlying factor to the lack of studies in LMIC has been the lack of availability of measures translated into appropriate languages, which this study addresses. Hence, our findings will contribute to a growing body of mental health measures that can be used for cross-cultural comparison.In addition, the study will also correlate outcomes on the CPIS with other validated measures of well-being and psychological distress and provide essential psychometric information on scale reliability and validity. Although, using pandemic-related scales in combination with standardised measures has been adopted by a few studies,There are, however, limitations associated with the proposed study design. This study makes use of a novel CPIS developed during the COVID-19 pandemic and a cross-sectional design. As a consequence, there is no prepandemic comparison data. Repeated use of the CPIS over time and during different phases of the pandemic is needed to inform whether the CPIS is responsive to changing impacts of the pandemic. As the data will be gathered through an online survey, it will only include participants with access to the internet. As a result, the sample might be less representative of persons who are illiterate or have limited access to or proficiency with computers or mobile phones. Since none of the sites systematically recruit, there are limitations associated with selective recruitment. As a result, we are unable to generalise the findings to the population of the relevant sites. In addition, the exposure and response rate will vary between countries, making cross-country comparisons challenging. These limitations will be mitigated with the use of multi-level modelling techniques to understand country-wise or cross-cultural predictor variables to obtain meaningful findings. Even though random sampling would be ideal for providing an unbiased representative sample of the overall population, this is not always possible due to resource and time constraints, as the majority of multinational studies relied on non-representative samples. Finally, to minimise participant burden, the survey did not include an assessment of certain relevant variables—such as COVID-19-related stigmatisation, resilience, religious coping or pre-existing mental health conditions. | PMC10105919 |
Summary | post-traumatic, post-traumatic stress | This cross-sectional observational research examines the psychosocial impacts of the COVID-19 pandemic across seven LMICs (Indonesia, Iran, Iraq, Malaysia, Pakistan, Somalia and Turkey) using a novel 32-item CPIS and standardised measures examining well-being, psychological distress, post-traumatic stress and post-traumatic growth. The findings will contribute to the understanding of the psychosocial impacts of the COVID-19 pandemic in different LMICs. In addition, it will provide psychometric data regarding CPIS in the countries of interest. This is a major contribution as there is currently limited access to newly developed scales relating to COVID-19 and associated measures of distress in appropriate languages. As a result, our research will contribute to a growing trend of establishing mental health measures that allow cross-cultural comparisons. | PMC10105919 | |
Ethics and dissemination | Ethical approval was granted by the Human Ethics Committee, University of Otago, New Zealand (Ref. No. 21/102). In addition, international collaborators obtained local authorisation or ethical approval in their respective host universities (Indonesia (Universitas Gadjah Mada Ethics Committee Ref. No. KE/UGM/008/EC/2021); Iraq (Ibn Sina University of Medical and Pharmaceutical Sciences, Institutional Review Board (IRB)—Ethical Committee); Malaysia (Universiti Malaya Research Ethics Committee, Ref. No. UM.TNC 2/UMREC); Pakistan (International Islamic University Islamabad, Institutional Ethical Review Committee, Ref. No. IIUI/ORIC/Ethical-certificate/2021); Somalia (Washington Human Subjects Division (HSD) IRB ID: STUDY00015135) and Turkey (Hasan Kalyoncu Üniversitesi Etik Ethics Committee Ref. No. E-97105791-050.01.01-2342)) before data collection commenced.Participants will give informed consent to participate in the study before taking part. All data will be fully anonymised and collected and stored securely on the University of Otago, New Zealand Qualtrics platform using an auto-generated non-identifiable letter-number string. Data will be available on reasonable request. Findings will be disseminated by publication in scientific journals and/or conference presentations. | PMC10105919 | ||
Supplementary Material | PMC10105919 | |||
Reviewer comments | PMC10105919 | |||
Ethics statements | PMC10105919 | |||
Patient consent for publication | Not applicable. | PMC10105919 | ||
References | PMC10105919 | |||
Key Points | PMC10415963 | |||
Question | AKI, acute kidney injury | Does correcting serum creatinine for fluid balance identify previously missed episodes of acute kidney injury (AKI) in premature neonates? | PMC10415963 | |
Findings | AKI | LUNG DISEASE | In this post hoc cohort analysis of a placebo-controlled, randomized clinical trial of 923 premature neonates, fluid correction increased the number of premature neonates with a diagnosis of AKI. Correction for fluid balance was associated with increased odds of adverse clinical outcomes, including ventilation and severe lung disease. | PMC10415963 |
Meaning | AKI | These findings suggest that failing to correct serum creatinine for fluid balance underestimates the prevalence and severity of AKI in premature neonates, and future studies should consider correcting serum creatinine for fluid status to improve identification of AKI in premature neonates. | PMC10415963 | |
Importance | AKI, Acute kidney injury | ACUTE KIDNEY INJURY | Acute kidney injury (AKI) and disordered fluid balance are common in premature neonates; a positive fluid balance dilutes serum creatinine, and a negative fluid balance concentrates serum creatinine, both of which complicate AKI diagnosis. Correcting serum creatinine for fluid balance may improve diagnosis and increase diagnostic accuracy for AKI. | PMC10415963 |
Objective | AKI | To determine whether correcting serum creatinine for fluid balance would identify additional neonates with AKI and alter the association of AKI with short-term and long-term outcomes. | PMC10415963 | |
Design, Setting, and Participants | This study was a post hoc cohort analysis of the Preterm Erythropoietin Neuroprotection Trial (PENUT), a phase 3, randomized clinical trial of erythropoietin, conducted at 19 academic centers and 30 neonatal intensive care units in the US from December 2013 to September 2016. Participants included extremely premature neonates born at less than 28 weeks of gestation. Data analysis was conducted in December 2022. | PMC10415963 | ||
Exposure | AKI | Diagnosis of fluid-corrected AKI during the first 14 postnatal days, calculated using fluid-corrected serum creatinine (defined as serum creatinine multiplied by fluid balance [calculated as percentage change from birth weight] divided by total body water [estimated 80% of birth weight]). | PMC10415963 | |
Main Outcomes and Measures | death | BRONCHOPULMONARY DYSPLASIA (BPD) | The primary outcome was invasive mechanical ventilation on postnatal day 14. Secondary outcomes included death, hospital length of stay, and severe bronchopulmonary dysplasia (BPD). Categorical variables were analyzed by proportional differences with the χ | PMC10415963 |
Results | AKI, BPD | A total of 923 premature neonates (479 boys [51.9%]; median [IQR] birth weight, 801 [668-940] g) were included, of whom 215 (23.3%) received a diagnosis of AKI using uncorrected serum creatinine. After fluid balance correction, 13 neonates with AKI were reclassified as not having fluid-corrected AKI, and 111 neonates previously without AKI were reclassified as having fluid-corrected AKI (ie, unveiled AKI). Therefore, fluid-corrected AKI was diagnosed in 313 neonates (33.9%). Neonates with unveiled AKI were similar in clinical characteristics to those with AKI whose diagnoses were made with uncorrected serum creatinine. Compared with those without AKI, neonates with unveiled AKI were more likely to require ventilation (81 neonates [75.0%] vs 254 neonates [44.3%] and have longer hospital stays (median [IQR], 102 [84-124] days vs 90 [71-110] days). In multivariable analysis, a diagnosis of fluid-corrected AKI was associated with increased odds of adverse clinical outcomes, including ventilation (adjusted OR, 2.23; 95% CI, 1.56-3.18) and severe BPD (adjusted OR, 2.05; 95% CI, 1.15-3.64). | PMC10415963 | |
Conclusions and Relevance | AKI, BPD | In this post hoc cohort study of premature neonates, fluid correction increased the number of premature neonates with a diagnosis of AKI and was associated with increased odds of adverse clinical outcomes, including ventilation and BPD. Failing to correct serum creatinine for fluid balance underestimates the prevalence and impact of AKI in premature neonates. Future studies should consider correcting AKI for fluid balance. | PMC10415963 | |
Trial Registration | ClinicalTrials.gov Identifier: | PMC10415963 | ||
Introduction | AKI, critically ill, Acute kidney injury | CRITICALLY ILL, ACUTE KIDNEY INJURY | Acute kidney injury (AKI) commonly occurs in extremely low gestational age neonates (ELGANS)In critically ill children and adults, correcting serum creatinine for fluid balance increases the precision and accuracy of AKI diagnosisThe Preterm Erythropoietin Neuroprotection (PENUT) study captured robust data on kidney function and fluid status, as well as short-term and long-term outcomes in ELGANS. | PMC10415963 |
Methods | PMC10415963 | |||
Study Population | Performed in December 2022, this study was a post hoc analysis of the PENUT Trial (NCT01378273), a phase 3, placebo-controlled, randomized clinical trial of erythropoietin in ELGANS in 19 academic centers and 30 NICUs in the US. | PMC10415963 | ||
Fluid Balance and Fluid-Corrected Serum Creatinine Definitions | The PENUT trial included daily weights for the first 14 postnatal days. Fluid balance was based on recent consensus guidelines | PMC10415963 | ||
AKI and Covariate Definition | AKI | KIDNEY DISEASE | AKI was defined using the serum creatinine criteria neonatal modified Kidney Disease: Improving Global Outcomes (KDIGO) definition. | PMC10415963 |
AKI Class Switching | AKI | We defined class switching as neonates who moved from 1 stage of AKI to another after correcting for fluid balance. For example, a neonate with a positive fluid balance with no AKI by uncorrected serum creatinine may have had stage 2 AKI after correcting serum creatinine for fluid balance (ie, unveiled AKI). Conversely, a neonate with substantial diuresis and stage 1 AKI based on uncorrected serum creatinine may have been recategorized to no AKI after correction for a negative fluid balance (ie, overdiagnosed AKI) (eTable 1 in | PMC10415963 | |
Outcomes | SECONDARY, JENSEN | The primary outcome was the need for invasive mechanical ventilation (ie, high-frequency or conventional ventilation) on postnatal day 14. Our secondary short-term outcomes included (1) BPD, defined by Neonatal Research Network definitions and Jensen criteria as neonates receiving respiratory support at 28 days of age, | PMC10415963 | |
Statistical Analysis | Categorical variables were analyzed by proportional differences with the χ | PMC10415963 | ||
Results | PMC10415963 | |||
Patient Characteristics | Of the 941 neonates who were enrolled in the PENUT trial, 923 (479 boys [51.9%]; median [IQR] birth weight 801 [668-940] g) were included in this analysis (eFigure in | PMC10415963 | ||
Comparison of Maternal and Neonatal Characteristics by Fluid-Corrected AKI Status | AKI, acute kidney injury | Abbreviation: AKI, acute kidney injury.Based on χOther maternal race category includes American Indian or Alaska Native, Asian, Native Hawaiian, or Other Pacific Islander. | PMC10415963 | |
Serum Creatinine Curves During the First 2 Postnatal Weeks | A total of 8757 serum creatinine values were obtained during the first 2 postnatal weeks with a median (IQR) of 11 (7 to 13) values per patient. The median (IQR) peak negative fluid balance was −10.3% (−14.6% to −5.6%) on median (IQR) postnatal day 3 (2 to 5). Median (IQR) peak positive fluid balance in the first 2 postnatal weeks in this population was 11.1% (4.3% to 19.6%) and occurred on median (IQR) postnatal day 12 (8 to 14). A total of 93 (10.1%) neonates never dropped below their birth weight.Uncorrected and fluid-corrected serum creatinine curves are shown for the entire cohort and by gestational age group ( | PMC10415963 | ||
Uncorrected and Fluid-Corrected Serum Creatinine Curves | The figure shows uncorrected serum creatinine and fluid-corrected serum creatinine curves for the entire cohort (A) and by gestational age group (B). | PMC10415963 | ||
AKI Diagnosis and Class Switching | AKI | AKI diagnosis using uncorrected serum creatinine occurred for 215 neonates (23.3%), which included 154 neonates at stage 1, 45 at stage 2, and 16 at stage 3. No neonates in this study were treated with dialysis. Correcting for fluid balance increased the incidence of AKI to 33.9% (313 neonates), of which 101 neonates (32.3%) had severe AKI ( | PMC10415963 | |
Acute Kidney Injury (AKI) Status and Class Switching After Fluid Correction | AKI | The figure displays a Sankey diagram visualizing the change in AKI status and AKI class switching after correction for fluid status.After correcting serum creatinine for fluid balance, 124 neonates switched AKI classes. A total of 111 neonates were newly classified as having unveiled AKI, including 104 who went from no AKI to stage 1 AKI, and 7 who went from no AKI to stage 2 or 3 AKI. In 36 neonates, AKI severity increased from stage 1 to stage 2 or 3 AKI. After correcting for fluid balance, 16 neonates had their AKI stage decrease (13 patients went from stage 1 AKI to no AKI and 3 went from stage 2 or 3 AKI to stage 1 AKI). A summary of the shifts in the AKI staging before and after fluid correction is shown in | PMC10415963 | |
Short-Term and Long-Term Outcomes | A total of 408 neonates (52.0%) were mechanically ventilated at postnatal day 14 ( | PMC10415963 | ||
Association of Fluid-Corrected AKI With Outcomes | The bivariable associations with our primary outcome of mechanical ventilation on postnatal day 14 is described in eTable 2 in | PMC10415963 | ||
Association of AKI With Short-Term and Long-Term Outcomes | AKI, sepsis, enteritis, acute kidney injury | BRONCHOPULMONARY DYSPLASIA, INTRAVENTRICULAR HEMORRHAGE, BRONCHOPULMONARY DYSPLASIA, ENTERITIS, SEPSIS | Abbreviations: AKI, acute kidney injury; aOR, adjusted odds ratio; OR, odds ratio.Adjusted for gestational age, sex, small for gestational age status, 5-minute Apgar score, intubation, epinephrine, chest compressions, necrotizing enteritis, sepsis, and intraventricular hemorrhage.Refers to hospital length of stay longer than median of 93 days.Bronchopulmonary dysplasia is defined as oxygen requirement on day 28 of age.Grade 3 bronchopulmonary dysplasia is defined as invasive mechanical ventilation at 36 weeks corrected gestational age. | PMC10415963 |
Association of Severe AKI With Short-Term and Long-Term Outcomes in Extremely Low Gestational Age Neonates | enteritis, AKI, BPD, sepsis, acute kidney injury | BRONCHOPULMONARY DYSPLASIA, INTRAVENTRICULAR HEMORRHAGE, BRONCHOPULMONARY DYSPLASIA, ENTERITIS, SEPSIS | Abbreviations: AKI, acute kidney injury; aOR, adjusted odds ratio; OR, odds ratio.Adjusted for gestational, sex, small for gestational age status, 5-minute Apgar score, intubation, epinephrine, chest compressions, necrotizing enteritis, sepsis, and intraventricular hemorrhage.Refers to hospital length of stay longer than median of 93 days.Bronchopulmonary dysplasia is defined as oxygen requirement on day 28 of age.Grade 3 bronchopulmonary dysplasia is defined as invasive mechanical ventilation at 36 weeks corrected gestational age.Although the association of AKI with the short-term outcomes of BPD and prolonged hospital stay were not statistically significant after multivariable adjustment, exposure was associated with increased odds of adverse outcomes after adjustment for fluid balance ( | PMC10415963 |
Association of AKI Class Switching With Outcomes | AKI | With regard to most demographic and clinical characteristics, neonates with unveiled AKI were similar to those with AKI diagnosed using uncorrected serum creatinine (Compared with those without AKI, neonates with unveiled AKI were more likely to require invasive mechanical ventilation on postnatal day 14 (81 neonates [75.0%] vs 254 neonates [44.3%]) and have longer hospital stays (median [IQR] stay, 102 [84-124] days vs 90 [71-110] days). There was no difference in mortality between these groups. Neonates with unveiled severe AKI were more likely to require ventilation on postnatal day 14 (33 neonates [82.5%] vs 400 neonates [50.7%]) compared with those without AKI, but we saw no difference in hospital length of stay or mortality ( | PMC10415963 | |
Discussion | AKI, BPD, diuretic-induced | SECONDARY, PREMATURE | In this secondary analysis of a large, prospective, multicenter, randomized clinical trial of ELGANS, we evaluated the impact of fluid correction of serum creatinine on AKI diagnosis and its association with short-term and long-term outcomes. We found that fluid correction identified many neonates with previously undiagnosed AKI, and that correcting for fluid balance changed AKI staging in many patients. Fluid-corrected AKI correlated better with clinically relevant outcomes and was associated with increased odds of short-term clinical outcomes, including mechanical ventilation and grade 3 BPD. Furthermore, correcting serum creatinine for fluid balance created a new serum creatinine curve for neonates over the first 2 weeks of life, with a slow improvement in kidney function over time, which challenges the often cited peak and then fall serum creatinine trajectory over the first several postnatal days.Over the past several decades, the study of AKI has been most impacted by consensus definitions for diagnosis and staging.Our findings should be interpreted in the context of the unique physiology of the premature neonate. Premature neonates differ from older children in that they are subject to the full spectrum of fluid balance during the first 2 postnatal weeks including positive fluid balance, physiologic diuresis, and diuretic-induced diuresis, which impacts the diagnosis of AKI in neonates, because changes in fluid balance complicate the AKI diagnosis when using serum creatinine diagnostic criteria. | PMC10415963 |
Strengths and Limitations | AKI, kidney dysfunction | KIDNEY DYSFUNCTION, SECONDARY | This multicenter prospective study has several strengths, including the robust high-quality data available in a large, prospective, multicenter study allowing for the detailed exploration of the impact of fluid balance on AKI diagnosis. Furthermore, the study has long-term kidney-specific outcomes for the cohort.Despite these strengths, there are several limitations of this secondary analysis. Our findings were limited by clinically obtained serum creatinine, and weights and urine output were not collected. However, weights were available for 97% of potential patient days, and this analysis imputed missing values; therefore, misclassification is likely infrequent. Because the PENUT database only included daily weights from the first 2 postnatal weeks, our conclusions are limited to this period. Longer observation periods are necessary to extend our findings. We note that there are other variables, such as clinical conditions and management practices, that may result in changes in weight and are not captured in this analysis. Third, although defining AKI by neonatal modified KDIGO definitions is the current standard for this patient population, this may not be the optimal marker for detection of kidney dysfunction in premature neonates. | PMC10415963 |
Conclusion | AKI | SECONDARY | In this secondary analysis of the multicenter PENUT trial, we describe fluid-corrected AKI and evaluate associations with short-term and long-term outcomes in premature neonates with fluid-corrected AKI. Taken together, the current study suggests a paradigm shift in how we describe kidney function in premature neonates in the first 2 postnatal weeks. The current study suggests that fluid balance should be considered in future definitions to improve the diagnosis of AKI in premature neonates. Failing to correct serum creatinine for fluid balance underestimates the prevalence and severity of AKI in premature neonates. Future studies should consider correcting AKI for fluid balance in the first 2 weeks to improve identification of neonates at high risk for poor outcomes. | PMC10415963 |
Author summary | We declare that there is no relationship or support which might be perceived as constituting a conflict of interest.Dogs living in areas of Dogs play an important role in the transmission of | PMC9931096 | ||
Data Availability | The data are available from | PMC9931096 | ||
Material and methods | PMC9931096 | |||
Ethics statement | This study followed the recommendation of the Brazilian Federal Law for animal studies. It was approved by the Ethic Committee for Use of Animals in Research (CEUA: 017–2020) of the Instituto Gonçalo Moniz (IGM), Fundação Oswaldo Cruz (FIOCRUZ-BA). | PMC9931096 | ||
Case definition and study design | This study is a randomized controlled clinical trial designed to evaluate the efficacy and effectivity of intralesional meglumine antimoniate compared with intralesional sodium chloride solution in dogs with CTL caused by the | PMC9931096 | ||
Soluble | The SLA was obtained from an isolate of | PMC9931096 | ||
Real-time PCR for detection of | In order to detect | PMC9931096 | ||
Statistical analysis | Continuous variables following a normal distribution, as age, are presented as mean and SD and mean differences were analyzed by the Student T test. Continuous variables that did not follow a normal distribution, such as lesion size, are presented as median and interquartile range (IQR). Differences were analyzed by the Mann-Whitney test followed by the post Dunn test. The difference in proportions were analyzed using the Fisher exact test. The GraphPad Prism was used to perform the statistical analysis. The Kaplan-Meier survival curve was performed to compare the healing time proportion in the two groups and the log-rank test was used to compare the curves. | PMC9931096 | ||
Results | The demographic and clinical features of the dogs participating in the study according to the type of therapy received are shown in | PMC9931096 | ||
Pictures of two animals on days zero, 30, 60, and 90; “the first, A,” from a dog scrotal sac ulcer treated with Glucantime and “B” from a dog with a muzzle lesion treated with saline. | cutaneous lesion | While the dog receiving Glucantime was cured on day 30, the cutaneous lesion remained active until day 90 in the animal treated with placebo. | PMC9931096 | |
Kaplan-Meier curve | A Kaplan-Meier curve was performed to compare the proportion of dogs in both groups who achieved cure according to the healing time ( | PMC9931096 | ||
Survival analysis in dogs with CTL. | Kaplan-Meier survival analysis of differences in healing time between dogs treated with Glucantime and placebo revealed shorter healing times in dogs treated with Glucantime (P<0.0001, log-rank test). | PMC9931096 | ||
Discussion | infection | INFECTION, DISEASE, HEAT, INFECTION TOE | CTL is a relevant public health subject; morbidity is high, the disease remains active for up to a long time, which may contribute to the transmission of the infection to humans. There are, however, no policies for the treatment of CTL. Sick dogs die or are sacrificed. While there is no clear evidence about the role of dogs in All dogs in the study lived in houses, had good nutritional status, and received the recommended vaccines for dogs in Brazil. There were no differences among the groups regarding age, gender, duration of illness, main lesion site, and lesion size. Of note, 24 (75%) of the 32 dogs participating in the trial were males. In humans, CL is also more frequent among males than females, but in such cases, this is explained due to men working more in the forests than women and consequently being more exposed to the infection. However, in Brazil boys have more VL than girls, and In humans infected with Dogs with CTL have been treated with different drugs, such as meglumine antimoniate administered intramuscular or intralesional, allopurinol, furazolidone, and domperidone, as well as radio frequency induced heat therapy [In our endemic area, because failure of therapy with intravenous Glucantime may be observed in up to 70% of patients, depending on the clinical forms of the disease and the illness duration [We recognize this study has some limitations. The sample size was small, and the duration of the illness was almost twice higher in the test group compared to the placebo, although statistical difference had not been documented. The dogs remained during the whole period of the study at home with their owners, and we cannot rule out that other popular therapies were used. However, the differences in cure rate and in the decrease of the healing time of the dogs in the groups, emphasize that intralesional Glucantime might be recommended for treating dogs with CTL caused by We are grateful to Dr. Mary Wilson and Dr. Selma Jeronimo for the suggestions and revision of the manuscript and Cristiano Sampaio Franco for the assistance in the preparation of the manuscript. | PMC9931096 |
References | PMC9931096 | |||
Background | obesity, cardiovascular disease, inflammation, abdominal obesity, metabolic syndrome, weight loss | OBESITY, CARDIOVASCULAR DISEASE, INFLAMMATION, METABOLIC SYNDROME, TYPE 2 DIABETES | Identifying and reducing cardiometabolic risks driven by obesity remains a healthcare challenge. The metabolic syndrome is associated with abdominal obesity and inflammation and is predictive of long-term risk of developing type 2 diabetes and cardiovascular disease in otherwise healthy individuals living with obesity. Therefore, we investigated the effects of adherent exercise, a glucagon-like peptide 1 receptor agonist (GLP-1 RA), or the combination on severity of metabolic syndrome, abdominal obesity, and inflammation following weight loss. | PMC9960425 |
Methods | obesity, diabetes | OBESITY, DIABETES | This was a randomized, double-blinded, placebo-controlled trial. During an 8-week low-calorie diet (800 kcal/day), 195 adults with obesity and without diabetes lost 12% in body weight. Participants were then evenly randomized to four arms of one-year treatment with: | PMC9960425 |
Results | weight loss | The diet-induced weight loss decreased the severity of MetS-Z from 0.57 to 0.06, which was maintained in the placebo and exercise groups after one year. MetS-Z was further decreased by liraglutide (− 0.37, 95% CI − 0.58 to − 0.16, P < 0.001) and the combination treatment (− 0.48, 95% CI − 0.70 to − 0.25, P < 0.001) compared to placebo. Abdominal fat percentage decreased by 2.6, 2.8, and 6.1 percentage points in the exercise, liraglutide, and combination groups compared to placebo, respectively, and hsCRP decreased only in the combination group compared with placebo (by 43%, P = 0.03). | PMC9960425 | |
Supplementary Information | The online version contains supplementary material available at 10.1186/s12933-023-01765-z. | PMC9960425 | ||
Keywords | PMC9960425 | |||
Background | obesity, inflammation, cardiometabolic disease, MetS, weight loss | OBESITY, INFLAMMATION, SECONDARY | Identifying and reducing cardiometabolic risks driven by obesity remains a major healthcare challenge [MetS denotes a cluster of common risk factors and was intended as an early measure for cardiometabolic disease risk [High-sensitivity C-reactive protein (hsCRP) is an established biomarker of inflammation [Exercise and glucagon-like peptide–1 receptor agonists (GLP-1 RAs) may be different strategies in the primary and secondary prevention of MetS, abdominal fat, and inflammation [A meta-analysis has shown that moderate-to-vigorous aerobic exercise for at least 12 weeks can improve the factors of MetS [The GLP-1 RA, liraglutide, approved for obesity therapy, induces weight loss and improves glycemic control and cardiovascular risk factors (e.g., lipid profile and blood pressure) [We recently showed that a diet-induced 12% weight loss was maintained after one year with either exercise or liraglutide treatment. Combining the two treatments led to additional weight loss, while the placebo group regained body weight [ | PMC9960425 |
Materials and methods | PMC9960425 | |||
Study design | weight loss | SECONDARY | This study is based on a randomized, double-blind (regarding liraglutide treatment), placebo-controlled trial (S-LiTE Randomized trial) conducted at Hvidovre Hospital and the University of Copenhagen, Denmark, from August 2016 to November 2019 (EudraCT number, 2015-005585-32; ClinicalTrials.gov number, NCT04122716) [Included participants were asked to complete a low-calorie diet for eight weeks before being randomized to either exercise, pharmacological treatment with liraglutide, the combination of exercise and liraglutide, or placebo for one year. All participants attended 12 individual consultations to support weight loss maintenance after randomization. These consultations included measurements of body weight and dietary support in compliance with the Danish Authorities’ dietary recommendations [The trial was approved by the Committee of Health Research Ethics and the Danish Medicines Agency and was conducted according to the Declaration of Helsinki and Good Clinical Practice guidelines. Participants provided written informed consent before inclusion. Investigators, assessors, and participants were blinded to study medication. Unblinding was done after the statistical analysis of the primary and secondary endpoints [ | PMC9960425 |
Participants | obesity | OBESITY | Recruited participants were adults living with obesity (18–65 years of age, BMI 32–43 kg/mThe per-protocol population was defined as participants that met the pre-defined criteria of performing at least 75% of WHO recommendations on physical activity (150 min/week of moderate-intensity, or 75 min/week of vigorous-intensity aerobic physical activity, or an equivalent combination of both) and having administered 2.4 or 3.0 mg/day of liraglutide/placebo for at least 75% of the intervention period [ | PMC9960425 |
Interventions | ADVERSE EVENTS, EVENTS | Participants followed a low-calorie diet of 800 kcal/day (meal replacement products, Cambridge Weight Plan) for eight weeks [The exercise intervention was designed to meet the WHO recommendations on physical activity: a minimum of 150 min/week of moderate-intensity or 75 min/week of vigorous-intensity aerobic physical activity or an equivalent combination to reach adequate exercise volume (duration × intensity). Participants randomized to exercise were encouraged to attend supervised group sessions twice a week and perform exercise individually twice a week. Exercise was targeted at 80% of maximal heart rate, and heart rate monitors were worn at all exercise sessions to assess adherence. Participants not randomized to exercise were instructed to maintain habitual physical activity until the end of the trial. Details on the exercise intervention have been reported elsewhere [Study medication, liraglutide 6 mg/mL (Saxenda), or volume-matched placebo was injected subcutaneously via pens by the participants, commencing at 0.6 mg/day with weekly increments of 0.6 mg/day after consultation, eventually reaching 3.0 mg/day. Participants who had unacceptable adverse events at the targeted dose received the maximally tolerated dose at which they did not have such events. Participants remained enrolled if the medication was discontinued [ | PMC9960425 | |
Outcomes | metabolic syndrome, Vascular Injury Panel 2, inflammation | METABOLIC SYNDROME, SECONDARY, ADVERSE EVENT, INFLAMMATION | MetS-Z (metabolic syndrome severity z-score) was a prespecified secondary endpoint in the trial protocol [The participants were also scored on the traditional MetS factors according to the harmonized metabolic syndrome definition: Waist circumference > 94 cm (in males) and > 80 cm (in females), HDL-c < 1.0 mmol/L in males and < 1.3 mmol/L in females, triglycerides ≥ 1.7 mmol/L, fasting glucose ≥ 5.6 mmol/L, and systolic blood pressure ≥ 130 mmHg or diastolic blood pressure ≥ 85 mmHg [The procedure for blood samples, anthropometric measurements, and blood pressure is reported in the protocol article of the trial [Dual-energy x-ray absorptiometry (Hologic, Discovery A) full-body scans were used to assess body composition in the fasting state. Fat mass, including android fat (an estimate of abdominal fat) and gynoid fat (an estimate of gluteofemoral fat), were determined by the scanner using APEX System Software Version 3.4.2; see Additional file The inflammation marker hsCRP was assessed using V-PLEX Vascular Injury Panel 2 (human) Kits (MDS MULTI-SPOT Assay System). Only complete data sets were analyzed (i.e., participants with a blood sample from all three visits) for hsCRP.Outcomes were obtained before the low-calorie diet (at week -8), after the low-calorie diet (week 0, at randomization), and at the end of the trial (week 52). Adverse events were registered at all visits and have previously been published [ | PMC9960425 |
Statistical analysis | infection | INFECTION, DISEASES | Continuous variables are summarized as means with ± standard deviations (± SD) or medians with interquartile range. Continuous outcomes with repeated measures were analyzed using a mixed linear model in the per-protocol population (i.e., the 130 participants adherent to the prescribed interventions), which might provide a better mechanistic understanding of the interventions, and in the intention-to-treat population (i.e., all 195 participants randomized). Significance testing was performed using α = 0.05 on MetS-Z, android fat percentage, and hsCRP outcomes. The following fixed effects were included in the model: time (factorial), group, age group (< / ≥ 40 years), sex, a time-group interaction, and a repeated effect for visit. A supplementary analysis further adjusting for blood pressure or lipid-lowering medication, smoking, and alcohol consumption at inclusion was also performed. All missing data were assumed to be missing at random. The analyses were unadjusted for multiplicity; therefore, definite inferences cannot be made. Results are reported as estimated changes with 95% confidence intervals (95% CI). Statistical sample size power analysis has previously been published and was based on body weight change (a 4 kg difference between the four groups was estimated to require at least 30 participants per group) [Regarding hsCRP, the non-normal distributed results were log-transformed before analysis and back-transformed as ratios with 95% CI. Three samples were excluded before analysis due to sample dilution error or hsCRP values consistent with concurrent infection or other diseases. | PMC9960425 |
Results | PMC9960425 | |||
Changes in metabolic syndrome | INSULIN RESISTANCE | The MetS-Z decreased by 0.52 to 0.06, P < 0.001, during the low-calorie diet (Table One year after the low-calorie diet, the MetS-Z was unchanged in the placebo and exercise groups (Table Adjusting for blood pressure or lipid-lowering medication, smoking, and alcohol consumption at inclusion did not affect the analysis results (Additional file The reduced insulin resistance seen during low-calorie was maintained in the adherent exercise groups, while insulin resistance increased in the placebo and liraglutide groups (Table | PMC9960425 | |
Changes in fat distribution | Android fat percentage was 44.3% ± 4.7 before the low-calorie diet and decreased by 2.9%-points, P < 0.001 to 41.4% ± 6.0 after the diet (Table After one year, android and gynoid fat percentages were unchanged in the placebo group; however, android and gynoid fat masses increased (Table | PMC9960425 | ||
Changes in high-sensitivity C-reactive protein | inflammation | INFLAMMATION | The median concentration of the inflammation marker hsCRP was 3.8 mg/L before the low-calorie diet and decreased by 32% to 2.4 mg/L after the diet, P < 0.001, Table After one year, the hsCRP concentrations did not change in the placebo and exercise groups (Table | PMC9960425 |
Adherence to interventions | In the per-protocol population, the exercise group performed 156 ± 54 min/week at an intensity of 78 ± 4% of maximum heart rate, and the combination group performed 144 ± 67 min/week at 78 ± 5% of maximum heart rate. The average dose of study medication was at least 2.6 mg/day in all groups. Details regarding exercise and study medication adherence in the intention-to-treat population have previously been published [ | PMC9960425 | ||
Safety | vomiting, Gastrointestinal adverse, diarrhea, nausea, | ADVERSE EVENTS | Gastrointestinal adverse events (e.g., one or more experiences of nausea, diarrhea, or vomiting during one year) were more commonly reported in the groups receiving liraglutide (placebo group: 45%, exercise group: 65%, liraglutide group: 86%, combination group: 71%). The frequency of serious adverse events was 4%, 8%, 12%, and 8% in the placebo, exercise, liraglutide, and combination groups, respectively. All safety outcomes have previously been reported [ | PMC9960425 |
Discussion | obesity, mass loss, inflammation, cardiometabolic disease, diet-induced reductions, abdominal obesity, metabolic syndrome, reduced fasting glucose, weight loss | OBESITY, INFLAMMATION, METABOLIC SYNDROME, METABOLIC SYNDROME | Identifying and managing the risk of cardiometabolic disease associated with obesity remains a major healthcare challenge. Metabolic syndrome, abdominal obesity, and low-grade inflammation constitute risk factors for future cardiometabolic disease. Therefore, we investigated improvements in metabolic syndrome, abdominal obesity, and low-grade inflammation during exercise, a glucagon-like peptide 1 receptor agonist, or the combination of the two following an eight-week low-calorie diet.The diet-induced weight loss reduced MetS-Z, abdominal obesity, and inflammation marker hsCRP. After one year, the combination of exercise and liraglutide treatment reduced MetS-Z, android fat percentage, and hsCRP compared to placebo. Exercise treatment maintained MetS-Z and hsCRP and reduced android fat percentage compared to placebo. Liraglutide treatment reduced Mets-Z and android fat percentage while maintaining hsCRP compared to placebo. Placebo treatment was associated with maintenance of the diet-induced reductions in MetS-Z, hsCRP, and android fat percentage, even though 50% of the weight lost during the low-calorie diet was regained in the placebo group, while MetS prevalence and fat masses increased again. In addition, we have previously reported that the placebo group became sedentary one year after the initial weight loss [Large reductions in MetS-Z, abdominal obesity, and hsCRP compared to placebo were seen in the combination group, providing large potential reductions in cardiometabolic risk. Furthermore, the combination group showed a reduction of android fat percentage that was about twice as large as the reduction seen in both the exercise and liraglutide groups, underlining the complementary effects of combined treatment.Liraglutide treatment alone further reduced MetS-Z following the diet-induced reductions, largely due to reduced fasting glucose, an expected effect of liraglutide treatment [If the comparative risks, illustrated in Fig. The combination group reduced body weight due to fat mass loss with a preferential reduction of android fat rather than gynoid fat. Thus, during the entire trial, abdominal obesity of participants in the combination group was reduced by almost 8%-points while maintaining total lean mass. This finding contrasts with other weight loss strategies, including the low-calorie diet used in this trial, which often lead to large amounts of lost lean mass (e.g., 20–50% lost by bariatric surgery, 30–47% by GLP-1 RA treatment before weight loss) [The liraglutide group reduced android fat percentage without changing body weight, suggesting a reduction of android fat percentage independent of weight loss. This is consistent with recent findings from a 36-week study examining changes to visceral fat estimated by magnetic resonance imaging in response to treatment with liraglutide [Despite similar reductions in android fat in the exercise and liraglutide group, exercise did not significantly decrease hsCRP after one year. However, studies that demonstrate reduced inflammation as an effect of exercise do often not have an initial weight loss phase [In a clinical setting, hsCRP levels higher than 3 mg/L indicate increased cardiovascular risk [A strength of this study is the longitudinal, randomized, placebo-controlled design with four separate groups to assess single and combined effects of treatments with exercise and liraglutide 3.0 mg/day. Another strength is the novelty of analyzing the effects of maintained interventions on a clinically relevant continuous metabolic syndrome score combined with assessments of abdominal obesity and inflammation, translating to potential cardiometabolic risk.In this study, we present the findings from the participants who completed the trial according to the prescribed interventions to better observe the effects of actually performed exercise, often confounded by inadequate adherence [ | PMC9960425 |
Conclusion | obesity, inflammation, reduced abdominal obesity, cardiometabolic disease, abdominal obesity | OBESITY, INFLAMMATION | In people with obesity at risk of developing cardiometabolic disease, the low-calorie diet improved MetS-Z, abdominal obesity, and inflammation marker hsCRP. After one year, intervention with exercise further reduced abdominal obesity, liraglutide treatment further reduced MetS-Z and abdominal obesity, and liraglutide combined with adherent exercise further reduced MetS-Z, abdominal obesity as well as hsCRP compared to placebo. The combination treatment thereby reduced all outcomes compared to placebo, potentially providing the largest risk reductions of future cardiometabolic disease in an adult population with obesity. | PMC9960425 |
Acknowledgements | The authors would like to thank the participants of the trial. We would also like to thank all the pre-graduate students involved in the execution of the trial. | PMC9960425 |
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