Multidisciplinary Initiative to Increase Guideline-concordant Antibiotic Prescription at Discharge for Hospitalized Children with Uncomplicated Community-acquired Pneumonia.

Background: Clinical practice guidelines recommend using narrow-spectrum antibiotics to treat uncomplicated pneumonia in children. This quality improvement (QI) project aimed to evaluate if QI methods could improve guideline-concordant antibiotic prescribing at hospital discharge for children with uncomplicated pneumonia. Methods: For this single-center QI project, we implemented QI interventions in serial plan-do-study-act cycles, focusing on the key drivers targeting general pediatric inpatient resident teams. Interventions included: (1)Small bimonthly group didactic sessions, (2)Visual job aids posted in resident work areas, and (3) A noon conference session. Balancing measures included postdischarge emergency room visits, readmission and adverse drug reactions. Results: To establish a baseline rate, we conducted a chart review of 112 children diagnosed with uncomplicated community-acquired pneumonia during hospitalization from July 2017 through January 2019. The average monthly percentage of children discharged with guideline-concordant antibiotics was 67%. The intervention period was from February 2019 through February 2020, with 118 children meeting the criteria after a review of 262 charts. After our interventions, the average monthly percentage of children discharged with guideline-concordant antibiotics increased to 87%, with the increase persisting for at least 12 months. There were no significant differences in balancing measures pre- and post-interventions. Conclusions: Our QI initiative sustained increased rates of uncomplicated community-acquired pneumonia guideline-concordant antibiotic prescribing at discharge over 12 months without an increase in balancing measures. The enduring changes in prescribing behavior suggest a lasting impact of our interventions.

Ganciclovir-resistant cytomegalovirus retinitis in a 4-month-old infant.

We present a case of ganciclovir-resistant cytomegalovirus retinitis (CMV) in a 4-month-old boy with congenital CMV infection. This case highlights the potential utility of a combination of intermittent viral load monitoring and retinal examinations in cases of congenital CMV with retinitis.

Multisystem Inflammatory Syndrome after Breakthrough SARS-CoV-2 Infection in 2 Immunized Adolescents, United States.

Eight weeks after having laboratory-confirmed SARS-CoV-2 breakthrough infections, 2 otherwise healthy, fully immunized adolescent patients in the United States who were experiencing related signs and symptoms were diagnosed with multisystem inflammatory syndrome in children. Our findings indicate that COVID-19 vaccination does not completely protect adolescents against multisystem inflammatory syndrome.

Impact of Anaerobic Antibacterial Spectrum on Cystic Fibrosis Airway Microbiome Diversity and Pulmonary Function.

BACKGROUND: The role of anaerobic organisms in the cystic fibrosis (CF) lung microbiome is unclear. Our objectives were to investigate the effect of broad (BS) versus narrow (NS) spectrum antianaerobic antibiotic activity on lung microbiome diversity and pulmonary function, hypothesizing that BS antibiotics would cause greater change in microbiome diversity without a significant improvement in lung function. METHODS: Pulmonary function tests and respiratory samples were collected prospectively in persons with CF before and after treatment for pulmonary exacerbations. Treatment antibiotics were classified as BS or NS. Gene sequencing data from 16S rRNA were used for diversity analysis and bacterial genera classification. We compared the effects of BS versus NS on diversity indices, lung function and anaerobic/aerobic ratios. Statistical significance was determined by multilevel mixed-effects generalized linear models and mixed-effects regression models. RESULTS: Twenty patients, 6-20 years of age, experienced 30 exacerbations. BS therapy had a greater effect on beta diversity than NS therapy when comparing time points before antibiotics to after and at recovery. After antibiotics, the NS therapy group had a greater return toward baseline forced expiratory volume at 1 second and forced expiratory flow 25%-75% values than the BS group. The ratio of anaerobic/aerobic organisms showed a predominance of anaerobes in the NS group with aerobes dominating in the BS group. CONCLUSIONS: BS antianaerobic therapy had a greater and possibly longer lasting effect on the lung microbiome of persons with CF, without achieving the recovery of pulmonary function seen with the NS therapy. Specific antibiotic therapies may affect disease progression by changing the airway microbiome.

Epiglottitis Associated With Intermittent E-cigarette Use: The Vagaries of Vaping Toxicity.

An adolescent female patient presenting with subacute onset of dysphagia and hoarseness underwent a direct laryngoscopy, which revealed epiglottitis. After 2 hospitalizations and multiple consultations and biopsies, all infectious testing results for viral, bacterial, fungal, and acid-fast bacilli etiologies were negative. The patient's use of electronic cigarettes was the only exposure elicited with a likely role in her presentation. This case, combined with the growing body of evidence revealing the toxic effects of vaping and the increasing use of electronic cigarettes among adolescent patients, highlights the many unknowns and risks regarding the biological effects of this practice.

Impact of decolonization on methicillin-resistant Staphylococcus aureus transmission and infection in a neonatal intensive care unit.

BACKGROUND: The value of decolonization as a strategy for preventing methicillin-resistantStaphylococcus aureus (MRSA) in the neonatal intensive care unit (NICU) remains to be determined. OBJECTIVE: After adding decolonization to further reduce MRSA transmission in our NICU, we conducted this retrospective review to evaluate its effectiveness. METHOD: The review included patients who were admitted to our NICU between April 2015 and June 2018 and were eligible for decolonization including twice daily intranasal mupirocin and daily chlorhexidine gluconate bathing over 5 consecutive days. Patients were considered successfully decolonized if 3 subsequent MRSA screenings conducted at 1-week intervals were negative. The MRSA acquisition rate (AR) was calculated as hospital-acquired (HA) MRSA per 1,000 patient days (PD) and was used to measure the effectiveness of the decolonization. RESULTS: Of the 151 MRSA patients being reviewed, 78 (51.6%) were HA-MRSA, resulting in an overall AR of 1.27 per 1,000 PD. Between April 2015 and February 2016, when only the decolonization was added, the AR was 2.38 per 1,000 PD. Between March 2016 and June 2018 after unit added a technician dedicated to the cleaning of reusable equipment, the AR decreased significantly to 0.92 per 1,000 PD (P < .05). Of the 78 patients who were started on the decolonization, 49 (62.8%) completed the protocol, 11 (14.1%) remained colonized, and 13 (16.7%) were recolonized prior to NICU discharge. CONCLUSION: In a NICU with comprehensive MRSA prevention measures in place, enhancing the cleaning of reusable equipment, not decolonization, led to significant reduction of MRSA transmission.

From paper to practice: Strategies for improving antibiotic stewardship in the pediatric ambulatory setting.

Antibiotic stewardship aims to better patient outcomes, reduce antibiotic resistance, and decrease unnecessary health care costs by improving appropriate antibiotic use. More than half of annual antibiotic expenditures for antibiotics in the United States are prescribed in the ambulatory setting. This review provides a summary of evidence based strategies shown to improve antibiotic prescribing in ambulatory care settings including: providing education to patients and their families, providing education to clinicians regarding best practices for specific conditions, providing communications training to clinicians, implementing disease-specific treatment algorithms, implementing delayed prescribing for acute otitis media, supplying prescribing feedback to providers with peer comparisons, using commitment letters, and prompting providers to justify antibiotic prescribing for diagnoses for which antibiotics are not typically recommended. These various mechanisms to improve stewardship can be tailored to a specific practice's work flow and culture. Interventions should be used in combination to maximize impact. The intent with this review is to provide an overview of strategies that pediatric providers can take from paper to practice.

Hypersensitivity to contact inhibition provides a clue to cancer resistance of naked mole-rat.

The naked mole-rat is the longest living rodent with a maximum lifespan exceeding 28 years. In addition to its longevity, naked mole-rats have an extraordinary resistance to cancer as tumors have never been observed in these rodents. Furthermore, we show that a combination of activated Ras and SV40 LT fails to induce robust anchorage-independent growth in naked mole-rat cells, while it readily transforms mouse fibroblasts. The mechanisms responsible for the cancer resistance of naked mole-rats were unknown. Here we show that naked mole-rat fibroblasts display hypersensitivity to contact inhibition, a phenomenon we termed "early contact inhibition." Contact inhibition is a key anticancer mechanism that arrests cell division when cells reach a high density. In cell culture, naked mole-rat fibroblasts arrest at a much lower density than those from a mouse. We demonstrate that early contact inhibition requires the activity of p53 and pRb tumor suppressor pathways. Inactivation of both p53 and pRb attenuates early contact inhibition. Contact inhibition in human and mouse is triggered by the induction of p27(Kip1). In contrast, early contact inhibition in naked mole-rat is associated with the induction of p16(Ink4a). Furthermore, we show that the roles of p16(Ink4a) and p27(Kip1) in the control of contact inhibition became temporally separated in this species: the early contact inhibition is controlled by p16(Ink4a), and regular contact inhibition is controlled by p27(Kip1). We propose that the additional layer of protection conferred by two-tiered contact inhibition contributes to the remarkable tumor resistance of the naked mole-rat.

DNA repair by nonhomologous end joining and homologous recombination during cell cycle in human cells.

DNA double-strand breaks (DSBs) are dangerous lesions that can lead to potentially oncogenic genomic rearrangements or cell death. The two major pathways for repair of DSBs are nonhomologous end joining (NHEJ) and homologous recombination (HR). NHEJ is an intrinsically error-prone pathway while HR results in accurate repair. To understand the origin of genomic instability in human cells it is important to know the contribution of each DSB repair pathway. Studies of rodent cells and human cancer cell lines have shown that the choice between NHEJ or HR pathways depends on cell cycle stage. Surprisingly, cell cycle regulation of DSB repair has not been examined in normal human cells with intact cell cycle checkpoints. Here we measured the efficiency of NHEJ and HR at different cell cycle stages in hTERT-immortalized diploid human fibroblasts. We utilized cells with chromosomally-integrated fluorescent reporter cassettes, in which a unique DSB is introduced by a rare-cutting endonuclease. We show that NHEJ is active throughout the cell cycle, and its activity increases as cells progress from G1 to G2/M (G1 < S < G2/M). HR is nearly absent in G1, most active in the S phase, and declines in G2/M. Thus, in G2/M NHEJ is elevated, while HR is on decline. This is in contrast to a general belief that NHEJ is most active in G1, while HR is active in S, G2 and M. The overall efficiency of NHEJ was higher than HR at all cell cycle stages. We conclude that human somatic cells utilize error-prone NHEJ as the major DSB repair pathway at all cell cycle stages, while HR is used, primarily, in the S phase.

Distinct tumor suppressor mechanisms evolve in rodent species that differ in size and lifespan.

Large, long-lived species experience more lifetime cell divisions and hence a greater risk of spontaneous tumor formation than smaller, short-lived species. Large, long-lived species are thus expected to evolve more elaborate tumor suppressor systems. In previous work, we showed that telomerase activity coevolves with body mass, but not lifespan, in rodents: telomerase activity is repressed in the somatic tissues of large rodent species but remains active in small ones. Without telomerase activity, the telomeres of replicating cells become progressively shorter until, at some critical length, cells stop dividing. Our findings therefore suggested that repression of telomerase activity mitigates the increased risk of cancer in larger-bodied species but not necessarily longer-lived ones. These findings imply that other tumor suppressor mechanisms must mitigate increased cancer risk in long-lived species. Here, we examined the proliferation of fibroblasts from 15 rodent species with diverse body sizes and lifespans. We show that, consistent with repressed telomerase activity, fibroblasts from large rodents undergo replicative senescence accompanied by telomere shortening and overexpression of p16(Ink4a) and p21(Cip1/Waf1) cycline-dependent kinase inhibitors. Interestingly, small rodents with different lifespans show a striking difference: cells from small shorter-lived species display continuous rapid proliferation, whereas cells from small long-lived species display continuous slow proliferation. We hypothesize that cells of small long-lived rodents, lacking replicative senescence, have evolved alternative tumor-suppressor mechanisms that prevent inappropriate cell division in vivo and slow cell growth in vitro. Thus, large-bodied species and small but long-lived species have evolved distinct tumor suppressor mechanisms.

Comparison of nonhomologous end joining and homologous recombination in human cells.

The two major pathways for repair of DNA double-strand breaks (DSBs) are homologous recombination (HR) and nonhomologous end joining (NHEJ). HR leads to accurate repair, while NHEJ is intrinsically mutagenic. To understand human somatic mutation it is essential to know the relationship between these pathways in human cells. Here we provide a comparison of the kinetics and relative contributions of HR and NHEJ in normal human cells. We used chromosomally integrated fluorescent reporter substrates for real-time in vivo monitoring of the NHEJ and HR. By examining multiple integrated clones we show that the efficiency of NHEJ and HR is strongly influenced by chromosomal location. Furthermore, we show that NHEJ of compatible ends (NHEJ-C) and NHEJ of incompatible ends (NHEJ-I) are fast processes, which can be completed in approximately 30 min, while HR is much slower and takes 7h or longer to complete. In actively cycling cells NHEJ-C is twice as efficient as NHEJ-I, and NHEJ-I is three times more efficient than HR. Our results suggest that NHEJ is a faster and more efficient DSB repair pathway than HR.

Rodents for comparative aging studies: from mice to beavers.

After humans, mice are the best-studied mammalian species in terms of their biology and genetics. Gerontological research has used mice and rats extensively to generate short- and long-lived mutants, study caloric restriction and more. Mice and rats are valuable model organisms thanks to their small size, short lifespans and fast reproduction. However, when the goal is to further extend the already long human lifespan, studying fast aging species may not provide all the answers. Remarkably, in addition to the fast-aging species, the order Rodentia contains multiple long-lived species with lifespans exceeding 20 years (naked mole-rat, beavers, porcupines, and some squirrels). This diversity opens great opportunities for comparative aging studies. Here we discuss the evolution of lifespan in rodents, review the biology of slow-aging rodents, and show an example of how the use of a comparative approach revealed that telomerase activity coevolved with body mass in rodents.