A revealed preference analysis to develop composite scores approximating lung allocation policy in the U.S.

BACKGROUND: The patient ranking process for donor lung allocation in the United States is carried out by a classification-based, computerized algorithm, known as the match system. Experts have suggested that a continuous, points-based allocation framework would better serve waiting list candidates by removing hard boundaries and increasing transparency into the relative importance of factors used to prioritize candidates. We applied discrete choice modeling to match run data to determine the feasibility of approximating current lung allocation policy by one or more composite scores. Our study aimed to demystify the points-based approach to organ allocation policy; quantify the relative importance of factors used in current policy; and provide a viable policy option that adapts the current, classification-based system to the continuous allocation framework. METHODS: Rank ordered logistic regression models were estimated using 6466 match runs for 5913 adult donors and 534 match runs for 488 pediatric donors from 2018. Four primary attributes are used to rank candidates and were included in the models: (1) medical priority, (2) candidate age, (3) candidate's transplant center proximity to the donor hospital, and (4) blood type compatibility with the donor. RESULTS: Two composite scores were developed, one for adult and one for pediatric donor allocation. Candidate rankings based on the composite scores were highly correlated with current policy rankings (Kendall's Tau ~ 0.80, Spearman correlation > 90%), indicating both scores strongly reflect current policy. In both models, candidates are ranked higher if they have higher medical priority, are registered at a transplant center closer to the donor hospital, or have an identical blood type to the donor. Proximity was the most important attribute. Under a points-based scoring system, candidates in further away zones are sometimes ranked higher than more proximal candidates compared to current policy. CONCLUSIONS: Revealed preference analysis of lung allocation match runs produced composite scores that capture the essence of current policy while removing rigid boundaries of the current classification-based system. A carefully crafted, continuous version of lung allocation policy has the potential to make better use of the limited supply of donor lungs in a manner consistent with the priorities of the transplant community.

Effects of Alcohol Interventions on Other Drug Use in the Cherokee Nation.

OBJECTIVES: To evaluate effects of 2 alcohol prevention interventions-Communities Mobilizing for Change on Alcohol (CMCA), a community organizing intervention designed to reduce youth alcohol access, and CONNECT, an individual-level screening and brief intervention approach-on other drug use outcomes. METHODS: We conducted a community intervention trial with quarterly surveys over 3 years (2012-2015) of high school students living within the jurisdictional service area of the Cherokee Nation in Oklahoma. We used generalized estimating equations and linear probability models to examine intervention spillover effects on other drug use. RESULTS: We found significant reductions in drug use other than alcohol attributable to CMCA and CONNECT. CMCA was associated with a 35% reduction in chewing tobacco use, a 39% reduction in marijuana use, and a 48% reduction in prescription drug misuse. CONNECT was associated with a 26% reduction in marijuana use and a 31% reduction in prescription drug misuse. CONCLUSIONS: Nonalcohol drug use was consistently reduced as a result of 2 theoretically and operationally distinct alcohol prevention strategies. Evaluations of alcohol prevention efforts should continue to include other drug use to understand the broader effects of such interventions.

Multilevel Prevention Trial of Alcohol Use Among American Indian and White High School Students in the Cherokee Nation.

OBJECTIVES: To evaluate the effectiveness of a multilevel intervention designed to prevent underage alcohol use among youths living in the Cherokee Nation. METHODS: We randomly assigned 6 communities to a control, Communities Mobilizing for Change on Alcohol (CMCA; a community-organizing intervention targeting alcohol access) only, CONNECT (a school-based universal screening and brief intervention) only, or a combined condition. We collected quarterly surveys 2012-2015 from students starting in 9th and 10th grades and ending in 11th and 12th grades. Response rates ranged from 83% to 90%; 46% of students were American Indian (of which 80% were Cherokee) and 46% were White only. RESULTS: Students exposed to CMCA, CONNECT, and both showed a significant reduction in the probability over time of 30-day alcohol use (25%, 22%, and 12% reduction, respectively) and heavy episodic drinking (24%, 19%, and 13% reduction) compared with students in the control condition, with variation in magnitude of effects over the 2.5-year intervention period. CONCLUSIONS: CMCA and CONNECT are effective interventions for reducing alcohol use among American Indian and other youths living in rural communities. Challenges remain for sustaining intervention effects.

Reactions of Benzylboronate Nucleophiles.

This short review summarizes our laboratory's development of benzylboronic esters as nucleophiles. Activation of the benzylboronic ester is achieved by irreversible coordination of an alkyllithium Lewis base to form a nucleophilic benzylboronate. This boronate was found to react with aldehydes, imines, ketones and alkyl bromides. A copper catalyst was employed in reactions of the boronate with epoxides and aziridines.

Study protocol for a cluster randomized trial of a school, family, and community intervention for preventing drug misuse among older adolescents in the Cherokee Nation.

BACKGROUND: The national opioid crisis has disproportionately burdened rural White populations and American Indian/Alaska Native (AI/AN) populations. Therefore, Cherokee Nation and Emory University public health scientists have designed an opioid prevention trial to be conducted in rural communities in the Cherokee Nation (northeast Oklahoma) with AI and other (mostly White) adolescents and young adults. Our goal is to implement and evaluate a theory-based, integrated multi-level community intervention designed to prevent the onset and escalation of opioid and other drug misuse. Two distinct intervention approaches-community organizing, as implemented in our established Communities Mobilizing for Change and Action (CMCA) intervention protocol, and universal school-based brief intervention and referral, as implemented in our established Connect intervention protocol-will be integrated with skill-based training for adults to strengthen social support for youth and also with strategic media. Furthermore, we will test systems for sustained implementation within existing organizational structures of the Cherokee Nation and local schools and communities. This study protocol describes the cluster randomized trial, designed to measure implementation and evaluate the effectiveness on primary and secondary outcomes. METHODS: Using a cluster randomized controlled design and constrained randomization, this trial will allocate 20 high schools and surrounding communities to either an intervention or delayed-intervention comparison condition. With a proposed sample of 20 high schools, all enrolled 10th grade students in fall 2021 (ages 15 to 17) will be eligible for participation. During the trial, we will (1) implement interventions through the Cherokee Nation and measure implementation processes and fidelity, (2) measure opioid and other drug use and secondary outcomes every 6 months among a cohort of high school students followed over 3 years through their transition out of high school, (3) test via a cluster randomized trial the effect of the integrated CMCA-Connect intervention, and (4) analyze implementation costs. Primary outcomes include the number of days during the past 30 days of (1) any alcohol use, (2) heavy alcohol use (defined as having at least four, among young women, or five, among young men, standard alcoholic drinks within a couple of hours), (3) any marijuana use, and (4) prescription opioid misuse (defined as "without a doctor's prescription or differently than how a doctor or medical provider told you to use it"). DISCUSSION: This trial will expand upon previous research advancing the scientific evidence regarding prevention of opioid and other drug misuse during the critical developmental period of late adolescent transition to young adulthood among a sample of American Indian and other youth living within the Cherokee Nation reservation. TRIAL REGISTRATION: ClinicalTrials.gov NCT04839978 . Registered on April 9, 2021. Version 4, January 26, 2022.

Square-wave retarder for polarization computer-generated holography.

An etched calcite square-wave retarder is designed, fabricated, and demonstrated as an illuminator for an interlaced polarization computer-generated hologram (PCGH). The calcite square-wave retarder enables alternating columns of orthogonal linear polarizations to illuminate the interlaced PCGH. Together, these components produce a speckled, tangentially polarized PCGH diffraction pattern with a measured ratio of polarization of 84% and a degree of linear polarization of 0.81. An experimental alignment tolerance analysis is also reported.

Polarization synthesis by computer-generated holography using orthogonally polarized and correlated speckle patterns.

An interlaced polarization computer-generated hologram (PCGH) is designed to produce specific irradiance and polarization states in the image plane. The PCGH produces a tangentially polarized annular pattern with correlated speckle, which is achieved by a novel application of the diffuser optimization method. Alternating columns of orthogonal linear polarizations illuminate an interlaced PCGH, producing a ratio of polarization of 88% measured on a fabricated sample. The demonstrated technique can be applied to designs for arbitrary irradiance and polarization states in the image plane.

Pelvic organ prolapse.

Pelvic organ prolapse, or genital prolapse, is the descent of one or more of the pelvic structures (bladder, uterus, vagina) from the normal anatomic location toward or through the vaginal opening. Women of all ages may be affected, although pelvic organ prolapse is more common in older women. The cause is a loss of pelvic support from multiple factors, including direct injury to the levator ani, as well as neurologic injury from stretching of the pudendal nerves that may occur with vaginal childbirth. Previous hysterectomy for pelvic organ prolapse; ethnicity; and an increase in intra-abdominal pressure from chronic coughing, straining with constipation, or repeated heavy lifting may contribute. Most patients with pelvic organ prolapse are asymptomatic. A sense of bulging or protrusion in the vagina is the most specific symptom. Evaluation includes a systematic pelvic examination. Management options for women with symptomatic prolapse include observation, pelvic floor muscle training, mechanical support (pessaries), and surgery. Pessary use should be considered before surgery in women who have symptomatic prolapse. Most women can be fitted with a pessary regardless of the stage or site of predominant prolapse. Surgical procedures are obliterative or reconstructive.

Phorbol esters and SDF-1 induce rapid endocytosis and down modulation of the chemokine receptor CXCR4.

The chemokine receptor CXCR4 is required, together with CD4, for entry by some isolates of HIV-1, particularly those that emerge late in infection. The use of CXCR4 by these viruses likely has profound effects on viral host range and correlates with the evolution of immunodeficiency. Stromal cell-derived factor-1 (SDF-1), the ligand for CXCR4, can inhibit infection by CXCR4-dependent viruses. To understand the mechanism of this inhibition, we used a monoclonal antibody that is specific for CXCR4 to analyze the effects of phorbol esters and SDF-1 on surface expression of CXCR4. On human T cell lines SupT1 and BC7, CXCR4 undergoes slow constitutive internalization (1.0% of the cell surface pool/min). Addition of phorbol esters increased this endocytosis rate >6-fold and reduced cell surface CXCR4 expression by 60 to 90% over 120 min. CXCR4 was internalized through coated pits and coated vesicles and subsequently localized in endosomal compartments from where it could recycle to the cell surface after removal of the phorbol ester. SDF-1 also induced the rapid down modulation (half time approximately 5 min) of CXCR4. Using mink lung epithelial cells expressing CXCR4 and a COOH-terminal deletion mutant of CXCR4, we found that an intact cytoplasmic COOH-terminal domain was required for both PMA and ligand-induced CXCR4 endocytosis. However, experiments using inhibitors of protein kinase C indicated that SDF-1 and phorbol esters trigger down modulation through different cellular mechanisms. SDF-1 inhibited HIV-1 infection of mink cells expressing CD4 and CXCR4. The inhibition of infection was less efficient for CXCR4 lacking the COOH-terminal domain, suggesting at least in part that SDF-1 inhibition of virus infection was mediated through ligand-induced internalization of CXCR4. Significantly, ligand induced internalization of CXCR4 but not CD4, suggesting that CXCR4 and CD4 do not normally physically interact on the cell surface. Together these studies indicate that endocytosis can regulate the cell-surface expression of CXCR4 and that SDF-1-mediated down regulation of cell-surface coreceptor expression contributes to chemokine-mediated inhibition of HIV infection.

Rapid acclimation of the cortisol stress response in adult turquoise killifish Nothobranchius furzeri.

The turquoise killifish Nothobranchius furzeri is an increasingly popular model species for comparative vertebrate research, and the basic physiology including responses to stressful stimuli are of primary interest. We exposed adult killifish to a single or repeated periods of acute confinement followed by analysis of tissue cortisol and plasma cortisol concentrations. Individuals were also sampled for messenger RNA (mRNA) expression of corticotropin-releasing hormone (CRH), mineralocorticoid receptor (MR), and glucocorticoid receptor (GR) in the brain to examine the effects of repeated stress events on constitutive expression of these important stress axis components. Following a single 30-minute confinement stress, male plasma cortisol significantly differed from baseline (p = 0.04). Both male and female whole-body cortisol were significantly increased (p = 0.004 and p = 0.04, respectively) at 15 and 30 minutes poststress. Despite obvious dimorphic behavior and morphology, cortisol concentrations did not differ between the sexes. Exposure to daily repeated confinement for one week altered the cortisol response in both sexes. Time 0, 15, and 60 minutes poststress cortisol concentrations were depressed in repeatedly stressed males (p ≤ 0.05), and times 0, 30 and 120 minutes poststress cortisol concentrations were depressed in repeatedly stressed females (p ≤ 0.05). Constitutive expression of CRH, MR, and GR mRNA in the brain following one week of repeated stress events did not differ among treatments or sexes. This study introduces the first description of hypothalamic-pituitary-interrenal axis activity in this important model species. Reduced cortisol production in repeatedly stressed adult killifish suggests acclimation to repeated stressors. Furthermore, acclimation was rapid, and plasma cortisol concentrations altered significantly in as little as one week.

Communities mobilizing for change on alcohol (CMCA): secondary analyses of a randomized controlled trial showing effects of community organizing on alcohol acquisition by youth in the Cherokee nation.

AIMS: We evaluated the effects of a community organizing intervention, Communities Mobilizing for Change on Alcohol (CMCA), on the propensity of retail alcohol outlets to sell alcohol to young buyers without age identification and on alcohol acquisition behaviors of underage youth. DESIGN: Random assignment of community to treatment (n = 3) or control (n = 2). Student surveys were conducted four times per year for 3 years; the cohort was in 9th and 10th grades in the 2012-13 academic year. Alcohol purchase attempts were conducted every 4 weeks at alcohol retailers in each community (31 repeated waves). SETTING: The Cherokee Nation, located in northeastern Oklahoma, USA. PARTICIPANTS: A total of 1399 high school students (50% male; 45% American Indian) and 113 stores licensed to sell alcohol across five study communities. INTERVENTION: Local community organizers formed independent citizen action teams to advance policies, procedures and practices of local institutions in ways to reduce youth access to alcohol and foster community norms opposed to teen drinking. MEASUREMENTS: Perceptions regarding police enforcement and perceived difficulty of and self-reported actual acquisition of alcohol from parents, adults, peers and stores. FINDINGS: Alcohol purchases by young-appearing buyers declined significantly, an 18 [95% confidence interval (CI) = 3, 33] percentage-point reduction over the intervention period. Student survey results show statistically significant differences in the trajectory of perceived police enforcement, increasing 7 (4, 10) percentage points, alcohol acquisition from parents, decreasing 4 (0.1, 8) percentage points, acquisition from 21+ adults, decreasing 6 (0.04, 11) percentage points, from < 21 peers decreasing 8 (3, 13) percentage points and acquisition from stores decreasing 5 (1, 9) percentage points. CONCLUSIONS: A community organizing intervention, Communities Mobilizing for Change on Alcohol (CMCA), is effective in reducing the availability of alcohol to underage youth in the United states. Furthermore, results indicate that the previously reported significant effects of CMCA on teen drinking operate, at least in part, through effects on alcohol access.

The Human Immune Response to HIV and its Impact in the Potential Development of an Inactivated HIV Vaccine.

There is evidence that the transmission and acute phase of HIV infection triggers an immune response capable of controlling HIV subverted by the process of virus integration, essential to the replicative cycle of retroviruses. We review here two aspects that deserve consideration in light of recent developments concerning HIV transmission and vaccine development: vaccines directed against transmitted/founder viruses, and a reconsideration of inactivation as a viable means to obtain a preventive HIV vaccine. Since 80% of sexually transmitted HIV infections are caused by a single transmitted/founder variant, it is appropriate to target transmitted/founder viruses for vaccine development. Transmitted/founder virus transmission is subject to strong natural selection based on conserved signatures present in all forms of transmitted/founder HIV viruses. This provides an opportunity to pursue inactivation methods of vaccine development that allow antigenic preservation of HIV transmitted/founder viruses. The presentation to the immune system of an inactivated but antigenically preserved transmitted/founder virus should allow the development of an effective immune response against transmitted/founder viruses. This could be the base for an inactivated transmitted/founder virus HIV vaccine. We have devised a method of inactivation of HIV reverse transcriptase through the use of a novel photo-labeling procedure based on the use of photo-labeled analogs of antiretroviral compounds with specific affinity for HIV reverse transcriptase. We believe this method fulfills the required conditions for an effective preventive vaccine development: inactivation and antigenic preservation.

Analysis of two genes encoding heat-labile toxins and located on a single Ent plasmid from Escherichia coli.

A clinical isolate of Escherichia coli harbored two copies of the heat-labile toxin (LT)-encoding gene (elt) on a 157-kb plasmid. The arrangement of the gene copies is different from the cholera toxin-encoding gene duplication described for some strains of Vibrio cholerae. The nucleotide sequences of the elt alleles are not identical (differing by 2 bp) and the duplicated region flanking the alleles extends 314 bp on one side and 1122 bp on the other side of each copy. Different partial copies of IS600 were identified 280 bp 3' to the stop codon of each allele. Partial and complete copies of other IS were also identified near the elt alleles. The data suggest that the regions surrounding the genes are hot spots for IS which would account for the observed heterogeneity in DNA flanking elt genes.

Computer-simulated lung nodules in digital chest radiographs for detection studies.

Computer simulations of lung nodules overcome many shortcomings of creating radiographs using anthropomorphic nodule phantoms for lung nodule detection studies, but these algorithms can be cumbersome and involved. A simple, fast, and flexible computer program to simulate lung nodules in digital chest radiographs for detection studies is reported. To verify the realism of the simulated nodules, a psychophysical study and a statistical study were conducted. In the psychophysical study, six radiologists and four nonradiologists were asked to distinguish between 17 real lung nodules and 17 computer-simulated lung nodules shown in eight radiographs. The results show that the computer-simulated lung nodules are indistinguishable visually from real lung nodules. Using parameters from the Rose model of vision, results show that the simulated and real nodules are the same statistically. Thus, besides visual validity, statistical analysis in confirming the validity of the simulated lung nodules is included.

Functional cloning of the dihydropteroate synthase gene of Staphylococcus haemolyticus.

A 1,7-kilobase fragment of the Staphylococcus haemolyticus chromosome containing the dihydropteroate synthase gene has been cloned by complementation in a temperature-sensitive mutant of Escherichia coli. The gene, designated folP, predicts a gene product of 29613 Da which shares significant amino acid sequence identity with other known bacterial dihydropteroate synthases. Analysis of the DNA sequence upstream and downstream of folP identified two further, incomplete open reading frames, one of which shows predicted amino acid sequence similarity to a second bacterial folic acid synthesis enzyme, dihydroneopterin aldolase.

Evaluation of the ACR-NEMA standard for communications in digital radiology.

An implementation and evaluation of a prototype multivendor communications system which complies with the American College of Radiology (ACR) and the National Electrical Manufacturers Association (NEMA) standard for communications in digital radiology is discussed. The system allows communications between interfaces from different manufacturers within a networked environment. The implementation includes network software compatible with the International Standards Organization's Open Systems Interconnect standard. The experience of the implementation effort and the evaluation of the system provide the basis for a critique of the ACR-NEMA standard. It is concluded that the ACR-NEMA standard is not well suited for application to the networked environment of picture archiving and communications systems. Two possible solutions are recommended for this problem. The first is a major revision of the existing standard. The second is the development of a family of network communications standards for digital radiology.

Design and testing of artifact-suppressed adaptive histogram equalization: a contrast-enhancement technique for display of digital chest radiographs.

One of the goals of our research in the field of digital radiography has been to develop contrast-enhancement algorithms for eventual use in the display of chest images on video devices with the aim of preserving the diagnostic information presently available with film, some of which would normally be lost because of the smaller dynamic range of video monitors. The ASAHE algorithm discussed in this article has been tested by investigating observer performance in a difficult detection task involving phantoms and simulated lung nodules, using film as the output medium. The results of the experiment showed that the algorithm is successful in providing contrast-enhanced, natural-looking chest images while maintaining diagnostic information. The algorithm did not effect an increase in nodule detectability, but this was not unexpected because film is a medium capable of displaying a wide range of gray levels. It is sufficient at this stage to show that there is no degradation in observer performance. Future tests will evaluate the performance of the ASAHE algorithm in preparing chest images for video display.

Monoclonal antibody B9-2 recognizes an 8 amino acid sequence that spans an autocatalytic cleavage site between the two subunits of human procaspase 8.

Caspase 8 is synthesized in a zymogen form and must be proteolytically cleaved to be activated. The catalytically active enzyme is composed of two of the four cleavage products. We have determined that the monoclonal antibody B9-2 recognizes the octomer EMDLSSPQ. This sequence is shared by two of the cleavage products: a decamer linker region released after autocatalysis and the smaller subunit of the active enzyme.

High-affinity monoclonal antibodies to PED/PEA-15 generated using 5 microg of DNA.

Class-switched, affinity-matured murine monoclonal antibody (MAb) producing cell lines reactive with PED/PEA-15 were generated and isolated in less than 4 weeks following polynucleotide immunizations using only 5 microg of DNA in conjunction with the Powderject gene gun. Somatic fusions of peripheral lymph node cells were performed 13 days after initiating delivery of DNA encoding the target antigen. The data presented demonstrates the rapid production, identification, and characterization of class-switched, affinity-matured MAbs that bind PED/PEA-15. The reported strategy enabled the rapid development of MAbs that are useful in enzyme-linked immunoadsorbent assay (ELISA), Western blotting, and immunoprecipitations.