Identifying optimal dosing strategies for meropenem in the paediatric intensive care unit through modelling and simulation.

BACKGROUND: Meropenem, a ß-lactam antibiotic commonly prescribed for severe infections, poses dosing challenges in critically ill patients due to highly variable pharmacokinetics. OBJECTIVES: We sought to develop a population pharmacokinetic model of meropenem for critically ill paediatric and young adult patients. PATIENTS AND METHODS: Paediatric intensive care unit patients receiving meropenem 20-40 mg/kg every 8 h as a 30 min infusion were prospectively followed for clinical data collection and scavenged opportunistic plasma sampling. Nonlinear mixed effects modelling was conducted using Monolix®. Monte Carlo simulations were performed to provide dosing recommendations against susceptible pathogens (MIC ≤ 2 mg/L). RESULTS: Data from 48 patients, aged 1 month to 30 years, with 296 samples, were described using a two-compartment model with first-order elimination. Allometric body weight scaling accounted for body size differences. Creatinine clearance and percentage of fluid balance were identified as covariates on clearance and central volume of distribution, respectively. A maturation function for renal clearance was included. Monte Carlo simulations suggested that for a target of 40% fT > MIC, the most effective dosing regimen is 20 mg/kg every 8 h with a 3 h infusion. If higher PD targets are considered, only continuous infusion regimens ensure target attainment against susceptible pathogens, ranging from 60 mg/kg/day to 120 mg/kg/day. CONCLUSIONS: We successfully developed a population pharmacokinetic model of meropenem using real-world data from critically ill paediatric and young adult patients with an opportunistic sampling strategy and provided dosing recommendations based on the patients' renal function and fluid status.

Ceftriaxone Pharmacokinetics and Pharmacodynamic Target Attainment for Three Pediatric Patients Receiving Continuous Kidney Replacement Therapy.

Ceftriaxone is used commonly for sepsis, including in children requiring continuous kidney replacement therapy (CKRT). No reports exist of pharmacokinetic (PK) parameters for children receiving ceftriaxone on CKRT. We enrolled children admitted to our pediatric intensive care unit (PICU) who received CKRT for >24 hours and received >1 dose of ceftriaxone while on and off CKRT. We measured free ceftriaxone -concentrations from residual blood samples then used Bayesian estimation with PK modeling software to generate concentration-time profiles and determine PK parameters and the percentage of time free ceftriaxone concentrations were above 1× or 4× MIC (% fT >MIC). Three patients aged 2 to 17 years were included; all were anuric at CKRT initiation and received 50 mg/kg (max 2000 mg) ceftriaxone every 12 to 24 hours. Total ceftriaxone clearance (CL) was 0.50 to 3.67 L/hr while receiving CKRT and 0.29 to 2.71 L/hr while off, indicating CKRT provided 25% to 42% of total ceftriaxone CL. All achieved 100% fT >1× and 4× MIC using an estimated MIC (1 mg/L) for patients 1 to 2 (no culture data) and a measured MIC (0.016 mg/L) for patient 3. Therefore, CKRT contributed significantly to total ceftriaxone clearance in 3 children though the dosing strategies used in each patient attained PD targets.

Cystatin C Outperforms Creatinine in Predicting Cefepime Clearance in Pediatric Stem Cell Transplant Recipients.

Pediatric hematopoietic stem cell transplant (HSCT) patients are at risk of developing both sepsis and altered kidney function. Cefepime is used for empiric coverage post-HSCT and requires dose adjustment based on kidney function. Since cefepime's antimicrobial efficacy is determined by the time free concentrations exceed bacterial minimum inhibitory concentration (MIC), it is important to assess kidney function accurately to ensure adequate concentrations. Serum creatinine (SCr) is routinely used to estimate glomerular filtration rate (eGFR) but varies with muscle mass, which can be significantly lower in HSCT patients, making SCr an inaccurate kidney function biomarker. Cystatin C (CysC) eGFR is independent of muscle mass, though steroid use increases CysC. Objectives of this study were to describe how eGFR impacts cefepime pharmacokinetic/pharmacodynamic (PK/PD) target attainment in pediatric HSCT patients, to investigate which method of estimating GFR (SCr, CysC, combined) best predicts cefepime clearance, and to explore additional predictors of cefepime clearance. Patients admitted to the pediatric HSCT unit who received ≥2 cefepime doses were prospectively enrolled. We measured total cefepime peak/trough concentrations between the second and fourth cefepime doses and measured SCr and CysC if not already obtained clinically within 24h of cefepime samples. eGFRs were calculated with Chronic Kidney Disease in Children U25 equations. Bayesian estimates of cefepime clearance were determined with a pediatric cefepime PK model and PK software MwPharm++. Simple linear regression was used to compare cefepime clearance normalized to body surface area (BSA) to BSA-normalized SCr-, CysC-, and SCr-/CysC-eGFRs, while multiple linear regression was used to account for additional predictors of cefepime clearance. For target attainment, we assessed the percentage of time free cefepime concentrations exceeded 1x MIC (%fT>1x MIC) and 4x MIC (%fT>4x MIC) using a susceptibility breakpoint of 8 mg/L for Pseudomonas aeruginosa. We enrolled 53 patients (ages 1 to 30 years, median 8.9 years). SCr- and CysC-eGFRs were lower in patients who attained 100% fT>1xMIC compared to those who did not attain this target: 115 versus 156 mL/min/1.73m2 (p = .01) for SCr-eGFR and 73.5 versus 107 mL/min/1.73m2 (p < .001) for CysC-eGFR. SCr-eGFR was weakly positively correlated with cefepime clearance (adjusted [a]r2= 0.14), while CysC-eGFR and SCr-/CysC-eGFR had stronger positive correlations (ar2 = 0.30 CysC, ar2 = 0.28 combo. There was a weak, significant linear association between increasing CysC-eGFR and decreased %fT>1xMIC (ar2 = 0.32) and %fT>4xMIC (ar2 = 0.14). No patients with a CysC-eGFR >120 mL/min/1.73 m2 achieved 100% fT>1xMIC or 50% fT>4x MIC. In multiple regression models, underlying diagnosis of hemoglobinopathy (in all models) and being pretransplant (in SCr and combined models) were associated with increased cefepime clearance, while concomitant use of calcineurin inhibitors was associated with decreased cefepime clearance in all models. Overall, the combo-eGFR model with timing pretransplant, hemoglobinopathy, and use of calcineurin inhibitors had the best performance (ar2 = 0.63). CysC-based eGFRs (CysC alone and combined) predicted cefepime clearance better than SCr-eGFR, even after considering steroid use. Increasing CysC eGFR correlated with decreased probability of PD target attainment, raising concerns for underdosing at high eGFRs. CysC should be included when estimating kidney function to provide adequate dosing of cefepime in pediatric HSCT patients.

Hemolytic Uremic Syndrome-Induced Acute Kidney Injury Treated via Immunomodulation with the Selective Cytopheretic Device.

INTRODUCTION: Shiga-toxin associated-hemolytic uremic syndrome (STEC-HUS) is a severe cause of acute kidney injury (AKI) in children. Although most children recover, about 5% die and 30% develop chronic renal morbidity. HUS pathophysiology includes activated neutrophils damaging vascular endothelial cells. Therapeutic immunomodulation of activated neutrophils may alter the progression of disease. We present 3 pediatric patients treated with the selective cytopheretic device (SCD). METHODS: We describe a 12 y.o. (patient 1) and two 2 y.o. twins (patients 2 and 3) with STEC-HUS requiring continuous renal replacement therapy (CRRT) who were enrolled in two separate studies of the SCD. RESULTS: Patient 1 presented with STEC-HUS causing AKI and multisystem organ failure and received 7 days of SCD and CRRT treatment. After SCD initiation, the patient had gradual recovery of multi-organ dysfunction, with normal kidney and hematologic parameters at 60-day follow-up. Patients 2 and 3 presented with STEC-HUS with AKI requiring dialysis. Each received 24 h of SCD therapy. Thereafter, both gradually improved, with normalization (patient 2) and near-normalization (patient 3) of kidney function at 60-day follow-up. CONCLUSION: Immunomodulatory treatment with the SCD was associated with improvements in multisystem stigmata of STEC-HUS-induced AKI and was well-tolerated without any device-related adverse events.

Cefepime pharmacokinetics in critically ill children and young adults undergoing continuous kidney replacement therapy.

OBJECTIVES: Cefepime is an antibiotic commonly used to treat sepsis and is cleared by renal excretion. Cefepime dosing requires adjustment in patients with decreased kidney function and in those receiving continuous kidney replacement therapy (CKRT). We aimed to characterize cefepime PK in a diverse cohort of critically ill paediatric patients on CKRT. METHODS: Patients were identified from an ongoing pharmacokinetic/pharmacodynamic (PK/PD) study of beta-lactam antibiotics, and were included if they had received at least two cefepime doses in the ICU and were on CKRT for at least 24 h. PK parameters were estimated using MwPharm++ with Bayesian estimation and a paediatric population PK model. Target attainment was assessed as time of free cefepime concentrations above minimum inhibitory concentration (fT > 1× or 4 × MIC). RESULTS: Seven patients were included in the study (ages 2 to 20 years). CKRT indications included liver failure (n = 1), renal failure (n = 4) and fluid overload (n = 2). Total effluent flow rates ranged from 1833 to 3115 (mean 2603) mL/1.73 m2/h, while clearance was 2.11-3.70 (mean 3.0) L/h/70 kg. Effluent flows were lower, but clearance and fT > MIC were similar to paediatric data published previously. Using Pseudomonas aeruginosa MIC breakpoints, all patients had 100% of dosing interval above MIC, but only one had 100% of dosing interval above 4× MIC. CONCLUSIONS: Since most patients failed to attain stringent targets of 100% fT > 4×  MIC, model-informed precision dosing may benefit such patients.

ß-lactam precision dosing in critically ill children: Current state and knowledge gaps.

There has been emerging interest in implementing therapeutic drug monitoring and model-informed precision dosing of ß-lactam antibiotics in critically ill patients, including children. Despite a position paper endorsed by multiple international societies that support these efforts in critically ill adults, implementation of ß-lactam precision dosing has not been widely adopted. In this review, we highlight what is known about ß-lactam antibiotic pharmacokinetics and pharmacodynamics in critically ill children. We also define the knowledge gaps that present barriers to acceptance and implementation of precision dosing of ß-lactam antibiotics in critically ill children: a lack of consensus on which subpopulations would benefit most from precision dosing and the uncertainty of how precision dosing changes outcomes. We conclude with opportunities for further research to close these knowledge gaps.

Role of the Trifluoropropynyl Ligand in Blue-Shifting Charge-Transfer States in Emissive Pt Diimine Complexes and an Investigation into the PMMA-Imposed Rigidoluminescence and Rigidochromism.

Square-planar PtII complexes are of interest as dopants for the emissive layer of organic light-emitting diodes. Herein, the photophysics of three Pt bipyridyl complexes with the strongly e- withdrawing, high-field, 3,3,3-trifluoropropynyl ligand has been investigated. One complex, (phbpy)PtC2CF3 (phbpy = 6-phenyl-2,2'-dipyridyl), has also been characterized by single-crystal X-ray diffraction. All complexes reported are emissive in both RT CH2Cl2 solution (ΦPL = 0.007 to 0.027) and PMMA film (ΦPL = 0.25 to 0.42). The trifluoropropynyl ligand elevates the energy of the MLCT and LL'CT states above that of the IL π-π* state, resulting in IL emission in all cases. The emission energies of the trifluoropropynyl compounds are also blue-shifted relative to the analogous pentafluorophenylethynyl compounds, suggesting that the trifluoropropynyl ligand is one of the most electron-withdrawing alkynyl ligands. Rate constants for radiative and nonradiative deactivation were determined from experimentally determined values of ΦPL and excited-state lifetimes in both solution and PMMA films. The increase in ΦPL upon incorporation into PMMA film (rigidoluminescence) results from a decrease in the rate constant for non-radiative relaxation. Experimental activation energies for excited-state decay in combination with TDDFT are consistent with the rigidoluminescence resulting from an increase in the energy of the non-emissive triplet metal-centered state. Two of the complexes investigated, (Ph2bpy)Pt(C2CF3)2 and (t-Bu2bpy)Pt(C2CF3)2, where t-Bu2bpy = 4,4'-di-tert-butyl-2,2'-dipyridyl and Ph2bpy = 4,4'-diphenyl-2,2'-dipyridyl, exhibit concentration-dependent excimer emission (orange) along with monomer emission (blue), enabling fine-tuning of the emission color. However, excimer emission was absent in cured PMMA films up to the solubility limit for solution processing of (Ph2bpy)Pt(C2CF3)2 in CH2Cl2, demonstrating the diffusional nature of excimer formation.

Sex Tourism, Condomless Anal Intercourse, and HIV Risk Among Men Who Have Sex With Men.

Sex tourism affects the sexual health of tourists and locals with whom they interact. However, a few studies have examined whether sex tourism is a risk factor for the acquisition of HIV and other sexually transmitted infections among men who have sex with men, and no such studies have been conducted in Western Europe. Almost 28% of our respondents reported engaging in sex tourism in their lifetime. Sex tourism was associated with an elevated risk of engagement in condomless receptive anal intercourse, use of alcohol/drugs during sex, participation in group sex, and an elevated risk of diagnosis with any type of sexually transmitted infection over the previous year, specifically gonorrhea and chlamydia. Research with men who have sex with men who engage in sex tourism should explore high-risk sexual behavior during sex tourism and also the feasibility and acceptability of the use of episodic pre-exposure prophylaxis for short periods of participation in elevated risk behaviors by tourists and local sex partners.

City of love: group sex is associated with risks for HIV and other sexually transmissible infections among gay and bisexual men in Paris, France.

Background This study explored the relationships between participation in group sex and risk for HIV and other sexually transmissible infections (STIs). METHODS: An anonymous online survey collected data from 580 gay and bisexual men using a mobile sex and dating application in Paris, France. Logistic regression analyses were conducted, which controlled for HIV status, HIV pre-exposure prophylaxis (PrEP) use and participants' sociodemographic characteristics. RESULTS: Compared with men with no recent group sex experience, those reporting group sex in the 3 months before the survey (30.7% of the sample) were more likely to have had condomless receptive anal sex at least once in the same period [adjusted odds ratio (aOR)=1.6, 95% confidence interval (CI)=1.1-2.4, P = 0.02], condomless insertive anal sex (aOR=2.0, 95%CI: 2.4-8.7, P < 0.001) and substance use before or during sex (aOR=1.6, 95%CI: 1.1-2.3, P = 0.02). Even when controlling for condom use, men involved with group sex were more likely to be have been diagnosed with a bacterial STI in the previous year (aOR=2.1, 95%CI: 1.3-3.3, P = 0.002). CONCLUSIONS: Group sex remains a useful marker of risk among gay and bisexual men, but research is needed that moves beyond individual practice in order to assess the epidemiological networks comprising group sex and the risks they pose relevant to HIV and other STIs.

Transactional Sex and Preferences for Pre-Exposure Prophylaxis (PrEP) Administration Modalities Among Men Who Have Sex With Men (MSM).

Pre-exposure prophylaxis (PrEP) is an important biomedical human immunodeficiency virus (HIV) prevention tool gaining more popularity among Parisian men who have sex with men (MSM) who engage in transactional sex. This study examines the knowledge of, and willingness to use, different modalities of PrEP among this subgroup. Broadcast advertisements were placed on a geosocial-networking smartphone application with a link to a Web-based survey during three 24-hour periods in October 2016. Modified Poisson regression models were used to assess the association between engagement in transactional sex and preferences for each of these PrEP modalities. A total of 444 respondents were included. About 14% reported engagement in transactional sex. In all, 90% of MSM who engaged in transactional sex were knowledgeable of daily oral PrEP, while 13.3% were knowledgeable about long-acting injectable PrEP or penile or rectal microbicides. They were more likely to be aware of long-acting injectable PrEP (aRR = 2.52, 95% CI = 1.16 to 5.47) and willing to use daily oral PrEP (aRR = 1.48; 95% CI = 1.11 to 1.98) or long-acting injectable PrEP (aRR = 1.40; 95% CI = 1.09 to 1.81) than MSM who had not engaged in transactional sex. Long-acting injectable PrEP may be an important HIV-prevention option for MSM who engage in transactional sex if this modality is proven effective.

Perceived Candidacy for Pre-exposure Prophylaxis (PrEP) Among Men Who Have Sex with Men in Paris, France.

Low perception of HIV risk is a challenge to PrEP implementation. We analyzed associations between perceptions of PrEP candidacy, behavioral indications for PrEP, and sexual behaviors. We recruited a sample of 580 MSM from a geosocial-networking smartphone application in Paris, France. A modified Poisson regression model was conducted to examine associations between perceived candidacy for PrEP and behavioral indications for PrEP, and relationships among engagement in group sex, transactional sex, HIV test history, and indications for PrEP. Adjusted risk ratios (aRR) and 95% confidence intervals (CIs) were calculated. For the outcome of perceived candidacy for PrEP, a multinomial logistic regression was performed, and adjusted relative risk ratios (aRRR) were calculated. Multivariate analyses were adjusted for socio-demographics. Respondents who considered themselves PrEP candidates were more likely to meet PrEP eligibility criteria compared to those who did not consider themselves candidates (aRR 1.65; 95% CI 1.34-2.03). Those who had engaged in group or transactional sex were more likely to have behavioral indications for PrEP (aRR 1.27; 95% CI 1.07-1.50, aRR 1.32; 95% CI 1.13-1.56, respectively), whereas HIV test history was not significantly associated with behavioral indications for PrEP. Respondents who had engaged in group sex or transactional sex were more likely to perceive themselves as candidates for PrEP (aRRR 2.24; 95% CI 1.21-4.16, aRRR 2.58; 95% CI 1.09-6.13, respectively), although those never tested for HIV were less likely to perceive themselves as candidates for PrEP (aRRR 0.18; 95% CI 0.03-0.91). The elucidation of candidacy perceptions and risk behaviors is key to furthering the effective implementation of PrEP engagement interventions.

Sexual Orientation Disparities in Prescription Opioid Misuse Among U.S. Adults.

INTRODUCTION: The opioid epidemic in the U.S. continues to increase in severity, and misuse of prescription opioids is of particular concern since it commonly precedes heroin use. This study examined whether sexual orientation (i.e., sexual identity and sexual attraction) is a risk factor for prescription opioid misuse and use disorder among a nationally representative sample of adults in the U.S. METHODS: This study used data from adult participants (ages ≥18 years) in the 2015 National Survey on Drug Use and Health. Chi-square tests and logistic regression examined how sexual identity and sexual attraction relate to past-year and past-month prescription opioid misuse and past-year prescription opioid use disorder. Multivariable models examined associations controlling for demographic characteristics and other drug use. Gender-stratified analyses were also conducted. Data were analyzed in 2018. RESULTS: In multivariable analyses, compared with those identifying as heterosexual, bisexual individuals were at 1.53 (95% CI=1.20, 1.97) and 1.66 (95% CI=1.14, 2.42) higher odds of reporting past-year and past-month misuse, respectively. In stratified analyses, female bisexuals remained at high risk. Regarding sexual attraction, compared with being attracted to only the opposite sex, being attracted to mostly the opposite sex (AOR=2.15, 95% CI=1.77, 2.63) or being equally attracted to both sexes (AOR=1.78, 95% CI=1.38, 2.30) were associated with higher odds for past-year opioid misuse. In stratified analyses, these associations were limited to females. CONCLUSIONS: Sexual orientation disparities in opioid misuse and use disorder among a nationally representative sample of U.S. adults was found.

Use of poppers and HIV risk behaviours among men who have sex with men in Paris, France: an observational study.

The use of inhaled nitrites, or poppers, among men who have sex with men (MSM) is prevalent, yet has been associated with HIV seroconversion. We surveyed 580 MSM from a geosocial networking smartphone application in Paris, France, in 2016. Of the respondents, 46.7% reported popper use within the previous 3 months. Regression models adjusted for sociodemographic characteristics found that the use of poppers was significantly (P<0.05) associated with the following during the prior 3 months: condomless anal intercourse (adjusted relative risk (aRR) 1.27, 95% confidence interval (CI) 1.07-1.50), use of alcohol and/or drugs during sex once or twice (adjusted relative risk ratio (aRRR) 2.33, 95% CI 1.44-2.03), three to five times (aRRR 5.41, 95% CI 2.98-9.84) or six or more times (aRRR 4.09, 95% CI 2.22-7.56), participation in group sex (aRRR 3.70, 95% CI 2.33-5.90) and self-reported diagnosis with any sexually transmissible infection over the previous year (aRR 1.63, 95% CI 1.18-2.27), specifically chlamydia (aRR 2.75, 95% CI 1.29-4.29) and syphilis (aRR 2.27, 95% CI 1.29-4.29).

Characterizing Geosocial-Networking App Use Among Young Black Men Who Have Sex With Men: A Multi-City Cross-Sectional Survey in the Southern United States.

BACKGROUND: Understanding where and how young black men who have sex with men (YBMSM) in the southern United States meet their sexual partners is germane to understanding the underlying factors contributing to the ongoing HIV transmission in this community. Men who have sex with men (MSM) commonly use geosocial networking apps to meet sexual partners. However, there is a lack of literature exploring geosocial networking app use in this particular population. OBJECTIVE: Our aim was to examine the characteristics, preferences, and behaviors of a geographically diverse sample of geosocial networking app-using YBMSM in the southern United States. METHODS: Data were collected from a sample of 75 YBMSM across three cities (Gulfport, Mississippi; Jackson, Mississippi; and New Orleans, Louisiana). Multiple aspects of geosocial networking app use were assessed, including overall app use, age of participant at first app use, specific apps used, reasons for app use, photos presented on apps, logon times and duration, number of messages sent and received, and characteristics of and behaviors with partners met on apps. Survey measures of app-met partner and sexual behavior characteristics assessed at midpoint (Day 7) and completion visits (Day 14) were compared using McNemar's test or Wilcoxon signed-rank test. In addition, we assessed activity spaces derived from GPS devices that participants wore for 2 weeks. RESULTS: Of the 70 participants who responded to the overall app-use item, almost three-quarters (53/70, 76%) had ever used geosocial networking apps. Jack'd was the most commonly used geosocial networking app (37/53, 70%), followed by Adam4Adam (22/53, 42%), and Grindr (19/53, 36%). The mean and median number of apps used were 4.3 (SD 2.7) and 4.0 (range 0-13), respectively. Most app-using participants displayed their face on the profile picture (35/52, 67%), whereas fewer displayed their bare legs (2/52, 4%) or bare buttocks (or ass; 2/52, 4%). The mean age at the initiation of app use was 20.1 years (SD 2.78) ranging from 13-26 years. Two-thirds (35/53, 66%) of the sample reported using the apps to "kill time" when bored. A minority (9/53, 17%) reported using the apps to meet people to have sex/hook up with. The vast majority of participants reported meeting black partners for sex. Over two-thirds (36/53, 68%) reported that the HIV status of their app-met partners was negative, and 26% (14/53) reported that they did not know their partner's HIV status. There was a significant difference in GPS activity spaces between app using YBMSM compared to nonapp using YBMSM (2719.54 km2 vs 1855.68 km2, P=.011). CONCLUSIONS: Use of geosocial networking apps to meet sexual partners among our sample of YBMSM in the southern United States was common, with a diverse range of app use behaviors being reported. Further research should characterize the association between geosocial networking app use and engagement in sexual behaviors that increase risk for HIV acquisition and transmission. In addition, geosocial networking apps present a promising platform for HIV prevention interventions targeting YBMSM who use these apps.

Poppers and PrEP: Use of Pre-exposure Prophylaxis Among Men Who Have Sex with Men Who Use Inhaled Nitrites.

Men who have sex with men (MSM) commonly use inhaled nitrites, or poppers, though their use is a risk factor HIV seroconversion. Pre-exposure prophylaxis, or PrEP, is effective for HIV prevention, but is not widely used, and little is known regarding PrEP use and acceptability among MSM who use inhaled nitrites. We surveyed 580 MSM in Paris, France in 2016 about popper use, sexual behaviors including condomless anal intercourse (CAI), serosorting, and sexual positioning, PrEP use, PrEP candidacy, and interest in alternate PrEP delivery modalities. We included 444 HIV negative participants for the current study. 46.2% reported popper use in the prior 3 months. Using multivariate adjusted logistic regression, we found that popper users were more likely than non-users to consider themselves candidates for PrEP [adjusted relative risk ratio (aRRR) = 2.73; 95% CI 1.54-4.83], but they were not more likely to be current (aRRR = 1.54; 95% CI 0.71-3.33) or past (aRRR = 1.37; 95% CI 0.44-4.28) PrEP users. Mediation analyses indicated that increased CAI and serosorting partly explained the relationship between popper use and PrEP candidacy. There was considerable interest in alternate proposed PrEP delivery modalities, particularly long-acting injectable PrEP [adjusted risk ratio (aRR) = 1.43; 95% CI 1.15-1.79].