Faculty Bibliography

OBJECTIVE:To confirm feasibility and safety of the Da Vinci Single-Port (SP) System to perform pulmonary lobectomy procedures utilizing a subcostal, uniportal approach. METHODS:We performed a prospective, multicenter, single arm, clinical study evaluating performance and safety of the da Vinci SP Surgical System for pulmonary lobectomy. RESULTS:Nineteen subjects (benign, n=1; malignant, n=18) were enrolled at six academic medical centers in the United States and underwent robotic-assisted SP subcostal lobectomy. All SP lobectomy procedures were completed without conversion to multiport thoracoscopic/robotic or open approaches. No intraoperative adverse events or unanticipated adverse device effects were observed; 13 postoperative adverse events (AEs) commonly experienced after lobectomy were reported, 4 of which were Clavien-Dindo grade III. Rate of complete (R0) resection was 100%. The median (interquartile (IQR)) number nodal stations sampled was 6.5 (6.0-8.0) with a median of 17.5 (7.0-34.0) nodes resected per patient. CONCLUSIONS:Robotic SP subcostal lobectomy is feasible and is associated with acceptable perioperative and oncologic quality outcomes. Additional clinical experience and research is necessary to determine whether this alternative single incision approach has clinical benefit compared to standard transthoracic, multiport robotic lobectomy.

The survival of malignant cells within tumours is often seen as depending on ruthless competition for nutrients and other resources^1,2. Although competition is certainly critical for tumour evolution and cancer progression, cooperative interactions within tumours are also important, albeit poorly understood^3,4. Cooperative populations at all levels of biological organization risk extinction if their population size falls below a critical tipping point^5,6. Here we examined whether cooperation among tumour cells may be a potential therapeutic target. We identified a cooperative mechanism that enables tumour cells to proliferate under the amino acid-deprived conditions found in the tumour microenvironment. Disruption of this mechanism drove cultured tumour populations to the critical extinction point and resulted in a marked reduction in tumour growth in vivo. Mechanistically, we show that tumour cells collectively digest extracellular oligopeptides through the secretion of aminopeptidases. The resulting free amino acids benefit both aminopeptidase-secreting cells and neighbouring cells. We identified CNDP2 as the key enzyme that hydrolyses these peptides extracellularly, and loss of this aminopeptidase prevents tumour growth in vitro and in vivo. These data show that cooperative scavenging of nutrients is key to survival in the tumour microenvironment and reveal a targetable cancer vulnerability.

Gastrointestinal (GI) colonization by methicillin-resistant Staphylococcus aureus (MRSA) is associated with a high risk of transmission and invasive disease in vulnerable populations. The immune and microbial factors that permit GI colonization remain unknown. Male sex is correlated with enhanced Staphylococcus aureus nasal carriage, skin and soft tissue infections, and bacterial sepsis. Here, we established a mouse model of sexual dimorphism during GI colonization by MRSA. Our results show that in contrast to male mice that were susceptible to persistent colonization, female mice rapidly cleared MRSA from the GI tract following oral inoculation in a manner dependent on the gut microbiota. This colonization resistance displayed by female mice was mediated by an increase in IL-17A+ CD4+ T cells (Th17) and dependent on neutrophils. Ovariectomy of female mice increased MRSA burden, but gonadal female mice that have the Y chromosome retained enhanced Th17 responses and colonization resistance. Our study reveals a novel intersection between sex and gut microbiota underlying colonization resistance against a major widespread pathogen.

BACKGROUND:Children born very preterm (VPT) are at high risk for attention problems. This study's purpose was to describe the Conners Kiddie Continuous Performance Test (K-CPT) assessment in children born VPT, including rates of clinically elevated scores, change over time, and associations between K-CPT scores and parent reported attention problems. METHODS:We studied 305 children from a multi-site study of children born VPT who completed at least one K-CPT assessment at age 5, 6, and/or 7 years. Parent-reported ADHD symptoms and diagnosis were also collected. We calculated K-CPT completion rates, mean scores, and rates of clinically elevated scores at each timepoint. Linear mixed models examined change over time in K-CPT scores. Correlations and generalized linear models investigated associations between K-CPT scores and ADHD symptoms and diagnoses. RESULTS:K-CPT scores showed expected age-related improvements from age 5-7, with significant intra- and inter-individual variability. Up to 1/3 of children had clinically elevated attention problems and another 1/3 had subclinical elevations. K-CPT scores were modestly correlated with parent-rated ADHD symptoms and children with a parent-reported ADHD diagnosis performed worse on nearly all K-CPT metrics. CONCLUSION/CONCLUSIONS:Performance-based measures like the K-CPT can be useful for research and clinical practice in VPT populations. IMPACT/CONCLUSIONS:Attention problems are a specific area of weakness for children born very preterm. Performance-based tests of attention have benefits and drawbacks compared to parent report measures yet are understudied in this population. We examined one performance-based measure (the Conners Kiddie Continuous Performance Test [K-CPT]) in 305 children born very preterm. We observed improving task scores from age 5-7 years with significant intra- and inter-individual variability, a sizable proportion of children with clinically and subclinically elevated scores, and modest associations between K-CPT scores and parent reported attention problems. The K-CPT could be a useful clinical and research tool in this population.

The COVID-19 pandemic profoundly impacted global health, with disproportionate consequences for healthcare workers (HCWs). Religious beliefs and practices may improve psychological resilience by fostering community, providing purpose and giving meaning to hardships. Yet, how religiosity impacts HCWs during a time of crisis is unclear. We therefore performed a cross-sectional study to investigate how religiosity contributes to resilience among HCWs who were routinely exposed to high levels of stress during the pandemic, through a physiological measure (the Auditory Sustained Attention Test; ASAT) and psychological self-reports. Forty-two HCWs were recruited from COVID-19 units and 44 HCWs from general internal medicine units during June and July 2022. COVID-19 HCWs showed significantly elevated emotional and attentional dysregulation with the ASAT, as measured by acoustic startle and prepulse inhibition, that was undetectable with self-reports. Furthermore, after dividing the HCWs into a 'high' and 'low' religiosity group, those in the 'low' group showed higher emotional and attentional dysregulation with the ASAT. Findings suggest that the ASAT has greater sensitivity at detecting emotional and attentional dysregulations than self-reports. Moderate or high religiosity may lead to better performance on the ASAT which could suggest greater resilience to mental health problems in the face of a crisis.

Racial/ethnic disparities in COVID-19 morbidity and mortality are serious in the United States, particularly among African American/Black and Latine (AABL) populations. Staying up-to-date on COVID-19 vaccination is essential for mitigating risk, but AABL vaccination rates are low. The present qualitative study explores perspectives on COVID-19 among AABL persons at high-risk for exposure to the SARS-CoV- 2 virus: frontline essential workers engaged in public-facing professions (e.g., retail). From a larger study of AABL frontline essential workers not up-to-date on COVID-19 vaccination, N = 50 participants were purposively sampled for maximum variability. Participants engaged in semi-structured qualitative interviews in English or Spanish that were audio-recorded, professionally transcribed, and translated into English as needed. Data were analyzed using a directed content analysis approach that was both inductive and theory-driven. Participants were 37 years old, on average, and most (65%) were men. Approximately half (56%) were Latine/Hispanic and 44% were African American/Black. Occupations included food preparation (40%), retail (28%), construction (12%), in-home health care (8%), and building maintenance and personal services (12%). Approximately a third (38%) had received ≥ 1 COVID-19 vaccine dose. We found COVID-19 vaccination perspectives were grounded in a larger context of medical and institutional distrust and past/ongoing systemic racism. In this context, results were organized into the following themes: general perspectives on COVID-19; barriers/facilitators related to race/ethnicity, social class, and community; specific aspects of the COVID-19 vaccine as barriers; mandates, incentives, and pressures to be vaccinated; and mixed effects of public health initiatives. Overall, participants were knowledgeable about COVID-19. Social norms reduced vaccine intentions but altruism and community/family concern could motivate it. Aspects of the public health response (e.g., advertisement campaigns targeting AABL populations) increased distrust and reduced vaccination willingness. However, at least some ambivalence about vaccination was common (participants would consider it). Yet there was a large gap between considering and receiving vaccination. Thus, barriers to COVID-19 vaccination for AABL frontline essential workers operate at multiple levels of influence, but are addressable. The present study yields recommendations to improve vaccination, including increasing the trustworthiness of systems and institutions, reducing systemic/structural barriers, harnessing social forces, and engaging AABL communities in program planning.

OBJECTIVE:Intravaginal rings (IVRs) are marketed or in development for contraception and other indications. We sought to develop and validate the IVR Acceptability Scale (IVR-AS) as a multidimensional, standardized tool for assessing IVR acceptability among end-users in the United States. METHODS:Scale items reflect specific aspects of IVR acceptability for women and male partners. Response options range from 1 (not-at-all acceptable) to 5 (highly acceptable). We evaluated the IVR-AS within a randomized, crossover clinical trial of three nonmedicated silicone IVRs of differing external diameters (46, 56, 66 mm) in heterosexual couples who used each for ~30 days, then completed a self-administered survey. We conducted exploratory factor analysis and multivariable regression to assess convergent validity. Follow-up in-depth interviews with all participants explored scale salience. RESULTS:Twenty-four couples participated (mean age 27). The final 19-item women's scale (Cronbach's alpha = 0.93) included six subdimensions: ease of use; experience and sensation; effect on sexual desire/engagement, and effect on vaginal sex (all alphas > 0.78). The final eight-item men's scale comprised two subdimensions: effect on sexual desire/engagement and effect on vaginal sex (all alphas > 0.89). For both sexes, higher overall/subdimension scores were consistently associated with favorable assessments of the ring, for example, ease of insertion/removal; adherence (most p < 0.001). The 46/56 mm IVRs had higher overall and subdimension scores than the 66 mm IVR (most p < 0.001). Qualitative reports reinforced the salience of scale subdimensions and item content. CONCLUSION/CONCLUSIONS:The IVR-AS captures multiple dimensions of IVR acceptability among women and their partners. The scales demonstrated excellent reliability and convergent validity. Further validation is warranted in future studies. TRIAL REGISTRATION/BACKGROUND:Clinical Trials.gov: NCT05128136. https://clinicaltrials.gov/study/NCT05128136?intr=non-medicated%20silicone%20ring&rank=2.