Prenatally Diagnosed Large Lung Lesions: Timing of Resection and Perinatal Outcomes.

INTRODUCTION: Fetuses with large lung lesions including congenital cystic adenomatoid malformations (CCAMs) are at risk for cardiopulmonary compromise. Prenatal maternal betamethasone and cyst drainage for micro- and macrocystic lesions respectively have improved outcomes yet some lesions remain large and require resection before birth (open fetal surgery, OFS), at delivery via an Ex Utero Intrapartum Treatment (EXIT), or immediately post cesarean section (section-to-resection, STR). We sought to compare prenatal characteristics and outcomes in fetuses undergoing OFS, EXIT, or STR to inform decision-making and prenatal counseling. METHODS: A single institution retrospective review was conducted evaluating patients undergoing OFS, EXIT, or STR for prenatally diagnosed lung lesions from 2000 to 2021. Specimens were reviewed by an anatomic pathologist. Lesions were divided into "CCAMs" (the largest pathology group) and "all lung lesions" since pathologic diagnosis is not possible during prenatal evaluation when care decisions are made. Prenatal variables included initial, greatest, and final CCAM volume-ratio (CVR), betamethasone use/frequency, cyst drainage, and the presence of hydrops. Outcomes included survival, ECMO utilization, NICU length of stay (LOS), postnatal nitric oxide use, and ventilator days. RESULTS: Sixty-nine percent (59 of 85 patients) of lung lesions undergoing resection were CCAMs. Among patients with pathologic diagnosis of CCAM, the initial, largest, and final CVRs were greatest in OFS followed by EXIT and STR patients. Similarly, the incidence of hydrops was significantly greater and the rate of hydrops resolution was lower in the OFS group. Although the rate of cyst drainage did not differ between groups, maternal betamethasone use varied significantly (OFS 60.0%, EXIT 100.0%, STR 74.3%; p = 0.0378). Notably, all OFS took place prior to 2014. There was no difference in survival, ventilator days, nitric oxide, NICU LOS, or ECMO between groups. In multiple variable logistic modeling, determinants of survival to NICU discharge among patients undergoing resection with a pathologic diagnosis of CCAM included initial CVR <3.5 and need for <3 maternal betamethasone doses. CONCLUSION: For CCAMs that remain large despite maternal betamethasone or cyst drainage, surgical resection via OFS, EXIT, or STR are viable options with favorable and comparable survival between groups. In the modern era there has been a shift from OFS and EXIT procedures to STR for fetuses with persistently large lung lesions. This shift has been fueled by the increased use of maternal betamethasone and introduction of a Special Delivery Unit during the study period and the appreciation of similar fetal and neonatal outcomes for STR vs. EXIT and OFS with reduced maternal morbidity associated with a STR. Accordingly, efforts to optimize multidisciplinary perinatal care for fetuses with large lung lesions are important to inform patient selection criteria and promote STR as the preferred surgical approach in the modern era. LEVEL OF EVIDENCE: Level IV.

Ionizable Lipid Nanoparticles for Therapeutic Base Editing of Congenital Brain Disease.

Delivery of mRNA-based therapeutics to the perinatal brain holds great potential in treating congenital brain diseases. However, nonviral delivery platforms that facilitate nucleic acid delivery in this environment have yet to be rigorously studied. Here, we screen a diverse library of ionizable lipid nanoparticles (LNPs) via intracerebroventricular (ICV) injection in both fetal and neonatal mice and identify an LNP formulation with greater functional mRNA delivery in the perinatal brain than an FDA-approved industry standard LNP. Following in vitro optimization of the top-performing LNP (C3 LNP) for codelivery of an adenine base editing platform, we improve the biochemical phenotype of a lysosomal storage disease in the neonatal mouse brain, exhibit proof-of-principle mRNA brain transfection in vivo in a fetal nonhuman primate model, and demonstrate the translational potential of C3 LNPs ex vivo in human patient-derived brain tissues. These LNPs may provide a clinically translatable platform for in utero and postnatal mRNA therapies including gene editing in the brain.

Foetal genome editing.

PURPOSE OF REVIEW: The development of modern gene editing tools alongside promising innovations in gene sequencing and prenatal diagnostics as well as a shifting regulatory climate around targeted therapeutics offer an opportunity to address monogenic diseases prior to the onset of pathology. In this review, we seek to highlight recent progress in preclinical studies evaluating the potential in-utero gene editing as a treatment for monogenic diseases that cause morbidity or mortality before or shortly after birth. RECENT FINDINGS: There has been significant recent progress in clinical trials for postnatal gene editing. Corresponding advances have been made with respect to in-utero cell and enzyme replacement therapies. These precedents establish the foundation for 'one-shot' treatments by way in-utero gene editing. Compelling preclinical data in liver, pulmonary and multisystemic diseases demonstrate the potential benefits of in-utero editing approaches. SUMMARY: Recent proof-of-concept studies have demonstrated the safety and feasibility of in-utero gene editing across multiple organ systems and in numerous diseases. Clinical translation will require continued evolution of vectors and editing approaches to maximize efficiency and minimize unwanted treatment effects.

Fetal allotransplant recipients are resistant to graft-versus-host disease.

In utero hematopoietic cell transplantation (IUHCT) is an experimental treatment for congenital hemoglobinopathies, including Sickle cell disease and thalassemias. One of the principal advantages of IUHCT is the predisposition of the developing fetus toward immunologic tolerance. This allows for engraftment across immune barriers without immunosuppression and, potentially, decreased susceptibility to graft-versus-host disease (GVHD). We demonstrate fetal resistance to GVHD following T cell-replete allogeneic hematopoietic cell transplantation compared with the neonate. We show that this resistance is associated with elevated fetal serum interleukin-10 conducive to the induction of regulatory T cells (Tregs). Finally, we demonstrate that the adoptive transfer of Tregs from IUHCT recipients to neonates uniformly prevents GVHD, recapitulating the predisposition to tolerance observed after fetal allotransplantation. These findings demonstrate fetal resistance to GVHD following hematopoietic cell transplantation and elucidate Tregs as important contributors.

Ethics Considerations Regarding Artificial Womb Technology for the Fetonate.

Since the early 1980's, with the clinical advent of in vitro fertilization resulting in so-called "test tube babies," a wide array of ethical considerations and concerns regarding artificial womb technology (AWT) have been described. Recent breakthroughs in the development of extracorporeal neonatal life support by means of AWT have reinitiated ethical interest about this topic with a sense of urgency. Most of the recent ethical literature on the topic, however, pertains not to the more imminent scenario of a physiologically improved method of neonatal care through AWT, but instead to the remote scenario of "complete ectogenesis" that imagines human gestation occurring entirely outside of the womb. This scoping review of the ethical literature on AWT spans from more abstract concerns about complete ectogenesis to more immediate concerns about the soon-to-be-expected clinical life support of what we term the fetal neonate or fetonate. Within an organizing framework of different stages of human gestational development, from conception to the viable premature infant, we discuss both already identified and newly emerging ethical considerations and concerns regarding AWT and the care of the fetonate.

Enteral nutrition support for infants with pulmonary hypoplasia: A qualitative evaluation of caregiver and provider perspectives.

BACKGROUND: Enteral nutrition is a critical intervention that supports the growth of children with pulmonary hypoplasia (PH). We explored the experiences of caregivers and providers caring for children with PH to better understand gaps in knowledge transfer and identify barriers and facilitators to caregiving to inform interventions that may improve support. METHODS: This qualitative study included 10 interviews with caregivers and 10 clinical team members at a single integrated care program for children with PH. An inductive and iterative coding strategy was employed to produce a codebook. After cluster analysis, themes were generated to capture participant sentiments. RESULTS: Themes were defined along a care continuum (1) initiation, (2) adaptation, and (3) maintenance that represented distinct phases of adjustment to enteral nutrition support (1) in the perinatal period and initial neonatal intensive care unit (NICU) admission, (2) from discharge planning through the family's first days at home and establishment of a stable feeding regime, and (3) through long-term follow-up and weaning. Notable subthemes included uncertainty, partnerships in training, and obstacles to adaptation. CONCLUSIONS: Among children with PH, the caregiver-provider relationship during the perinatal and NICU course is critical to promoting caregiver adaptation to the needs of the child. Ongoing considerations to support resource alignment and transition to a stable feeding regimen may facilitate caregiver adjustment to a "new normal," culminating in successful growth and/or weaning. These findings will inform interventions focused on training curricula, discharge planning, and the provision of follow-up in the context of an integrated care program for PH.

The role of race in pediatric legal intervention as a cause of injury.

BACKGROUND: Previous studies have assessed the prevalence and nature of traumatic injuries due to legal intervention in adults. The purpose of this study is to characterize and understand legal intervention trauma in children. METHODS: The National Trauma Data Bank (NTDB) was queried from 2007 to 2015. Patients (0-18 years old) who sustained injuries due to legal intervention were compared to those injured from other causes in the general NTDB population. Descriptive statistics were used to characterize the study population. Multivariate logistic regression models were utilized to predict firearm trauma and mortality. RESULTS: 622 patients sustained injuries involving legal intervention. Compared to general NTDB pediatric population, those who sustained legal intervention injuries were more likely to be older (age 16.5 vs. 10.6, p < 0.01), male (91.96% vs. 34.95%, p < 0.01), test positive for illegal drugs (64.64% vs. 38.35%, p < 0.01) or alcohol (26.36% vs. 17.25%, p < 0.01), and be African-American (44.37% vs. 17.00%, p < 0.01), Latino (22.82% vs. 15.10%, p < 0.01), or Native American (0.96% vs.. 0.94%, p < 0.01). Logistic regression models identified an 11% increased odds (95% CI 1.02-1.21, p = 0.02) of death among African-Americans when compared to other racial groups receiving legal intervention trauma. African-American status was associated with a 12% increased odds (95% CI 1.02-1.22, p = 0.01) of firearm trauma when compared to other racial groups receiving legal intervention trauma. CONCLUSION: Legal intervention-related pediatric trauma disproportionately affects the African-American population. This is particularly pronounced in cases of firearm related injuries. LEVEL OF EVIDENCE: III.

Amniotic fluid stabilized lipid nanoparticles for in utero intra-amniotic mRNA delivery.

Congenital disorders resulting in pathological protein deficiencies are most often treated postnatally with protein or enzyme replacement therapies. However, treatment of these disorders in utero before irreversible disease onset could significantly minimize disease burden, morbidity, and mortality. One possible strategy for the prenatal treatment of congenital disorders is in utero delivery of messenger RNA (mRNA). mRNA is a nucleic acid therapeutic that has previously been investigated as a platform for protein replacement therapies and gene editing technologies. While viral vectors have been explored to induce intracellular expression of mRNA, they are limited in their clinical application due to risks associated with immunogenicity and genomic integration. As an alternative to viral vectors, safe and efficient in utero mRNA delivery can be achieved using ionizable lipid nanoparticles (LNPs). While LNPs have demonstrated potent in vivo mRNA delivery to the liver following intravenous administration, intra-amniotic delivery has the potential to deliver mRNA to cells and tissues beyond those in the liver, such as in the skin, lung, and digestive tract. However, LNP stability in fetal amniotic fluid and how this stability affects mRNA delivery has not been previously investigated. Here, we engineered a library of LNPs using orthogonal design of experiments (DOE) to evaluate how LNP structure affects their stability in amniotic fluid ex utero and whether a lead candidate identified from these stability measurements enables intra-amniotic mRNA delivery in utero. We used a combination of techniques including dynamic light scattering (DLS), transmission electron microscopy (TEM), and chromatography followed by protein content quantification to screen LNP stability in amniotic fluids. These results identified multiple lead LNP formulations that are highly stable in amniotic fluids ranging from small animals to humans, including mouse, sheep, pig, and human amniotic fluid samples. We then demonstrate that stable LNPs from the ex utero screen in mouse amniotic fluid enabled potent mRNA delivery in primary fetal lung fibroblasts and in utero following intra-amniotic injection in a murine model. This exploration of ex utero stability in amniotic fluids demonstrates a means by which to identify novel LNP formulations for prenatal treatment of congenital disorders via in utero mRNA delivery.

In utero adenine base editing corrects multi-organ pathology in a lethal lysosomal storage disease.

In utero base editing has the potential to correct disease-causing mutations before the onset of pathology. Mucopolysaccharidosis type I (MPS-IH, Hurler syndrome) is a lysosomal storage disease (LSD) affecting multiple organs, often leading to early postnatal cardiopulmonary demise. We assessed in utero adeno-associated virus serotype 9 (AAV9) delivery of an adenine base editor (ABE) targeting the Idua G→A (W392X) mutation in the MPS-IH mouse, corresponding to the common IDUA G→A (W402X) mutation in MPS-IH patients. Here we show efficient long-term W392X correction in hepatocytes and cardiomyocytes and low-level editing in the brain. In utero editing was associated with improved survival and amelioration of metabolic, musculoskeletal, and cardiac disease. This proof-of-concept study demonstrates the possibility of efficiently performing therapeutic base editing in multiple organs before birth via a clinically relevant delivery mechanism, highlighting the potential of this approach for MPS-IH and other genetic diseases.

InUtero Gene Therapy: Progress and Challenges.

In utero gene therapy has the potential to treat lethal and morbid perinatal diseases before birth. Small fetal size, a tolerogenic immune system, and dosing efficiency make the fetus a compelling patient. Numerous clinical, social, and institutional factors must be considered to achieve the promise of genetic treatment before birth.

Ionizable lipid nanoparticles for in utero mRNA delivery.

Clinical advances enable the prenatal diagnosis of genetic diseases that are candidates for gene and enzyme therapies such as messenger RNA (mRNA)-mediated protein replacement. Prenatal mRNA therapies can treat disease before the onset of irreversible pathology with high therapeutic efficacy and safety due to the small fetal size, immature immune system, and abundance of progenitor cells. However, the development of nonviral platforms for prenatal delivery is nascent. We developed a library of ionizable lipid nanoparticles (LNPs) for in utero mRNA delivery to mouse fetuses. We screened LNPs for luciferase mRNA delivery and identified formulations that accumulate within fetal livers, lungs, and intestines with higher efficiency and safety compared to benchmark delivery systems, DLin-MC3-DMA and jetPEI. We demonstrate that LNPs can deliver mRNAs to induce hepatic production of therapeutic secreted proteins. These LNPs may provide a platform for in utero mRNA delivery for protein replacement and gene editing.

The Cost of Quarantine: Projecting the Financial Impact of Canceled Elective Surgery on the Nation's Hospitals.

OBJECTIVE: We sought to quantify the financial impact of elective surgery cancellations in the US during COVID-19 and simulate hospitals' recovery times from a single period of surgery cessation. BACKGROUND: COVID-19 in the US resulted in cessation of elective surgery-a substantial driver of hospital revenue-and placed patients at risk and hospitals under financial stress. We sought to quantify the financial impact of elective surgery cancellations during the pandemic and simulate hospitals' recovery times. METHODS: Elective surgical cases were abstracted from the Nationwide Inpatient Sample (2016-2017). Time series were utilized to forecast March-May 2020 revenues and demand. Sensitivity analyses were conducted to calculate the time to clear backlog cases and match expected ongoing demand in the post-COVID period. Subset analyses were performed by hospital region and teaching status. RESULTS: National revenue loss due to major elective surgery cessation was estimated to be $22.3 billion (B). Recovery to market equilibrium was conserved across strata and influenced by pre- and post-COVID capacity utilization. Median recovery time was 12-22 months across all strata. Lower pre-COVID utilization was associated with fewer months to recovery. CONCLUSIONS: Strategies to mitigate the predicted revenue loss of $22.3B due to major elective surgery cessation will vary with hospital-specific supply-demand equilibrium. If patient demand is slow to return, hospitals should focus on marketing of services; if hospital capacity is constrained, efficient capacity expansion may be beneficial. Finally, rural and urban nonteaching hospitals may face increased financial risk which may exacerbate care disparities.

Knowledge, attitudes, and perceptions regarding the future of artificial intelligence in oral radiology in India: A survey.

PURPOSE: This study investigated knowledge, attitudes, and perceptions regarding the future of artificial intelligence (AI) for radiological diagnosis among dental specialists in central India. MATERIALS AND METHODS: An online survey was conducted consisting of 15 closed-ended questions using Google Forms and circulated among dental professionals in central India. The survey consisted of questions regarding participants' recognition of and attitudes toward AI, their opinions on directions of AI development, and their perceptions regarding the future of AI in oral radiology. RESULTS: Of the 250 participating dentists, 68% were already familiar with the concept of AI, 69% agreed that they expect to use AI for making dental diagnoses, 51% agreed that the major function of AI would be the interpretation of complicated radiographic scans, and 63% agreed that AI would have a future in India. CONCLUSION: This study concluded that dental specialists were well aware of the concept of AI, that AI programs could be used as an adjunctive tool by dentists to increasing their diagnostic precision when interpreting radiographs, and that AI has a promising role in radiological diagnosis.

ATS Core Curriculum 2020. Pediatric Pulmonary Medicine.

The American Thoracic Society Core Curriculum updates clinicians annually in adult and pediatric pulmonary disease, medical critical care, and sleep medicine, in a 3- to 4-year recurring cycle of topics. These topics will be presented at the 2020 International Conference. Below is the pediatric pulmonary medicine core, including pediatric hypoxemic respiratory failure; modalities in noninvasive management of chronic respiratory failure in childhood; surgical and nonsurgical management of congenital lung malformations; an update on smoke inhalation lung injury; an update on vaporizers, e-cigarettes, and other electronic delivery systems; pulmonary complications of sarcoidosis; pulmonary complications of congenital heart disease; and updates on the management of congenital diaphragmatic hernia.

Fast-Track Pancreaticoduodenectomy: Factors Associated with Early Discharge.

BACKGROUND: Pancreaticoduodenectomy is a complex surgery frequently associated with prolonged hospitalizations. However, there are a subset of patients discharged within 5 days from surgery; the preoperative and intraoperative characteristics of this subset are unknown. METHODS: The NSQIP Targeted Pancreatectomy Dataset was used from 2014 to 2016. Patients who died within 30 days were excluded. A total of 10,741 patients undergoing pancreaticoduodenectomy were identified. Univariable and multivariable logistic regression analyses were performed for preoperative and intraoperative ACS-NSQIP variables to identify predictors of early discharge. Early discharge was defined as discharge 3-5 days after surgery. RESULTS: A total of 1105 patients (10.3%) were discharged within 5 days following pancreaticoduodenectomy. On multivariable analysis, preoperative factors associated with early discharge included younger age (OR 0.988, p < 0.001), non-obesity (OR 0.737, p = 0.001), those receiving neoadjuvant chemotherapy (OR 1.424, p < 0.001), and lack of COPD (OR 0.489, p = 0.005) or hypertension (OR 0.805, p = 0.007). Intraoperative factors associated with early discharge on multivariable analysis were shorter operation duration (OR 0.999, p = 0.002), minimally invasive surgery (OR 3.537, p < 0.001), and hard pancreatic texture (OR 1.480, p < 0.001). Intraoperative factors associated with non-early discharge were epidural placement (OR 0.485, p < 0.001), drain placement (OR 0.308, p < 0.001), and jejunostomy tube placement (OR 0.278, p < 0.001). Patients discharged within 5 days had a 14.7% readmission rate compared to 17.0% for later discharges (p = 0.047). CONCLUSIONS: Multiple preoperative and intraoperative factors, including some that are potentially modifiable, were significantly associated with early discharge after pancreaticoduodenectomy. Patients with these characteristics may benefit from enhanced recovery after surgery programs and expedited disposition planning postoperatively.

Predictors of pediatric blunt cerebrovascular injury.

BACKGROUND/PURPOSE: Blunt cerebrovascular injury (BCVI) is clinically challenging because these injuries are hard to detect and can have serious neurological consequences, and optimal screening criteria have not been established for children. This study aims to determine risk factors for BCVI in pediatric patients and to evaluate screening practices in a single institutional series. METHODS: A retrospective review of all pediatric blunt trauma patients evaluated over a 10-year period was performed. Demographic, clinical, and radiographic data were reviewed, including the presence of adult risk factors for BCVI. Logistic regression analyses were performed with statistical significance established at p<0.05. RESULTS: Of the 11,596 patients evaluated during the study period, 1018 (8.8%) had at least one adult risk factor for BCVI, but only 62 (6.1% of those with risk factors) underwent angiographic evaluation. Overall, 11 BCVIs were observed, resulting in an incidence of 0.095%. All 11 patients with BCVI had at least one risk factor. Multivariate logistic regression analysis identified cervical spine fracture (OR 36.88 [8.36, 169.95]), GCS score ≤ 8 (OR 16.42 [2.16, 102.33]), male gender (OR 10.52 [1.33, 363.30]), Le Fort II or III facial fracture (OR 63.71 [2.16, 1124.68]), and ISS (unit OR 1.10 [1.04, 1.17]) as independent risk factors for BCVI. CONCLUSION: Adult screening criteria for BCVI appear appropriate for pediatric patients, but most at-risk children are not being screened. LEVEL OF EVIDENCE: Level III (retrospective case-control study).

Vessel sealing comparison: old school is still hip.

BACKGROUND: Ligation with either absorbable or non-absorbable sutures has been the traditional state of the art, but a proliferation of technology now offers a host of methods to close and divide vessels. Only limited data are available that objectively compare different vessel sealing methods. The objective of this study was to compare a broad variety of methods of surgical vessel closure in a reproducible, independent, standardized test-to-failure ex vivo pressure challenge. METHODS: Ten of the most common surgical sealing devices were represented in this study, including both mechanical and energy devices. Unfixed porcine carotid arteries were selected for testing. They were connected to a pump, and automated controlled infusion was initiated. Upon identification of a leak at the source of sealing, the maximum pressure in mmHg was logged. RESULTS: There were a total of 184 trials conducted using the 10 vessel sealing methods. The average burst pressure across all trials was 1100 mmHg with a range of 51.3-5171 mmHg. Suture-based methods displayed the highest average pressure until failure. Stapling methods showed the lowest burst pressures. All methods showed mean burst pressures above the "physiologically relevant" level of 250 mmHg. CONCLUSIONS: This study presents an independent, reproducible, ex vivo comparison of multiple methods of surgical arterial closure. In these laboratory conditions, tests to failure demonstrated widely varying sealing strength, highly dependent on method. All hemostatic modalities tested are capable of securing vessels safely and well above physiologic blood pressures, while suture-based methods were significantly stronger than other mechanical methods or modern energy devices.