Receipt Of Parenteral Nutrition Research Articles

Nutritional management in newborn babies receiving therapeutic hypothermia: two retrospective observational studies using propensity score matching.

Therapeutic hypothermia is standard of care for babies with moderate to severe hypoxic-ischaemic encephalopathy. There is limited evidence to inform provision of nutrition during hypothermia. To assess the association during therapeutic hypothermia between (1) enteral feeding and outcomes, such as necrotising enterocolitis and (2) parenteral nutrition and outcomes, such as late-onset bloodstream infection. A retrospective cohort study using data held in the National Neonatal Research Database and applying propensity score methodology to form matched groups for analysis. NHS neonatal units in England, Wales and Scotland. Babies born at ≥ 36 gestational weeks between 1 January 2010 and 31 December 2017 who received therapeutic hypothermia for 72 hours or who died during treatment. Enteral feeding analysis - babies who were enterally fed during therapeutic hypothermia (intervention) compared with babies who received no enteral feeds during therapeutic hypothermia (control). Parenteral nutrition analysis - babies who received parenteral nutrition during therapeutic hypothermia (intervention) compared with babies who received no parenteral nutrition during therapeutic hypothermia (control). Primary outcomes were severe and pragmatically defined necrotising enterocolitis (enteral feeding analysis) and late-onset bloodstream infection (parenteral nutrition analysis). Secondary outcomes were survival at neonatal discharge, length of neonatal stay, breastfeeding at discharge, onset of breastfeeding, time to first maternal breast milk, hypoglycaemia, number of days with a central line in situ, duration of parenteral nutrition, time to full enteral feeds and growth. A total of 6030 babies received therapeutic hypothermia. Thirty-one per cent of babies received enteral feeds and 25% received parenteral nutrition. Seven babies (0.1%) were diagnosed with severe necrotising enterocolitis, and further comparative analyses were not conducted on this outcome. A total of 3236 babies were included in the matched enteral feeding analysis. Pragmatically defined necrotising enterocolitis was rare in both groups (0.5% vs. 1.1%) and was lower in babies who were fed during hypothermia (rate difference -0.5%, 95% confidence interval -1.0% to -0.1%; p = 0.03). Higher survival to discharge (96.0% vs. 90.8%, rate difference 5.2%, 95% confidence interval 3.9% to 6.6%; p < 0.001) and higher breastfeeding at discharge (54.6% vs. 46.7%, rate difference 8.0%, 95% confidence interval 5.1% to 10.8%; p < 0.001) rates were observed in enterally fed babies who also had a shorter neonatal stay (mean difference -2.2 days, 95% confidence interval -3.0 to -1.2 days). A total of 2480 babies were included in the matched parenteral nutrition analysis. Higher levels of late-onset bloodstream infection were seen in babies who received parenteral nutrition (0.3% vs. 0.9%, rate difference 0.6%, 95% confidence interval 0.1% to 1.2%; p = 0.03). Survival was lower in babies who did not receive parenteral nutrition (90.0% vs. 93.1%, rate difference 3.1%, 95% confidence interval 1.5% to 4.7%; p < 0.001). Propensity score methodology can address imbalances in observed confounders only. Residual confounding by unmeasured or poorly recorded variables cannot be ruled out. We did not analyse by type or volume of enteral or parenteral nutrition. Necrotising enterocolitis is rare in babies receiving therapeutic hypothermia, and the introduction of enteral feeding is associated with a lower risk of pragmatically defined necrotising enterocolitis and other beneficial outcomes, including rates of higher survival and breastfeeding at discharge. Receipt of parenteral nutrition during therapeutic hypothermia is associated with a higher rate of late-onset infection but lower mortality. These results support introduction of enteral feeding during therapeutic hypothermia. Randomised trials to assess parenteral nutrition during therapeutic hypothermia. Current Controlled Trials ISRCTN474042962. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 36. See the NIHR Journals Library website for further project information.

Pathophysiology and risk factors for cholelithiasis in patients with Crohn's disease.

Cholelithiasis is more common in patients with Crohn's disease (CD) than in the healthy population. The aim here was to examine risk factors for cholelithiasis in a cohort of CD patients and to compare the prevalence of cholelithiasis in a cohort of CD patients with that in a control group. This was a single-center retrospective case-control study. The cohort comprised all consecutive CD patients who underwent abdominal ultrasound from January 2007 to January 2018. The control group comprised age- and gender-matched non-CD patients referred for upper gastrointestinal tract dyspepsia. The study included 238 CD patients and 238 controls. The prevalence of cholelithiasis in the CD and control groups was 12.6 % and 9.2 %, respectively (risk ratio (RR), 1.36; p=0.24). Univariate analysis revealed that cholelithiasis was associated with multiple risk factors. Multivariate analysis identified age (OR, 1.077; 95 % CI, 1.043-1.112; p<0.001) and receipt of parenteral nutrition (OR, 1.812; 95 % CI, 1.131-2.903; p=0.013) as independent risk factors for cholelithiasis in CD patients. The prevalence of cholelithiasis in CD patients was higher than that in the control group; however, the difference was not statistically significant. Age and receipt of parenteral nutrition were independent risk factors for cholelithiasis in CD patients.

Disparate Candida albicans Biofilm Formation in Clinical Lipid Emulsions Due to Capric Acid-Mediated Inhibition.

Receipt of parenteral nutrition (PN) remains an independent risk factor for developing catheter-related bloodstream infections (CR-BSI) caused by fungi, including by the polymorphic fungus Candida albicans, which is notoriously adept at forming drug-resistant biofilm structures. Among a variety of macronutrients, PN solutions contain lipid emulsions to supply daily essential fats and are often delivered via central venous catheters (CVCs). Therefore, using an in vitro biofilm model system, we sought to determine whether various clinical lipid emulsions differentially impacted biofilm growth in C. albicans We observed that the lipid emulsions Intralipid and Omegaven both stimulated C. albicans biofilm formation during growth in minimal medium or a macronutrient PN solution. Conversely, Smoflipid inhibited C. albicans biofilm formation by approximately 50%. Follow-up studies revealed that while Smoflipid did not impair C. albicans growth, it did significantly inhibit hypha formation and hyphal elongation. Moreover, growth inhibition could be recapitulated in Intralipid when supplemented with capric acid-a fatty acid present in Smoflipid but absent in Intralipid. Capric acid was also found to dose dependently inhibit C. albicans biofilm formation in PN solutions. This is the first study to directly compare different clinical lipid emulsions for their capacity to affect C. albicans biofilm growth. Results derived from this study necessitate further research regarding different lipid emulsions and rates of fungus-associated CR-BSIs.

Large Outbreaks of Fungal and Bacterial Bloodstream Infections in a Neonatal Unit, South Africa, 2012–2016

Candidemia is a major cause of healthcare-associated infections. We describe a large outbreak of Candida krusei bloodstream infections among infants in Gauteng Province, South Africa, during a 4-month period; a series of candidemia and bacteremia outbreaks in the neonatal unit followed. We detected cases by using enhanced laboratory surveillance and audited hospital wards by environmental sampling and epidemiologic studies. During July–October 2014, among 589 patients, 48 unique cases of C. krusei candidemia occurred (8.2% incidence). Risk factors for candidemia on multivariable analyses were necrotizing enterocolitis, birthweight <1,500 g, receipt of parenteral nutrition, and receipt of blood transfusion. Despite initial interventions, outbreaks of bloodstream infection caused by C. krusei, rarer fungal species, and bacterial pathogens continued in the neonatal unit through July 29, 2016. Multiple factors contributed to these outbreaks; the most functional response is to fortify infection prevention and control.

Parenteral Nutrition Use and Associated Outcomes in a Select Cohort of Low Birth Weight Neonates

The aim of this study is to assess the influence of parenteral nutrition (PN) on the time to regain birth weight in premature neonates born between 1,500 and 2,499 g. A retrospective analysis stratified premature neonates born between 1,500 and 2,499 g by receipt of PN or intravenous dextrose at ≤ 72 hours of age. The primary outcome was the time to regain birth weight. Secondary measures included preterm-associated morbidities, time to achieve predefined enteral nutrition milestones, and length of stay. Multivariable regression estimated associations between PN and time to achieve nutrition milestones. Among 260 eligible neonates, those receiving PN (53%) were less mature, weighed less at birth, had a higher index of illness severity, and higher prevalence of preterm-associated morbidities (p < 0.01). The time to regain birth weight (PN, 9.4 ± 3.5 d; no PN, 9.5 ± 3.4 d) was similar between groups. Regression analysis adjusting for gestational age, illness severity, and sepsis demonstrated that PN exposure was associated with a greater time to achieve nutrition milestones and length of stay (p < 0.05). Although its impact on growth remains uncertain among premature neonates born between 1,500 and 2,499 g, PN was independently associated with a greater time to achieve nutrition milestones.

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Introduction: While argatroban dosing requirements are generally reduced in patients with critical illness, there is substantial variability from patient to patient. Thus, achieving therapeutic anticoagulation quickly and safely remains a challenge. This project aims to identify clinically relevant factors that predict argatroban dose response (ADR) in patients admitted to a cardiothoracic surgery intensive care unit (CTICU). Methods: This retrospective, single-center study was IRB approved at the University of Pennsylvania. Patients admitted to the CTICU from July 2005 to July 2012 who received argatroban for > 24 hours and achieved steady state (SS) were included. SS was defined as the initial set of 3 consecutive aPTT values obtained while receiving a constant infusion rate, where each aPTT value was within 10% of the average of those 3 consecutive aPTT values. Potential predictors of ADR were: age, abnormal (>1.2 mg/dL) total bilirubin (tbili), left ventricular ejection fraction, mean arterial blood pressure (MAP), enteral vs. parenteral nutrition, vasoactive medication exposure (yes/no), and SOFA score. ADR was measured using a novel parameter: the dose response ratio (DRR), defined as the mean SS aPTT ÷ SS infusion rate, with units of seconds/mcg/kg/min. Univariate and multivariate linear regression was used to evaluate the relationship between predictor variables and the DRR. Results: 53 patients were included. Median SS aPTT was 54.9 seconds (range 40.2-80.0 seconds). Median argatroban SS infusion rate was 0.37 mcg/kg/min (range 0.08-4.5 mcg/kg/min). This corresponds to a median DRR of 144.4 seconds/mcg/kg/min (range 14.6-657.5). Predictors of DRR in univariate analysis were: age, tbili, treatment with milrinone, norepinephrine, dopamine, MAP >65 mmHg, and receipt of parenteral nutrition. Independent predictors in multivariate analysis (R²=0.32) were: tbili (ß=97.2, p=0.027), treatment with milrinone (ß= -97.3, p=0.035), and MAP >65 mmHg (ß= -109.7, p=0.014). Conclusions: In a CTICU population, argatroban infusion requirements are significantly lower in patients with abnormal tbili and significantly higher in patients treated with milrinone and those with MAP >65 mmHg.

Invasive Fungal Infections in Infants—Focus on Anidulafungin

Introduction:Invasive fungal infection in pediatric intensive care units (PICU) is a rising challenge. Candida species are the most common microorganisms in these infections. Due to growing resistance against fluconazole, echinocandins are being used for the appropriate therapy. However, the recent IDSA guidelines recommend them only in cases where fluconazole or Amphotericin B cause treatment failure or are contraindicated. In a literature review, the importance of invasive fungal infections in PICU settings and the role of anidulafungin shall be examined.Materials and Methods:Articles were retrieved form PubMed covering the years 2000–2012. Various search terms were used. Then the articles were clustered in different types like ‘review,’ ‘pharmacokinetics,’ ‘case reports’ and others.Results:From 67 search results, 14 articles were selected. Of these, 7 were related to anidulafungin, while 7 were related to echinocandins or fungal infections in the PICU. Anidulafungin was examined in 4 PK/PD studies where a good safety profile was found. No serious adverse events occurred. The articles reporting risk factors show that central venous catheters, receipt of antibiotics, receipt of parenteral nutrition, and neutropenia are the most important independent risk factors for invasive fungal infections in PICU. Three reviews of antifungal agents show that echinocandins may be useful due to their safety profile; micafungin is the best examined one and further trials are needed.Discussion:The published literature on invasive fungal infections in PICU settings has grown over the years. There are only a few articles, however, which are directly related to the use of anidulafungin in this setting. A most recent publication showed good PK/PD dynamics and a good safety profile for anidulafungin. So far, no RCT in the area of invasive candidiasis in infants and neonates has been published. A review of currently registered trials at ClinicalTrials.gov has shown one more trial related to PK/PD and two trials that investigate the use of anidulafungin or anidulafungin in combination with Voriconazole in pediatrics.Conclusion:The small body of existing literature on anidulafungin in infants shows success in treatment, no drug-related adverse events, and good pharmacodynamics. A dosing of 0.75 mg/kg/day or 1.5 mg/kg/day is as effective as 50 mg/day or 100 mg/day in adults. More trials on the use in clinical reality of PICU or NICU should follow.

Risk Factors for Central Line–Associated Bloodstream Infection in Pediatric Intensive Care Units

We sought to identify risk factors for central line-associated bloodstream infection (CLABSI) to describe children who might benefit from adjunctive interventions. Case-control study of children admitted to the medical-surgical intensive care unit (ICU) or cardiac ICU from January 1, 2004, through December 31, 2007. Children's Hospital Boston is a freestanding, 396-bed quaternary care pediatric hospital with a 29-bed medical-surgical ICU and a 24-bed cardiac ICU. Case patients were patients with CLABSI who were identified by means of prospective surveillance. Control subjects were patients with a central venous catheter who were matched by ICU admission date. Multivariate conditional logistic regression models were used to identify independent risk factors for CLABSI and to derive and to validate a prediction rule. Two hundred three case patients were matched with 406 control subjects. Independent predictors of CLABSI included duration of ICU central access (odds ratio [OR] for 15 or more days, 18.41 [95% confidence interval {CI}, 4.10-82.56]; P < .001), central venous catheter placement in the ICU (OR for 2 or more ICU-placed catheters, 8.63 [95% CI, 2.63-28.38]; P = .001), nonoperative cardiovascular disease (OR, 7.44 [95% CI, 2.13-25.98]; P = .012), presence of gastrostomy tube (OR, 3.48 [95% CI, 1.55-7.79]; P = .003), receipt of parenteral nutrition (OR, 3.12 [95% CI, 1.55-6.32]; P = .002), and receipt of blood transfusion (OR, 2.55 [95% CI, 1.21-5.36]; P = .014). By use of risk factors known before central venous catheter placement, our model predicted CLABSI with a positive predictive value of 54% and a negative predictive value of 79%. Duration of central access, receipt of parenteral nutrition, and receipt of blood transfusion were confirmed as risk factors for CLABSI among children in the ICU. Newly identified risk factors include presence of gastrostomy tube, nonoperative cardiovascular disease, and ICU placement of central venous catheter. Children with these risk factors may be candidates for adjunctive interventions for CLABSI prevention.

Determinants of Nosocomial Infection in 6 Neonatal Intensive Care Units: An Italian Multicenter Prospective Cohort Study

Nosocomial infections are still a major cause of morbidity and mortality among neonates admitted to neonatal intensive care units (NICUs). To describe the epidemiology of nosocomial infections in NICUs and to assess the risk of nosocomial infection related to the therapeutic procedures performed and to the clinical characteristics of the neonates at birth and at admission to the NICU, taking into account the time between the exposure and the onset of infection. A multicenter, prospective cohort study. A total of 1,692 neonates admitted to 6 NICUs in Italy were observed and monitored for the development of nosocomial infection during their hospital stay. Data were collected on the clinical characteristics of the neonates admitted to the NICUs, their therapeutic interventions and treatments, their infections, and their mortality rate. The cumulative probability of having at least 1 infection and the cumulative probability of having at least 1 infection or dying were estimated. The hazard ratio (HR) for the first infection and the HR for the first infection or death were also estimated. A total of 255 episodes of nosocomial infection were diagnosed in 217 neonates, yielding an incidence density of 6.9 episodes per 1,000 patient-days. The risk factors related to nosocomial infection in very-low-birth-weight neonates were receipt of continuous positive airway pressure (HR, 3.8 [95% confidence interval {CI}, 1.7-8.1]), a Clinical Risk Index for Babies score of 4 or greater (HR, 2.2 [95% CI, 1.4-3.4]), and a gestational age of less than 28 weeks (HR, 2.1 [95% CI, 1.2-3.8]). Among heavier neonates, the risk factors for nosocomial infection were receipt of parenteral nutrition (HR, 8.1 [95% CI, 3.2-20.5]) and presence of malformations (HR, 2.3 [95% CI, 1.5-3.5]). Patterns of risk factors for nosocomial infection differ between very-low-birth-weight neonates and heavier neonates. Therapeutic procedures appear to be strong determinants of nosocomial infection in both groups of neonates, after controlling for clinical characteristics.

Cholelithiasis and Cholecystitis

1. Susan Guralnick, MD 1. Stony Brook University Medical Center Stony Brook, NY Biliary Tract Disease in Children. McEvoy CF, Suchy FJ. Pediatr Clin North Am. 1996; 42: 75–98[OpenUrl][1] Cholelithiasis. Friedman JR, Crawford Kennedy M. eMedicine Specialties, Pediatrics: General Medicine, Gastroenterology. 2009. Available at: http://www.emedicine.com/ped/topic381.htm. Accessed June 2009 Cholecystitis. Hebra A, Miller M. eMedicine Specialties, Pediatrics: General Medicine, Gastroenterology. 2008. Available at: http://emedicine.medscape.com/article/927340-overview. Accessed June 2009 Gallbladder Disease. O'Neill J, Grosfeld J, Fonkalsrud E. In: Principles of Pediatric Surgery. 2nd ed. St. Louis, Mo: Mosby; 2004 Cholelithiasis is an uncommon occurrence in healthy children, with an incidence ranging from 0.15% to 0.22%. The condition is seen more frequently in children who have certain predisposing conditions. Cholelithiasis can occur at any age, including prenatally, but is most common during puberty. Females are at significantly higher risk, with an overall 4:1 female-to-male predominance that increases to 11 to 22:1 during adolescence. Gallstones form when bile is supersaturated with cholesterol or bilirubin to the point that the substances no longer are soluble. This effect, along with bile stasis, allows the cholesterol or calcium bilirubinate crystals to remain in the gallbladder (or ductal system for brown stones) long enough to … [1]: {openurl}?query=rft.jtitle%253DPediatr%2BClin%2BNorth%2BAm.%26rft.volume%253D42%26rft.spage%253D75%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx

Candida glabrata Fungemia: Experience in a Tertiary Care Center

During the past decade, Candida glabrata has emerged as an important cause of fungemia. We reviewed demographic data, risk factors, treatment, and outcomes associated with C. glabrata fungemia from 1995-2002 and performed susceptibility testing of isolates. Data on all episodes of fungemia were prospectively recorded, and the associated isolates were saved. Medical records were reviewed retrospectively. Susceptibility testing was performed for fluconazole, itraconazole, and voriconazole. C. glabrata caused 103 (17%) of 609 fungemic episodes during the 8-year period that we studied. Medical records and isolates were available for 94 episodes that occurred in 91 patients. The patients included 42 men and 49 women. The mean age was 51 years. Thirty-four episodes (36%) occurred in patients >60 years old; only 3 episodes occurred in patients <1 year old. The most common predisposing factors were use of broad-spectrum antibiotics (in 86% of episodes), use of central venous catheters (77%), stay in an intensive care unit (48%), renal failure (46%), and receipt of parenteral nutrition (45%). Of the 94 episodes, 83 were treated with antifungal agents. The overall mortality rate at day 30 was 29%. For the 11 episodes that were not treated, the mortality rate was 64% (7 of 11 episodes). Outcome appeared to be unrelated to whether fluconazole or amphotericin B was administered. In vitro, 60% of isolates were resistant to fluconazole, 83% to itraconazole, and 44% to voriconazole. Susceptibility to these azoles did not change over the 8 years of the study. C. glabrata fungemia was most often seen in older adults and was associated with a mortality rate of 29%. Outcomes appeared to be unrelated to in vitro susceptibility results and to the antifungal agent used.

Risk factors for candidal bloodstream infections in surgical intensive care unit patients: the NEMIS prospective multicenter study. The National Epidemiology of Mycosis Survey.

To assess risk factors for development of candidal blood stream infections (CBSIs), a prospective cohort study was performed at 6 sites that involved all patients admitted to the surgical intensive care unit (SICU) for >48 h over a 2-year period. Among 4276 such patients, 42 CBSIs occurred (9.82 CBSIs per 1000 admissions). The overall incidence was 0.98 CBSIs per 1000 patient days and 1.42 per 1000 SICU days with a central venous catheter in place. In multivariate analysis, factors independently associated with increased risk of CBSI included prior surgery (relative risk [RR], 7.3), acute renal failure (RR, 4.2), receipt of parenteral nutrition (RR, 3.6), and, for patients who had undergone surgery, presence of a triple lumen catheter (RR, 5.4). Receipt of an antifungal agent was associated with decreased risk (RR, 0.3). Prospective clinical studies are needed to identify which antifungal agents are most protective and which high-risk patients will benefit from antifungal prophylaxis.

Risk of infection due to central venous catheters: effect of site of placement and catheter type.

To determine the influence of catheter site and type (single- vs triple-lumen) on infection rates associated with central venous catheterization. Prospective observational study of all nontunneled central venous catheters over a 28-month period. Data collected included patient characteristics, insertion site, catheter type, and receipt of parenteral nutrition. End points were clinical infection (bacteremia or site infection) and catheter contamination (clinical infection or colonization with >15 colonies on semiquantitative culture). Medical-surgical wards of Veterans' Affairs hospital. Three hundred catheters were inserted into 204 patients. Seventy percent were inserted into upper-body sites, and 30% were inserted into the femoral vein. Forty-five percent were triple-lumen catheters. Bacteremia occurred in 2.7% of catheter insertions; insertion-site infections developed in 1.3%, and catheter colonization developed in 12%. Catheter contamination was associated with emergent insertion (odds ratio [OR], 6.2; 95% confidence interval [CI95], 1.1-36.7; P=.04) by logistic regression and with femoral location (hazard, 4.2; CI95, 2.0-8.8; P=.0001) and history of transplantation (hazard, 2.8; CI95, 1.1-6.7; P=.024) by Cox regression. Clinical infection was not associated with any of the risk factors evaluated, although there was a trend for association with femoral location by Cox regression (hazard, 4.7; CI95, 0.82-26; P=.08). We did not identify an association between infection and use of triple-lumen catheters or parenteral nutrition. Our data support an association between intravenous catheter contamination and insertion at a femoral site.

Effect of HGH replacement therapy on concentration of 15 serum proteins.

<h3>Background</h3> Parenteral nutrition is commonly administered during therapeutic hypothermia. Randomised trials in critically ill children indicate that parenteral nutrition may be harmful. <h3>Objective</h3> To examine the association between parenteral nutrition during therapeutic hypothermia and clinically important outcomes. <h3>Design</h3> Retrospective, population-based cohort study using the National Neonatal Research Database; propensity scores were used to create matched groups for comparison. <h3>Setting</h3> National Health Service neonatal units in England, Scotland and Wales. <h3>Participants</h3> 6030 term and near-term babies, born 1/1/2010 and 31/12/2017, who received therapeutic hypothermia; 2480 babies in the matched analysis. <h3>Exposure</h3> We compared babies that received any parenteral nutrition during therapeutic hypothermia with babies that did not. <h3>Main outcome measures</h3> Primary outcome: blood culture confirmed late-onset infection; secondary outcomes: treatment for late onset infection, necrotising enterocolitis, survival, length of stay, measures of breast feeding, hypoglycaemia, central line days, time to full enteral feeds, discharge weight. <h3>Results</h3> 1475/6030 babies (25%) received parenteral nutrition. In comparative matched analyses, the rate of culture positive late onset infection was higher in babies that received parenteral nutrition (0.3% vs 0.9%; difference 0.6; 95% CI 0.1, 1.2; p=0.03), but treatment for presumed infection was not (difference 0.8%, 95% CI −2.1 to 3.6, p=0.61). Survival was higher in babies that received parenteral nutrition (93.1% vs 90.0%; rate difference 3.1, 95% CI 1.5, 4.7; p&lt;0.001). <h3>Conclusions</h3> Receipt of parenteral nutrition during therapeutic hypothermia is associated with higher late-onset infection but lower mortality. This finding may be explained by residual confounding. Research should address the risks and benefits of parenteral nutrition in this population.