Defining the influence of Rad51 and Dmc1 lineage-specific amino acids on genetic recombination.

The vast majority of eukaryotes possess two DNA recombinases: Rad51, which is ubiquitously expressed, and Dmc1, which is meiosis-specific. The evolutionary origins of this two-recombinase system remain poorly understood. Interestingly, Dmc1 can stabilize mismatch-containing base triplets, whereas Rad51 cannot. Here, we demonstrate that this difference can be attributed to three amino acids conserved only within the Dmc1 lineage of the Rad51/RecA family. Chimeric Rad51 mutants harboring Dmc1-specific amino acids gain the ability to stabilize heteroduplex DNA joints with mismatch-containing base triplets, whereas Dmc1 mutants with Rad51-specific amino acids lose this ability. Remarkably, RAD-51 from Caenorhabditis elegans, an organism without Dmc1, has acquired "Dmc1-like" amino acids. Chimeric C. elegans RAD-51 harboring "canonical" Rad51 amino acids gives rise to toxic recombination intermediates, which must be actively dismantled to permit normal meiotic progression. We propose that Dmc1 lineage-specific amino acids involved in the stabilization of heteroduplex DNA joints with mismatch-containing base triplets may contribute to normal meiotic recombination.

Increased chromosomal mobility after DNA damage is controlled by interactions between the recombination machinery and the checkpoint.

During homologous recombination, cells must coordinate repair, DNA damage checkpoint signaling, and movement of chromosomal loci to facilitate homology search. In Saccharomyces cerevisiae, increased movement of damaged loci (local mobility) and undamaged loci (global mobility) precedes homolog pairing in mitotic cells. How cells modulate chromosome mobility in response to DNA damage remains unclear. Here, we demonstrate that global chromosome mobility is regulated by the Rad51 recombinase and its mediator, Rad52. Surprisingly, rad51Δ rad52Δ cells display checkpoint-dependent constitutively increased mobility, indicating that a regulatory circuit exists between recombination and checkpoint machineries to govern chromosomal mobility. We found that the requirement for Rad51 in this circuit is distinct from its role in recombination and that interaction with Rad52 is necessary to alleviate inhibition imposed by mediator recruitment to ssDNA. Thus, interplay between recombination factors and the checkpoint restricts increased mobility until recombination proteins are assembled at damaged sites.

Pediatric Antimicrobial Stewardship Programs Reduce Antibiotic Use at Combined Adult-Pediatric Hospitals.

Implementation of dedicated pediatric antimicrobial stewardship programs (ASPs) at two combined adult-pediatric hospitals with existing ASPs was associated with sustained decreases in pediatric antibiotic use (AU) out of proportion to declines seen in adult inpatient units. ASPs in combined hospitals may not detect excessive pediatric AU without incorporating pediatric expertise.

A Phase 2 Clinical Trial to Evaluate the Safety, Reactogenicity, and Immunogenicity of Different Prime-Boost Vaccination Schedules of 2013 and 2017 A(H7N9) Inactivated Influenza Virus Vaccines Administered With and Without AS03 Adjuvant in Healthy US Adults.

INTRODUCTION: A surge of human influenza A(H7N9) cases began in 2016 in China from an antigenically distinct lineage. Data are needed about the safety and immunogenicity of 2013 and 2017 A(H7N9) inactivated influenza vaccines (IIVs) and the effects of AS03 adjuvant, prime-boost interval, and priming effects of 2013 and 2017 A(H7N9) IIVs. METHODS: Healthy adults (n = 180), ages 19-50 years, were enrolled into this partially blinded, randomized, multicenter phase 2 clinical trial. Participants were randomly assigned to 1 of 6 vaccination groups evaluating homologous versus heterologous prime-boost strategies with 2 different boost intervals (21 vs 120 days) and 2 dosages (3.75 or 15 µg of hemagglutinin) administered with or without AS03 adjuvant. Reactogenicity, safety, and immunogenicity measured by hemagglutination inhibition and neutralizing antibody titers were assessed. RESULTS: Two doses of A(H7N9) IIV were well tolerated, and no safety issues were identified. Although most participants had injection site and systemic reactogenicity, these symptoms were mostly mild to moderate in severity; injection site reactogenicity was greater in vaccination groups receiving adjuvant. Immune responses were greater after an adjuvanted second dose, and with a longer interval between prime and boost. The highest hemagglutination inhibition geometric mean titer (95% confidence interval) observed against the 2017 A(H7N9) strain was 133.4 (83.6-212.6) among participants who received homologous, adjuvanted 3.75 µg + AS03/2017 doses with delayed boost interval. CONCLUSIONS: Administering AS03 adjuvant with the second H7N9 IIV dose and extending the boost interval to 4 months resulted in higher peak antibody responses. These observations can broadly inform strategic approaches for pandemic preparedness. Clinical Trials Registration. NCT03589807.

Opportunistic dried blood spot sampling validates and optimizes a pediatric population pharmacokinetic model of metronidazole.

Pharmacokinetic models rarely undergo external validation in vulnerable populations such as critically ill infants, thereby limiting the accuracy, efficacy, and safety of model-informed dosing in real-world settings. Here, we describe an opportunistic approach using dried blood spots (DBS) to evaluate a population pharmacokinetic model of metronidazole in critically ill preterm infants of gestational age (GA) ≤31 weeks from the Metronidazole Pharmacokinetics in Premature Infants (PTN_METRO, NCT01222585) study. First, we used linear correlation to compare 42 paired DBS and plasma metronidazole concentrations from 21 preterm infants [mean (SD): post natal age 28.0 (21.7) days, GA 26.3 (2.4) weeks]. Using the resulting predictive equation, we estimated plasma metronidazole concentrations (ePlasma) from 399 DBS collected from 122 preterm and term infants [mean (SD): post natal age 16.7 (15.8) days, GA 31.4 (5.1) weeks] from the Antibiotic Safety in Infants with Complicated Intra-Abdominal Infections (SCAMP, NCT01994993) trial. When evaluating the PTN_METRO model using ePlasma from the SCAMP trial, we found that the model generally predicted ePlasma well in preterm infants with GA ≤31 weeks. When including ePlasma from term and preterm infants with GA >31 weeks, the model was optimized using a sigmoidal Emax maturation function of postmenstrual age on clearance and estimated the exponent of weight on volume of distribution. The optimized model supports existing dosing guidelines and adds new data to support a 6-hour dosing interval for infants with postmenstrual age >40 weeks. Using an opportunistic DBS to externally validate and optimize a metronidazole population pharmacokinetic model was feasible and useful in this vulnerable population.

Use of the Child Opportunity Index to Examine Racial Variations in Outpatient Antibiotic Prescribing to Children.

To examine further racial and ethnic variations in antibiotic prescribing to children, we used the Child Opportunity Index. Black children were less likely to be prescribed an antibiotic. Low- and moderate-opportunity areas were associated with greater rates of antibiotic prescribing, after adjusting for race and other factors.

Law Enforcement and Patient Privacy Among Survivors of Violence: A Nationwide Mixed-Methods Study.

INTRODUCTION: During the emergent treatment of violently injured patients, law enforcement (LE) officers and health care providers frequently interact. Both have duties to protect patient health, rights, and public health, however, the balance of these duties may feel at odds. The purpose of this study is to assess hospital-based violence intervention program (HVIP) representatives' experiences with LE officers among survivors of violence and the impact of hospital policies on interactions with LE officers. MATERIALS AND METHODS: A nationwide survey was distributed to the 35 HVIPs that form the Health Alliance for Violence Intervention. Data regarding respondent affiliation, programs, and perceptions of hospital policies outlining LE activity were collected. Follow-up video interviews were open coded and qualitatively analyzed using grounded theory. RESULTS: Respondents from 32 HVIPs completed the survey (91%), and 22 interviews (63%) were conducted. Common themes from interviews were: police-patient interactions; racism, bias, and victims' treatment as suspects; and training and education. Only 39% of respondents knew that policies existed and were familiar with them. Most representatives believed their hospitals' existing policies were inadequate, ineffective, or biased. Programs that reported good working relationships with LE officers offered insight on how their programs maintain these partnerships and work with LE officers towards a common goal. CONCLUSIONS: Unclear or inadequate policies relating to LE activity may jeopardize the health and privacy of violently injured patients. Primary areas identified for improvement include clarifying and revising hospital policies, education of staff and LE officers, and improved communication between health care providers and LE officers to better protect patient rights.

Prehospital Sepsis Recognition and Outcomes for Patients with Sepsis by Race and Ethnicity.

BACKGROUND: First medical contact for patients with sepsis often initiates in the prehospital setting, yet limited studies have explored the EMS sepsis recognition-mortality relationship. Racial and ethnic minority patients often have worse sepsis outcomes, yet the role of prehospital recognition in this inequity has not been explored. Our objective was to describe prehospital sepsis recognition and hospital mortality, with analysis by patient race and ethnicity. METHODS: Using linked EMS and hospital records from the 2021 ESO Data Collaborative, we retrospectively analyzed 9-1-1 EMS transports for adult patients with emergency department ICD-10 sepsis diagnosis codes. EMS sepsis recognition was defined as a primary or secondary sepsis impression, use of an electronic health record specialty sepsis form, or a prehospital sepsis alert. We used multivariable logistic regression to assess the association between EMS sepsis recognition and hospital mortality, adjusting for age, sex, race and ethnicity, scene socioeconomic status, and documented clinical characteristics: altered mental status, hypotension, tachypnea, tachycardia, fever. We conducted a secondary analysis of patients who were positive for the quick sequential organ failure assessment (qSOFA) using first prehospital vital signs. RESULTS: We analyzed 20,172 records for EMS-transported patients with diagnosed sepsis. Overall, 8% of patients were Black, 8% were Hispanic, and 72% were White. Prehospital sepsis recognition was 18%. Prehospital sepsis recognition was similar across racial and ethnic groups (Black: 17.2%, Hispanic: 17.4%, White: 18.1%) and adjusted odds of sepsis recognition did not differ between racial and ethnic groups. Overall mortality was 11% (2,186). Prehospital sepsis recognition was associated with a 18% reduction in adjusted odds of mortality (OR: 0.82, 95% CI: 0.70-0.94). Of patients who were qSOFA positive in the field (n = 2,168), EMS sepsis recognition was 32% and was similar across race and ethnicities. Adjusted odds of mortality were 0.68 (95% CI: 0.53-0.88) when sepsis was recognized in the prehospital setting. CONCLUSION: EMS identified sepsis in fewer than one in three patients even after limiting to those positive for qSOFA, without differences by race and ethnicity. EMS sepsis recognition was associated with reduced odds of mortality; however, Black patients remained at greater odds of death suggesting additional factors that warrant investigation.

Prevention of pneumococcal infections in childhood: two decades of progress.

PURPOSE OF REVIEW: This review highlights progress in combating pediatric pneumococcal disease in the era of pneumococcal conjugate vaccines (PCVs). This review is timely given the development of increased valency PCVs for potential use in children. RECENT FINDINGS: Countries implementing vaccination programs with PCVs have witnessed dramatic reductions in cases of childhood invasive pneumococcal disease (IPD). In the US, the largest decline of IPD followed the introduction of 7-valent PCV with additional decreases following the switch to 13-valent PCV (PCV13). Despite these gains, IPD still occurs in the US but at much lower rates. Likewise, pneumonia hospitalizations and office visits for otitis media have decreased. Nasopharyngeal colonization with pneumococci has persisted due to replacement by nonvaccine serotypes: colonizing non-PCV13 serotypes have less invasive potential. The PCV era has also been marked by reductions in the proportions of pneumococcus showing nonsusceptibility or resistance to some antimicrobial agents. Furthermore, PCVs have an excellent safety profile. SUMMARY: Despite proven safety and efficacy, childhood vaccination programs in some countries do not include PCVs, resulting in the majority of global deaths attributable to pneumococcus. Increased worldwide vaccination of children and the development of higher valency vaccines holds additional promise for further reductions in childhood IPD.

Myocarditis Cases Reported After mRNA-Based COVID-19 Vaccination in the US From December 2020 to August 2021.

Importance: Vaccination against COVID-19 provides clear public health benefits, but vaccination also carries potential risks. The risks and outcomes of myocarditis after COVID-19 vaccination are unclear. Objective: To describe reports of myocarditis and the reporting rates after mRNA-based COVID-19 vaccination in the US. Design, Setting, and Participants: Descriptive study of reports of myocarditis to the Vaccine Adverse Event Reporting System (VAERS) that occurred after mRNA-based COVID-19 vaccine administration between December 2020 and August 2021 in 192 405 448 individuals older than 12 years of age in the US; data were processed by VAERS as of September 30, 2021. Exposures: Vaccination with BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna). Main Outcomes and Measures: Reports of myocarditis to VAERS were adjudicated and summarized for all age groups. Crude reporting rates were calculated across age and sex strata. Expected rates of myocarditis by age and sex were calculated using 2017-2019 claims data. For persons younger than 30 years of age, medical record reviews and clinician interviews were conducted to describe clinical presentation, diagnostic test results, treatment, and early outcomes. Results: Among 192 405 448 persons receiving a total of 354 100 845 mRNA-based COVID-19 vaccines during the study period, there were 1991 reports of myocarditis to VAERS and 1626 of these reports met the case definition of myocarditis. Of those with myocarditis, the median age was 21 years (IQR, 16-31 years) and the median time to symptom onset was 2 days (IQR, 1-3 days). Males comprised 82% of the myocarditis cases for whom sex was reported. The crude reporting rates for cases of myocarditis within 7 days after COVID-19 vaccination exceeded the expected rates of myocarditis across multiple age and sex strata. The rates of myocarditis were highest after the second vaccination dose in adolescent males aged 12 to 15 years (70.7 per million doses of the BNT162b2 vaccine), in adolescent males aged 16 to 17 years (105.9 per million doses of the BNT162b2 vaccine), and in young men aged 18 to 24 years (52.4 and 56.3 per million doses of the BNT162b2 vaccine and the mRNA-1273 vaccine, respectively). There were 826 cases of myocarditis among those younger than 30 years of age who had detailed clinical information available; of these cases, 792 of 809 (98%) had elevated troponin levels, 569 of 794 (72%) had abnormal electrocardiogram results, and 223 of 312 (72%) had abnormal cardiac magnetic resonance imaging results. Approximately 96% of persons (784/813) were hospitalized and 87% (577/661) of these had resolution of presenting symptoms by hospital discharge. The most common treatment was nonsteroidal anti-inflammatory drugs (589/676; 87%). Conclusions and Relevance: Based on passive surveillance reporting in the US, the risk of myocarditis after receiving mRNA-based COVID-19 vaccines was increased across multiple age and sex strata and was highest after the second vaccination dose in adolescent males and young men. This risk should be considered in the context of the benefits of COVID-19 vaccination.

Prickle is phosphorylated by Nemo and targeted for degradation to maintain Prickle/Spiny-legs isoform balance during planar cell polarity establishment.

Planar cell polarity (PCP) instructs tissue patterning in a wide range of organisms from fruit flies to humans. PCP signaling coordinates cell behavior across tissues and is integrated by cells to couple cell fate identity with position in a developing tissue. In the fly eye, PCP signaling is required for the specification of R3 and R4 photoreceptors based upon their positioning relative to the dorso-ventral axis. The 'core' PCP pathway involves the asymmetric localization of two distinct membrane-bound complexes, one containing Frizzled (Fz, required in R3) and the other Van Gogh (Vang, required in R4). Inhibitory interactions between the cytosolic components of each complex reinforce asymmetric localization. Prickle (Pk) and Spiny-legs (Pk-Sple) are two antagonistic isoforms of the prickle (pk) gene and are cytoplasmic components of the Vang complex. The balance between their levels is critical for tissue patterning, with Pk-Sple being the major functional isoform in the eye. Here we uncover a post-translational role for Nemo kinase in limiting the amount of the minor isoform Pk. We identified Pk as a Nemo substrate in a genome-wide in vitro band-shift screen. In vivo, nemo genetically interacts with pkpk but not pksple and enhances PCP defects in the eye and leg. Nemo phosphorylation limits Pk levels and is required specifically in the R4 photoreceptor like the major isoform, Pk-Sple. Genetic interaction and biochemical data suggest that Nemo phosphorylation of Pk leads to its proteasomal degradation via the Cullin1/SkpA/Slmb complex. dTAK and Homeodomain interacting protein kinase (Hipk) may also act together with Nemo to target Pk for degradation, consistent with similar observations in mammalian studies. Our results therefore demonstrate a mechanism to maintain low levels of the minor Pk isoform, allowing PCP complexes to form correctly and specify cell fate.

Hurricane Evacuation Laws in Eight Southern U.S. Coastal States - December 2018.

National Preparedness month is observed every September as a public service reminder of the importance of personal and community preparedness for all events; it coincides with the peak of the hurricane season in the United States. Severe storms and hurricanes can have long-lasting effects at all community levels. Persons who are prepared and well-informed are often better able to protect themselves and others (1). Major hurricanes can devastate low-lying coastal areas and cause injury and loss of life from storm surge, flooding, and high winds (2). State and local government entities play a significant role in preparing communities for hurricanes and by evacuating coastal communities before landfall to reduce loss of life from flooding, wind, and power outages (3). Laws can further improve planning and outreach for catastrophic events by ensuring explicit statutory authority over evacuations of communities at risk (4). State evacuation laws vary widely and might not adequately address information and communication flows to reach populations living in disaster-prone areas who are at risk. To understand the range of evacuation laws in coastal communities that historically have been affected by hurricanes, a systematic policy scan of the existing laws supporting hurricane evacuation in eight southern coastal states (Alabama, Florida, Georgia, Louisiana, Mississippi, North Carolina, South Carolina, and Texas) was conducted. After conducting a thematic analysis, this report found that all eight states have laws to execute evacuation orders, traffic control (egress/ingress), and evacuation to shelters. However, only four of the states have laws related to community outreach, delivery of public education programs, and public notice requirements. The findings in this report suggest a need for authorities in hurricane-prone states to review how to execute evacuation policies, particularly with respect to community outreach and communication to populations at risk. Implementation of state evacuation laws and policies that support hurricane evacuation management can help affected persons avoid harm and enhance community resiliency (5). Newly emerging and re-emerging infectious diseases, such as SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), have and will continue to additionally challenge hurricane evacuations.

Asymmetric Synthesis of Griffipavixanthone Employing a Chiral Phosphoric Acid-Catalyzed Cycloaddition.

Asymmetric synthesis of the biologically active xanthone dimer griffipavixanthone is reported along with its absolute stereochemistry determination. Synthesis of the natural product is accomplished via dimerization of a p-quinone methide using a chiral phosphoric acid catalyst to afford a protected precursor in excellent diastereo- and enantioselectivity. Mechanistic studies, including an unbiased computational investigation of chiral ion-pairs using parallel tempering, were performed in order to probe the mode of asymmetric induction.

Violating the Energy-Momentum Proportionality of Photonic Crystals in the Low-Frequency Limit.

We theoretically show that the frequency and momentum of a photon are not necessarily proportional to one another at low frequencies in photonic crystals comprising materials with positive- and negative-valued material properties. We rigorously determine closed-form conditions for the light cone to emanate from points other than the origin of k space, ultimately decoupling the first band from the origin and demonstrating light propagation at zero energy with nonzero crystal momentum. We also numerically show that first bands can originate from an arbitrary Bloch coordinate as well as from multiple coordinates simultaneously.

Variability in Antibiotic Use Across PICUs.

OBJECTIVES: To characterize and compare antibiotic prescribing across PICUs to evaluate the degree of variability. DESIGN: Retrospective analysis from 2010 through 2014 of the Pediatric Health Information System. SETTING: Forty-one freestanding children's hospital. SUBJECTS: Children aged 30 days to 18 years admitted to a PICU in children's hospitals contributing data to Pediatric Health Information System. INTERVENTIONS: To normalize for potential differences in disease severity and case mix across centers, a subanalysis was performed of children admitted with one of the 20 All Patient Refined-Diagnosis Related Groups and the seven All Patient Refined-Diagnosis Related Groups shared by all PICUs with the highest antibiotic use. RESULTS: The study included 3,101,201 hospital discharges from 41 institutions with 386,914 PICU patients. All antibiotic use declined during the study period. The median-adjusted antibiotic use among PICU patients was 1,043 days of therapy/1,000 patient-days (interquartile range, 977-1,147 days of therapy/1,000 patient-days) compared with 893 among non-ICU children (interquartile range, 805-968 days of therapy/1,000 patient-days). For PICU patients, the median adjusted use of broad-spectrum antibiotics was 176 days of therapy/1,000 patient-days (interquartile range, 152-217 days of therapy/1,000 patient-days) and was 302 days of therapy/1,000 patient-days (interquartile range, 220-351 days of therapy/1,000 patient-days) for antimethicillin-resistant Staphylococcus aureus agents, compared with 153 days of therapy/1,000 patient-days (interquartile range, 130-182 days of therapy/1,000 patient-days) and 244 days of therapy/1,000 patient-days (interquartile range, 203-270 days of therapy/1,000 patient-days) for non-ICU children. After adjusting for potential confounders, significant institutional variability existed in antibiotic use in PICU patients, in the 20 All Patient Refined-Diagnosis Related Groups with the highest antibiotic usage and in the seven All Patient Refined-Diagnosis Related Groups shared by all 41 PICUs. CONCLUSIONS: The wide variation in antibiotic use observed across children's hospital PICUs suggests inappropriate antibiotic use.

Parent Perspectives of Support Received from Physicians and/or Genetic Counselors Following a Decision to Continue a Pregnancy with a Prenatal Diagnosis of Trisomy 13/18.

Families that choose to continue a pregnancy with a prenatal diagnosis of Trisomy 13/18 are a minority that present unique challenges for those in charge of their care. This study investigated the extent to which these patients felt supported by their healthcare providers, and any differences in the perceived level of support experienced by those working with a physician versus those working with a genetic counselor. Two online support groups, SOFT and Hope for Trisomy, distributed an online survey to their members. Means, standard deviations and chi-square analysis were calculated to describe their responses. One-hundred fourteen surveys were included in the final analysis. Respondents were more likely to agree that genetic counselors provided unbiased information in a way that they understood, compared to physicians. Review of qualitative responses found that portrayal of Trisomy 13/18 by healthcare providers used directive language when describing the lethality, morbidity and burden of the condition. Language included terms such as "incompatible with life" and comments on burden to other family members. Healthcare providers can assist families that receive a prenatal diagnosis of Trisomy 13 or 18 by providing up-to-date written resources and connecting them with support groups for parents who have received a similar diagnosis. Our study found that involving genetic counselors in the prenatal care of these patients is likely beneficial.

Community pharmacists' beliefs regarding improvement of Star Ratings scores using the Theory of Planned Behavior.

OBJECTIVES: The Centers for Medicare and Medicaid Services (CMS) is moving toward a value-based model, which includes the Five-Star Quality Rating System (Star Ratings). Prescription Drug Plans include multiple pharmacy measures associated with adherence and patient safety that contribute to CMS Star Ratings scores. This study, using the Theory of Planned Behavior (TPB), explored factors associated with community pharmacists' beliefs to improve Star Ratings scores. DESIGN: Exploratory, qualitative, use of focus groups, and the TPB. SETTING AND PARTICIPANTS: Focus groups were performed in conference rooms at the College of Pharmacy main and satellite campuses. Participants were community retail pharmacists with an active Oklahoma license and 1 year of work experience. MAIN OUTCOME MEASURES: Each focus group was audio recorded and the recording transcribed to documents and analyzed with the use of a hybrid deductive and inductive qualitative approach rooted in a constant comparative framework. Coding of the data back to the TPB constitutes a deductive approach. The generation of themes and subthemes from other coded nodes constitutes an inductive approach. Analysts agreed on common themes, differences in findings, and saturation of the data gathered. RESULTS: Four focus groups were conducted with 26 participants in 2 categories: pharmacists with and without experience improving Star Ratings. Pharmacists shared and contrasted in salient, normative, and control beliefs about patient outcomes, data, financial implications, staff, technology, and other stakeholders associated with performance of improving Star Ratings. Themes regarding medication adherence, patient safety, and intention were also found. CONCLUSION: The TPB was used to explore beliefs of community pharmacists about improving Star Ratings scores. Themes that were identified will assist in future research for measuring intention to improve CMS Star Ratings scores and the development of training and education programs.

Biomimetic Total Synthesis of (±)-Griffipavixanthone via a Cationic Cycloaddition-Cyclization Cascade.

We report the concise, biomimetic total synthesis of the dimeric, Diels-Alder natural product griffipavixanthone from a readily accessible prenylated xanthone monomer. The key step utilizes a novel intermolecular [4+2] cycloaddition-cyclization cascade between a vinyl p-quinone methide and an in situ generated isomeric diene promoted by either Lewis or Brønsted acids. Experimental and computational studies of the reaction pathway suggest that a stepwise, cationic Diels-Alder cycloaddition is operative.

Pharmacokinetics of Clindamycin in Obese and Nonobese Children.

Although obesity is prevalent among children in the United States, pharmacokinetic (PK) data for obese children are limited. Clindamycin is a commonly used antibiotic that may require dose adjustment in obese children due to its lipophilic properties. We performed a clindamycin population PK analysis using data from three separate trials. A total of 420 samples from 220 children, 76 of whom had a body mass index greater than or equal to the 95th percentile for age, were included in the analysis. Compared to other metrics, total body weight (TBW) was the most robust measure of body size. The final model included TBW and a sigmoidal maturation relationship between postmenstrual age (PMA) and clearance (CL): CL (liters/hour) = 13.8 × (TBW/70)0.75 × [PMA2.83/(39.52.83+PMA2.83)]; volume of distribution (V) was associated with TBW, albumin (ALB), and alpha-1 acid glycoprotein (AAG): V (liters) = 63.6 × (TBW/70) × (ALB/3.3)-0.83 × (AAG/2.4)-0.25 After accounting for differences in TBW, obesity status did not explain additional interindividual variability in model parameters. Our findings support TBW-based dosing for obese and nonobese children.