Fc-Silent Anti-TIGIT Antibodies Potentiate Antitumor Immunity without Depleting Regulatory T Cells.

T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) is an inhibitory receptor on immune cells that outcompetes an activating receptor, CD226, for shared ligands. Tumor-infiltrating lymphocytes express TIGIT and CD226 on regulatory T cells (Treg) and on CD8+ T cells with tumor-reactive or exhausted phenotypes, supporting the potential of therapeutically targeting TIGIT to enhance antitumor immunity. To optimize the efficacy of therapeutic antibodies against TIGIT, it is necessary to understand IgG Fc (Fcγ) receptor binding for therapeutic benefit. In this study, we showed that combining Fc-enabled (Fce) or Fc-silent (Fcs) anti-TIGIT with antiprogrammed cell death protein 1 in mice resulted in enhanced control of tumors by differential mechanisms: Fce anti-TIGIT promoted the depletion of intratumoral Treg, whereas Fcs anti-TIGIT did not. Despite leaving Treg numbers intact, Fcs anti-TIGIT potentiated the activation of tumor-specific exhausted CD8+ populations in a lymph node-dependent manner. Fce anti-TIGIT induced antibody-dependent cell-mediated cytotoxicity against human Treg in vitro, and significant decreases in Treg were measured in the peripheral blood of patients with phase I solid tumor cancer treated with Fce anti-TIGIT. In contrast, Fcs anti-TIGIT did not deplete human Treg in vitro and was associated with anecdotal objective clinical responses in two patients with phase I solid tumor cancer whose peripheral Treg frequencies remained stable on treatment. Collectively, these data provide evidence for pharmacologic activity and antitumor efficacy of anti-TIGIT antibodies lacking the ability to engage Fcγ receptor. SIGNIFICANCE: Fcs-silent anti-TIGIT antibodies enhance the activation of tumor-specific pre-exhausted T cells and promote antitumor efficacy without depleting T regulatory cells.

Molecular and histological correlates of cognitive decline across age in male C57BL/6J mice.

INTRODUCTION: Increasing age is the number one risk factor for developing cognitive decline and neurodegenerative disease. Aged humans and mice exhibit numerous molecular changes that contribute to a decline in cognitive function and increased risk of developing age-associated diseases. Here, we characterize multiple age-associated changes in male C57BL/6J mice to understand the translational utility of mouse aging. METHODS: Male C57BL/6J mice from various ages between 2 and 24 months of age were used to assess behavioral, as well as, histological and molecular changes across three modalities: neuronal, microgliosis/neuroinflammation, and the neurovascular unit (NVU). Additionally, a cohort of 4- and 22-month-old mice was used to assess blood-brain barrier (BBB) breakdown. Mice in this cohort were treated with a high, acute dose of lipopolysaccharide (LPS, 10 mg/kg) or saline control 6 h prior to sacrifice followed by tail vein injection of 0.4 kDa sodium fluorescein (100 mg/kg) 2 h later. RESULTS: Aged mice showed a decline in cognitive and motor abilities alongside decreased neurogenesis, proliferation, and synapse density. Further, neuroinflammation and circulating proinflammatory cytokines were increased in aged mice. Additionally, we found changes at the BBB, including increased T cell infiltration in multiple brain regions and an exacerbation in BBB leakiness following chemical insult with age. There were also a number of readouts that were unchanged with age and have limited utility as markers of aging in male C57BL/6J mice. CONCLUSIONS: Here we propose that these changes may be used as molecular and histological readouts that correspond to aging-related behavioral decline. These comprehensive findings, in the context of the published literature, are an important resource toward deepening our understanding of normal aging and provide an important tool for studying aging in mice.

Risks to global biodiversity and Indigenous lands from China's overseas development finance.

China has become one of the world's largest lenders in overseas development finance. Development projects, such as roads, railways and power plants, often drive biodiversity loss and infringe on Indigenous lands, yet the risks implicit in China's overseas development finance are poorly understood. Here we examine the extent to which projects financed by China's policy banks between 2008 and 2019 occur within and adjacent to areas where large-scale investment can present considerable risks to biodiversity and Indigenous peoples. Further, we compare these risks with those posed by similar projects financed by the World Bank, previously the world's largest source of development finance. We found that 63% of China-financed projects overlap with critical habitats, protected areas or Indigenous lands, with up to 24% of the world's threatened birds, mammals, reptiles and amphibians potentially impacted by the projects. Hotspots of the risks are primarily distributed in northern sub-Saharan Africa, Southeast Asia and parts of South America. Overall, China's development projects pose greater risks than those of the World Bank, particularly within the energy sector. These results provide an important global outlook of socio-ecological risks that can guide strategies for greening China's development finance around the world.

Geolocated dataset of Chinese overseas development finance.

China is now the world's largest source of bilateral development finance and will likely continue to play a prominent role in sovereign lending through its multi-billion-dollar Belt and Road Initiative. This paper introduces major methodological enhancements in tracking this finance: the use of an original application programming interface (API) to gathers news in multiple languages; double-verification of every record to ensure every finance commitment has been formalized; and visual geo-location to trace the precise footprint of every project. The resulting dataset enables economic, environmental, and social analyses with high-precision spatial accuracy, as well as spatiotemporal monitoring by project stakeholders and enhanced planning by project managers. It covers the years 2008-2019 to enable analysis before and after the announcement of the Belt and Road Initiative. It includes 862 finance commitments, 669 of which have geographic location, to 94 countries across the world.

Safety and tolerability of GRF6019 in mild-to-moderate Alzheimer's disease dementia.

INTRODUCTION: This phase 2 trial evaluated the safety, tolerability, and feasibility of repeated infusions of the plasma fraction GRF6019 in mild-to-moderate Alzheimer's disease. METHODS: In this randomized, double-blind, dose-comparison trial, 47 patients were randomized 1:1 to receive daily infusions of 100 mL (n = 24) or 250 mL (n = 23) of GRF6019 for 5 consecutive days over two dosing periods separated by a treatment-free interval of 3 months. RESULTS: The mean (standard deviation [SD]) age of the enrolled patients was 74.3 (6.9), and 62% were women. Most adverse events (55%) were mild, with no clinically significant differences in safety or tolerability between the two dose levels. The mean (SD) baseline Mini-Mental State Examination score was 20.6 (3.7) in the 100 mL group and 19.6 (3.7) in the 250 mL group; at 24 weeks, the within-patient mean change from baseline was -1.0 points (95% confidence interval [CI], -3.1 to 1.1) in the 100 mL group and +1.5 points (95% CI, -0.4 to 3.3) in the 250 mL group. The within-patient mean change from baseline on the Alzheimer's Disease Assessment Scale-Cognitive subscale was -0.4 points (95% CI, -2.9 to 2.2) in the 100 mL group, while in the 250 mL group it was -0.9 points (95% CI, -3.0 to 1.2). The within-patient mean change from baseline on the Alzheimer's Disease Cooperative Study-Activities of Daily Living was -0.7 points in the 100 mL group (95% CI, -4.3 to 3.0) and -1.3 points (95% CI, -3.4 to 0.7) in the 250 mL group. The mean change from baseline on the Category Fluency Test, Clinical Dementia Rating Scale-Sum of Boxes, Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change, and Neuropsychiatric Inventory Questionnaire was similar for both treatment groups and did not show any worsening. DISCUSSION: GRF6019 was safe and well tolerated, and patients experienced no cognitive decline and minimal functional decline. These results support further development of GRF6019.

Cross-sectional associations between [18F]GTP1 tau PET and cognition in Alzheimer's disease.

The regional relationships between tau positron emission tomography (PET) imaging and cognitive impairment in Alzheimer's disease (AD) remain uncertain. We examined cross-sectional associations between cognitive performance, cerebral uptake of the novel tau PET tracer [18F]GTP1, and other neuroimaging indices ([18F]florbetapir amyloid PET, magnetic resonance imaging) in 71 participants with normal cognition, prodromal AD, or AD dementia. Greater [18F]GTP1 uptake was seen with increasing clinical severity and correlated with poorer cognition. [18F]GTP1 uptake and cortical volume (but not [18F]florbetapir uptake) were independently associated with cognitive performance, particularly within the temporal lobe. Delayed memory was more specifically associated with temporal [18F]GTP1 uptake; other domains correlated with a broader range of regional [18F]GTP1 uptake. These data confirm that [18F]GTP1 tau PET uptake significantly correlates with cognitive performance in AD, but regional correlations between performance in non-memory cognitive domains were less specific than reported by tau PET imaging studies that included participants with atypical focal cortical AD syndromes. Tau PET imaging may have utility as a surrogate biomarker for clinical AD progression in therapeutic trials of disease-modifying interventions.

Research Residents' perceptions of skill decay: Effects of repeated skills assessments and scenario difficulty.

INTRODUCTION: Skills decay is a known risk for surgical residents who have dedicated research time. We hypothesize that simulation-based assessments will reveal significant differences in perceived skill decay when assessing a variety of clinical scenarios in a longitudinal fashion. METHODS: Residents (N = 46; Returning: n = 16, New: n = 30) completed four simulated procedures: urinary catheterization, central line, bowel anastomosis, and laparoscopic ventral hernia repair. Perception surveys were administered pre- and post-simulation. RESULTS: Perceptions of skill decay and task difficulty were similar for both groups across three procedures pre- and post-simulation. Due to a simulation modification, new residents were more confident in urinary catheterization than returning residents (F(1,4) = 11.44, p = 0.002). In addition, when assessing expectations for skill reduction, returning residents perceived greater skill reduction upon reassessment when compared to first time residents (t(35) = 2.37, p = 0.023). CONCLUSION: Research residents may benefit from longitudinal skills assessments and a wider variety of simulation scenarios during their research years. TABLE OF CONTENTS SUMMARY: As part of a longitudinal study, we assessed research residents' confidence, perceptions of task difficulty and surgical skill reduction. Residents completed surveys pre- and post-experience with four simulated procedures: urinary catheterization, subclavian central line insertion, bowel anastomosis, and laparoscopic ventral hernia repair. Returning residents perceived greater skill reduction upon reassessment when compared to residents participating for the first time. In addition, modification of the clinical scenarios affected perceptions of skills decay.

Do errors and critical events relate to hernia repair outcomes?

BACKGROUND: The study aimed to validate an error checklist for simulated laparoscopic ventral hernia (LVH) repair procedures. We hypothesize that residents' errors can be assessed with a structured checklist and the results will correlate significantly with procedural outcomes. METHODS: Senior residents' (N = 7) performance on a LVH simulator were video-recorded and analyzed using a human error checklist. Junior residents (N = 38) performed two steps of the same simulated LVH procedure. Performance was evaluated using the error checklist and repair quality scores. RESULTS: There were no significant differences between senior and junior residents' checklist errors (p > 0.1). Junior residents' errors correlated with hernia repair quality (p = 0.05). CONCLUSIONS: The newly developed assessment tool showed significant correlations between performance errors, critical events, and hernia repair quality. These results provide validity evidence for the use of errors in performance assessments. SUMMARY: This study validated an error checklist for simulated laparoscopic ventral hernia (LVH) repair procedures. The checklist was designed based on errors committed by chief surgery residents during LVH repairs. In a separate data collection, junior residents were evaluated using the checklist. Hernia repair quality was also assessed. Errors significantly correlated with hernia repair quality (p = 0.05).

Errors in bladder catheterization: are residents ready for complex scenarios?

BACKGROUND: The aim of this study was to investigate whether junior surgical residents had successfully mastered bladder catheterization. Our hypothesis was that surgical residents would be overly confident in their abilities and underestimate the potential for case complexity. MATERIALS AND METHODS: PGY 2-4 surgery residents (n = 44) were given 15 min. to complete three of four bladder catheterization simulations. Participants reported their mastery by rating confidence using a 5-point Likert scale. Multiple linear regression analysis was used to test predictors of procedure performance. RESULTS: Participants made a total of 228 errors with an average of 5.1 errors (standard deviation = 2.6) per participant. The most common errors included not maintaining the sterile field (52.0%), failure to get urine return (20.3%), and inflating the catheter balloon before urine return (8.4%). Some residents committed the same error more than once. Presimulation confidence ratings ranged from "1" being not confident to "5" being extremely confident. Average presimulation confidence was 4.42 (range 1-5, standard deviation = 0.85). Sixteen (36%) residents ranked their presimulation confidence in problem-solving abilities as "moderately confident" or below, whereas 28 (64%) were "very confident" or above. The lower the resident's presimulation confidence in problem-solving, the more errors they committed during the simulation (beta = -0.33, t = -2.15, P = 0.04). CONCLUSIONS: The residents did not perform as well as they anticipated when presented with more complicated bladder catheterization scenarios. Simulation can be used to identify and expose potential errors that may occur during complex presentations of basic procedures. This type of training and assessment may facilitate mastery.

Do resident's leadership skills relate to ratings of technical skill?

BACKGROUND: This study sought to compare general surgery research residents' survey information regarding self-efficacy ratings to their observed performance during a simulated small bowel repair. Their observed performance ratings were based on their leadership skills in directing their assistant. METHODS: Participants were given 15 min to perform a bowel repair using bovine intestines with standardized injuries. Operative assistants were assigned to help assist with the repair. Before the procedure, participants were asked to rate their expected skills decay, task difficulty, and confidence in addressing the small bowel injury. Interactions were coded to identify the number of instructions given by the participants to the assistant during the repair. Statistical analyses assessed the relationship between the number of directional instructions and participants' perceptions self-efficacy measures. Directional instructions were defined as any dialog by the participant who guided the assistant to perform an action. RESULTS: Thirty-six residents (58.3% female) participated in the study. Participants who rated lower levels of decay in their intraoperative decision-making and small bowel repair skills were noted to use their assistant more by giving more instructions. Similarly, a higher number of instructions correlated with lower perceived difficulty in selecting the correct suture, suture pattern, and completing the entire surgical task. CONCLUSIONS: General surgery research residents' intraoperative leadership skills showed significant correlations to their perceptions of skill decay and task difficulty during a bowel repair. Evaluating resident's directional instructions may provide an additional individualized intraoperative assessment metric. Further evaluation relating to operative performance outcomes is warranted.

Resident performance in complex simulated urinary catheter scenarios.

BACKGROUND: Urinary catheter insertion is a common procedure performed in hospitals. Improper catheterization can lead to unnecessary catheter-associated urinary tract infections and urethral trauma, increasing patient morbidity. To prevent such complications, guidelines were created on how to insert and troubleshoot urinary catheters. As nurses have an increasing responsibility for catheter placement, resident responsibility has shifted to more complex scenarios. This study examines the clinical decision-making skills of surgical residents during simulated urinary catheter scenarios. We hypothesize that during urinary catheterization, residents will make inconsistent decisions relating to catheter choices and clinical presentations. METHODS: Forty-five general surgery residents (postgraduate year 2-4) in Midwest training programs were presented with three of four urinary catheter scenarios of varying difficulty. Residents were allowed 15 min to complete the scenarios with five different urinary catheter choices. A chi-square test was performed to examine the relation between initial and subsequent catheter choices and to evaluate for consistency of decision-making for each scenario. RESULTS: Eighty-two percent of residents performed scenario A; 49% performed scenario B; 64% performed scenario C, and 82% performed scenario D. For initial attempt for scenario A-C, the 16 French Foley catheter was the most common choice (38%, 54%, 50%, P's < 0.001), whereas for scenario D, the 16 French Coude was the most common choice (37%, P < 0.01). Residents were most likely to be successful in achieving urine output in the initial catheterization attempt (P < 0.001). Chi-square analyses showed no relationship between residents' first and subsequent catheter choices for each scenario (P's > 0.05). CONCLUSIONS: Evaluation of clinical decision-making shows that initial catheter choice may have been deliberate based on patient background, as evidenced by the most popular choice in scenario D. Analyses of subsequent choices in each of the catheterization models reveal inconsistency. These findings suggest a possible lack of competence or training in clinical decision-making with regard to urinary catheter choices in residents.

Relationship Between Technical Errors and Decision-Making Skills in the Junior Resident.

OBJECTIVE: The purpose of this study is to coevaluate resident technical errors and decision-making capabilities during placement of a subclavian central venous catheter (CVC). We hypothesize that there would be significant correlations between scenario-based decision-making skills and technical proficiency in central line insertion. We also predict residents would face problems in anticipating common difficulties and generating solutions associated with line placement. DESIGN: Participants were asked to insert a subclavian central line on a simulator. After completion, residents were presented with a real-life patient photograph depicting CVC placement and asked to anticipate difficulties and generate solutions. Error rates were analyzed using chi-square tests and a 5% expected error rate. Correlations were sought by comparing technical errors and scenario-based decision-making skills. SETTING: This study was performed at 7 tertiary care centers. PARTICIPANTS: Study participants (N = 46) largely consisted of first-year research residents who could be followed longitudinally. Second-year research and clinical residents were not excluded. RESULTS: In total, 6 checklist errors were committed more often than anticipated. Residents committed an average of 1.9 errors, significantly more than the 1 error, at most, per person expected (t(44) = 3.82, p < 0.001). The most common error was performance of the procedure steps in the wrong order (28.5%, p < 0.001). Some of the residents (24%) had no errors, 30% committed 1 error, and 46 % committed more than 1 error. The number of technical errors committed negatively correlated with the total number of commonly identified difficulties and generated solutions (r (33) = -0.429, p = 0.021, r (33) = -0.383, p = 0.044, respectively). CONCLUSIONS: Almost half of the surgical residents committed multiple errors while performing subclavian CVC placement. The correlation between technical errors and decision-making skills suggests a critical need to train residents in both technique and error management.

Error tolerance: an evaluation of residents' repeated motor coordination errors.

BACKGROUND: The study investigates the relationship between motor coordination errors and total errors using a human factors framework. We hypothesize motor coordination errors will correlate with total errors and provide validity evidence for error tolerance as a performance metric. METHODS: Residents' laparoscopic skills were evaluated during a simulated laparoscopic ventral hernia repair for motor coordination errors when grasping for intra-abdominal mesh or suture. Tolerance was defined as repeated, failed attempts to correct an error and the time required to recover. RESULTS: Residents (N = 20) committed an average of 15.45 (standard deviation [SD] = 4.61) errors and 1.70 (SD = 2.25) motor coordination errors during mesh placement. Total errors correlated with motor coordination errors (r[18] = .572, P = .008). On average, residents required 5.09 recovery attempts for 1 motor coordination error (SD = 3.15). Recovery approaches correlated to total error load (r[13] = .592, P = .02). CONCLUSIONS: Residents' motor coordination errors and recovery approaches predict total error load. Error tolerance proved to be a valid assessment metric relating to overall performance.

Mitochondrial DNA Profiling of Illegal Tortoiseshell Products Derived from Hawksbill Sea Turtles.

The hawksbill sea turtle (Eretmochelys imbricata) is a highly endangered species, commonly poached for its ornate shell. "Tortoiseshell" products made from the shell are widely, although illegally, available in many countries. Hawksbills have a circumglobal distribution; thus, determining their origin is difficult, although genetic differences exist geographically. In the research presented, a procedure was developed to extract and amplify mitochondrial DNA from tortoiseshell items, in an effort to better understand where the species is being poached. Confiscated tortoiseshell items were obtained from the U.S. Fish and Wildlife Service, and DNA from 56 of them was analyzed. Multiple mitochondrial haplotypes were identified, including five not previously reported. Only one tortoiseshell item proved to be of Atlantic origin, while all others corresponded to genetic stocks in the Indo-Pacific region. The developed methodology allows for unique, and previously unattainable, genetic information on the illegal poaching of sea turtles for the decorative tortoiseshell trade.

Exploring Senior Residents' Intraoperative Error Management Strategies: A Potential Measure of Performance Improvement.

OBJECTIVE: The study aim was to determine whether residents' error management strategies changed across 2 simulated laparoscopic ventral hernia (LVH) repair procedures after receiving feedback on their initial performance. We hypothesize that error detection and recovery strategies would improve during the second procedure without hands-on practice. DESIGN: Retrospective review of participant procedural performances of simulated laparoscopic ventral herniorrhaphy. A total of 3 investigators reviewed procedure videos to identify surgical errors. Errors were deconstructed. Error management events were noted, including error identification and recovery. SETTING: Residents performed the simulated LVH procedures during a course on advanced laparoscopy. Participants had 30 minutes to complete a LVH procedure. After verbal and simulator feedback, residents returned 24 hours later to perform a different, more difficult simulated LVH repair. PARTICIPANTS: Senior (N = 7; postgraduate year 4-5) residents in attendance at the course participated in this study. RESULTS: In the first LVH procedure, residents committed 121 errors (M = 17.14, standard deviation = 4.38). Although the number of errors increased to 146 (M = 20.86, standard deviation = 6.15) during the second procedure, residents progressed further in the second procedure. There was no significant difference in the number of errors committed for both procedures, but errors shifted to the late stage of the second procedure. Residents changed the error types that they attempted to recover (χ25=24.96, p<0.001). For the second procedure, recovery attempts increased for action and procedure errors, but decreased for strategy errors. Residents also recovered the most errors in the late stage of the second procedure (p < 0.001). CONCLUSION: Residents' error management strategies changed between procedures following verbal feedback on their initial performance and feedback from the simulator. Errors and recovery attempts shifted to later steps during the second procedure. This may reflect residents' error management success in the earlier stages, which allowed further progression in the second simulation. Incorporating error recognition and management opportunities into surgical training could help track residents' learning curve and provide detailed, structured feedback on technical and decision-making skills.

Development and Analysis of Psychomotor Skills Metrics for Procedural Skills Decay.

In this paper we develop and analyze the metrics associated with a force production task involving a stationary target with the help of advanced VR and Force Dimension Omega 6 haptic device. We study the effects of force magnitude and direction on the various metrics namely path length, movement smoothness, velocity and acceleration patterns, reaction time and overall error in achieving the target. Data was collected from 47 participants who were residents. Results show a positive correlation between the maximum force applied and the deflection error, velocity while reducing the path length and increasing smoothness with a force of higher magnitude showing the stabilizing characteristics of higher magnitude forces. This approach paves a way to assess and model procedural skills decay.

Working volume: validity evidence for a motion-based metric of surgical efficiency.

BACKGROUND: The aim of this study was to evaluate working volume as a potential assessment metric for open surgical tasks. METHODS: Surgical attendings (n = 6), residents (n = 4), and medical students (n = 5) performed a suturing task on simulated connective tissue (foam), artery (rubber balloon), and friable tissue (tissue paper). Using a motion tracking system, effective working volume was calculated for each hand. Repeated measures analysis of variance assessed differences in working volume by experience level, dominant and/or nondominant hand, and tissue type. RESULTS: Analysis revealed a linear relationship between experience and working volume. Attendings had the smallest working volume, and students had the largest (P = .01). The 3-way interaction of experience level, hand, and material type showed attendings and residents maintained a similar working volume for dominant and nondominant hands for all tasks. In contrast, medical students' nondominant hand covered larger working volumes for the balloon and tissue paper materials (P < .05). CONCLUSIONS: This study provides validity evidence for the use of working volume as a metric for open surgical skills. Working volume may provide a means for assessing surgical efficiency and the operative learning curve.

Residents' perception of skill decay during dedicated research time.

BACKGROUND: Surgery residents may take years away from clinical responsibilities for dedicated research time. As part of a longitudinal project, the study aim was to investigate residents' perceptions of clinical skill reduction during dedicated research time. Our hypothesis was that residents would perceive a greater potential reduction in skill during research time for procedures they were less confident in performing. MATERIALS AND METHODS: Surgical residents engaged in dedicated research training at multiple training programs participated in four simulated procedures: urinary catheterization, subclavian central line, bowel anastomosis, and laparoscopic ventral hernia (LVH) repair. Using preprocedure and postprocedure surveys, participants rated procedures for confidence and difficulty. Residents also indicated the perceived level of skills reduction for the four procedures as a result of time in the laboratory. RESULTS: Thirty-eight residents (55% female) completed the four clinical simulators. Participants had between 0-36 mo in a laboratory (M = 9.29 mo, standard deviation = 9.38). Preprocedure surveys noted lower confidence and higher perceived difficulty for performing the LVH repair followed by bowel anastomosis, central line insertion, and urinary catheterization (P < 0.05). Residents perceived the greatest reduction in bowel anastomosis and LVH repair skills compared with urinary catheterization and subclavian central line insertion (P < 0.001). Postprocedure surveys showed significant effects of the simulation scenarios on resident perception for urinary catheterization (P < 0.05) and LVH repair (P < 0.05). CONCLUSIONS: Residents in this study expected greater skills decay for the procedures they had lower confidence performing and greater perceived difficulty. In addition, carefully adapted simulation scenarios had a significant effect on resident perception and may provide a mechanism for maintaining skills and keeping confidence grounded in experience.