Phase I Study Assessing the Pharmacokinetic Profile, Safety, and Tolerability of a Single Dose of Ceftazidime-Avibactam in Hospitalized Pediatric Patients.

This study aimed to investigate the pharmacokinetics (PK), safety, and tolerability of a single dose of ceftazidime-avibactam in pediatric patients. A phase I, multicenter, open-label PK study was conducted in pediatric patients hospitalized with an infection and receiving systemic antibiotic therapy. Patients were enrolled into four age cohorts (cohort 1, ≥12 to <18 years; cohort 2, ≥6 to <12 years; cohort 3, ≥2 to <6 years; cohort 4, ≥3 months to <2 years). Patients received a single 2-h intravenous infusion of ceftazidime-avibactam (cohort 1, 2,000 to 500 mg; cohort 2, 2,000 to 500 mg [≥40 kg] or 50 to 12.5 mg/kg [<40 kg]; cohorts 3 and 4, 50 to 12.5 mg/kg). Blood samples were collected to describe individual PK characteristics for ceftazidime and avibactam. Population PK modeling was used to describe characteristics of ceftazidime and avibactam PK across all age groups. Safety and tolerability were assessed. Thirty-two patients received study drug. Mean plasma concentration-time curves, geometric mean maximum concentration (Cmax), and area under the concentration-time curve from time zero to infinity (AUC0-∞) were similar across all cohorts for both drugs. Six patients (18.8%) reported an adverse event, all mild or moderate in intensity. No deaths or serious adverse events occurred. The single-dose PK of ceftazidime and avibactam were comparable between each of the 4 age cohorts investigated and were broadly similar to those previously observed in adults. No new safety concerns were identified. (This study has been registered at ClinicalTrials.gov under registration no. NCT01893346.).

A Novel Public Library-Based Sexually Transmitted Infection Screening Program for Younger High-Risk Groups in Omaha, Nebraska, USA.

Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) are the two most commonly reported sexually transmitted infections (STIs) in the United States (U.S.) and Douglas County, Nebraska has STI rates consistently above the U.S. average. The Douglas County Health Department (DCHD) developed an outreach CT and NG screening program in public libraries to address the problem beyond the traditional STI clinic setting. This study evaluates the effectiveness of the program and identifies factors predictive of CT and NG infections. A retrospective review of surveys of library patrons and DCHD traditional STI clinic clients who submitted urine tests for CT and NG from June 2010 through April 2014 was done. Chi square, Fisher exact, Student's t tests, univariate and multivariate logistic regression were conducted. A total of 977 library records and 4871 DCHD clinic records were reviewed. The percent positive was lower in the library than in the traditional clinic for CT (9.9 vs. 11.2 %) and NG (2.74 vs. 5.3 %) (p = 0.039 and p < 0.001, respectively). Library clients were more likely to be 19 years and younger (OR 6.14, 95 % CI: 5.0, 7.5), Black (OR 3.4, 95 % CI: 2.8, 4.1), and asymptomatic (OR 12.4, 95 % CI: 9.9, 15.5) compared to traditional clinic clients. The library STI screening program effectively reaches a younger, asymptomatic, and predominantly Black population compared to a traditional health department clinic site.

Early-onset neonatal sepsis.

Early-onset sepsis remains a common and serious problem for neonates, especially preterm infants. Group B streptococcus (GBS) is the most common etiologic agent, while Escherichia coli is the most common cause of mortality. Current efforts toward maternal intrapartum antimicrobial prophylaxis have significantly reduced the rates of GBS disease but have been associated with increased rates of Gram-negative infections, especially among very-low-birth-weight infants. The diagnosis of neonatal sepsis is based on a combination of clinical presentation; the use of nonspecific markers, including C-reactive protein and procalcitonin (where available); blood cultures; and the use of molecular methods, including PCR. Cytokines, including interleukin 6 (IL-6), interleukin 8 (IL-8), gamma interferon (IFN-γ), and tumor necrosis factor alpha (TNF-α), and cell surface antigens, including soluble intercellular adhesion molecule (sICAM) and CD64, are also being increasingly examined for use as nonspecific screening measures for neonatal sepsis. Viruses, in particular enteroviruses, parechoviruses, and herpes simplex virus (HSV), should be considered in the differential diagnosis. Empirical treatment should be based on local patterns of antimicrobial resistance but typically consists of the use of ampicillin and gentamicin, or ampicillin and cefotaxime if meningitis is suspected, until the etiologic agent has been identified. Current research is focused primarily on development of vaccines against GBS.

Using e-modules for acquisition of complex diabetes skills in diabetes care providers in Rwanda.

Type 1 Diabetes (T1D) is life-threatening without appropriate treatment. Though pediatric endocrinology care is limited in Rwanda, a decentralized health system allows access to local non-communicable disease (NCD) nurses through a network of 42 district hospitals. Recent rapid expansion of internet access in the country makes virtual diabetes education initiatives possible. We investigated whether Rwandan NCD nurses receiving diabetes education via online e-modules could make similar educational gains in insulin adjustment skills (IAS) compared to NCD nurses educated in a conference-style setting, and whether they would maintain equivalent competency at 1 year after education. We randomized 21 district hospitals and their NCD nurses to participate in a 1.5-day educational conference centered around care of type 1 diabetes (Group 1), while nurses from the remaining 21 hospitals (Group 2) received accommodation and access to equivalent educational materials in e-module form. Both groups were requested to review initial course materials at 4, 8, and 12 months. Ten-point IAS assessments were administered before and after education or review at each time point. Groups 1 and 2 had equal improvement after education (+2.0 vs. +2.0, p = 0.47) and equal final score at baseline (6.0 vs. 6.0, p = 0.74). However, both groups showed a diminishing improvement over time, so that any gains were lost by 4 months in Group 1 and 8 months in Group 2. Group 1 showed greater attrition in participation over time (19% vs 58% continued participation at one year, p = 0.002). Groups did not differ in subjective confidence in IAS after education. Both groups identified existing or potential access barriers to their respective educational method. While further modifications should be trialed to ensure equitable access and to maintain long-term engagement, online education is a feasible method to teach complex subspecialty skills to providers working in low-resource settings.

Using an Adaptive Listening Tour and Survey to Promote Faculty Reflection on Diversity, Equity, and Inclusion (DEI) in the Pre-clinical Undergraduate Medical Curriculum.

Descriptive studies regarding how to integrate diversity, equity, and inclusion (DEI) into medical education are lacking. We utilized the AAMC's Key Steps for Assessing Institutional Culture and Climate framework to evaluate our current curriculum via listening tours (n = 34 participants) and a survey of the 10 pre-clinical block directors, to better understand the opportunities and challenges of improving DEI in the pre-clinical curriculum. Opportunities included diversifying cases and standardized patients, enhancing information on systemic racism and social determinants of health, and increasing racial humility and population genetics/epigenetics training. Faculty had issues with "correct ways" to incorporate DEI and time constraints. Supplementary Information: The online version contains supplementary material available at 10.1007/s40670-023-01924-7.

Ending Race-Conscious College Admissions and Its Potential Impact on the Infectious Disease Workforce.

On 29 June 2023, the Supreme Court of the United States ruled that race-conscious consideration for college admission is unconstitutional. We discuss the consequences of this ruling on the delivery of equitable care and health system readiness to combat current and emerging pandemics. We propose strategies to mitigate the negative impact of this ruling on diversifying the infectious disease (ID) workforce.

The association between influenza vaccine effectiveness and egg-based manufacturing technology: literature review and US expert consensus.

BACKGROUND: Influenza is associated with significant disease burden in the US and is currently best controlled by vaccination programs. Influenza vaccine effectiveness (VE) is low and may be reduced by several factors, including egg adaptations. Although non-egg-based influenza vaccines reportedly have greater VE in egg-adapted seasons, evidence for egg adaptations' reduction of VE is indirect and dissociated, apart from two previous European consensuses. METHODS: This study replicated the methodology used in a 2020 literature review and European consensus, providing an updated review and consensus opinion of 10 US experts on the evidence for a mechanistic basis for reduction of VE due to egg-based manufacturing methods. A mechanistic basis was assumed if sufficient evidence was found for underlying principles proposed to give rise to such an effect. Evidence for each principle was brought forward from the 2020 review and identified here by structured literature review and expert panel. Experts rated the strength of support for each principle and a mechanistic basis for reduction of VE due to egg-based influenza vaccine manufacture in a consensus method (consensus for strong/very strong evidence = ≥ 3.5 on 5-point Likert scale). RESULTS: Experts assessed 251 references (from previous study: 185; this study: 66). The majority of references for all underlying principles were rated as strong or very strong supporting evidence (52-86%). Global surveillance, WHO candidate vaccine virus selection, and manufacturing stages involving eggs were identified as most likely to impact influenza VE. CONCLUSION: After review of extensive evidence for reduction of VE due to egg-based influenza vaccine manufacture, influenza experts in the US joined those in Europe in unanimous agreement for a mechanistic basis for the effect. Vaccine providers and administrators should consider use of non-egg-based influenza vaccine manufacture to reduce the risk of egg adaptations and likely impact on VE.

Vitamin D Metabolites in Mother-Infant Dyads and Associated Clinical Outcomes in a Population of Nigerian Women.

Low levels of vitamin D in maternal and cord blood have been associated with neonatal sepsis. This study assessed the association of vitamin D metabolites (25(OH)D, 3-epi-25(OH)D3, and 24,25(OH)2D3) levels in maternal and cord blood with newborn sepsis evaluation in Nigerian mother-infant dyads. Maternal and cord blood from 534 mothers and 536 newborns were processed using liquid chromatography-tandem mass spectrometry. Spearman correlation was used to compare continuous variables, Mann-Whitney for dichotomous variables, and Kruskal-Wallis for two or more groups. High cord percent 3-epi-25(OH)D3 levels were positively associated with newborn evaluation for sepsis (p = 0.036), while maternal and cord 25(OH)D and 24,25(OH)2D3 levels were not. Being employed was positively associated with maternal and newborn 3-epi-25(OH)D3 concentrations (p = 0.007 and p = 0.005, respectively). The maternal 3-epi-25(OH)D3 and percent 3-epi-25(OH)D3 were positively associated with vaginal delivery (p = 0.013 and p = 0.012, respectively). Having a weight-for-age Z-score ≤ -2 was positively associated with newborn percent 3-epi-25(OH)D3 levels (p = 0.004), while a weight-for-length Z-score ≤ -3 was positively associated with maternal and newborn percent 3-epi-25(OH)D3 levels (p = 0.044 and p = 0.022, respectively). Our study highlights the need to further investigate the biological role of 3-epi-25(OH)D3 and its clinical significance in fetal growth and newborn outcome.

Cross-sectional survey of parental barriers to participation in pediatric participant research registries.

Research registries are a powerful tool for boosting recruitment into clinical trials. However, little is known about how parents approach the decision to enroll their child in a pediatric participant research registry (PPRR). We conducted in-person, written, or telephone surveys with parents/guardians of children hospitalized at Children's Hospital of Omaha, Nebraska to identify attitudes towards and barriers to enrollment in PPRRs. Overall, our population (N = 36) had positive attitudes toward PPRRs, with 77.8% (CI: 61.6, 88.4) of participants stating they were "somewhat" or "very" likely to enroll their child. Likelihood to enroll differed between various recruitment and enrollment methods, with participants stating they would be more likely to enroll their child in a PPRR if they were recruited by their child's primary care provider or a nurse in clinic (p = 0.02) and less likely to enroll if they were recruited through social media (p<0.001). Additionally, over 90% of participants who were likely to enroll their child in a PPRR (N = 28) were also willing to provide demographic, medical, and lifestyle information. However, these participants remained concerned about inappropriate sharing of their information with insurance or for-profit companies (53.6%, CI: 35.8, 70.4) and about receiving unwanted telephone calls from the registry (78.6%, CI: 60.0, 90.0). Parents are generally willing to enroll their child in a PPRR. However, to optimize enrollment, investigators must understand parental preferences for and concerns surrounding enrollment in a PPRR.

Strategies to Increase Workforce Diversity in Pediatric Infectious Diseases.

The number of physicians who are underrepresented in medicine within the pediatric infectious diseases workforce remains disproportionate compared to the US population. Physician workforce diversity plays an important role in reducing health care disparities. Pathways to careers in pediatric infectious diseases require that a diverse pool of students enter medicine and subsequently choose pediatric residency followed by subspecialty training. Efforts must be made to expose learners to pediatric infectious diseases earlier in the education timeline. Along with recruitment and creation of pathways, cultures of inclusivity must be created and fostered within institutions of learning along the entire spectrum of medical training.

Aureobasidium pullulans var. melanigenum fungemia in a pediatric patient.

This report describes a chronically ill child who presented with high fever and was diagnosed with catheter-related sepsis. Aureobasidium pullulans variety melanigenum, a dematiaceous fungus that rarely causes opportunistic infections, was recovered from multiple blood cultures. Antifungal susceptibilities were performed and the minimum inhibitory concentration (MIC) for fluconazole was 64 mg/l, suggestive of fluconazole resistance. The patient made a full recovery after removal of the catheter line and treatment with liposomal amphotericin B. This is the first case report of an elevated in vitro fluconazole MIC of an A. pullulans isolate and only the third case of successful treatment of A. pullulans fungemia.

A quantitative affinity-profiling system that reveals distinct CD4/CCR5 usage patterns among human immunodeficiency virus type 1 and simian immunodeficiency virus strains.

The affinity of human immunodeficiency virus (HIV) envelope for CD4 and CCR5 appears to be associated with aspects of R5 virus (virus using the CCR5 coreceptor) pathogenicity. However, entry efficiency results from complex interactions between the viral envelope glycoprotein and both CD4 and CCR5, which limits attempts to correlate viral pathogenicity with surrogate measures of envelope CD4 and CCR5 affinities. Here, we present a system that provides a quantitative and comprehensive characterization of viral entry efficiency as a direct interdependent function of both CD4 and CCR5 levels. This receptor affinity profiling system also revealed heretofore unappreciated complexities underlying CD4/CCR5 usage. We first developed a dually inducible cell line in which CD4 and CCR5 could be simultaneously and independently regulated within a physiologic range of surface expression. Infection by multiple HIV type 1 (HIV-1) and simian immunodeficiency virus isolates could be examined simultaneously for up to 48 different combinations of CD4/CCR5 expression levels, resulting in a distinct usage pattern for each virus. Thus, each virus generated a unique three-dimensional surface plot in which viral infectivity varied as a function of both CD4 and CCR5 expression. From this functional form, we obtained a sensitivity vector along with corresponding metrics that quantified an isolate's overall efficiency of CD4/CCR5 usage. When applied to viral isolates with well-characterized sensitivities to entry/fusion inhibitors, the vector metrics were able to encapsulate their known biological phenotypes. The application of the vector metrics also indicated that envelopes derived from elite suppressors had overall-reduced entry efficiencies compared to those of envelopes derived from chronically infected viremic progressors. Our affinity-profiling system may help to refine studies of R5 virus tropism and pathogenesis.

Breastfeeding practices in Masaya, Nicaragua: a facility based cross-sectional study.

BACKGROUND: The World Health Organization recommends exclusive breastfeeding for 6 months and total breastfeeding for at least 2 years. Despite this and multiple interventions promoting breastfeeding, early breastfeeding cessation remains high with little data as to the ongoing barriers contributing to early cessation. METHODS: Two groups of Nicaraguan mothers in an urban hospital were approached to complete a questionnaire to determine what newborn, maternal, and socioeconomic factors contributed to early cessation of breastfeeding. Group 1 participants were mothers of newborns in the newborn units, while group 2 were mothers of children 5 years or younger in the emergency room and pediatric ward. Descriptive statistics summarized the data. Fisher's exact test evaluated factors associated with early breastfeeding cessation. RESULTS: In group 1, 97 participants were enrolled with 81% of mothers planning to fulfill the guideline for exclusive breastfeeding for 6 months. In group 2, there were 139 mothers of which 58% reported they had exclusively breastfed for 6 months. Only 25 and 27% of mothers in group 1 and 2 respectively planned to breastfeed or breastfed for 2 years. In group 1, mothers reported lack of knowledge regarding breastfeeding techniques and older mothers tended to plan for early cessation of exclusive breastfeeding. In group 2, mothers reported feeling uncomfortable with breastfeeding in public or had difficulty with latching. Cessation of any breastfeeding prior to 12 months was associated with being uncomfortable breastfeeding in public and knowing the WHO guidelines. In both groups, social media represented an expanding platform for receiving breastfeeding information. CONCLUSIONS: Interventions focusing on reaching younger mothers and addressing breastfeeding knowledge and techniques while leveraging the increasing influence of social media platforms may help improve compliance with breastfeeding recommendations.

Erratum: Status of Retinoids and Carotenoids and Associations with Clinical Outcomes in Maternal-Infant Pairs in Nigeria. Nutrients 2018, 10, 1286.

Due to a mistake during the production process, there were spelling errors in four of the author names in the original published version [...].

Status of Retinoids and Carotenoids and Associations with Clinical Outcomes in Maternal-Infant Pairs in Nigeria.

Vitamin A is an essential nutrient in pregnancy, and other carotenoids have been independently associated with maternal-infant outcomes. The objective of this study was to quantify the status of vitamin A and carotenoids in Nigerian maternal-infant pairs at delivery, compare these to a cohort from a developed nation, and determine the impact on clinical outcomes. Maternal and cord blood samples were collected in 99 Nigerian mother-infant pairs. Concentrations of lutein + zeaxanthin, ß-cryptoxanthin, lycopene, α- and ß-carotenes, and retinol were measured using HPLC. Descriptive statistics were calculated and Spearman coefficients were used to assess correlations between maternal and cord measurements; Mann-Whitney tests were used to compare median plasma values between dichotomous variables. Linear regression models were used to adjust for relevant confounders. A p < 0.05 was considered statistically significant. Thirty-five percent of mothers had plasma retinol concentrations ≤0.70 µmol/L; 82% of infants had plasma retinol concentrations ≤0.70 µmol/L at delivery. Maternal and infant concentrations of vitamin A compounds were highly correlated and were associated with newborn growth and Apgar scores. Despite plasma concentrations of pro-vitamin A carotenoids higher than those reported in other populations, pregnant Nigerian women have a high prevalence of vitamin A deficiency. As vitamin A related compounds are modifiable by diet, future research determining the clinical impact of these compounds is warranted.

A Comparison of Vitamin E Status and Associated Pregnancy Outcomes in Maternal⁻Infant Dyads between a Nigerian and a United States Population.

Oxidative stress is associated with adverse pregnancy outcomes, and vitamin E has powerful anti-oxidant properties with the potential to impact health outcomes. Tocopherol isomers of vitamin E differ in their ability to modulate inflammation and vary in concentration in diets containing high proportions of processed versus unprocessed foods. The purpose of this study was to compare vitamin E status and associated pregnancy outcomes (mode of delivery, chorioamnionitis, APGARs (measure of appearance, pulse, grimace, activity, respiration), gestational age at delivery, and fetal growth) between maternal⁻infant dyads in a developed and a developing nation to identify potentially modifiable differences that may impact pregnancy and neonatal outcomes and provide a way to improve maternal and neonatal health. Plasma tocopherol levels were evaluated in 189 Midwestern United States (US) mother⁻infant pairs and 99 Central Nigerian mother⁻infant pairs. Maternal and infant concentrations of α-, γ-, and δ-tocopherol were measured using HPLC with diode-array detection. Descriptive statistics were calculated and tocopherol concentrations were associated with clinical outcomes such as mode of delivery, chorioamnionitis, APGARS, and fetal growth. Alpha- and γ-tocopherol levels were higher in the US mothers, (alpha: 12,357.9 (175.23⁻34,687.75) vs. 8333.1 (1576.59⁻16,248.40) (mcg/L); p < 0.001) (gamma: 340.7 (224.59⁻4385.95) vs. 357.5 (66.36⁻1775.31) (mcg/L); p < 0.001), while δ-tocopherol levels were higher in the Nigerian mothers (delta: 261.7 (24.70⁻1324.71) vs. 368.9 (43.06⁻1886.47) (mcg/L); p < 0.001). US infants had higher γ-tocopherol levels than Nigerian infants (203.1 (42.53⁻1953.23) vs. 113.8 (0.00⁻823.00) (mcg/L); p < 0.001), while both the Nigerian mothers and infants had higher α:γ-tocopherol ratios (8.5 vs. 26.2, and 8.9 vs. 18.8, respectively; p < 0.001). Our results in both populations show associations between increased circulating γ-tocopherol and negative outcomes like Caesarian sections, in contrast to the associations with positive outcomes such as vaginal delivery seen with increased α:γ-tocopherol ratios. Growth was positively associated with α- and γ-tocopherols in cord blood in the US population, and with cord blood δ-tocopherols in the Nigerian population. Tocopherol levels likely impact health outcomes in pregnancy in a complicated metabolism across the maternal⁻fetal axis that appears to be potentially influenced by culture and available diet.

Neonatal group B streptococcus disease in developing countries: are we ready to deploy a vaccine?

Group B streptococcus (GBS) disease is the leading cause of neonatal sepsis in developed countries and has high case fatality rates. In developing countries, however, the burden of GBS is less clear; this is due to a lack of studies using optimal diagnostic, clinical and laboratory techniques and is complicated by the wide availability of non-prescription antibiotics to the general population and in peripartum patients. There is an urgent need for prospective, population-based surveillance to provide an accurate assessment of neonatal GBS disease burden in developing countries, which remains largely unrecognized, and consequently obscures the potential relevance of GBS vaccination in these populations. Preliminary data on GBS vaccines are promising as a preventive tool for neonatal GBS infection, more so than any other currently available public health initiative. However, how do we assess the true impact of a GBS vaccine without accurate surveillance data on the real burden of disease?

Los anticuerpos monoclonales y su aplicabilidad clínica / Monoclonal antibodies and their clinical applicability

Los procesos de la evolución llegaron a una brillante solución. Crearon una molécula adaptable que de por sí era capaz no sólo de activar el sistema de complemento y de estimular las células fagocíticas, sino además de adherirse al microorganismo invasor. Esta molécula adaptable presentaba tres regiones principales, dos afectadas con la comunicación con el complemento y los fagocitos (funciones biológicas), y uno relacionado con la unión al microorganismo como individuo (la función de reconocimiento externo). El organismo debe producir cientos de miles, o aun millones de moléculas adaptables con sitios de reconocimiento diferentes. Esta molécula adaptadora se conoce como anticuerpo. En un principio se creía que los anticuerpos derivaban de una molécula plástica maestra que podía moldearse hasta adquirir la forma adecuada, con el antígeno como patrón, en la actualidad se sabe que los anticuerpos son formados antes de siquiera ver al antígeno, y que son seleccionados por él. El sistema funciona de la siguiente manera: cada linfocito de un subtipo denominado linfocitos B, es programado para formar uno y sólo un anticuerpo, y coloca ese anticuerpo sobre su superficie externa para actuar como receptor. Cuando un antígeno penetra en el organismo, es confrontado con un número deslumbrante de linfocitos, cada uno con un anticuerpo diferente, con un sitio individual de reconocimiento. El antígeno sólo se une a los receptores con los que se acopla en forma adecuada. Los linfocitos cuyos receptores están ligados a antígeno reciben una señal desencadenante y se desarrollan a células plasmáticas formadoras de anticuerpos, y dado que los linfocitos están programados para formar un único anticuerpo, el secretado por las células plasmáticas será idéntico al que actuó originalmente como receptor del linfocitos, es decir, se unirá bien al antígeno. De esta manera, el antígeno selecciona los anticuerpos que lo reconocen en forma eficaz...