Near-miss and maternal sepsis mortality: A qualitative study of survivors and support persons.

BACKGROUND: Prior studies have shown that maternal deaths due to sepsis occur due to delays in recognition, treatment, and escalation of care through medical chart reviews. This study was conducted to obtain the patient perspective for near-miss and maternal mortality cases due to sepsis. OBJECTIVE: To identify quality improvement opportunities for improving maternal sepsis through patient and support person experiences. STUDY DESIGN: Twenty semi-structured interviews and three follow-up focus groups with patients who experienced critical illness from maternal sepsis in the United States and their support persons (when available) were conducted from May 23, 2022, through October 14, 2022. In this qualitative study, data were analyzed using inductive thematic analysis. RESULTS: In this qualitative study of patients with maternal sepsis and their support persons, four main quality improvement themes were identified. The themes were the following: (1) participants reported a lack of awareness of pregnancy-related warning signs and symptoms of when to seek care, (2) many of the presenting symptoms participants experienced were not typical of expected warning signs of maternal sepsis, such as severe pain, overwhelming tiredness, and lack of fever (3) participant concerns were met with dismissal leading to delays in diagnosis, (4) participants experienced long-term sequelae but had difficulty receiving screening and referrals for treatment. CONCLUSIONS: The findings of this study suggest that standardized patient education about the warning signs of maternal sepsis and provider education about the presentation of maternal sepsis, improved listening to patients, and follow-up for sequalae of sepsis are needed.

Moving from Principle to Practice: A Researcher's Guide to Co-Leading Engaged Research with Community Partners and Patients with Lived Experience to Reduce Maternal Mortality and Morbidity for Maternal Sepsis.

OBJECTIVES: Maternal mortality and morbidity disproportionately affect birthing people from racialized populations. Unfortunately, researchers can often compound these poor outcomes through a lack of authentic community engagement in research beyond the role of the research subject, leading to ineffective strategies for improving care and increasing equity. This article details the real-life strategies utilized to develop a community-engaged research project of a phased federally funded grant employing community engagement principles of co-leadership and co-creation. It also includes reflections from the researchers and advisory board on promising practices and lessons learned for equitably engaging patients and community partners in research. METHODS: This article details the application of principles of community-engaged research in a federally funded phased research project focused on understanding disparities in maternal sepsis to develop better clinical and community interventions. Specifically, it discusses early steps in the research partnership to create a sustainable partnership with a Community Leadership Board guided by the principles of transparency, respect, compensation, and increasing research justice. RESULTS: TBased on the authors' experience, recommendations are provided for funders, researchers, and institutions to improve the quality and outcomes of communityengaged research. This work adds to community-based participatory and community-engaged research literature by providing concrete and practical steps for equitably engaging in research partnerships with a variety of collaborators. CONCLUSIONS: In conclusion, integrated patient and community co-leadership enhances research by providing insight, access to communities for education and dissemination of information, and identifying critical areas needing change. This report may help others address fundamental principles in this journey.

Cancer Precision-Prevention trial of Metformin in adults with Li Fraumeni syndrome (MILI) undergoing yearly MRI surveillance: a randomised controlled trial protocol.

BACKGROUND: Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disease caused by inherited or de novo germline pathogenic variants in TP53. Individuals with LFS have a 70-100% lifetime risk of developing cancer. The current standard of care involves annual surveillance with whole-body and brain MRI (WB-MRI) and clinical review; however, there are no chemoprevention agents licensed for individuals with LFS. Preclinical studies in LFS murine models show that the anti-diabetic drug metformin is chemopreventive and, in a pilot intervention trial, short-term use of metformin was well-tolerated in adults with LFS. However, metformin's mechanism of anticancer activity in this context is unclear. METHODS: Metformin in adults with Li-Fraumeni syndrome (MILI) is a Precision-Prevention phase II open-labelled unblinded randomised clinical trial in which 224 adults aged ≥ 16 years with LFS are randomised 1:1 to oral metformin (up to 2 mg daily) plus annual MRI surveillance or annual MRI surveillance alone for up to 5 years. The primary endpoint is to compare cumulative cancer-free survival up to 5 years (60 months) from randomisation between the intervention (metformin) and control (no metformin) arms. Secondary endpoints include a comparison of cumulative tumour-free survival at 5 years, overall survival at 5 years and clinical characteristics of emerging cancers between trial arms. Safety, toxicity and acceptability of metformin; impact of metformin on quality of life; and impact of baseline lifestyle risk factors on cancer incidence will be assessed. Exploratory end-points will evaluate the mechanism of action of metformin as a cancer preventative, identify biomarkers of response or carcinogenesis and assess WB-MRI performance as a diagnostic tool for detecting cancers in participants with LFS by assessing yield and diagnostic accuracy of WB-MRI. DISCUSSION: Alongside a parallel MILI study being conducted by collaborators at the National Cancer Institute (NCI), MILI is the first prevention trial to be conducted in this high-risk group. The MILI study provides a unique opportunity to evaluate the efficacy of metformin as a chemopreventive alongside exploring its mechanism of anticancer action and the biological process of mutated P53-driven tumourigenesis. TRIAL REGISTRATION: ISRCTN16699730. Registered on 28 November 2022. URL: https://www.isrctn.com/ EudraCT/CTIS number 2022-000165-41.

Kruppel-family zinc finger proteins as emerging epigenetic biomarkers in head and neck squamous cell carcinoma.

BACKGROUND: Krüppel-type zinc finger protein genes located on chromosome 19q13 are aberrantly hypermethylated with high frequency in all anatomic sub-sites of head and neck cancers as well as other epithelial tumours resulting in decreased expression. METHODS: We examined prognostic significance of ZNF154 and ZNF132 expression and DNA methylation in independent patient cohort of about 500 head and neck cancer patients in the Cancer Genome Atlas (TCGA). We also overexpressed these genes in HEK-293 cells, as well as the oral cancer cell line UM-SCC-1. RESULTS: In 20 patients from the TCGA cohort of HNSCC patients where ZNF154 and ZNF132 DNA methylation and RNA expression could be compared in tumor and adjacent normal tissue, there was increased DNA methylation and decreased expression of both ZNF154 and ZNF132 in primary tumours. Low ZNF154 and low ZNF132 expression were associated with shorter overall survival in both head and neck squamous cell carcinoma (HNSCC) and lung adenocarcinoma (LUAC patients). While expression of these proteins in HEK-293 cells produced full-length protein, only truncated copies could be expressed in head and neck cancer cells (UM-SCC-1). The truncated version of ZNF154 protein increased doubling time and reduced cell migration in UM-SCC-1 cancer cells. CONCLUSIONS: Both ZNF132 and ZNF154 represent novel clinically significant biomarkers in head and neck cancer with potential tumour suppressive properties. Future studies will address the underlying molecular mechanisms by which ZNF154 expression in HNSCC contributes to the control of cell growth and migration.

Coping With Disasters and Pandemics Through Experience and Community: How African American Older Adults Navigate Disaster Planning, Response, and Recovery.

OBJECTIVE: Studies have reported that minorities are disproportionately impacted by the COVID-19 pandemic. Few studies have elucidated the lived experiences of African American older adults, and the resiliency displayed in combatting the COVID-19 pandemic and other disasters. METHODS: This study used 4 recorded focus groups with 26 African American older adults who have spent most of their lives living in Houston, Texas to assess safety, economic, and health concerns related to the pandemic and similarities or differences with other types of disasters that are specific to Houston/ the Gulf Region of Texas, such as Hurricane Harvey. RESULTS: Key themes emerged from the thematic analysis: 1) previous disasters provided important coping and preparation skills, although each occurrence was still a major stressor, 2) while telehealth was a significant benefit, regular health maintenance and chronic disease management were not completed during the COVID-19 pandemic, 3) information from the federal and state authorities were inconsistent and spurred fear and anxiety, 4) participants experienced few to no disruptions to their income but were heavily called on to support family members, and 5) participants experienced anxiety and isolation, but many used existing social connections to cope. CONCLUSIONS: These findings demonstrate how African American older adults navigate disaster response and recovery through experience and community. Providing unambiguous information to older adults could prove useful in preparing for future disaster events and coping with disasters.

"Ignored and Invisible": Perspectives from Black Women, Clinicians, and Community-Based Organizations for Reducing Preterm Birth.

OBJECTIVES: The preterm birth rate for Black women in the U.S. is consistently higher than other racial groups. The crisis of preterm birth and adverse birth outcomes among Black people is a historical, systematic confluence of racism, stressors, and an unsupportive and hostile healthcare system. To inform the development of preterm birth risk reduction interventions, this study aimed to collect and synthesize the experiences of Black women who gave birth preterm along with clinicians and community-based organizations who serve them. METHODS: A qualitative study design was employed whereby nine focus groups and 17 key informant interviews that included Black women, clinicians, and representatives from community-based organizations were facilitated in Los Angeles County from March 2019 to March 2020. Participants were recruited through the organizations and the focus groups took place virtually and in person. The process of thematic analysis was employed to analyze the focus group and interview transcripts. RESULTS: Five overarching themes emerged from the data. Black women experience chronic and pregnancy-related stress, and have lasting trauma from adverse maternal health experiences. These issues are exacerbated by racism and cultural incongruence within healthcare and social services systems. Black women have relied on self-education and self-advocacy to endure the barriers related to racism, mistreatment, and their experiences with preterm birth. CONCLUSIONS FOR PRACTICE: Healthcare and social service providers must offer more holistic care that prioritizes, rather than ignores, the racial components of health, placing increased importance on implementing inclusive and culturally-appropriate patient education, attentiveness to patient needs, respectful care, and support for Black women.

Alcohol use disorder in active duty service members: Incidence rates over a 19-year period.

Background: Alcohol use is a concerning issue for the military given its potential negative impact on human performance. Limited data are available regarding the incidence of alcohol use disorder in the military, which is critical to understand to evaluate force readiness, as well as for preventative initiatives and treatment planning. The aim was to examine the alcohol use disorder incidence rates (overall and across demographics) among active duty service members from 2001 to 2018. Methods: Data on 208,870 active duty service members between 2001 and 2018 from the Defense Medical Epidemiology Database was examined. Incidence rates were analyzed to determine the diagnostic rates of AUD (including both alcohol abuse and dependence), which were then examined by sex, age, service branch, military pay grade, marital status, and race. Results: Incidence rates of AUD in active duty service members (per 1,000 service members) ranged from 6.45 to 10.50 for alcohol abuse and 5.21 to 7.11 for alcohol dependence. Initial diagnoses of new-onset AUD occurred most frequently within 20-24 year-old, white, male, and non-married U.S. Army service members in the enlisted pay grades of E-1 to E-4. Statistically significant differences (p <.001) were found between observed and expected counts across all examined demographic variables. Conclusions: To our knowledge, this is the first study to provide a comprehensive examination of AUD incidence rates in an active-duty military population over an extended 18-year period and during the last decade. Incidence rates were higher than expected for alcohol dependence and lower than expected for alcohol abuse. Given the untoward effects of AUD on overall health and force readiness, active-duty service members may benefit from more advanced preventative interventions to decrease incidence rates of AUD over time. Future research should use these data to develop targeted interventions for the demographics at greatest risk.

Correlates of Social Isolation Among Community-Dwelling Older Adults During the COVID-19 Pandemic.

Background: The past year has severely curtailed social interactions among older adults given their high rates of COVID-19 morbidity and mortality. This study examined social, behavioral, and medical correlates of social isolation among community-dwelling older adults during the COVID-19 pandemic and stratified findings to explore unique differences in two typically neglected populations, African American and Hispanic older adults. Methods: Working with community-based organizations and senior living centers, the research team administered a survey to older adults 55 years of age and older (n = 575). The survey assessed COVID-19 prevention behaviors, medical conditions, and lived experiences, including feelings of social isolation, in the target population. Responses to a previously validated social isolation question informed a dichotomous social isolation dependent variable. Multivariable logistic regression was used to adjust for sociodemographic characteristics, medical conditions, unmet caregiving needs, and COVID-19 prevention behaviors. Results from the regression model were stratified by race/ethnicity to examine correlates of social isolation in African American and Hispanic older adults, separately. Results: Overall, female sex and a higher level of education were also positively associated with social isolation (OR = 2.46, p = 0.04; OR = 5.49, p = 0.02) while having insurance exhibited an inverse relationship (OR = 0.25, p = 0.03). Unmet caregiving needs were strongly associated with social isolation (OR = 6.41, p < 0.001) as was having any chronic conditions (OR = 2.99, p = 0.02). Diabetes was the single strongest chronic condition predictor of social isolation. Among minority older adults, a different pattern emerged. For Hispanic older adults, language, unmet caregiving needs, and social distancing were strongly associated with social isolation; while unmet caregiving needs, having 1+ chronic conditions and adhering to social distancing guidelines were significant predictors in African American older adults. Conclusion: These findings suggest that social isolation affects older adults in a myriad of ways and support the need for culturally sensitive initiatives to mitigate the effect of social isolation in these vulnerable populations.

Interprofessional ECMO telerounding: a novel approach to neonatal ECMO clinical participation and education.

OBJECTIVE: Determine the feasibility, strengths, and barriers of offering extracorporeal membrane oxygenation (ECMO) telerounding to neonatal intensive care unit (NICU) care providers. STUDY DESIGN: NICU providers were invited to join ECMO rounds by teleconference. Data were collected on telerounding participation and ECMO concepts discussed. A survey was sent to all providers. RESULTS: From March 2018 to February 2020, telerounding on 24 neonatal ECMO patients (168 ECMO days) was performed in a Level IV NICU. A mean of four providers joined telerounds per ECMO day with an increase from 3 to 6 providers over the study period. Nearly all respondents felt telerounding lowered barriers to attending ECMO rounds (94%), promoted engagement (89%), and improved continuity of care (78%). Barriers to ECMO telerounding were suboptimal audio connections and limited ability to participate in the clinical discussion. CONCLUSION: ECMO telerounding is well-received by NICU providers. It can improve provider participation, complement existing in-person ECMO rounds, and ECMO education.

Health Disparities and Climate Change: The Intersection of Three Disaster Events on Vulnerable Communities in Houston, Texas.

Although evidence suggests that successive climate disasters are on the rise, few studies have documented the disproportionate impacts on communities of color. Through the unique lens of successive disaster events (Hurricane Harvey and Winter Storm Uri) coupled with the COVID-19 pandemic, we assessed disaster exposure in minority communities in Harris County, Texas. A mixed methods approach employing qualitative and quantitative designs was used to examine the relationships between successive disasters (and the role of climate change), population geography, race, and health disparities-related outcomes. This study identified four communities in the greater Houston area with predominantly non-Hispanic African American residents. We used data chronicling the local community and environment to build base maps and conducted spatial analyses using Geographic Information System (GIS) mapping. We complemented these data with focus groups to assess participants' experiences in disaster planning and recovery, as well as community resilience. Thematic analysis was used to identify key patterns. Across all four communities, we observed significant Hurricane Harvey flooding and significantly greater exposure to 10 of the 11 COVID-19 risk factors examined, compared to the rest of the county. Spatial analyses reveal higher disease burden, greater social vulnerability, and significantly higher community-level risk factors for both pandemics and disaster events in the four communities, compared to all other communities in Harris County. Two themes emerged from thematic data analysis: (1) Prior disaster exposure prepared minority populations in Harris County to better handle subsequent disaster suggesting enhanced disaster resilience, and (2) social connectedness was key to disaster resiliency. Long-standing disparities make people of color at greater risk for social vulnerability. Addressing climate change offers the potential to alleviate these health disparities.

Therapeutic Plasma Exchange in Neonatal Septic Shock: A Retrospective Cohort Study.

OBJECTIVE: This study aimed to examine the use of therapeutic plasma exchange (TPE) as adjunctive therapy in neonatal septic shock. STUDY DESIGN: This retrospective cohort study was performed on a convenience sample of neonates in a quaternary children's hospital between January 2018 and February 2019. RESULTS: We identified three neonates with septic shock who received TPE. Two neonates had adenovirus sepsis, and one had group B streptococcal sepsis. All neonates were on extracorporeal life support (ECLS) when TPE was started. The median duration of TPE was 6 days (interquartile range [IQR]: 3-15), with a median of four cycles (IQR: 3-5). Lactate levels decreased significantly after TPE (median before TPE: 5.4 mmol/L [IQR: 2.4-6.1] vs. median after TPE: 1.2 mmol/L [IQR: 1.0-5.8]; p < 0.001). Platelet levels did not change (median before TPE: 73,000/mm3 [IQR: 49,000-100,000] vs. median after TPE: 80,000/mm3 (IQR: 62,000-108,000); p = 0.2). Organ failure indices improved after TPE in two of the three neonates. Hypocalcemia was seen in all cases despite prophylactic calcium infusions. One neonate died, and two survived to ICU discharge. CONCLUSION: TPE can be safely performed in neonates with septic shock. TPE may have a role as an adjunctive therapy in neonates with septic shock requiring ECLS.

A dominant RAD51C pathogenic splicing variant predisposes to breast and ovarian cancer in the Newfoundland population due to founder effect.

BACKGROUND: RAD51C is important in DNA repair and individuals with pathogenic RAD51C variants have increased risk of hereditary breast and ovarian cancer syndrome (HBOC), an autosomal dominant genetic predisposition to early onset breast and/or ovarian cancer. METHODS: Five female HBOC probands sequenced negative for moderate- and high-risk genes but shared a recurrent variant of uncertain significance in RAD51C (NM_058216.3: c.571 + 4A > G). Participant recruitment was followed by haplotype and case/control analyses, RNA splicing analysis, gene and protein expression assays, and Sanger sequencing of tumors. RESULTS: The RAD51C c.571 + 4A > G variant segregates with HBOC, with heterozygotes sharing a 5.07 Mbp haplotype. RAD51C c.571 + 4A > G is increased ~52-fold in the Newfoundland population compared with the general Caucasian population and positive population controls share disease-associated alleles, providing evidence of a founder effect. Splicing analysis confirmed in silico predictions that RAD51C c.571 + 4A > G causes exon 3 skipping, creating an immediate premature termination codon. Gene and protein expression were significantly reduced in a RAD51C c.571 + 4G > A heterozygote compared with a wild-type relative. Sanger sequencing of tumors from two probands indicates loss-of-heterozygosity, suggesting loss of function. CONCLUSION: The RAD51C c.571 + 4A > G variant affects mRNA splicing and should be re-classified as pathogenic according to American College of Medical Genetics and Genomics guidelines.

Standing enhances cognitive control and alters visual search.

Postural changes and the maintenance of postural stability have been shown to affect many aspects of cognition. Here we examined the extent to which selective visual attention may differ between standing and seated postures in three tasks: the Stroop color-word task, a task-switching paradigm, and visual search. We found reduced Stroop interference, a reduction in switch costs, and slower search rates in the visual search task when participants stood compared to when they sat while performing the tasks. The results suggest that the postural demands associated with standing enhance cognitive control, revealing broad connections between body posture and cognitive mechanisms.

Effect of Video-based Telemedicine on Transport Management of Simulated Newborns.

OBJECTIVE: Video-based telemedicine is a reliable tool to assess the severity of respiratory distress in children, increasing the appropriateness of triage and disposition for acutely ill children. Telemedicine simulations may identify patterns in regional transport management and influence attitudes toward telemedicine. METHODS: The objective was to determine the effect of videos on simulated neonatal transport care compared with telephone management. Participants received information about a newborn requiring respiratory support by an audio recording and made management decisions based on only that information. Four videos of varying respiratory distress on respiratory support were then shown. After each video, participants again rated patient stability and recommended management. RESULTS: Sixteen neonatologists completed the cases. Compared with the telephone call, there were significant differences in ratings of patient stability and confidence in their assessment after watching the videos. When given the same information, participants were less likely to recommend intubation after viewing an infant in mild respiratory distress than after the telephone call (P < .05). Most participants felt that viewing the videos was helpful in formulating their assessment and plan. CONCLUSION: Video-based telemedicine simulations influenced the perceived stability of neonates during transport. Viewing the patient increased provider confidence in their assessment and recommendations.

Motion onset really does capture attention.

Several properties of visual stimuli have been shown to capture attention, one of which is the onset of motion. However, whether motion onset truly captures attention has been debated. It has been argued that motion onset only captured attention in previous studies because properties of the animated motion used in those experiments caused it to be "jerky" (i.e., there were gaps between successive images during animated motion). The present study sought to determine whether natural motion onset captures attention. Additionally, the present study further examined the circumstances under which animated motion onset, the only type of motion onset that can be produced on a computer display, does and does not capture attention. In Experiment 1, participants identified target letters in search arrays containing distinct animated motion types, either accompanied or unaccompanied by a new object. Animated motion onset captured attention, but not when the motion onset was accompanied by a new object, indicating that prior failures to replicate capture by animated motion onset were limited because a new object had always been included in the display. Experiment 2 employed natural motion rather than animated motion and found that participants were fastest at identifying motion-onset targets compared to other target types. These results provide further support for the claim that motion onset captures attention.

Boundary Extension Is Sensitive to Hand Position in Young and Older Adults.

Objectives: Based on preliminary reports, we expected an age-related increase in boundary extension (BE), a phenomenon in which people falsely remember seeing more of a scene than was presented. Given recent data suggesting hand-centered attentional frames in young adults contrasted with body-centered attentional frames in older adults, we predicted hand-position effects on BE in young adults only. Method: Participants (59 young, 60 older adults) viewed photographs of complex scenes (e.g., a market) and answered yes/no questions about each. Half answered with key presses while their hands were framing the computer monitor; half while their hands were on a lapdesk. At test, participants indicated whether photographs were the same as, or at a closer or wider angle than at study. Results: Both age groups demonstrated BE. When study-test angles were the same, participants rated test pictures as closer than at study. When study-test angles differed, older adults showed less BE than young adults. For both same- and different-angle conditions, there was a main effect of hand position (less BE when hands framed the monitor than when on participants' laps). Discussion: The data confirm older adults show BE but show no age-related increase. Surprisingly, both young and older adults showed hand-centered attention.

Self-Care Practices and the Professional Self.

Consistently and actively engaging in self-care has been shown to improve the performance of mental health practitioners by reducing burnout, vicarious trauma, compassion fatigue, and other stress-related psychological problems. Not only is this important to the individual practitioner's well-being, but ethical standards also mandate the recognition and remediation of any physical, mental, or emotional self-impairment to maintain high standards of care for clients. Professionals in small communities, like the Deaf community, however, confront unique challenges in attending to their self-care. This article investigates these challenges-as well as the rewards-experienced by Deaf and hearing counselors working in mental health care with deaf clients.

Extracorporeal cardiopulmonary resuscitation outcomes in term and premature neonates*.

OBJECTIVE: Extracorporeal cardiopulmonary resuscitation appears to improve survival in patients with acute refractory cardiopulmonary failure. This analysis was performed to determine survival outcomes and predictors of in-hospital mortality for term and preterm neonates who received extracorporeal cardiopulmonary resuscitation. DESIGN: Retrospective review of data from the Extracorporeal Life Support Organization international registry. SETTING: Pediatric and neonatal ICUs. PATIENTS: Infants less than or equal to 30 days. INTERVENTIONS: Extracorporeal cardiopulmonary resuscitation. MEASUREMENTS AND MAIN RESULTS: Demographic, clinical, and survival data from patients who received extracorporeal cardiopulmonary resuscitation between 1998 and 2010 were analyzed to determine factors that affect in-hospital mortality. Overall survival to hospital discharge for the 641 neonates who received extracorporeal cardiopulmonary resuscitation was 39%. In univariate analysis, gestational age correlated inversely with stroke (odds ratio, 0.84 [95% CI, 0.75-0.95]; p = 0.006) and death (odds ratio, 0.87 [95% CI, 0.78-0.96]; p = 0.005) as did corrected gestational age (odds ratio, 0.89 [95% CI, 0.81-0.97]; p = 0.006) and birth weight (odds ratio, 0.53 [95% CI, 0.38-0.74]; p < 0.001). Dysrhythmia as the primary diagnosis had significantly lower odds of death than single-ventricle cardiac disease (odds ratio, 0.24 [95% CI, 0.06-0.95]; p = 0.04). Higher pre-extracorporeal cardiopulmonary resuscitation oxygenation decreased the odds of death (odds ratio, 0.996 [95% CI, 0.994-0.999]; p = 0.01), whereas complications occurring on extracorporeal life support increased the odds of death. In the multivariate analysis, lower birth weight and pre-extracorporeal cardiopulmonary resuscitation oxygenation, as well as complications including CNS hemorrhage, pulmonary hemorrhage, acidosis, renal replacement therapy, and mechanical complications, increased the odds of death. CONCLUSIONS: Overall survival for neonates receiving extracorporeal cardiopulmonary resuscitation is similar to older pediatric patients but decreases with lower gestational age and weight. Despite this, many low-birth weight neonates survive to hospital discharge.

Replication competent molecular clones of HIV-1 expressing Renilla luciferase facilitate the analysis of antibody inhibition in PBMC.

Effective vaccine development for human immunodeficiency virus type 1 (HIV-1) will require assays that ascertain the capacity of vaccine immunogens to elicit neutralizing antibodies (NAb) to diverse HIV-1 strains. To facilitate NAb assessment in peripheral blood mononuclear cell (PBMC)-based assays, we developed an assay-adaptable platform based on a Renilla luciferase (LucR) expressing HIV-1 proviral backbone. LucR was inserted into pNL4-3 DNA, preserving all viral open reading frames. The proviral genome was engineered to facilitate expression of diverse HIV-1 env sequences, allowing analysis in an isogenic background. The resulting Env-IMC-LucR viruses are infectious, and LucR is stably expressed over multiple replications in PBMC. HIV-1 neutralization, targeting TZM-bl cells, was highly correlative comparing virus (LucR) and cell (firefly luciferase) readouts. In PBMC, NAb activity can be analyzed either within a single or multiple cycles of replication. These results represent advancement toward a standardizable PBMC-based neutralization assay for assessing HIV-1 vaccine immunogen efficacy.

A prospective, randomized pilot trial of perfluorocarbon-induced lung growth in newborns with congenital diaphragmatic hernia.

BACKGROUND/PURPOSE: Initial laboratory and clinical data suggest that partial liquid ventilation (PLV) can enhance pulmonary function and that lung growth can be induced via distension of the newborn lung using perfluorocarbon in patients with congenital diaphragmatic hernia (CDH). The authors, therefore, performed a prospective, randomized pilot study evaluating PLV and perfluorocarbon-induced lung growth (PILG) in newborns with CDH on extracorporeal life support (ECLS) at 6 medical centers. METHODS: Patients were selected randomly using a permuted block design to PLV/PILG (n = 8) or conventional mechanical ventilation (CMV/control, n = 5). Patients in the PILG group received daily doses which filled the lungs with perflubron for up to 7 days and were placed on continuous positive airway pressure of 5 to 8 cm H2O. CMV patients were treated with standard mechanical ventilation while on extracorporeal membrane oxygenation (ECMO). RESULTS: A total of 13 patients were evaluated in this study. All 3 patients enrolled without being on ECLS rapidly transitioned to ECLS. The study, therefore, effectively evaluated PILG (n = 8) versus standard ventilation (control, n = 5) on ECLS. Mean (+/- SE) gestational age was 37 +/- 1 weeks and weight was 3.1 +/- 0.1 kg. Time on ECMO was 9.8 +/- 2.3 days in the PILG and 14.5 +/- 3.5 days (P =.58) in the control group. Survival rate in the PILG group was 6 of 8 (75%), whereas survival rate was 2 of 5 (40%) in the control group (P =.50). The number of days free from the ventilator in the first 28 days (VFD) was 6.3 +/- 3.3 days with PILG and 4.6 +/- 4.6 days with control (P =.9). Causes of death in the PILG group included sepsis and renal failure in one patient and pulmonary hypertension in the other. There were no safety issues, and the deaths in the PILG group did not appear to be related to the administration of perflubron. CONCLUSIONS: These data show that PILG can be performed safely. The survival rate, VFD, and time on ECMO data, although not conclusive, are encouraging and indicate the need for a definitive trial of this novel intervention in these neonates with high mortality.