Phase II Trial of Risk-Enabled Therapy After Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer (RETAIN 1).

Purpose: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by cystectomy is the standard of care for patients with muscle-invasive bladder cancer (MIBC). Mutations in DNA damage repair genes are associated with pathologic downstaging after NAC. We hypothesized that a combination of biomarker selection and clinical staging would identify patients for cystectomy-sparing active surveillance (AS).

Mechanisms of Alternative Lengthening of Telomeres.

In recent years, significant advances have been made in understanding the intricate details of the mechanisms underlying alternative lengthening of telomeres (ALT). Studies of a specialized DNA strand break repair mechanism, known as break-induced replication, and the advent of telomere-specific DNA damaging strategies and proteomic methodologies to profile the ribonucleoprotein composition of telomeres enabled the discovery of networks of proteins that coordinate the stepwise homology-directed DNA repair and DNA synthesis processes of ALT. These networks couple mediators of homologous recombination, DNA template-switching, long-range template-directed DNA synthesis, and DNA strand resolution with SUMO-dependent liquid condensate formation to create discrete nuclear bodies where telomere extension occurs.

Neonatal Morbidities, Neurodevelopmental Impairments, and Positive Health among Children Surviving Birth before 32 Weeks of Gestation.

Objectives: To evaluate positive health outcomes among children born at < 32 weeks of gestation and to determine whether children with three common neonatal morbidities and 2 neurodevelopmental impairments would have similar positive health outcomes to children and adolescents without these exposures and impairments.

Study Design: In this secondary analysis of prospectively acquired data derived from 3 multicenter cohorts of children born very preterm (the Extremely Low Gestational Age Newborn cohort [birth years 2001 to 2004], the Neurobehavior And Outcomes in Very Preterm Infants cohort [birth years 2014 to 2016], and the Developmental Impact of Neurobehavior And Outcomes in Very Preterm Infants Exposures cohort [birth years 2010 to 2020]), we examined associations between the 3 common neonatal morbidities (bronchopulmonary dysplasia, necrotizing enterocolitis, and intraventricular hemorrhage, diagnosed before hospital discharge), 2 neurodevelopmental impairments (developmental delays and cerebral palsy, diagnosed at preschool age follow-up), and perceptions of physical, mental, and social well-being (in either early childhood or adolescence), using the Patient-Reported Outcomes Measurement Information System scales for positive health.

Results: After adjusting for confounders, bronchopulmonary dysplasia, intraventricular hemorrhage, and cerebral palsy were associated with lower positive health scores, reported by parent-proxy during early childhood.

Crossing the border: Replication fork adducts move to lysosomes for autophagic repair.

In a recent study in Cell, Lascaux et al. implicate TEX264 in the autophagy-driven resolution of nuclear topoisomerase 1 cleavage complexes (TOP1cc) in lysosomes, altering current concepts on the mechanism of action for clinically relevant doses of TOP1 inhibitors.

Diagnosing a genetic disease in a donor-conceived child: case report and discussion of the ethical, legal, and practical issues.

We describe the unexpected challenges pediatricians may experience when children conceived with assisted reproduction are diagnosed with a rare genetic condition. A local case series triggered a dialogue between many stakeholders with varied expertise. Indeed, diagnosing a genetic disease in a child conceived by embryo, egg, or sperm donation is becoming more common now that genetic testing and in vitro fertilization (IVF) are readily accessible.

Pharmacoepidemiology of combination pulmonary vasodilator therapy in critically ill infants.

Background: New drugs to target different pathways in pulmonary hypertension has resulted in increased combination therapy, but details of this use in infants are not well described. In this large multicenter database study, we describe the pharmacoepidemiology of combination pulmonary vasodilator therapy in critically ill infants.

Methods: We identified inborn infants discharged home from a Pediatrix neonatal ICU from 1997 to 2020 exposed to inhaled nitric oxide, sildenafil, epoprostenol, or bosentan for greater than two consecutive days.

Internet-based, parent-led cognitive behavioral therapy for autistic youth with anxiety-related disorders: A randomized trial comparing email vs. telehealth support.

This study tested two versions of parent-led, Internet-delivered cognitive behavioral therapy for anxiety among autistic youth; one that provided weekly email support (iCBT-Email), and one that provided alternating bi-weekly emails and video calls (iCBT-Video) across 12 weeks. It was expected that those in the iCBT-Video condition would complete more treatment content, which in turn would lead to more anxiety improvement. Fifty-seven autistic youth (7-15 years-old) with anxiety disorders were randomized to iCBT-Email or iCBT-Video.

Long-term impact of COVID-19 pandemic: Moral tensions, distress, and injuries of healthcare workers.

Given the longevity of the COVID-19 pandemic, it is important to address the perceptions and experiences associated with the progression of the pandemic. This narrative can inform future strategies aimed at mitigating moral distress, injury, and chronic stress that restores resilience and well-being of HCWs. In this context, a longitudinal survey design was undertaken to explore how health care workers are experiencing the COVID-19 pandemic over time.

Molecular glues that inhibit deubiquitylase activity and inflammatory signalling.

Deubiquitylases (DUBs) are crucial in cell signalling and are often regulated by interactions within protein complexes. The BRCC36 isopeptidase complex (BRISC) regulates inflammatory signalling by cleaving K63-linked polyubiquitin chains on Type I interferon receptors (IFNAR1). As a Zn-dependent JAMM/MPN DUB, BRCC36 is challenging to target with selective inhibitors.

Social needs and healthcare utilization in NICU graduates.

Objective: Unplanned healthcare utilization after neonatal intensive care unit (NICU) discharge challenges families and healthcare systems. The impact of social needs on post-NICU healthcare utilization is underexplored. Our objective was to identify social needs among NICU graduates and examine associations between social needs and post-NICU healthcare utilization.

Equivalence of freeze-dried and liquid-frozen formulations of MVA-BN as smallpox and mpox vaccine.

Modified Vaccinia Ankara Bavarian Nordic (MVA-BN) as a smallpox and mpox vaccine has been approved in its liquid-frozen (LF) formulation in the US, Canada, and EU. A freeze-dried (FD) formulation may offer additional benefits, such as a longer shelf life and reduced dependence on cold chain storage and transport. In a phase 2 clinical trial, 651 vaccinia-naïve participants were vaccinated with two doses of MVA-BN LF or FD, 4 weeks apart.

Concordance of Cytomegalovirus Saliva and Urine Testing in Infants for the Detection of Congenital Infection.

Congenital cytomegalovirus is a leading cause of neurodevelopmental impairment and sensorineural hearing loss. We evaluated infants ≤21 days postnatal age who had both urine and saliva cytomegalovirus testing and determined concordance between the 2 tests and influence of very low birth weight on concordance. Discordance was low overall between urine and saliva testing; however, discordance was high in very low birth weight infants.

Use and utility of C-reactive protein (CRP) in neonatal early-onset sepsis: a secondary analysis of a prospective surveillance study.

Objective: Characterize C-reactive protein (CRP) within 72 postnatal hours in early-onset sepsis (EOS).

Study Design: Secondary analysis of a prospective surveillance study of neonates with EOS 2015-2017. We examined CRP use by center and neonatal characteristics, and CRP levels by time, neonatal characteristics, clinical signs, and pathogen.

The association of the room air challenge with long-term outcomes in extremely preterm infants.

Objective: Evaluate the association between results of the room air (RA) challenge and death, respiratory morbidity, and neurodevelopmental impairment (NDI) at 2 years' corrected age.

Study Design: Cohort study of infants born <27 weeks' gestational age who underwent a RA challenge to determine BPD diagnosis at 36 weeks postmenstrual age.

Results: Of 1022 infants eligible for the RA challenge, 554 underwent testing and 223 passed.

Epidemiology and outcomes of bacterial meningitis in the neonatal intensive care unit.

Objective: Examine pathogen distribution, antibiotic resistance patterns, and hospital outcomes of infants with bacterial meningitis in neonatal intensive care units (NICUs) in the US from 2013-2018.

Study Design: Infants were divided into 2 groups based on age at the time of meningitis: early-onset (0-3 days) and late-onset (>3 days). We compared demographics, clinical characteristics, epidemiology, hospital outcomes, distribution of organisms and resistance, and blood culture timing relative to cerebrospinal fluid culture.

PANGEN: an online platform for the comparison and creation of diagnostic gene panels.

Targeted gene panel sequencing is used to limit the search for causative genetic variants solely to genes with an established association with the phenotype. The design of gene panels is challenging due to the lack of consensus regarding phenotypic associations for some genes, which results in high variation in gene composition for the same panel offered by different laboratories. We developed PANGEN, a platform that provides a centralized resource for gene panel information, with the ability to compare and generate new intelligent diagnostic panels.

DCAF15 control of cohesin dynamics sustains acute myeloid leukemia.

The CRL4-DCAF15 E3 ubiquitin ligase complex is targeted by the aryl-sulfonamide molecular glues, leading to neo-substrate recruitment, ubiquitination, and proteasomal degradation. However, the physiological function of DCAF15 remains unknown. Using a domain-focused genetic screening approach, we reveal DCAF15 as an acute myeloid leukemia (AML)-biased dependency.

Acyclovir Dosing Practices Across a Multicenter Cohort of Neonatal Intensive Care Units.

Background: Acyclovir is the first-line therapy for neonatal herpes simplex virus infections. Therapy can mitigate morbidity and mortality but carries a risk for toxicity. We aimed to compare acyclovir dosing in neonatal intensive care units to published recommendations based on population pharmacokinetic (PopPK) analysis.

Postdiscontinuation Antibiotic Exposure in Hospitalized Infants at Risk for Late-onset Sepsis in the Neonatal Intensive Care Unit.

Background: In the neonatal intensive care unit, infants are at risk for late-onset sepsis. When blood cultures are negative, antibiotic stewardship efforts encourage stopping antibiotics, yet the duration of therapeutic exposure after the last dose is unknown.

Methods: This retrospective cohort study of simulated antibiotic exposures used published population pharmacokinetic models within drug-specific neonatal intensive care unit cohorts of preterm and term infants, postnatal age 7-60 days and exposed to cefepime, piperacillin-tazobactam or tobramycin.

Krause corpuscles are genital vibrotactile sensors for sexual behaviours.

Krause corpuscles, which were discovered in the 1850s, are specialized sensory structures found within the genitalia and other mucocutaneous tissues. The physiological properties and functions of Krause corpuscles have remained unclear since their discovery. Here we report the anatomical and physiological properties of Krause corpuscles of the mouse clitoris and penis and their roles in sexual behaviour.