A randomized controlled trial of a team science intervention to enhance collaboration readiness and behavior among early career scholars in the Clinical and Translational Science Award network.

Introduction: Despite the central importance of cross-disciplinary collaboration in the Clinical and Translational Science Award (CTSA) network and the implementation of various programs designed to enhance collaboration, rigorous evidence for the efficacy of these approaches is lacking. We conducted a novel randomized controlled trial (RCT; ClinicalTrials.gov identifier: NCT05395286) of a promising approach to enhance collaboration readiness and behavior among 95 early career scholars from throughout the CTSA network. Methods: Participants were randomly assigned (within two cohorts) to participate in an Innovation Lab, a week-long immersive collaboration experience, or to a treatment-as-usual control group. Primary outcomes were change in metrics of self-reported collaboration readiness (through 12-month follow-up) and objective collaboration network size from bibliometrics (through 21 months); secondary outcomes included self-reported number of grants submitted and, among Innovation Lab participants only, reactions to the Lab experience (through 12 months). Results: Short-term reactions from Innovation Lab participants were quite positive, and controlled evidence for a beneficial impact of Innovation Labs over the control condition was observed in the self-reported number of grant proposals in the intent-to-treat sample. Primary measures of collaboration readiness were near ceiling in both groups, limiting the ability to detect enhancement. Collaboration network size increased over time to a comparable degree in both groups. Conclusions: The findings highlight the need for systematic intervention development research to identify efficacious strategies that can be implemented throughout the CTSA network to better support the goal of enhanced cross-disciplinary collaboration.

Should Uterus Transplantation for Transwomen and Transmen Be Subsidized?

Success in uterus transplantation (UTx) among ciswomen suggests that transwomen and some transmen will also likely have interest in this intervention. It does not seem likely, however, that all parties interested in UTx will have the same standing when it comes to federal subsidies or insurance coverage benefits. This analysis describes the comparative moral strength of claims for financial support for UTx that different parties might make.

Adaptation of Nontypeable Haemophilus influenzae in Human Airways in COPD: Genome Rearrangements and Modulation of Expression of HMW1 and HMW2.

Chronic obstructive pulmonary disease (COPD) is a common debilitating disorder that is the third most common cause of death globally. Chronic lower airway infection by nontypeable Haemophilus influenzae (NTHi) in adults with COPD increases airway inflammation, causes increased symptoms, and accelerates progressive loss of lung function. Little is known about the mechanisms by which NTHi survives in COPD airways. To explore this question, the present study analyzes, in detail, 14 prospectively collected, serial isolates of a strain that persisted for 543 days in a patient with COPD, including analysis of four gap-free complete genomes. The NTHi genome underwent inversion of a ~400-kb segment three times during persistence. This inversion event resulted in switching of expression of the HMW1A and HMW2A adhesins as the inversion sites are in the promoter regions of HMW1 and HMW2. Regulation of the level of expression of HMW 1 and HMW2 in the human airways was controlled by the ~400-kb inversion and by 7-bp repeats in the HMW promoters. Analysis of knockout mutants of the persistent strain demonstrated that HMW1 and HMW2 proteins both function in the adherence of NTHi to human respiratory epithelial cells during persistence and that HMW1 also facilitates invasion of epithelial cells. An inverse relationship between biofilm formation and HMW1 expression was observed during persistence. This work advances understanding of the mechanisms of persistence of NTHi in COPD airways, which can inform the development of novel interventions to treat and prevent chronic NTHi infection in COPD. IMPORTANCE Nontypeable Haemophilus influenzae (NTHi) persists in the lower airways of adults with chronic obstructive pulmonary disease (COPD) for months to years, increasing airway inflammation that accelerates the progressive loss of lung function. Understanding the mechanisms of persistence in human airways by NTHi is critical in developing novel interventions. Here, in detail, we studied longitudinally collected sequential isolates of a strain of NTHi that persisted in an adult with COPD, including analysis of four gap-free genomes and knockout mutants to elucidate how the genome adapts in human airways. The NTHi genome underwent a genome rearrangement during persistence and this inversion impacted regulation of expression of key virulence phenotypes, including adherence to respiratory epithelial cells, invasion of epithelial cells and biofilm formation. These novel observations advance our understanding of the mechanisms of persistence of NTHi in the airways of adults with COPD.

A community-university run conference as a catalyst for addressing health disparities in an urban community.

The African American population of Buffalo, New York experiences striking race-based health disparities due to adverse social determinants of health. A team of community leaders and university faculty determined that a community dialogue was needed to focus research and advocacy on the root causes of these disparities. In response, we organized the annual Igniting Hope conference series that has become the premier conference on health disparities in the region. The series, now supported by an R13 conference grant from NCATS, has been held four times (2018-2021) and has attracted community members, community leaders, university faculty, and trainees. The agenda includes talks by national leaders and breakout/working groups that led to a new state law that has reduced disproportionate traffic-ticketing and drivers' license suspensions in Black neighborhoods; mitigation of the disproportionate COVID-19 fatalities in Black communities; and the launching of a university-supported institute. We describe the key elements of success for a conference series designed by a community-university partnership to catalyze initiatives that are having an impact on social determinants of health in Buffalo.

Rhinovirus increases Moraxella catarrhalis adhesion to the respiratory epithelium.

Rhinovirus causes many types of respiratory illnesses, ranging from minor colds to exacerbations of asthma. Moraxella catarrhalis is an opportunistic pathogen that is increased in abundance during rhinovirus illnesses and asthma exacerbations and is associated with increased severity of illness through mechanisms that are ill-defined. We used a co-infection model of human airway epithelium differentiated at the air-liquid interface to test the hypothesis that rhinovirus infection promotes M. catarrhalis adhesion and survival on the respiratory epithelium. Initial experiments showed that infection with M. catarrhalis alone did not damage the epithelium or induce cytokine production, but increased trans-epithelial electrical resistance, indicative of increased barrier function. In a co-infection model, infection with the more virulent rhinovirus-A and rhinovirus-C, but not the less virulent rhinovirus-B types, increased cell-associated M. catarrhalis. Immunofluorescent staining demonstrated that M. catarrhalis adhered to rhinovirus-infected ciliated epithelial cells and infected cells being extruded from the epithelium. Rhinovirus induced pronounced changes in gene expression and secretion of inflammatory cytokines. In contrast, M. catarrhalis caused minimal effects and did not enhance RV-induced responses. Our results indicate that rhinovirus-A or C infection increases M. catarrhalis survival and cell association while M. catarrhalis infection alone does not cause cytopathology or epithelial inflammation. Our findings suggest that rhinovirus and M. catarrhalis co-infection could promote epithelial damage and more severe illness by amplifying leukocyte inflammatory responses at the epithelial surface.

Gestation as mothering.

Some commentators maintain that gestational surrogates are not 'mothers' in a way capable of grounding a claim to motherhood. These commentators find that the practices that constitute motherhood do not extend to gestational surrogates. We argue that gestational surrogates should be construed as mothers of the children they bear, even if they fully intend to surrender those children at birth to the care of others. These women stand in a certain relationship to the expected children: they live in changed moral circumstances by reason of their pregnancy, and they engage in the practices said to define motherhood in the post-birth context. By contrast, ovum donors and embryo donors are not similarly 'mothers' because they do not find themselves involved in these circumstances. Not all women involved in three-parent in vitro fertilization qualify as mothers either. Given this analysis of mothering, we note that transmen who gestate children are engaged in mothering activity even if they otherwise function as a father to those children. By itself, this defence of the maternity of gestational surrogates does not confer moral title to the children they bear; gestation would not by itself override the contractual arrangements gestational surrogates have made regarding the disposition of their children. This interpretation of gestational surrogates as mothers does, however, undercut cultural understandings of these women as mere 'vessels', devoid of entitlement to respect as persons and parents. We also consider the meaning of mothering for 'brain-dead' women kept alive to give birth and for the prospect of extracorporeal gestation.

Synchrony in serum antibody response to conserved proteins of Moraxella catarrhalis in young children.

Conserved Moraxella catarrhalis (Mcat) proteins, oligopeptide permease (Opp)A, hemagglutinin (Hag), outer membrane protein (OMP) CD, Pilin A clade 2 (PilA2), and Moraxella surface protein (Msp) 22 have been studied as vaccine candidates. Children who experience frequent acute otitis media (AOM) confirmed with pathogen identification by tympanocentesis are referred to as stringently-defined otitis prone (sOP). Synchrony of serum antibody responses against 5 Mcat proteins, OppA, Hag, OMP CD, PilA2, and Msp22 resulting from nasopharyngeal colonization and AOM was studied for 85 non-otitis prone (NOP) children and 34 sOP children. Changes in serum IgG were quantitated with ELISA. Serum IgG antibody levels against OppA, Hag, OMP CD, and Msp22 rose in synchrony in NOP and sOP children; that is, the proteins appeared equally and highly immunogenic in children at age 6 to 22-25 months old and then leveled off in their rise at 22-25 to 30 months old. In contrast, rises of PilA2 were slow from 6 months old and kept constant and did not level off significantly before 30 months old. OppA, Hag, OMP CD, and Msp22 elicited a synchronous acquisition of naturally-induced serum antibody in young children. A multi-valent Mcat protein vaccine combining OppA, Hag, OMP CD, and Msp22 may exhibit less antigen competition when administered as a combination vaccine in young children.

Impact of Pseudomonas aeruginosa Isolation on Mortality and Outcomes in an Outpatient Chronic Obstructive Pulmonary Disease Cohort.

BACKGROUND: Tracheobronchial colonization by Pseudomonas aeruginosa (PA) has been shown to negatively impact outcomes in cystic fibrosis and bronchiectasis. There is uncertainty whether the same association is prevalent in chronic obstructive pulmonary disease (COPD), especially in the outpatient setting. Our objective was to determine (1) whether PA isolation is associated with mortality and (2) changes in exacerbation and hospitalization rates within a longitudinal cohort of COPD outpatients. METHODS: Pseudomonas aeruginosa colonization was ascertained in monthly sputum cultures in a prospective cohort of COPD patients from 1994 to 2014. All-cause mortality was compared between patients who were colonized during their follow-up period (PA + ) and those who remained free of colonization (PA - ); Cox proportional hazards models were used. Exacerbation and hospitalization rates were evaluated by 2-rate χ 2 and segmented regression analysis for 12 months before and 24 months after PA isolation. RESULTS: Pseudomonas aeruginosa was isolated from sputum in 73 of 181 (40%) patients. Increased mortality was seen with PA isolation: 56 of 73 (77%) PA +  patients died compared with 73 of 108 (68%) PA - patients (P = .004). In adjusted models, PA +  patients had a 47% higher risk of mortality (adjusted hazard ratio = 1.47; 95% confidence interval, 1.03-2.11; P = .04). Exacerbation rates were higher for the PA +  group during preisolation (15.4 vs 9.0 per 100 person-months, P < .001) and postisolation periods (15.7 vs 7.5, P < .001). Hospitalization rates were higher during the postisolation period among PA +  patients (6.25 vs 2.44, P < .001). CONCLUSIONS: Tracheobronchial colonization by PA in COPD outpatients was associated with higher morbidity and mortality. This suggests that PA likely contributes to adverse clinical outcomes rather than just a marker of worsening disease.

ReVac: a reverse vaccinology computational pipeline for prioritization of prokaryotic protein vaccine candidates.

BACKGROUND: Reverse vaccinology accelerates the discovery of potential vaccine candidates (PVCs) prior to experimental validation. Current programs typically use one bacterial proteome to identify PVCs through a filtering architecture using feature prediction programs or a machine learning approach. Filtering approaches may eliminate potential antigens based on limitations in the accuracy of prediction tools used. Machine learning approaches are heavily dependent on the selection of training datasets with experimentally validated antigens (positive control) and non-protective-antigens (negative control). The use of one or few bacterial proteomes does not assess PVC conservation among strains, an important feature of vaccine antigens. RESULTS: We present ReVac, which implements both a panoply of feature prediction programs without filtering out proteins, and scoring of candidates based on predictions made on curated positive and negative control PVCs datasets. ReVac surveys several genomes assessing protein conservation, as well as DNA and protein repeats, which may result in variable expression of PVCs. ReVac's orthologous clustering of conserved genes, identifies core and dispensable genome components. This is useful for determining the degree of conservation of PVCs among the population of isolates for a given pathogen. Potential vaccine candidates are then prioritized based on conservation and overall feature-based scoring. We present the application of ReVac, applied to 69 Moraxella catarrhalis and 270 non-typeable Haemophilus influenzae genomes, prioritizing 64 and 29 proteins as PVCs, respectively. CONCLUSION: ReVac's use of a scoring scheme ranks PVCs for subsequent experimental testing. It employs a redundancy-based approach in its predictions of features using several prediction tools. The protein's features are collated, and each protein is ranked based on the scoring scheme. Multi-genome analyses performed in ReVac allow for a comprehensive overview of PVCs from a pan-genome perspective, as an essential pre-requisite for any bacterial subunit vaccine design. ReVac prioritized PVCs of two human respiratory pathogens, identifying both novel and previously validated PVCs.

Non-typeable Haemophilus influenzae isolates from patients with chronic obstructive pulmonary disease contain new phase-variable modA methyltransferase alleles controlling phasevarions.

Phasevarions (phase-variable regulons) are emerging as an important area of bacterial gene regulation. Many bacterial pathogens contain phasevarions, with gene expression controlled by the phase-variable expression of DNA methyltransferases via epigenetic mechanisms. Non-typeable Haemophilus influenzae (NTHi) contains the phase-variable methyltransferase modA, of which multiple allelic variants exist (modA1-21). We have previously demonstrated 5 of 21 these modA alleles are overrepresented in NTHi strains isolated from children with middle ear infections. In this study we investigated the modA allele distribution in NTHi strains isolated from patients with chronic obstructive pulmonary disease, COPD. We demonstrate that the distribution of modA alleles in a large panel of COPD isolates is different to the distribution seen in middle ear infections, suggesting different modA alleles may provide distinct advantages in the differing niches of the middle ear and COPD airways. We also identified two new phase-variable modA alleles - modA15 and modA18 - and demonstrate that these alleles methylate distinct DNA sequences and control unique phasevarions. The modA15 and modA18 alleles have only been observed in COPD isolates, indicating that these two alleles may be markers for isolates likely to cause exacerbations of COPD.

Biogenetic ties and parent-child relationships: The misplaced critique.

According to an almost axiomatic standard in bioethics, moral commitment should ground parents' relationship with their children, rather than biogenetic relatedness. This standard has been used lately to express skepticism about extending existing assisted reproductive treatments (ARTs) to same-sex couples and to research into novel fertility interventions for those couples, but this skepticism is misplaced on several grounds. As a matter of access and equity, same-sex couples seem presumptively entitled to genetic relatedness to their children as far as possible both in regard to existing ARTs and to novel ARTs under investigation. For those worried about the effects of trying to secure biogenetic relatedness for same-sex couples, it may be noted that same-sex couples will only ever be a fraction of the parents implicated in propping up "biologism," as the expectation of biogenetic relatedness it is sometimes called. The cultural force of biologism would survive almost intact even if no same-sex couples were ever to have genetically related children. It is therefore hard to see why same-sex couples should forfeit aspirations to biogenetic relationships with their children or enjoy less subsidy for ARTs than the subsidy given to different-sex couples. As matter of moral consistency, the full implications of the biologism critique have yet to be evaluated relative to different-sex couples.

Transcriptome Sequencing Data Sets for Determining Gene Expression Changes Mediated by Phase-Variable DNA Methyltransferases in Nontypeable Haemophilus influenzae Strains Isolated from Patients with Chronic Obstructive Pulmonary Disease.

Nontypeable Haemophilus influenzae (NTHi) is a major bacterial cause of exacerbations in chronic obstructive pulmonary disease (COPD). Here, we report high-depth coverage transcriptome sequencing (RNA-seq) data from two NTHi strains, each encoding a different phase-variable methyltransferase. modA phase variation results in gene expression differences. These data will serve as an important resource for future studies.

Small-Molecule Inhibitors of Haemophilus influenzae IgA1 Protease.

Newly identified, nontypable Haemophilus influenzae (H. influenza) strains represent a serious threat to global health. Due to the increasing prevalence of antibiotic resistance, virulence factors have emerged as potential therapeutic targets that would be less likely to promote resistance. IgA1 proteases are secreted virulence factors of many Gram-negative human pathogens. These enzymes play important roles in tissue invasion as well as evasion of the immune response, yet there has been limited work on pharmacological inhibitors. Here, we report the discovery of the first small molecule, nonpeptidic inhibitors of H. influenzae IgA1 proteases. We screened over 47 000 compounds in a biochemical assay using recombinant protease and identified a hit compound with micromolar potency. Preliminary structure-activity relationships produced additional inhibitors, two of which showed improved inhibition and selectivity for IgA protease over other serine proteases. We further showed dose-dependent inhibition against four different IgA1 protease variants collected from clinical isolates. These data support further development of IgA protease inhibitors as potential therapeutics for antibiotic-resistant H. influenza strains. The newly discovered inhibitors also represent valuable probes for exploring the roles of these proteases in bacterial colonization, invasion, and infection of mucosal tissues.

The Laminin Interactome: A Multifactorial Laminin-Binding Strategy by Nontypeable Haemophilus influenzae for Effective Adherence and Colonization.

Laminin is a well-defined component of the airway basement membrane (BM). Efficient binding of laminin via multiple interactions is important for nontypeable Haemophilus influenzae (NTHi) colonization in the airway mucosa. In this study, we identified elongation factor thermo-unstable (EF-Tu), l-lactate dehydrogenase (LDH), protein D (PD), and peptidoglycan-associated lipoprotein P6 as novel laminin-binding proteins (Lbps) of NTHi. In parallel with other well-studied Lbps (protein 4 [P4], protein E [PE], protein F [PF], and Haemophilus adhesion and penetration protein [Hap]), EF-Tu, LDH, PD, and P6 exhibited interactions with laminin, and mediated NTHi laminin-dependent adherence to pulmonary epithelial cell lines. More importantly, the NTHi laminin interactome consisting of the well-studied and novel Lbps recognized laminin LG domains from the subunit α chains of laminin-111 and -332, the latter isoform of which is the main laminin in the airway BM. The NTHi interactome mainly targeted multiple heparin-binding domains of laminin. In conclusion, the NTHi interactome exhibited a high plasticity of interactions with different laminin isoforms via multiple heparin-binding sites.

Adolescents and Body Modification for Gender Identity Expression.

As a matter of ethics and law, adults enjoy wide berth in securing hormonal and surgical interventions to align their bodies with their desired gender appearance. In contrast, the exercise of choice by minors is more constrained, because they can be less well situated to grasp the nature and consequences of interventions having life-long effects. Even so, some minors hope for body modifications prior to adulthood. Starting very young, some minors may assert atypical gender identity: those with female-typical bodies assert a male identity and those with male-typical bodies assert a female identity. This assertion of identity is atypical only in a descriptive sense, because it is uncharacteristic, not because it is normatively unacceptable. Not all minors persist in their atypical gender identities, but some do. For those who do, it is desirable to minimize unwanted secondary sex characteristics and to maximize desired secondary sex characteristics. I outline here a theory of respect for decisions by minors in regard to hormonal and surgical interventions that help align their bodies with their gender identity. Of particular ethical interest here are body modifications for fertility preservation since certain interventions in the body can leave people unable to have genetically related children. In general, I will show that the degree of respect owed to minors in regard to body modifications for gender identity expression should be scaled according to their decision-making capacities, in the context of robust practices of informed consent.

Potential impact of a Moraxella catarrhalis vaccine in COPD.

Moraxella catarrhalis is the second most common cause of exacerbations in adults with COPD, resulting in enormous morbidity and mortality in this clinical setting. Vaccine development for M. catarrhalis has lagged behind the other two important causes of exacerbations in COPD, nontypeable Haemophilus influenzae and Streptococcus pneumoniae. While no licensed vaccine is currently available for M. catarrhalis, several promising candidate vaccine antigens have been identified and characterized and are close to entering clinical trials. Key steps that are required to advance vaccines for M. catarrhalis along the translational pipeline include standardization of assay systems to assess candidate antigens, identification of a reliable correlate of protection and expansion of partnerships between industry, academia and government to overcome regulatory hurdles. A vaccine to prevent M. catarrhalis infections in COPD would have a major impact in reducing morbidity, mortality and healthcare costs in COPD.