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Leukemia and lymphoma are cancers affecting children, adolescents, and young adults and may affect reproductive outcomes and maternal metabolism. We evaluated for metabolic changes in newborns of mothers with a history of these cancers.A cross-sectional study was conducted on California births from 2007 to 2011 with linked maternal hospital discharge records, birth certificate, and newborn screening metabolites. History of leukemia or lymphoma was determined using ICD-9-CM codes from hospital discharge data and newborn metabolite data from the newborn screening program.A total of 2,068,038 women without cancer history and 906 with history of leukemia or lymphoma were included. After adjusting for differences in maternal age, infant sex, age at metabolite collection, gestational age, and birthweight, among newborns born to women with history of leukemia/lymphoma, several acylcarnitines were significantly (The varied metabolite levels suggest history of leukemia or lymphoma has metabolic impact on newborn offspring, which may have implications for future metabolic consequences such as necrotizing enterocolitis and urea cycle enzyme disorders in children born to mothers with a history of leukemia or lymphoma.

Human adenoviruses typically cause self-limited respiratory, gastrointestinal, and conjunctival infections in healthy children. In late 2021 and early 2022, several previously healthy children were identified with acute hepatitis and human adenovirus viremia.We usedA total of 15 children were identified with acute hepatitis - 6 (40%) who had hepatitis with an identified cause and 9 (60%) who had hepatitis without a known cause. Eight (89%) of the patients with hepatitis of unknown cause tested positive for human adenovirus. These 8 patients plus 1 additional patient referred to this facility for follow-up were included in this case series (median age, 2 years 11 months; age range, 1 year 1 month to 6 years 5 months). Liver biopsies indicated mild-to-moderate active hepatitis in 6 children, some with and some without cholestasis, but did not show evidence of human adenovirus on immunohistochemical examination or electron microscopy. PCR testing of liver tissue for human adenovirus was positive in 3 children (50%). Sequencing of specimens from 5 children showed three distinct human adenovirus type 41 hexon variants. Two children underwent liver transplantation; all the others recovered with supportive care.Human adenovirus viremia was present in the majority of children with acute hepatitis of unknown cause admitted to Children's of Alabama from October 1, 2021, to February 28, 2022, but whether human adenovirus was causative remains unclear. Sequencing results suggest that if human adenovirus was causative, this was not an outbreak driven by a single strain. (Funded in part by the Centers for Disease Control and Prevention.).

Motor cortex (M1) has been thought to form a continuous somatotopic homunculus extending down the precentral gyrus from foot to face representations1,2, despite evidence for concentric functional zones3 and maps of complex actions4. Here, using precision functional magnetic resonance imaging (fMRI) methods, we find that the classic homunculus is interrupted by regions with distinct connectivity, structure and function, alternating with effector-specific (foot, hand and mouth) areas. These inter-effector regions exhibit decreased cortical thickness and strong functional connectivity to each other, as well as to the cingulo-opercular network (CON), critical for action5 and physiological control6, arousal7, errors8 and pain9. This interdigitation of action control-linked and motor effector regions was verified in the three largest fMRI datasets. Macaque and pediatric (newborn, infant and child) precision fMRI suggested cross-species homologues and developmental precursors of the inter-effector system. A battery of motor and action fMRI tasks documented concentric effector somatotopies, separated by the CON-linked inter-effector regions. The inter-effectors lacked movement specificity and co-activated during action planning (coordination of hands and feet) and axial body movement (such as of the abdomen or eyebrows). These results, together with previous studies demonstrating stimulation-evoked complex actions4 and connectivity to internal organs10 such as the adrenal medulla, suggest that M1 is punctuated by a system for whole-body action planning, the somato-cognitive action network (SCAN). In M1, two parallel systems intertwine, forming an integrate–isolate pattern: effector-specific regions (foot, hand and mouth) for isolating fine motor control and the SCAN for integrating goals, physiology and body movement.

Objective Develop and validate a resiliency score to predict survival and survival without neonatal morbidity in preterm neonates Study design Models using maternal, perinatal, and neonatal variables were developed using LASSO method in a population based Californian administrative dataset. Outcomes were survival and survival without severe neonatal morbidity. Discrimination was assessed in the derivation and an external dataset from a tertiary care center. Results Discrimination in the internal validation dataset was excellent with a c-statistic of 0.895 (95% CI 0.882–0.908) for survival and 0.867 (95% CI 0.857–0.877) for survival without severe neonatal morbidity, respectively. Discrimination remained high in the external validation dataset (c-statistic 0.817, CI 0.741–0.893 and 0.804, CI 0.770–0.837, respectively). Conclusion Our successfully predicts survival and survival without major morbidity in preterm babies born at

BACKGROUND: The services of Healthcare and Social Assistance (HCSA) workers are needed by society around the clock. As a result, these workers are exposed to shift work and long work hours. The combination of demanding work schedules and other hazards in the HCSA work environment increases the health and safety risks to these workers, as well as to their patients/clients and the public. METHODS: This paper has three aims: (1) provide an overview of the burden of shift work, long hours, and related sleep and fatigue problems in this sector; (2) suggest research priorities that would improve these ; and (3) discuss potential positive impacts of addressing these research priorities for the health and safety of workers and the public. The authors used a modified Delphi approach to anonymously rank-order priorities for improving HCSA worker health and safety and public safety. Input was also obtained from attendees at the 2019 National Institute for Occupational Safety and Health (NIOSH) Work Hours, Sleep, and Fatigue Forum. RESULTS: The highest rated research priorities were developing better designs for work schedules, and improving the HCSA culture and leadership approaches to shift work and long work hours. Additional priorities are identified. CONCLUSION: Research in these priority areas has the potential to benefit HCSA workers as well as their patients/clients, employers, and society.

Generic Escherichia coli is commonly used as an indicator of fecal contamination to assess water quality and human health risk. Where measured E. coli exceedances occur, the presence of other pathogenic microorganisms, such as Shiga toxin-producing E. coli (STEC), is assumed, but confirmatory data are lacking. Putative E. coli isolates (n = 709) were isolated from water, sediment, soil, periphyton, and feces samples (n = 189) from five sites representing native forest and agricultural environments. Ten E. coli isolates (1.41%) were stx2 positive, 19 (2.7%) were eae positive, and stx1-positive isolates were absent. At the sample level, stx2-positive E. coli (5 of 189, 2.6%) and eae-positive isolates (16 of 189, 8.5%) were rare. Using real-time PCR, these STEC-associated virulence factors were determined to be more prevalent in sample enrichments (stx1, 23.9%; stx2, 31.4%; eae, 53.7%) and positively correlated with generic E. coli isolate numbers (P < 0.05) determined using culture-based methods. Whole-genome sequencing (WGS) was undertaken on a subset of 238 isolates with assemblies representing seven E. coli phylogroups (A, B1, B2, C, D, E, and F), 22 Escherichia marmotae isolates, and 1 Escherichia ruysiae isolate. Virulence factors, including those from extraintestinal pathogenic E. coli, were extremely diverse in isolates from the different locations and were more common in phylogroup B2. Analysis of the virulome from WGS data permitted the identification of gene repertoires that may be involved in environmental fitness and broadly align with phylogroup. Although recovery of STEC isolates was low, our molecular data indicate that they are likely to be widely present in environmental samples containing diverse E. coli phylogroups.

The National Institute of Mental Health's Research Domain Criteria (RDoC) framework has prompted a paradigm shift from categorical psychiatric disorders to considering multiple levels of vulnerability for probabilistic risk of disorder. However, the lack of neurodevelopmentally based tools for clinical decision making has limited the real-world impact of the RDoC. Integration with developmental psychopathology principles and statistical methods actualize the clinical implementation of RDoC to inform neurodevelopmental risk. In this conceptual paper, we introduce the probabilistic mental health risk calculator as an innovation for such translation and lay out a research agenda for generating an RDoC- and developmentally informed paradigm that could be applied to predict a range of developmental psychopathologies from early childhood to young adulthood. We discuss methods that weigh the incremental utility for prediction based on intensity and burden of assessment, the addition of developmental change patterns, considerations for assessing outcomes, and integrative data approaches. Throughout, we illustrate the risk calculator approach with different neurodevelopmental pathways and phenotypes. Finally, we discuss real-world implementation of these methods for improving early identification and prevention of developmental psychopathology. We propose that mental health risk calculators can build a needed bridge between the RDoC multiple units of analysis and developmental science.

The effects of radiotherapy (RT) on tumor immunity in pancreatic ductal adenocarcinoma (PDAC) are not well understood. To better understand if RT can prime antigen-specific T-cell responses, we analyzed human PDAC tissues and mouse models. In both settings, there was little evidence of RT-induced T-cell priming. Using in vitro systems, we found that tumor–stromal components, including fibroblasts and collagen, cooperate to blunt RT efficacy and impair RT-induced interferon signaling. Focal adhesion kinase (FAK) inhibition rescued RT efficacy in vitro and in vivo, leading to tumor regression, T-cell priming, and enhanced long-term survival in PDAC mouse models. Based on these data, we initiated a clinical trial of defactinib in combination with stereotactic body RT in patients with PDAC (NCT04331041). Analysis of PDAC tissues from these patients showed stromal reprogramming mirroring our findings in genetically engineered mouse models. Finally, the addition of checkpoint immunotherapy to RT and FAK inhibition in animal models led to complete tumor regression and long-term survival. Significance: Checkpoint immunotherapeutics have not been effective in PDAC, even when combined with RT. One possible explanation is that RT fails to prime T-cell responses in PDAC. Here, we show that FAK inhibition allows RT to prime tumor immunity and unlock responsiveness to checkpoint immunotherapy. This article is highlighted in the In This Issue feature, p. 2711

Post-traumatic stress disorder (PTSD) is a common condition in post-deployment service members (SM). SMs of the conflicts in Iraq and Afghanistan also frequently experience traumatic brain injury (TBI) and exposure to blasts during deployments. This study evaluated the effect of these conditions and experiences on functional brain connectomes in post-deployment, combat-exposed veterans. Functional brain connectomes were created using 5-min resting-state magnetoencephalography data. Well-established clinical interviews determined current PTSD diagnosis, as well as deployment-acquired mild TBI and history of exposure to blast. Linear regression examined the effect of these conditions on functional brain connectomes beyond covariates. There were significant interactions between blast-related mild TBI and PTSD after correction for multiple comparisons including number of nodes (non-standardized parameter estimate [PE] = -12.47), average degree (PE = 0.05), and connection strength (PE = 0.05). A main effect of blast-related mild TBI was observed on the threshold level. These results demonstrate a distinct functional connectome presentation associated with the presence of both blast-related mild TBI and PTSD. These findings suggest the possibility that blast-related mild TBI alterations in functional brain connectomes affect the presentation or progression of recovery from PTSD. The current results offer mixed support for hyper-connectivity in the chronic phase of deployment TBI.

PURPOSE: Parents of neonates with seizures are at risk of mental health symptoms due to the impact of illness on family life, prognostic uncertainty, and the emotional toll of hospitalization. A family-centered approach is the preferred model to mitigate these challenges. We aimed to identify strategies to promote family-centered care through an analysis of parent-offered advice to clinicians caring for neonates with seizures. BASIC PROCEDURES: This prospective, observational, and multi-center (Neonatal Seizure Registry) study enrolled parents of neonates with acute symptomatic seizures. Parents completed surveys about family well-being at 12 months, 18 months, and 24 months corrected gestational age. Parents were asked open-ended questions eliciting their advice to clinicians caring for neonates with seizures. Responses were analyzed using a conventional content analysis approach. MAIN FINDINGS: Among the 310 parents who completed surveys, 118 (38%) shared advice for clinicians. These parents were predominantly mothers (n=103, 87%). Three overarching themes were identified. (1) Communicate information effectively: Parents appreciate when clinicians offer transparent and balanced information in an accessible way. (2) Understand and validate parent experience: Parents value clinicians who display empathy, compassion, and a commitment to parent-partnered clinical care. (3) Provide support and resources: Parents benefit from emotional support, education, connection with peers, and help navigating the healthcare system. PRINCIPAL CONCLUSIONS: Parents caring for neonates with seizures appreciate a family-centered approach in healthcare encounters, including skilled communication, understanding and validation of the parent experience, and provision of support and resources. Future interventions should focus on building structures to reinforce these priorities.

Background We previously reported that increasing severity of watershed (WS) injury in neonatal magnetic resonance imaging (MRI) is associated with worse language outcomes in early childhood. In the present study, we investigated the relationship between neonatal injury patterns and cognitive profile in adolescents with neonatal encephalopathy. Methods Term neonates with encephalopathy were prospectively enrolled and imaged using brain MRI from 1999 to 2008. Neonatal brain injury was scored according to the degree of injury in WS and basal ganglia/thalamus (BG/T) areas. The children underwent a neurocognitive assessment and follow-up brain MRI at the age of 10–16 years. The relationship between neonatal brain injury patterns and adolescent cognitive outcomes was assessed. Results In a cohort of 16 children, neonatal MRI showed WS injury in 7, BG/T injury in 2, and normal imaging in 7. Children with WS injury had lower estimated overall cognitive ability than those with normal imaging. Increasing WS injury score was associated with decreasing estimated overall cognitive ability, Perceptual Reasoning Index, and digit span score. Conclusions Children with the WS injury are at an increased risk of having problems in long-term intellectual ability. These cognitive outcomes may underlie early language difficulties seen in children with neonatal WS injury. Impact Adolescents with a history of neonatal encephalopathy and watershed pattern of injury on neonatal brain magnetic resonance imaging (MRI) had lower overall cognitive ability, perceptual reasoning skills, and auditory working memory than those with normal neonatal imaging. Children with post-neonatal epilepsy and cerebral palsy had the worst cognitive outcomes. Watershed pattern of injury confers high long-term differences in intellectual ability.

Dystonia is a disabling disease that manifests as prolonged involuntary twisting movements. DYT-THAP1 is an inherited form of isolated dystonia caused by mutations in THAP1 encoding the transcription factor THAP1. The phe81leu (F81L) missense mutation is representative of a category of poorly understood mutations that do not occur on residues critical for DNA binding. Here, we demonstrate that the F81L mutation (THAP1F81L) impairs THAP1 transcriptional activity and disrupts CNS myelination. Strikingly, THAP1F81L exhibits normal DNA binding but causes a significantly reduced DNA binding of YY1, its transcriptional partner that also has an established role in oligodendrocyte lineage progression. Our results suggest a model of molecular pathogenesis whereby THAP1F81L normally binds DNA but is unable to efficiently organize an active transcription complex.

To characterize the lived experiences of stress associated with having a preterm infant hospitalized in the NICU among Black and Hispanic mothers. We performed a qualitative content analysis of secondary data from two prior studies that included 39 in-depth interviews with Black and Hispanic mothers of preterm infants at 3 U.S. NICUs. We used a constant comparative method to select important concepts and to develop codes and subsequent themes. Black and Hispanic mothers described stressors in the following domains and categories: Individual (feeling overwhelmed, postpartum medical complications, previous stressful life events, competing priorities); Hospital (perceived poor quality of care, provider communication issues, logistical issues); Community (lack of social supports, lack of financial resources, work challenges). The findings of this study suggest that stressors both inside and outside of the hospital affect the lived experiences of stress by Black and Hispanic mothers during NICU hospitalization.

Unresectable metastatic colorectal cancer (mCRC) has a poor prognosis. Emerging treatment paradigms have improved outcomes in selected unresectable mCRC cases. Recent therapeutic advancements are due in part to a shift in trial designs. By examining CRC as a heterogeneous group of various tumor subtypes, researchers have identified molecular distinctions that have led to promising targets.Nineteen antineoplastic agents are included in the National Comprehensive Cancer Network guidelines for the palliative management of mCRC. However, not all patients will be candidates for each agent. New therapies for rare mCRC subtypes have emerged. Herein, the authors review these rare mCRC subtypes: microsatellite instability-high/deficient mismatch repair, BRAFV600E-mutant, and human epidermal growth factor receptor 2-positive tumors. Additionally, they provide an overview of unresectable mCRC management and future directions.Treatment in the majority of mCRC patients (RAS wild-type or RAS-mutant, microsatellite instability-stable or -low/mismatch repair-proficient, BRAFV600E wild-type, or HER2-negative) needs further advancement and remains an unmet need. The authors believe that the key to identifying more breakthroughs in these mCRC patients is to continue to differentiate their tumors molecularly and clinically.

Esophageal cancer (EC) represents a complicated heterogenous group of malignancies. ECs are divided broadly into two types, histologically: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Historically, EC study designs have used bucket type groupings (all subtypes and/or all gastroesophageal cancers) reducing contribution to developing precision oncology.Surgery remains the curative modality for resectable disease with reasonable patient physiology. Trimodality is recommended for localized ESCC. An exception is cervical EC. For EAC, preoperative chemoradiation or perioperative chemotherapy is utilized. For those who undergo trimodality, nivolumab is recommended as an adjuvant therapy for those with a non-pathological complete response (pCR). Additionally, immunotherapy and other targets have been added to advanced EC treatment.Organ sparing approaches for localized tumors are starting to be investigated in many solid tumors and have been standard approaches for decades in certain tumors (i.e. certain head and neck tumors and anal SCCs). pCR differs between esophageal histologies with trimodality indicating potential of discriminating localized approaches. To determine if a watch and wait approach is feasible, prospectively correlating clinical complete response to pCR is needed, determining the best active surveillance strategy, and the best use of tools like liquid biopsies.

Gastroesophageal cancers (GEC) are frequently found at the advanced stage. GEC treatment advancements have been limited and prognosis, therefore, remains poor. Through numerous clinical trials, the addition of immune checkpoint inhibitors, including nivolumab, to conventional therapy has demonstrated a survival benefit.Here, we focus on the function of nivolumab in patients with advanced GECs. We discuss the most recent trials that led to nivolumab's incorporation into therapy and pathways forward.Nivolumab in combination with chemotherapy appears well tolerated, with only a small number of patients reporting severe toxicity; therefore, it may be possible to add additional biological agents to improve outcomes. A number of 'nivolumab plus other agents' is currently being investigated, and we anticipate continued advancement in GEC management in the coming years.

Despite recognition and attempts to reduce racial disparities in perinatal outcomes, Black infants are still disproportionately represented among those who are born preterm. Postnatal investigations of racial disparities in comorbidities and outcomes after preterm birth are increasing, although their results and interpretations are conflicting. In the present review, we 1.) identify important methodological limitations of that literature 2.) summarize the conflicting literature investigating racial disparities, specifically Black-white differences, in postnatal comorbidities and outcomes after preterm birth 3.) describe mechanisms by which racism operates to contextualize our understanding to inform future work to actively reduce disparities in preterm birth and subsequently, its complications.

Recent studies defined a potentially important role of the microbiome in modulating pancreatic ductal adenocarcinoma (PDAC) and responses to therapies. We hypothesized that antibiotic usage may predict outcomes in patients with PDAC. We retrospectively analyzed clinical data of patients with resectable or metastatic PDAC seen at MD Anderson Cancer from 2003 to 2017. Demographic, chemotherapy regimen and antibiotic use, duration, type, and reason for indication were recorded. A total of 580 patients with PDAC were studied, 342 resected and 238 metastatic patients, selected retrospectively from our database. Antibiotic use, for longer than 48 hrs, was detected in 209 resected patients (61%) and 195 metastatic ones (62%). On resectable patients, we did not find differences in overall survival (OS) or progression‐free survival (PFS), based on antibiotic intake. However, in the metastatic cohort, antibiotic consumption was associated with a significantly longer OS (13.3 months vs. 9.0 months, HR 0.48, 95% CI 0.34–0.7, p = 0.0001) and PFS (4.4 months vs. 2 months, HR 0.48, 95% CI 0.34–0.68, p =, We have analyzed the effect of antibiotics’ intake on two cohorts of patients with pancreatic adenocarcinoma, resectable, and metastatic. We have found that on the metastatic cohort, antibiotics use was significantly associated with better outcomes, particularly, on patients that received gemcitabine based‐chemotherapy as the first line.

Background/purpose of study We aim to assess if distraction techniques improve patient comfort tolerability of SWL. Methods We carried out a prospective randomised controlled trial of SWL-naive patients attending for treatment. Patients were randomised into three groups and offered oral analgesia as standard of care. Group 1 (n = 19) received stress balls to squeeze during treatment. Group 2 (n = 19) listened to music during treatment. Group 3 (n = 17) received standard of care only. All patients completed a validated health anxiety inventory score prior to treatment. All patients completed a validated pain questionnaire and visual analogue scale (VAS) after treatment. Primary outcomes were completion of SWL treatment and pain score results. Results 55 patients attending for SWL were randomised. There was no difference in stone size or position, presence of a stent, height or weight between the groups. VAS scores were lower in controls compared to Group 1 (1.93 vs 3.69, p = 0.08). On subgroup analysis of non-anxious patients, pain questionnaire scores were lower in controls compared to Group 1 (2.58 vs 4.77, p = 0.06). VAS scores were lower in patients who received optional analgesia alone than in patients who received stress balls alone (1.92 vs 4.07, p = 0.05). Across all subgroups, pain scores were lower in the control group compared to the distraction groups, but did not achieve significance. Conclusions In conclusion, distraction techniques should not replace standard of care for analgesia during SWL. This study was registered with clinicaltrials.gov (identifier NCT03379922 ).

Objective Examine the risk of adverse perinatal outcomes among the United States (US)-born and foreign-born Black women in California. Study design The study comprised all singleton live births to Black women in California between 2011 and 2017. We defined maternal nativity as US-born or foreign-born. Using Poisson regression, we computed risk ratios (RR) and 95% confidence intervals (CI) for three adverse perinatal outcomes: preterm birth, small for gestational age deliveries, and infant mortality. Results Rates of adverse perinatal outcomes were significantly higher among US-born Black women. In adjusted models, US-born Black women experienced an increased risk of preterm birth (RR 1.51, 95% CI 1.39, 1.65) and small for gestational age deliveries (RR 1.52, 95% CI 1.41, 1.64), compared to foreign-born Black women. Conclusions Future studies should consider experiences of racism across the life course when exploring heterogeneity in the risk of adverse perinatal outcomes by nativity among Black women in the US.

BackgroundEarly skin-to-skin care (SSC) has been shown to improve outcomes after preterm birth, including improved clinical stability and establishment of breastfeeding. Recent evidence suggests the most unstable infants get the most benefit, yet these infants are not consistently offered opportunities for SSC because of safety concerns and discomfort of the care team.PurposeTo identify barriers and implement a multidimensional approach to increase SSC within the first 72 hours of life among infants born less than 28 weeks' gestation and less than 1,000 g in a Level IV university-based regional intensive care nursery.MethodsUsing Institute of Healthcare Improvement quality improvement methodology, a multidisciplinary team identified barriers to SSC and developed targeted interventions, including a unit-specific protocol; widespread parent, staff, and provider education; and an infant readiness checklist. The primary outcome was the rate of SSC within 72 hours. The balancing measure was the rate of severe intraventricular hemorrhage (IVH). Data were collected from monthly chart review and analyzed with statistical process control charts. The aim was to increase SSC within 72 hours of birth from 7 percent to greater than 80 percent within 12 months for infants born less than 28 weeks' gestation or less than 1,000 g.ResultsBetween June 2017 and December 2019, there were 52 extremely preterm infants included in the project (15 preintervention and 37 postintervention). The rate of SSC within the first 72 hours increased from 7 to 84 percent. There has been no increase in any or severe IVH during the project period despite the increased rate of SSC.Implications for PracticeImplementation of multidimensional, multidisciplinary interventions for reducing barriers to early SSC in extremely preterm infants resulted in rapid adoption of SSC in the first 72 hours of life without increasing severe IVH in this high-risk population.

BACKGROUND AND OBJECTIVES Black preterm infants are more likely to die than White preterm infants within the same NICU. Racism may lead to disparate quality of NICU care contributing to disparities in preterm infant health outcomes. The objective of our study was to understand Black mothers’ perspectives of the impact of racism on the quality of care for Black preterm infants in the NICU and what might be done to address it. METHODS Using qualitative research methods, we conducted in-depth, semistructured interviews with 20 Black mothers of preterm infants in a single Level IV NICU 6 to 18 months after hospital discharge regarding experiences with disparate quality of NICU care. We developed themes iteratively and conducted interviews until thematic saturation was reached. RESULTS The majority of mothers believed that racism impacted the quality of NICU care and described examples of racism in the NICU at structural, institutional, and interpersonal levels. Mothers also provided ideas for interventions that would decrease racism and improve quality of NICU care for Black families, including increased Black representation, increased peer support, and improved staff education and training. CONCLUSIONS Black mothers of preterm infants experienced racism during NICU hospitalization that impacted the quality of care they received. Interventional studies directed toward mitigating these racial disparities may focus on addressing racism during the NICU period and should include input from Black stakeholders at all stages of design, implementation, and analysis.

Neonatal hypoxic-ischemic encephalopathy is an important cause of death as well as long-term disability in survivors. Erythropoietin has been hypothesized to have neuroprotective effects in infants with hypoxic-ischemic encephalopathy, but its effects on neurodevelopmental outcomes when given in conjunction with therapeutic hypothermia are unknown.In a multicenter, double-blind, randomized, placebo-controlled trial, we assigned 501 infants born at 36 weeks or more of gestation with moderate or severe hypoxic-ischemic encephalopathy to receive erythropoietin or placebo, in conjunction with standard therapeutic hypothermia. Erythropoietin (1000 U per kilogram of body weight) or saline placebo was administered intravenously within 26 hours after birth, as well as at 2, 3, 4, and 7 days of age. The primary outcome was death or neurodevelopmental impairment at 22 to 36 months of age. Neurodevelopmental impairment was defined as cerebral palsy, a Gross Motor Function Classification System level of at least 1 (on a scale of 0 [normal] to 5 [most impaired]), or a cognitive score of less than 90 (which corresponds to 0.67 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition.Of 500 infants in the modified intention-to-treat analysis, 257 received erythropoietin and 243 received placebo. The incidence of death or neurodevelopmental impairment was 52.5% in the erythropoietin group and 49.5% in the placebo group (relative risk, 1.03; 95% confidence interval [CI], 0.86 to 1.24; P = 0.74). The mean number of serious adverse events per child was higher in the erythropoietin group than in the placebo group (0.86 vs. 0.67; relative risk, 1.26; 95% CI, 1.01 to 1.57).The administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment than placebo and was associated with a higher rate of serious adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT02811263.).

OBJECTIVE Late preterm infants have an increased risk of morbidity relative to term infants. We sought to determine the rate, temporal trend, risk factors, and reasons for 30-day readmission. METHODS This is a retrospective cohort study of infants born at 34 to 42 weeks’ gestation in California between January 1, 2011, and December 31, 2017. Birth certificates maintained by California Vital Statistics were linked to discharge records maintained by the California Office of Statewide Health Planning and Development. Multivariable logistic regression was used to identify risk factors and derive a predictive model. RESULTS Late preterm infants represented 4.3% (n = 122 014) of the study cohort (n = 2 824 963), of which 5.9% (n = 7243) were readmitted within 30 days. Compared to term infants, late preterm infants had greater odds of readmission (odds ratio [OR]: 2.34 [95% confidence interval (CI): 2.28–2.40]). The temporal trend indicated increases in all-cause and jaundice-specific readmission infants (P < .001). The common diagnoses at readmission were jaundice (58.9%), infections (10.8%), and respiratory complications (3.5%). In the adjusted model, factors that were associated with greater odds of readmission included assisted vaginal birth, maternal age ≥34 years, diabetes, chorioamnionitis, and primiparity. The model had predictive ability of 60% (c-statistic 0.603 [95% CI: 0.596–0.610]) in late preterm infants who had CONCLUSION The findings contribute important information on what factors increase or decrease the risk of readmission. Longitudinal studies are needed to examine promising hospital predischarge and follow-up care practices.

Primary non-function (PNF) in the early post-LT period in children leads to prolonged hospitalization, high graft loss, and significant mortality. However, there is a paucity of data available on the natural history of children relisted for LT due to PNF, including those who recover graft function and survive with their original allograft.We interrogated the United Network of Organ Sharing (UNOS) database for pediatric LT recipients who were relisted with a primary diagnosis of PNF from 2000 to 2020. Patients21-year-old and multiple organ transplants were excluded. Logistic regression and Cox proportional hazard models were employed to identify risk factors for early re-transplantation (within 30 days of relisting) and mortality after adjusting for baseline clinical characteristics.One hundred and eight patients were relisted for LT for PNF during the study period. Twenty-five patients survived beyond 30 days from relisting with their original LT, 76 underwent early re-transplantation, and 7 did not survive. Having a high-risk EBV mismatch (OR 2.03, 95% CI 0.66-6.27) and an elevated donor serum creatinine (OR: 2.19, 95% CI 0.54-8.84) were associated with increased odds of a patient requiring early re-transplantation. Donor characteristics including age, final total bilirubin, final AST/ALT, and final serum sodium, as well as vasopressor use prior to procurement, were not associated with increased odds of early re-transplantation (p 0.05). Operative characteristics including allograft type and cold-ischemia time were also not associated with early re-transplantation (p 0.05). Patients undergoing early re-transplantation showed a trend toward improved 1-year graft survival (69% vs 55%, p = 0.24). On multivariable Cox proportional hazards modeling, early re-transplantation was associated with reduced risk of overall patient mortality compared to those who survived with their original LT (HR 0.27, 95% CI 0.12-0.67).Early re-transplantation for PNF is associated with improved patient survival compared with patients who survive with their original LT.

Fire has transformative effects on soil biological, chemical, and physical properties in terrestrial ecosystems around the world. While methods for estimating fire characteristics and associated effects aboveground have progressed in recent decades, there remain major challenges in characterizing soil heating and associated effects belowground. Overcoming these challenges is crucial for understanding how fire influences soil carbon storage, biogeochemical cycling, and ecosystem recovery. In this paper, we present a novel framework for characterizing belowground heating and effects. The framework includes (1) an open-source model to estimate fire-driven soil heating, cooling, and the biotic effects of heating across depths and over time (Soil Heating in Fire model; SheFire) and (2) a simple field method for recording soil temperatures at multiple depths using self-contained temperature sensor and data loggers (i.e., iButtons), installed along a wooden stake inserted into the soil (i.e., an iStake). The iStake overcomes many logistical challenges associated with obtaining temperature profiles using thermocouples. Heating measurements provide inputs to the SheFire model, and modeled soil heating can then be used to derive ecosystem response functions, such as heating effects on microorganisms and tissues. To validate SheFire estimates, we conducted a burn table experiment using iStakes to record temperatures that were in turn used to fit the SheFire model. We then compared SheFire predicted temperatures against measured temperatures at other soil depths. To benchmark iStake measurements against those recorded by thermocouples, we co-located both types of sensors in the burn table experiment. We found that SheFire demonstrated skill in interpolating and extrapolating soil temperatures, with the largest errors occurring at the shallowest depths. We also found that iButton sensors are comparable to thermocouples for recording soil temperatures during fires. Finally, we present a case study using iStakes and SheFire to estimate in situ soil heating during a prescribed fire and demonstrate how observed heating regimes would influence seed and tree root vascular cambium survival at different soil depths. This measurement-modeling framework provides a cutting-edge approach for describing soil temperature regimes (i.e., soil heating) through a soil profile and predicting biological responses.

To determine the outcomes of patients with cystic biliary atresia by correlating the anatomy of the hepatic ducts with the choice of biliary reconstruction surgery.The Kasai hepatoportoenterostomy (Kasai) is the initial surgical procedure offered to most patients with biliary atresia. In contrast, a hepatic-cyst-jejunostomy has been reported to be effective in patients with the cystic form of biliary atresia.We performed an international multicenter retrospective review. Two hundred eighty-seven patients were included, and 33 cases of cystic biliary atresia were identified. Outcomes were the serum total bilirubin level 3 months post-surgery and native liver survival at 2 years of age and were compared between cases who received the Kasai versus hepatic-cyst-jejunostomy in correlation to the anatomy of proximal hepatic ducts. The patients were categorized into 3 anatomical groups: patent intact hepatic ducts (n = 10), patent hypoplastic hepatic ducts (n = 13), and obliterated hepatic ducts (n = 10). All 10 patients with patent intact hepatic duct group underwent hepatic-cyst-jejunostomy, and 9 experienced bile drainage and native liver survival. Among the 13 patients with hypoplastic hepatic ducts, 11 underwent the Kasai procedure, and 9 had bile drainage, whereas 2 underwent hepatic-cyst-jejunostomy, and one survived with the native liver. All of the patients with obliterated hepatic ducts underwent the Kasai procedure; 5 established biliary drainage and survived with the native liver. Of 5 who did not drain, 3 underwent liver transplantation.In patients with cystic biliary atresia, the subset with a connection between cyst and intrahepatic bile ducts via intact proximal hepatic ducts had favorable clinical outcomes following hepatic-cyst-jejunostomy.

T1- and T2-weighted (T1w and T2w) images are essential for tissue classification and anatomical localization in Magnetic Resonance Imaging (MRI) analyses. However, these anatomical data can be challenging to acquire in non-sedated neonatal cohorts, which are prone to high amplitude movement and display lower tissue contrast than adults. As a result, one of these modalities may be missing or of such poor quality that they cannot be used for accurate image processing, resulting in subject loss. While recent literature attempts to overcome these issues in adult populations using synthetic imaging approaches, evaluation of the efficacy of these methods in pediatric populations and the impact of these techniques in conventional MR analyses has not been performed. In this work, we present two novel methods to generate pseudo-T2w images: the first is based in deep learning and expands upon previous models to 3D imaging without the requirement of paired data, the second is based in nonlinear multi-atlas registration providing a computationally lightweight alternative. We demonstrate the anatomical accuracy of pseudo-T2w images and their efficacy in existing MR processing pipelines in two independent neonatal cohorts. Critically, we show that implementing these pseudo-T2w methods in resting-state functional MRI analyses produces virtually identical functional connectivity results when compared to those resulting from T2w images, confirming their utility in infant MRI studies for salvaging otherwise lost subject data.

Background Cerebral palsy (CP) is the most common motor disability of childhood. Its early identification is an important priority for parents and is critical for access to early intervention resources, which may optimize function. Methods A prospective cohort of term neonates at high risk for CP was assessed by neonatal magnetic resonance imaging (MRI) to determine myelination of the posterior limb of the internal capsule, General Movements Assessment to assess typical fidgety movements at age three months, and followed to at least age two years to determine diagnosis of CP based on neurological examination. Results Seven of 58 children developed CP (12%), two with moderate/severe CP. Sensitivity and specificity for abnormal myelination of the posterior limb of the internal capsule were (PLIC) was 29% and 94%, and for absent fidgety movements, 29% and 98%, respectively. Negative predictive value of both absent myelination of the PLIC and absent fidgety movements was 90% (79% to 96%) for any CP and 98% (90% to 100%) for moderate/severe CP cerebral palsy. None of the children with both normal PLIC and normal fidgety movements had moderate/severe CP. Conclusion Normal neonatal MRI and General Movements Assessment at age three months are reassuring that a high-risk term-born child is at low risk for moderate/severe CP. These results are important for counseling parents and individualizing therapy resources in the community.

To determine whether socioeconomic status (SES) and small birthweight for gestational age (SGA) exhibit independent or joint effects on infant levels of 42 metabolites.Population-based retrospective cohort of metabolic newborn screening information linked to hospital discharge data. SGA infants defined by birthweight10th percentile for gestational age by sex. SES was determined by a combined metric including education level, participation in the WIC nutritional assistance program, and receiving California MediCal insurance. We performed linear regression to determine the effects of SES independently, SGA independently, and the interaction of SGA and SES on 42 newborn metabolite levels.736,435 California infants born in 2005-2011 were included in the analysis. SGA was significantly associated with 36 metabolites. SES was significantly associated with 41 of 42 metabolites. Thirty-eight metabolites exhibited a dose-response relationship between SGA and metabolite levels as SES worsened. Fourteen metabolites showed significant interaction between SES and SGA. Eight metabolites showed significant individual and joint effects of SES and SGA: alanine, glycine, free carnitine, C-3DC, C-5DC, C-16:1, C-18:1, and C-18:2.SES and SGA exhibited independent effects on a majority of metabolites and joint effects on select metabolites. A better understanding of how SES and SGA status are related to infant metabolites may help identify maternal and newborn interventions that can lead to better outcomes for infants born SGA.

Augmented renal clearance (ARC, creatinine clearance > 130 mL/minute) makes difficult achievement of effective concentrations of renally cleared antibiotics in critically ill patients. This study examined the synergistic killing and resistance suppression for meropenem-ciprofloxacin combination dosage regimens against Pseudomonas aeruginosa isolates within the context of ARC. Clinically relevant meropenem and ciprofloxacin concentrations, alone and in combinations, were studied against three clinical isolates with a range of susceptibilities to each of the antibiotics. Isolate Pa1280 was susceptible to both meropenem and ciprofloxacin, Pa1284 had intermediate susceptibility to meropenem and was susceptible to ciprofloxacin, and CR380 was resistant to meropenem and had intermediate susceptibility to ciprofloxacin. Initially, isolates were studied in 72-hour static-concentration time-kill (SCTK) studies. Subsequently, the pharmacokinetic profiles expected in patients with ARC receiving dosage regimens, including at the highest approved daily doses (meropenem 6 g daily divided and administered as 0.5-hour infusions every 8 hours, or as a continuous infusion; ciprofloxacin 0.4 g as 1-hour infusions every 8 hours), were examined in a dynamic hollow-fiber infection model (HFIM) over 7-10 days. In both SCTK and HFIM, combination regimens were generally synergistic and suppressed growth of less-susceptible subpopulations, these effects being smaller for isolate CR380. The time-courses of total and less-susceptible bacterial populations in the HFIM were well-described by mechanism-based models, which enabled conduct of Monte Carlo simulations to predict likely effectiveness of approved dosage regimens at different creatinine clearances. Optimized meropenem-ciprofloxacin combination dosage regimens may be a viable consideration for P. aeruginosa infections in critically ill patients with ARC.

OBJECTIVES Congenital diaphragmatic hernia (CDH) can cause a significant mass effect in the fetal thorax, displacing the heart into the opposite hemithorax. In left-sided CDH (L-CDH), this is associated with smaller left-sided cardiac structures and reduced left-ventricular cardiac output (LVCO). The effect of these physiologic changes on cerebral blood flow is not well understood. We sought to describe the middle cerebral artery (MCA) pulsatility index (PI), a measure of cerebrovascular impedance, in fetuses with L-CDH and those with right-sided CDH (R-CDH) compared with unaffected fetuses, and the relationship between MCA-PI and LVCO. We hypothesized that MCA-PI would be lower in fetuses with L-CDH and similar in those with R-CDH compared to controls, and that MCA-PI would be correlated with LVCO. METHODS We identified all fetuses with CDH evaluated at The University of California San Francisco, San Francisco, CA, USA from 2011 to 2018. Fetal echocardiograms and ultrasound scans were reviewed. Umbilical artery and MCA Doppler examinations were assessed to calculate pulsatility indices. Ventricular outputs were calculated using Doppler-derived stroke volume and fetal heart rate. Lung-to-head ratio (LHR), estimated fetal weight, biparietal diameter (BPD) and head circumference (HC) were obtained from fetal sonograms. Measurements in fetuses with CDH, according to the side of the defect, were compared with those in unaffected, gestational age-matched controls. A subset of CDH survivors had available data on neurodevelopmental outcome, as assessed using the Bayley Scales of Infant Development, 3rd edition. RESULTS A total of 64 fetuses with CDH (L-CDH, n = 53; R-CDH, n = 11) comprised the study groups, with 27 unaffected fetuses serving as controls. Mean gestational age at evaluation was similar between the three groups. Compared to controls, fetuses with L-CDH had significantly lower LVCO expressed as a percentage of combined cardiac output (CCO) (32%; 95% CI, 29-35% vs 38%; 95% CI, 33-42%; P = 0.04) and lower MCA-PI Z-score (-1.3; 95% CI, -1.7 to -1.0 vs 0.08; 95% CI, -0.5 to 0.6; P

Children are particularly vulnerable to many classes of the volatile organic compounds (VOCs) detected in indoor environments. The negative health impacts associated with chronic and acute exposures of the VOCs might lead to health issues such as genetic damage, cancer, and disorder of nervous systems. In this study, 40 VOCs including aldehydes and ketones, aliphatic hydrocarbons, esters, aromatic hydrocarbons, cyclic terpenes, alcohols, and glycol ethers were identified and qualified in different locations at the University of Missouri (MU) Child Development Laboratory (CDL) in Columbia, Missouri. Our results suggested that the concentrations of the VOCs varied significantly among classrooms, hallways, and playground. The VOCs emitted from personal care and cleaning products had the highest indoor levels (2-ethylhexanol-1, 3-carene, homomenthyl salicylate with mean concentration of 5.15 µg/m3 , 1.57 µg/m3 , and 1.47 µg/m3 , respectively). A cancer risk assessment was conducted, and none of the 95th percentile dose estimates exceeded the age-specific no significant risk levels (NSRL) in all classrooms. Dimensionless toxicity index scores were calculated for all VOCs using a novel web-based framework called Toxicological Prioritization Index (ToxPi), which integrates multiple sources of toxicity data. According to the method, homomenthyl salicylate, benzothiazole, 2-ethylhexyl salicylate, hexadecane, and tridecane exhibited diverse toxicity profiles and ranked as the five most toxic indoor VOCs. The findings of this study provide critical information for policy makers and early education professionals to mitigate the potentially negative health impacts of indoor VOCs in the childcare facilities.

Background: The value of baseline fluorodeoxyglucose-positron emission tomography-computed tomography (PET-CT) remains uncertain once gastroesophageal cancer is metastatic. We hypothesized that assessment of detailed PET-CT parameters (maximum standardized uptake value [SUVmax] and/or total lesion glycolysis [TLG]), and the extent of metastatic burden could aid prediction of probability of response or prognosticate. Methods: We retrospectively analyzed treatment-naive patients with stage 4 gastroesophageal cancer (December 2002–August 2017) who had initial PET-CT for cancer staging at MD Anderson Cancer Center. SUVmax and TLG were compared with treatment outcomes for the full cohort and subgroups based on metastatic burden (≤2 or >2 metastatic sites). Results: We identified 129 patients with metastatic gastroesophageal cancer who underwent PET-CT before first-line therapy. The median follow-up time was 61 months. The median overall survival (OS) was 18.5 months; the first progression-free survival (PFS) was 5.5 months. SUVmax or TLG of the primary tumor or of all metastases combined had no influence on OS or PFS, whether the number of metastases was ≤2 or >2. Overall response rates (ORRs) to first-line therapy were 48% and 45% for patients with ≤2 and >2 metastases, respectively (nonsignificant). ORR did not differ based on low or high values of SUVmax or TLG. Conclusions: This is the first assessment of a unique set of PET-CT data and its association with outcomes in metastatic gastroesophageal cancer. In our large cohort of patients, detailed analyses of PET-CT (by SUVmax and/or TLG) did not discriminate any parameters examined. Thus, baseline PET-CT in untreated metastatic gastroesophageal cancer patients has limited or no utility.

The purpose of this study was to determine if radiation (RT)-resistant cervical cancers are dependent upon glutamine metabolism driven by activation of the PI3K pathway and test whether PI3K pathway mutation predicts radiosensitization by inhibition of glutamine metabolism. Cervical cancer cell lines with and without PI3K pathway mutations, including SiHa and SiHa PTEN−/− cells engineered by CRISPR/Cas9, were used for mechanistic studies performed in vitro in the presence and absence of glutamine starvation and the glutaminase inhibitor, telaglenastat (CB-839). These studies included cell survival, proliferation, quantification of oxidative stress parameters, metabolic tracing with stable isotope-labeled substrates, metabolic rescue, and combination studies with L-buthionine sulfoximine (BSO), auranofin (AUR), and RT. In vivo studies of telaglenastat ± RT were performed using CaSki and SiHa xenografts grown in immune-compromised mice. PI3K-activated cervical cancer cells were selectively sensitive to glutamine deprivation through a mechanism that included thiol-mediated oxidative stress. Telaglenastat treatment decreased total glutathione pools, increased the percent glutathione disulfide, and caused clonogenic cell killing that was reversed by treatment with the thiol antioxidant, N-acetylcysteine. Telaglenastat also sensitized cells to killing by glutathione depletion with BSO, thioredoxin reductase inhibition with AUR, and RT. Glutamine-dependent PI3K-activated cervical cancer xenografts were sensitive to telaglenastat monotherapy, and telaglenastat selectively radiosensitized cervical cancer cells in vitro and in vivo. These novel preclinical data support the utility of telaglenastat for glutamine-dependent radioresistant cervical cancers and demonstrate that PI3K pathway mutations may be used as a predictive biomarker for telaglenastat sensitivity.

The clinical benefits of Acute Care for Elders (ACE) units have been established for over 25 years. However, how widely disseminated ACE units are in the United States and the degree of fidelity to the key elements of this model of care are unknown. Our objective was to identify all existing ACE units in the United States and to obtain detailed information about variations in implementation.The strategy to identify current ACE units began with online searches and snowball sampling using contacts from professional societies and workgroups. Next, a request for information regarding the existence of ACE units was sent to the remaining US hospitals listed in a national hospital database. An online survey was sent to identified ACE unit contacts to capture information on implementation characteristics and the five key elements of ACE units.There were 3692 hospitals in the database with responses from 2055 (56%) hospitals reporting the presence or absence of an ACE unit. We identified 68 hospitals (3.3%) with an existing or previous ACE unit. Of these 68 hospitals, 50 (74%) completed the survey and reported that 43 ACE units were currently open and 7 had been closed. Of the 43 currently open ACE units, most are affiliated with an academic hospital and there is variable implementation of each of the five key ACE elements (from 69% to 98%).Among the 50 hospitals to complete the survey, 43 current ACE units were identified, with variable fidelity to the key elements. Estimates of prevalence of ACE units and fidelity to key elements are limited by nonresponses to the national survey request by nearly half of hospitals.

Exposure to early-life adversity alters the structural development of key brain regions underlying neurodevelopmental impairments. The association between prenatal exposure to adversity and brain structure at birth remains poorly understood.To examine whether prenatal exposure to maternal social disadvantage and psychosocial stress is associated with neonatal global and regional brain volumes and cortical folding.This prospective, longitudinal cohort study included 399 mother-infant dyads of sociodemographically diverse mothers recruited in the first or early second trimester of pregnancy and their infants, who underwent brain magnetic resonance imaging in the first weeks of life. Mothers were recruited from local obstetric clinics in St Louis, Missouri from September 1, 2017, to February 28, 2020.Maternal social disadvantage and psychosocial stress in pregnancy.Confirmatory factor analyses were used to create latent constructs of maternal social disadvantage (income-to-needs ratio, Area Deprivation Index, Healthy Eating Index, educational level, and insurance status) and psychosocial stress (Perceived Stress Scale, Edinburgh Postnatal Depression Scale, Everyday Discrimination Scale, and Stress and Adversity Inventory). Neonatal cortical and subcortical gray matter, white matter, cerebellum, hippocampus, and amygdala volumes were generated using semiautomated, age-specific, segmentation pipelines.A total of 280 mothers (mean [SD] age, 29.1 [5.3] years; 170 [60.7%] Black or African American, 100 [35.7%] White, and 10 [3.6%] other race or ethnicity) and their healthy, term-born infants (149 [53.2%] male; mean [SD] infant gestational age, 38.6 [1.0] weeks) were included in the analysis. After covariate adjustment and multiple comparisons correction, greater social disadvantage was associated with reduced cortical gray matter (unstandardized β = -2.0; 95% CI, -3.5 to -0.5; P = .01), subcortical gray matter (unstandardized β = -0.4; 95% CI, -0.7 to -0.2; P = .003), and white matter (unstandardized β = -5.5; 95% CI, -7.8 to -3.3; P .001) volumes and cortical folding (unstandardized β = -0.03; 95% CI, -0.04 to -0.01; P .001). Psychosocial stress showed no association with brain metrics. Although social disadvantage accounted for an additional 2.3% of the variance of the left hippocampus (unstandardized β = -0.03; 95% CI, -0.05 to -0.01), 2.3% of the right hippocampus (unstandardized β = -0.03; 95% CI, -0.05 to -0.01), 3.1% of the left amygdala (unstandardized β = -0.02; 95% CI, -0.03 to -0.01), and 2.9% of the right amygdala (unstandardized β = -0.02; 95% CI, -0.03 to -0.01), no regional effects were found after accounting for total brain volume.In this baseline assessment of an ongoing cohort study, prenatal social disadvantage was associated with global reductions in brain volumes and cortical folding at birth. No regional specificity for the hippocampus or amygdala was detected. Results highlight that associations between poverty and brain development begin in utero and are evident early in life. These findings emphasize that preventive interventions that support fetal brain development should address parental socioeconomic hardships.

Objective Management of delivery at periviable gestation requires complex counseling and decision making, including difficult choices about monitoring and potential cesarean delivery (CD) for fetal benefit. Our objective was to characterize decisions that patients make regarding fetal monitoring and potential CD for fetal benefit when delivering in the periviable period, and associations with perinatal and obstetric outcomes. We hypothesize that a significant number of patients forgo monitoring and potential CD for fetal benefit in the periviable period when offered the opportunity to do so. Study Design Retrospective cohort study of nonanomalous singleton pregnancies delivering between 230/7 and 256/7 weeks at a tertiary care center from 2015 to 2020 as based on our institutional clinical practice. Since 2015, these patients are offered the ability to accept or decline fetal monitoring, potential CD for fetal benefit, and active resuscitation of a liveborn neonate. The frequency of patients desiring potential CD for fetal benefit was identified, and associations with CD and intrapartum demise were analyzed. Results Fifty subjects were included. Seventy-eight percent (n = 39) desired monitoring and potential CD for fetal benefit, and 84% (n = 42) desired resuscitation if the neonate was born alive. This varied by gestational age: 55% (6/11) of patients delivering between 230/7 and 236/7 weeks desired fetal monitoring and potential CD for fetal benefit, while 90% (19/21) of patients delivering between 250/7 and 256/7 weeks desired fetal monitoring and potential CD for fetal benefit (p = 0.02). Sixty-nine percent of pregnancies in which potential CD for fetal benefit was desired resulted in CD (27/39), of which 85% were classical (23/27). Intrapartum fetal demise occurred in 45% (5/11) of pregnancies in which monitoring was not performed. Conclusion While a majority of patients delivering between 230/7 and 256/7 weeks desired monitoring and potential CD for fetal benefit, this varied significantly by gestational age. The decision to perform monitoring and potential CD for fetal benefit was associated with a high frequency of CD, while the decision to forgo monitoring was associated with high frequency of intrapartum demise. Key Points

For many decades, the U.S. military's general operational guideline has been to limit the use of trauma-focused treatments for combat and operational stress reactions in military service members until they have returned from deployment. Recently, published clinical trials have documented that active-duty military personnel with combat-related posttraumatic stress disorder (PTSD) can be treated effectively in garrison. However, there are limited data on the treatment of combat and operational stress reactions or combat-related PTSD during military deployments. This prospective, nonrandomized trial evaluated the treatment of active-duty service members (N = 12) with combat and operational stress reactions or combat-related PTSD while deployed to Afghanistan or Iraq. Service members were treated by deployed military behavioral health providers using modified Prolonged Exposure (PE; n = 6) or modified Cognitive Processing Therapy (CPT; n = 6), with protocol modifications tailored to individual mission requirements. The PTSD Checklist-Military Version (PCL-M) total score was the primary outcome measure. Results indicated that both groups demonstrated clinically significant change in PTSD symptoms as indicated by a reduction of 10 points or greater on the PCL-M. Participants treated with modified PE had significant reductions in PTSD symptoms, t = -3.83, p = .01; g = -1.32, with a mean reduction of 18.17 points on the PCL-M. Participants treated with modified CPT had a mean PCL-M reduction of 10.00 points, but these reductions were not statistically significant, t = -1.49, p = .12; g = -0.51. These findings provide preliminary evidence that modified forms of PE and CPT can be implemented in deployed settings for the treatment of combat and operational stress reactions and combat-related PTSD.

Author(s): Donovan, Anne L; Braehler, Matthias R; Robinowitz, David L; Lazar, Ann A; Finlayson, Emily; Rogers, Stephanie; Douglas, Vanja C; Whitlock, Elizabeth L; Anesthesia Resident Quality Improvement Committee | Abstract: BackgroundPostoperative delirium is a common and serious problem for older adults. To better align local practices with delirium prevention consensus guidelines, we implemented a 5-component intervention followed by a quality improvement (QI) project at our institution.MethodsThis hybrid implementation-effectiveness study took place at 2 adult hospitals within a tertiary care academic health care system. We implemented a 5-component intervention: preoperative delirium risk stratification, multidisciplinary education, written memory aids, delirium prevention postanesthesia care unit (PACU) orderset, and electronic health record enhancements between December 1, 2017 and June 30, 2018. This was followed by a department-wide QI project to increase uptake of the intervention from July 1, 2018 to June 30, 2019. We tracked process outcomes during the QI period, including frequency of preoperative delirium risk screening, percentage of "high-risk" screens, and frequency of appropriate PACU orderset use. We measured practice change after the interventions using interrupted time series analysis of perioperative medication prescribing practices during baseline (December 1, 2016 to November 30, 2017), intervention (December 1, 2017 to June 30, 2018), and QI (July 1, 2018 to June 30, 2019) periods. Participants were consecutive older patients (≥65 years of age) who underwent surgery during the above timeframes and received care in the PACU, compared to a concurrent control group l65 years of age. The a priori primary outcome was a composite of perioperative American Geriatrics Society Beers Criteria for Potentially Inappropriate Medication Use (Beers PIM) medications. The secondary outcome, delirium incidence, was measured in the subset of older patients who were admitted to the hospital for at least 1 night.ResultsDuring the 12-month QI period, preoperative delirium risk stratification improved from 67% (714 of 1068 patients) in month 1 to 83% in month 12 (776 of 931 patients). Forty percent of patients were stratified as "high risk" during the 12-month period (4246 of 10,494 patients). Appropriate PACU orderset use in high-risk patients increased from 19% in month 1 to 85% in month 12. We analyzed medication use in 7212, 4416, and 8311 PACU care episodes during the baseline, intervention, and QI periods, respectively. Beers PIM administration decreased from 33% to 27% to 23% during the 3 time periods, with adjusted odds ratio (aOR) 0.97 (95% confidence interval [CI], 0.95-0.998; P = .03) per month during the QI period in comparison to baseline. Delirium incidence was 7.5%, 9.2%, and 8.5% during the 3 time periods with aOR of delirium of 0.98 (95% CI, 0.91-1.05, P = .52) per month during the QI period in comparison to baseline.ConclusionsA perioperative delirium prevention intervention was associated with reduced administration of Beers PIMs to older adults.

Background Identifying preterm infants at risk for mortality or major morbidity traditionally relies on gestational age, birth weight, and other clinical characteristics that offer underwhelming utility. We sought to determine whether a newborn metabolic vulnerability profile at birth can be used to evaluate risk for neonatal mortality and major morbidity in preterm infants. Methods This was a population-based retrospective cohort study of preterm infants born between 2005 and 2011 in California. We created a newborn metabolic vulnerability profile wherein maternal/infant characteristics along with routine newborn screening metabolites were evaluated for their association with neonatal mortality or major morbidity. Results Nine thousand six hundred and thirty-nine (9.2%) preterm infants experienced mortality or at least one complication. Six characteristics and 19 metabolites were included in the final metabolic vulnerability model. The model demonstrated exceptional performance for the composite outcome of mortality or any major morbidity (AUC 0.923 (95% CI: 0.917-0.929). Performance was maintained across mortality and morbidity subgroups (AUCs 0.893-0.979). Conclusions Metabolites measured as part of routine newborn screening can be used to create a metabolic vulnerability profile. These findings lay the foundation for targeted clinical monitoring and further investigation of biological pathways that may increase the risk of neonatal death or major complications in infants born preterm. Impact We built a newborn metabolic vulnerability profile that could identify preterm infants at risk for major morbidity and mortality. Identifying high-risk infants by this method is novel to the field and outperforms models currently in use that rely primarily on infant characteristics. Utilizing the newborn metabolic vulnerability profile for precision clinical monitoring and targeted investigation of etiologic pathways could lead to reductions in the incidence and severity of major morbidities associated with preterm birth.

Metastatic squamous cell carcinoma anal cancer (SCCA) is rare. Prospective data recommends front-line platinum doublet combinations and second-line anti-programmed death-1 therapy. Standard therapy beyond these treatments are currently unknown. We evaluated anti-EGFR monoclonal antibody (mAb) outcomes in metastatic SCCA.Metastatic SCCA patients given anti-EGFR mAb from Oct 2011-May 2018 were included. Primary endpoints included best response, progression-free survival, and overall survival.56 patients were evaluated with a median of one prior therapy. Most patients (~90%) received anti-EGFR mAbs with chemotherapy. Response rate (any response) was 41%. Median PFS was 4.3 months with a median OS of 16 M. Seven patients with disease control proceeded onto maintenance therapy (anti-EGFR mAb ± a fluoropyrimidine) with a median PFS of 13.8 M. Next generation sequencing of 16 pts (28%) showed 4 pts had a PIK3CA mutation with 3 of these 4 patients demonstrating progression on initial restaging.Our analysis suggests anti-EGFR mAb therapy with chemotherapy provides clinical benefit in previously treated metastatic SCCA. Our maintenance therapy and the role of PIK3CA MT outcomes were thought-provoking.Metastatic SCCA patients have limited options; therefore, anti-EGFR mAbs may provide benefit in the treatment armamentarium and should be further explored.

Since the 20th century, health care institutions have used morbidity and mortality conferences (MMCs) as a forum to discuss complicated cases and fatalities to capitalize on lessons learned. Medical technology, health care processes, and the teams who provide care have evolved over time, but the format of the MMC has remained relatively unchanged. The present article outlines 5 key areas for improvement within the MMC along with prescriptive and actionable recommendations for mitigating these challenges. This work incorporates the contributions of numerous researchers and practitioners from the educational, training, debrief, and health care fields. With the best practices and lessons learned from various domains in mind, we recommend optimizing the MMC by (1) encouraging a culture that leverages expertise from multiple sources, (2) allocating ample time for innovative thinking, (3) using a global approach that considers individual, team, and system-level factors, (4) leveraging learnings from errors as well as near misses, and (5) promoting communication, innovative thinking, and actionable planning. The 5 evidence-based recommendations herein serve to ensure that MMCs are structured learning events that promote, encourage, and support safe, reliable care. Furthermore, the outlined recommendations seek to capitalize upon the MMC's opportunity to engage early discovery as well as proactive risk assessment and action-oriented solutions.

Background Gemcitabine (GEM) plus nab‐paclitaxel (NabP) (GEM 1000 mg/m2 IV over 30 minutes + NabP 125 mg/m2 IV given days 1, 8, and 15 every 28 days) is one of the two standard of care combination therapies for metastatic pancreatic ductal adenocarcinoma (PDAC). Our cancer center has utilized GEM‐NabP given every two‐weeks due to tolerability and patient convenience. Here, we review the safety and efficacy of this modified regimen. Methods Metastatic PDAC patients (pts) who initiated front‐line or second‐line GEM‐NabP during 2013‐2017 were retrospectively reviewed. Primary objective was overall survival. Secondary objectives were disease control rate, progression‐free survival, and the incidence of dose delays and/or adjustments. Results From a total of 235 patients, 140 pts received GEM‐NabP front‐line while 95 pts received GEM‐NabP second‐line. Median dosing was 600 mg/m2 at fixed‐dose rate for GEM and 125 mg/m2 for NabP given predominantly (~90%) every two‐weeks. Eastern Cooperative Group performance status of 0 and 1 pts had front‐line OS of 12.7 and 9.6 months and when given second‐line had OS of 8 months and 7.3 months, respectively. ECOG 0 and 1 pts had front‐line progression‐free survival (PFS) of 5.3 months and 2.8 months and second‐line PFS was 3.5 months and 2.4 months, respectively. Treatment was well tolerated with limited dose modifications. Conclusion Our analysis revealed safety with every two‐week low dose GEM‐NabP while maintaining efficacy. Patient schedule convenience should factor into metastatic incurable malignancies. We suggest the use of every two‐week GEM‐NabP particularly in patients desiring a modified schedule., Our real‐world data, outside the context of a clinical trial, suggests that every two‐week Gem‐NabP can be administered safely without compromising efficacy in patients with metastatic pancreatic adenocarcinoma (PDAC). In particular, the alternate (bi‐weekly) dosing regimen showed low rates of grades 3 and 4 toxicities and no treatment‐related deaths. This regimen is better tolerated than weekly Gem‐NabP, is convenient, and allows similar palliative benefits to patients with metastatic PDAC.

Background The aim of the study was to describe and contrast the brain development and outcome among very preterm infants that were and were not exposed to surgery requiring general anesthesia prior to term equivalent age (TEA). Methods Preterm infants born ≤30 weeks' gestation who did (n = 25) and did not (n = 59) have surgery requiring general anesthesia during the preterm period were studied. At TEA, infants had MRI scans performed with measures of brain tissue volumes, cortical surface area, Gyrification Index, and white matter microstructure. Neurodevelopmental follow-up with the Bayley Scales of Infant and Toddler Development, Third Edition was undertaken at 2 years of corrected age. Multivariate models, adjusted for clinical and social risk factors, were used to compare the groups. Results After controlling for clinical and social variables, preterm infants exposed to surgical anesthesia demonstrated decreased relative white matter volumes at TEA and lower cognitive and motor composite scores at 2-year follow-up. Those with longer surgical exposure demonstrated the greatest decrease in white matter volumes and lower cognitive and motor outcomes at age 2 years. Conclusions Very preterm infants who required surgery during the preterm period had lower white mater volumes at TEA and worse neurodevelopmental outcome at age 2 years. Impact In very preterm infants, there is an association between surgery requiring general anesthesia during the preterm period and reduced white mater volume on MRI at TEA and lower cognitive and motor composite scores at age 2 years.It is known that the very preterm infant's brain undergoes rapid growth during the period corresponding to the third trimester.The current study suggests an association between surgery requiring general anesthesia during this period and worse outcomes.

Glycoprotein CD44 and alternative splice variants are overexpressed in many cancers and cancer stem cells. Binding of hyaluronic acid to CD44 activates cell signaling pathways, inducing cell proliferation, cell survival, and invasion. As such, CD44 is regarded as an excellent target for cancer therapy when this interaction can be blocked. In this study, we developed a CD44-specific antibody fragment and evaluated it for imaging CD44-positive cancers using PET. Methods: A human single-chain fragment variable (scFv) was generated by phage display, using the extracellular domain of recombinant human CD44. The specificity and affinity of the scFv-CD44 were evaluated using recombinant and tumor cell–expressed CD44. Epitope mapping of the putative CD44 binding site was performed via overlapping peptide microarray. The scFv-CD44 was reformatted into a bivalent scFv-Fc-CD44, based on human IgG(1)–fragment crystallizable (Fc). The scFv-Fc-CD44 was radiolabeled with (64)Cu and (89)Zr. The purified reagents were injected into athymic nude mice bearing CD44-positive human tumors (MDA-MB-231, breast cancer, triple-negative). Biodistribution studies were performed at different times after injection of [(64)Cu]Cu-NOTA-scFv-Fc-CD44 or [(89)Zr]Zr-DFO-scFv-Fc-CD44. PET/CT imaging was conducted with [(89)Zr]Zr-DFO-scFv-Fc-CD44 on days 1 and 7 after injection and compared with a scFv-Fc control antibody construct targeting glycophorin A. Results: Epitope mapping of the scFv binding site revealed a linear epitope within the extracellular domain of human CD44, capable of blocking binding to native hyaluronic acid. Switching from a monovalent scFv to a bivalent scFv-Fc format improved its binding affinity toward native CD44 on human breast cancer cells by nearly 200-fold. In vivo biodistribution data showed the highest tumor uptake and tumor-to-blood ratios for [(89)Zr]Zr-DFO-scFv-Fc-CD44 between days 5 and 7. PET imaging confirmed excellent tumor specificity for [(89)Zr]Zr-DFO-scFv-Fc-CD44 when compared with the control scFv-Fc. Conclusion: We developed a CD44-specific scFv-Fc construct that binds with nanomolar affinity to human CD44. When radiolabeled with (64)Cu or (89)Zr, it demonstrated specific uptake in CD44-expressing MDA-MB-231 tumors. The high tumor uptake (∼56% injected dose/g) warrants clinical investigation of [(89)Zr]Zr-DFO-scFv-Fc-CD44 as a versatile PET imaging agent for patients with CD44-positive tumors.

ObjectiveNeonates with seizures have a high risk of mortality and neurological morbidity. We aimed to describe the experience of parents caring for neonates with seizures.DesignThis prospective, observational and multicentre (Neonatal Seizure Registry) study enrolled parents of neonates with acute symptomatic seizures. At the time of hospital discharge, parents answered six open-ended response questions that targeted their experience. Responses were analysed using a conventional content analysis approach.Results144 parents completed the open-ended questions (732 total comments). Four themes were identified. Sources of strength: families valued medical team consensus, opportunities to contribute to their child’s care and bonding with their infant. Uncertainty: parents reported three primary types of uncertainty, all of which caused distress: (1) the daily uncertainty of the intensive care experience; (2) concerns about their child’s uncertain future and (3) lack of consensus between members of the medical team. Adapting family life: parents described the many ways in which they anticipated their infant’s condition would lead to adaptations in their family life, including adjusting their family’s lifestyle, parenting approach and routine. Many parents described financial and work challenges due to caring for a child with medical needs. Emotional and physical toll: parents reported experiencing anxiety, fear, stress, helplessness and loss of sleep.ConclusionsParents of neonates with seizures face challenges as they adapt to and find meaning in their role as a parent of a child with medical needs. Future interventions should target facilitating parent involvement in clinical and developmental care, improving team consensus and reducing the burden associated with prognostic uncertainty.