Citations

AbstractPurposeEye plaques are widely used for ocular melanoma and provide an effective alternative to enucleation with adequate tumor control. A COMS plaque utilizes a Silastic insert for precise positioning of the radioactive seeds with respect to the scleral surface of the eye; however, due to manufacturing variability, the insert may unintentionally increase or decrease the distance between the sources and tumor. The purpose of this work is to provide guidance in measuring and identifying outliers in Silastic inserts. The importance of regular quality assurance (QA) is illustrated in an experience where a systematic problem was detected and the manufacturer's 22‐mm mold was corrected.MethodsA detailed description of the molds and manufacturing process used to produce Silastic inserts is provided, including photographs of the process steps. The variability in Silastic insert production was evaluated by measuring the thickness of 124 Silastic inserts. An estimate of how the observed Silastic thickness discrepancies impact the dose to the tumor and critical eye structures was performed using homogeneous dose calculations. A standard QA protocol was developed to guide the clinical user.ResultsThickness of the measured Silastic inserts ranged from 1.22 to 2.67 mm, demonstrating variation from the 2.25 mm standard. Six of the 22‐mm inserts were outliers (Δthickness >3 standard deviations) and were excluded from the statistics. The outliers were investigated with the help of the manufacturer, who discovered that a systematic error was accidentally introduced into the 22‐mm mold.ConclusionsDue to manufacturing errors or variability, the Silastic inserts used in COMS eye plaques may be thicker or thinner than the design standard. Such variations may impact tumor control or increase the risk of normal tissue side effects. A standardized QA program is recommended to detect variations and communicate unusual findings to the manufacturer.

Objective: Here, we describe a systematic approach to design, implement, and assess a robotic surgery curriculum for surgical residents. By describing our process, including identifying and addressing institutional challenges, we illustrate successful development of a robust curriculum. Summary Background Data: As robotic-assisted surgeries increase, educational challenges have emerged and illustrate an alarming impact on medical training. Robotic curricula are frequently grounded in the industry’s educational materials resulting in a variety of existing resident curricula that lack cognitive components and critical evaluation. As such, surgical educators struggle to identify the curricular restructuring needs that likely accompany emerging technologies. It is essential to develop a curricular framework for the surgical education community to approach the ongoing and inevitable integration of new technologies. Methods: Our process parallels the widely accepted approach to curricular development in medical education described by Kern et al. Using this 6-step model, we describe derivation of a curriculum that was data driven, features multimodal educational strategies, and provides documentation methods that allow for continued evaluation and assessment at the individual and departmental level. Results: This study highlights the systematic process of design, implementation and assessment of a robotic surgery curriculum for surgical residents. Built on a robust national and local needs assessment, and further strengthened by preemptive identification of institutional challenges, this curricular model includes a structured documentation system that allows for ongoing evaluation, assessment, and monitoring of curricular progress. Conclusions: We illustrate a robustly built curricular structure that can be adopted, adapted, and successfully implemented at other training institutions around the world.

The remarkable success of cancer immunotherapies has provided new hope to cancer patients. Unfortunately, a significant proportion of patients remain unable to respond to immunotherapy or maintain durable clinical responses. The lack of objective responses likely results from profound immune dysfunction often observed in patients with cancer. There is substantial evidence that exercise and physical activity can reduce incidence and improve outcomes in cancer patients. As the immune system is highly responsive to exercise, one potential avenue to improve immune function is through exercise and physical activity. A single event of dynamic exercise results in the substantial mobilization of leukocytes with increased functional capacities into the circulation. Chronic, or long-term, exercise leads to higher physical fitness in terms of greater cardiorespiratory function and/or muscle strength and endurance. High aerobic capacity, as measured by maximal oxygen uptake, has been associated with the reduction of dysfunctional T cells and improvements in the abundance of some T cell populations. To be sure, however, the mechanisms of exercise-mediated immune changes are both extensive and diverse. Here, we examine the evidence and theorize how acute and chronic exercise could be used to improve responses to cancer immunotherapies including immune checkpoint inhibitors, dendritic cell vaccines, natural killer cell therapies, and adoptive T cell therapies such as chimeric antigen receptor (CAR) T cells. Although the parameters of optimal exercise to yield defined outcomes remain to be determined, the available current data provide a compelling justification for additional human studies and clinical trials investigating the adjuvant use of exercise in immuno-oncology.

Abstract Background Despite safety communications from the Food and Drug Administration (FDA) regarding the outbreak of Mycobacterium chimaera infections (MCIs) from contaminated heater-cooler devices, new cases continue to be identified. Methods We retrospectively reviewed confirmed cases of MCI that were managed at Mayo Clinic sites (Arizona, Florida, and Minnesota) from 09/2015 to 01/2021. Clinical histories including prior cardiovascular surgery were recorded. Diagnostic workup including ophthalmologic examination, imaging, and laboratory testing was reviewed. Treatment and survival outcomes on follow-up were obtained. Results Twelve patients with MCI were included. All patients had aortic valve or graft replacement. Five patients had their surgical procedures following the 10/15/2015 FDA safety communication. The mean time from surgery to symptom onset (range) was 32 (13–73) months. Ten of 11 patients who underwent ophthalmologic examination had chorioretinal abnormalities. Three patients who underwent microbial cell-free deoxyribonucleic acid sequencing tested positive for M. chimaera, which was subsequently confirmed with blood culture growth. Echocardiography and positron emission tomography/computed tomography (PET/CT) revealed evidence of prosthetic valve/graft infection in 7/12 (58.3%) and 6/10 (60.0%) of cases, respectively. Seven patients (58.3%) underwent redo cardiovascular surgery. Of these, 1 patient died 2 days postdischarge, 1 experienced spinal osteomyelitis relapse, and another had interval prosthetic valve fluorodeoxyglucose (FDG) uptake on PET/CT suspicious for recurrent infection. Among 4 patients on medical therapy only, 3 expired or transitioned to hospice during follow-up. Conclusions MCI continues to occur despite the FDA communications. Incorporation of ophthalmologic examination and use of advanced tools may improve MCI diagnosis. The mortality in these patients is high even with aggressive surgical/medical management.

Growing evidence suggests that the larger conducting airways are smaller in women than men; however, evidence of this sex‐difference in airway geometry is yet to be demonstrated in a large cohort of adult, healthy non‐smokers. Furthermore, it is not known whether these sex differences persist after airway size is adjusted for its allometric relationship with absolute lung size. Purpose We examined the effect of sex on airway size in a large cohort of non‐smoking healthy adults after adjusting for the possible confounding effect of absolute lung size. Methods A total of 133 (75 men; 58 women) non‐smoking adults (50 ± 18 yrs) with normal pulmonary function (>80% pred.) participated in this study. Full thoracic CT scans were obtained in each participant during a breath‐hold at full inflation. Commercial software was used to automatically segment airways and assign 32 anatomical labels ranging from the 0 th to the 5 th generation. Intraluminal hydraulic diameters ( D h ) were obtained for each airway. An allometric relationship was assumed between D h and absolute lung size, as given by: D h = TLV β · e k , where TLV is the total lung volume at full inflation, β is the allometric scaling exponent, and k allowed for proportional effects of confounding variables. This allometric equation was log‐log transformed such that it could be examined using linear regression: e.g., ln( D h ) = β ·ln(TLV) + k . Sex, age and their interaction were allowed to contribute to both β and k as covariates. The model also included a term for reconstructed voxel size. Model averaging was used to provide parameter estimates of the log‐log transformed allometric equation. Results The allometric exponent, β , assigned to TLV was significant for all 32 anatomically labelled airways ( P < 0.05); neither sex nor age affected β . On the other hand, sex and age were significant mediators of k for the extra‐parenchymal airways only (Trachea, RMB, LMB, BronInt, see Figure 1, P < 0.05). Conclusions Our findings indicate that sex differences in D h remain present despite accounting for the allometric relationship between airway and lung size (see Figure 1). Importantly, however, this sex‐difference in airway size is seemingly confined to the extra‐parenchymal airways. Support or Funding Information This work was supported by NIH Grant HL71478. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Pulmonary artery capacitance (Pa CAP ) is the ability of the pulmonary artery to accept a volume of blood at a given pressure. Measured invasively with heart catheterization; Pa CAP can be estimated non‐invasively through the measurement of end‐tidal CO 2 (P ETCO2 ) and stroke volume (SV), known as gas‐exchange capacitance (GX CAP ). We have shown that GX CAP is decreased at rest as well as during peak exercise in patients with cystic fibrosis (CF), when compared to healthy subjects. To determine whether GX CAP is different in CF and controls at a workload that matches for SV. 9 CF patients (age=22±3yrs, BMI=23±1kg/m 2 , VO 2 =19±1mL/kg/min, FEV 1 =81±8%pred.) and 13 healthy subjects (age=28±3yrs, BMI=25±1kg/m 2 , VO 2 =23±2L/min, FEV 1 =93±3%pred.) were studied. Exercise testing was performed on a cycle ergometer. P ETCO2 was assessed using a metabolic cart, SV was calculated from heart rate and cardiac output (Q) using the acetylene rebreathe technique and GX CAP was calculated as the product of P ETCO2 and SV. When matched for workload which sought to match SV, there was a significant difference in CF and healthy subjects in workload (Watts=72±6 vs. 90±4W), but no difference in percent of max watts (%MaxW=63±4 vs. 66±5W), Q (11±1 vs. 13±1L/min), or SV (89±4 vs. 90±4ml/beat). When matched, the previous difference in GX CAP in healthy and CF was abolished (GX CAP =32±2 vs. 32±2mL/BEAT • min). P ETCO2 was similar between CF and healthy subjects (P ETCO2 36±1 and 35±1mmHg). When matched for SV, GX CAP was statistically similar in CF. In relatively healthy CF there is no evidence of pulmonary vasculature dysfunction. NIH RO1 HL108962‐02

Background Although lower vs. healthy individuals, diffusion capacity of lungs for carbon monoxide (DL CO ) and nitric oxide (DL NO ) (may influence oxygen uptake, VO 2 ) are higher during exercise vs. rest in cystic fibrosis patients (CF). Thus, because the Fick equation suggests cardiac output (Q) increases linearly with VO 2 , we sought to study relationships between VO 2 with cardiac function from rest to peak exercise as increases in Q, DL CO and DL NO occur during exercise in CF. Methods 50 individuals participated (ages 22 ± 2 vs. 27 ± 2, BSA = 1.7 ± 0.1 vs. 1.8 ± 0.0 m 2 , VO 2peak = 24 ± 2 vs. 35 ± 2 ml/kg/min, CF (n = 19) vs. controls (CTL, n = 31), mean ± SEM, p<0.05 for all). Acetylene rebreathe was used to assess Q and calculate stroke volume (SV), and standard gas‐exchange was used to assess VO 2 (mL/kg/min). Cardiac power (CP, Q i × MAP) and stroke work (SW, SV i × MAP) were calculated. Q and SV were indexed to BSA (Q i and SV i ). Results Linear regression (R 2 ) between VO 2 with SV i , Q i , CP, and SW at rest were similarly negligible for CF vs. CTL (p=ns). At 50 % VO 2peak , R 2 between VO 2 with SV i (0.25 and 0.43, p<0.05), Q i (0.37 and 0.41, p<0.05), CP (0.18, p=ns and 0.25, p<0.05), and SW (0.12 and 0.30, p=ns) improved for CF and CTL, respectively. At VO 2peak , stronger R 2 between VO 2 with SV i (0.41, p<0.05), Q i (0.47, p<0.05), CP (0.24, p<0.05), and SW (0.19, p=ns) occurred in CF; but, R 2 weakened in CTL (0.28, p<0.05; 0.33, p<0.05; 0.07, p=ns; 0.02, p=ns, respectively). Conclusions From rest to VO 2peak the relationship between VO 2 with cardiac function improves in CF patients. Participation in exercise may benefit relationships between gas‐transfer with cardiac hemodynamics in CF patients.

Mutations in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) lead to altered ion regulation, resulting in CF. CFTR also plays an important role in cardiac function. We have shown that β‐agonist inhalation results in increased cardiac output (Q), stroke volume (SV), and decreased systemic vascular resistance (SVR) in healthy humans, suggesting stimulation of the β‐adrenergic receptors via inhalation. We have also shown that this cardiovascular (CV) response is attenuated in CF, which could be due to receptor desensitization or inhibited drug delivery to the blood stream due to mucus build‐up. This study sought to determine the effects of epinephrine (EPI) and norepinephrine (NE) on CV function in CF. 11 CF patients and 27 controls completed a cycle ergometery test with measures of Q, SV, SVR, and HR along with EPI and NE. CF patients had lower Q corrected for NE at 50% and peak exercise (rest: Q/NE= 0.012 ±0.002 vs 0.017 ±0.002; 50%: Q/NE= 0.026 ±0.004 vs 0.045 ±0.004; peak: Q/NE= 0.03 ±0.004 vs 0.05 ±0.005, CF vs healthy, p<0.05) and lower SV corrected for NE at rest, 50%, and peak (rest: SV/NE= 0.12 ±0.03 vs 0.22 ±0.02; 50%: SV/NE= 0.17 ±0.04 vs 0.32 ±0.03; peak: SV/NE= 0.18 ±0.04 vs 0.35 ±0.03, CF vs healthy, p<0.05), no difference in SVR when corrected for EPI (rest: SVR/EPI= 53 ±13 vs 33 ±4; 50%: SVR/EPI= 28 ±7 vs 15 ±2; peak: SVR/EPI= 22 ±5 vs 15 ±3; in CF vs healthy). These results suggest that CF patients have lower cardiac function relative to circulating NE, no difference in SVR relative to EPI, indicating impairment in cardiac function, likely as a result from a loss of CFTR function.

Background Fluid flux in the lungs is influenced by factors altering accumulation or removal (e.g., stimulation of epithelium sodium channels, ENaC). Purpose To determine if ENaC are necessary in the normal fluid regulation with simulated altitude exposure. Methods/Results On separate occasions, 19 healthy subjects (27 ± 5 y) received either nebulized amiloride (ENaC antagonist) or placebo (nebulized saline) during 17 h normobaric hypoxia (FIO2 = 12.5%) in a randomized, double‐blind fashion. Lung diffusing capacity for carbon monoxide (DLCO), alveolar‐capillary membrane conductance (Dm) and pulmonary capillary blood volume (Vc) were measured via a rebreathe method before and after hypoxic exposure. DLCO was not different at baseline for the amiloride vs. placebo treatments (19 ± 5 vs. 21 ± 8 mL/min/mmHg). Hypoxic exposure increased Vc but did not change Dm in both treatments (Placebo: Vc = 43 ± 22 vs. 59±23 mL p=0.011, Dm = 35 ± 10 vs. 37 ± 12 mL/min/mmHg p=0.312; Amiloride: Vc = 38 ± 17 vs. 57 ± 22 mL p<0.01, Dm = 31 ± 8 vs. 34 ± 10 mL/min/mmHg p= 0.206). Conclusion Normobaric hypoxia did not differentially affect alveolar‐capillary conductance in amiloride and placebo conditions, suggesting that ENaC do not have a role in normal lung fluid regulation during acute hypoxic exposure. HL71478

Fluid clearance from the alveolar space is critically dependent on epithelial sodium channels (ENaC). A common polymorphism in the gene encoding the ENaC alpha subunit results in an alanine to threonine substitution (A663T), with higher ENaC channel activity. This variant influences ion and fluid regulation in the lung during exercise and in response to albuterol. We investigated the influence of the threonine variant (T663; AT/TT group) on the lung fluid response to exercise in conditions of normobaric hypoxia, which challenges lung fluid balance. Lung fluid balance was assessed using Exhaled Na + (ENa + ) and the diffusing capacity for carbon monoxide and nitric oxide (DLCO and DLNO, respectively) to determine alveolar‐capillary membrane conductance (Dm). 19 healthy subjects were grouped by ENaC genotype (n=8 vs. 11 for AA and AT/TT, %female=50 vs. 62%, age=27±1 vs. 28±2yrs., ht=171±3 vs. 173±2cm, wt=69±6 vs.72±3kg , BMI=23±1 vs.24±1kg/m 2 ) and completed two overnight visits in a hypoxic tent simulating just over 5,400m. The visits were randomized to inhaled placebo or inhaled amiloride (1.5mg in 5ml normal saline, used to inhibit ENaC activity) with ENa + , DLCO, and Dm assessed at baseline, following 12 hours of hypoxic exposure, and following hypoxic exercise at 65% peak power on a cycle ergometer. We found significant effects of the interaction between gender and ENaC genotype on DLCO, Dm, and Dm corrected for pulmonary capillary blood volume (p<0.05). Specifically, females with the more active T663 variant had a greater diffusing capacity and less ENa + under placebo conditions, suggesting a greater removal of Na + and fluid from the airspace. These results suggest that genetic variation of ENaC may influence lung fluid balance during hypoxia and hypoxic exercise. Grant Funding Source : Supported by HL71478, HL108962‐03, and HL007249