Recommendations of the Blue Ribbon Committee II for the Optimization of Surgical Education and Training in the United States: The Surgical Trainee Perspective.

OBJECTIVE: This study aims to appraise recommendations from an expert panel of surgical educators on optimizing surgical education and training in the setting of contemporary challenges. BACKGROUND: The Blue Ribbon Committee (BRC II), a group of surgical educators, was convened to make recommendations to optimize surgical training considering the current changes in the landscape of surgical education. Surgical trainees were recruited to assess their impressions of the recommendations. METHODS: A mixed-methods study design was employed, with a survey, followed by focus group interviews. Participating residents and fellows were recruited through a purposeful sampling approach. Descriptive statistics were applied to analyze the survey data, and a thematic data analysis on interview transcripts was employed. RESULTS: The majority of trainee respondents (n=16) thought that all of the subcommittee recommendations should be included in the final BRC II recommendations and paper. According to the interviews, overall, the feedback from the trainees was positive, with particular excitement around work-life integration, education support and faculty development, and funding pitfalls. Some themes about concerns included a lack of clarity about the recommendations, concern about some recommendations being in conflict with one another, and a disconnect between the initial BRC II survey and the subsequent recommendations. CONCLUSIONS: The residents gathered for this focus group were encouraged by the thought, effort, and intention that gathered the surgical leaders across the country to make the recommendations. While there were areas the trainees wanted clarity on, the overall opinion was in agreement with the recommendations.

Using a quality improvement tool, Plan-Do-Study-Act cycle, to boost TB notification in India post-Covid-19 pandemic.

Quality improvement tools such as the Plan-Do-Study-Act (PDSA) cycle hold tremendous potential to improve the quality of healthcare in India. The electronic-PDSA tool was previously developed by CETI (Collaboration to Eliminate TB among Indians) and successfully piloted in small groups. In this study the e-PDSA was scaled up across the nation over a brief 10 week period to boost TB notification by training District Tuberculosis Officers (DTOs) virtually post-Covid-19 pandemic. Quality improvement counselors, who were interns from Masters in Public Health Institutions, were liaisons to "hand-hold" and assist the DTOs through the PDSA cycle. The course was voluntary and offered to all DTOs through Central TB Division and State TB Officers from May 2022 to July 2022. Of the 779 Districts in India and nearly equal number of DTOs, 546 (70%) DTOs enrolled in the course and of these 437 (80%) conducted a PDSA while 342 (43%) districts/DTOs did not enroll or did not complete a PDSA. With a baseline notification in February-March-April 2022 and intervention in May-June-July 2022; 55% of the districts in the PDSA group showed improvement in TB Notification compared to 45% in the non-PDSA group. When data was analyzed by population (not district) there was a trend in increase in notification post-pandemic in both PDSA and non-PDSA groups, and the PDSA group had a slightly higher 5.6 per 100,000 population improvement compared to 5.0 per 100,000 in the non-PDSA group. The cost of intervention was $40,000 or $92 per DTO for three months. The course was highly acceptable with DTOs rating 4.3 out of 5 in recommending the course to other DTOs. Our data shows that a large scale-up of the PDSA cycle is feasible, economical and effective with little additional resources. The focus was on increasing the efficiency of the existing processes well within the authority of the DTO. Repeat cycle of PDSA with notification and other measures such as presumptive sputum examination could significantly impact the program and help to achieve TB Free India.

Adipose tissue-selective ablation of ADAM10 results in divergent metabolic phenotypes following long-term dietary manipulation.

A Disintegrin And Metalloproteinase domain-containing protein 10 (ADAM10), is involved in several metabolic and inflammatory pathways. We speculated that ADAM10 plays a modulatory role in adipose tissue inflammation and metabolism. To this end, we studied adipose tissue-specific ADAM10 knock-out mice (aKO). While young, regular chow diet-fed aKO mice showed increased insulin sensitivity, following prolonged (33 weeks) high-fat diet (HFD) exposure, aKO mice developed obesity and insulin resistance. Compared to controls, aKO mice showed less inflammatory adipokine profile despite the significant increase in adiposity. In brown adipose tissue, aKO mice on HFD had changes in CD8+ T cell populations indicating a lesser inflammatory pattern. Following HFD, both aKO and control littermates demonstrated decreased adipose tissue pro-inflammatory macrophages, and increased anti-inflammatory accumulation, without differences between the genotypes. Collectively, our observations indicate that selective deletion of ADAM10 in adipocytes results in a mitigated inflammatory response, leading to increased insulin sensitivity in young mice fed with regular diet. This state of insulin sensitivity, following prolonged HFD, facilitates energy storage resulting in increased fat accumulation which ultimately leads to the development of a phenotype of obesity and insulin resistance. In conclusion, the data indicate that ADAM10 has a modulatory effect of inflammation and whole-body energy metabolism.

Revision Total Ankle Arthroplasty Using a Novel Modular Fixed-Bearing Revision Ankle System.

INTRODUCTION: Large bone defects such as those encountered after failed total ankle replacement have previously been a relative contraindication to revision ankle replacement due to inadequate bone stock. We describe our experience and patient reported outcomes with a modular ankle replacement system with tibial and talar augments. METHODS: This is a retrospective case series analysis of patients who underwent a total ankle replacement using the INVISION system across 2 centers between 2016 and 2022. Patients completed the Manchester-Oxford Foot Questionnaire (MOXFQ), Ankle Osteoarthritis Scale (AOS), and EQ-5D pre-operatively and then post-operatively at 6 months, 1 year, 2 years, 3 years, and 5 years. Medical records were reviewed for complications and re-operations. X-rays were reviewed for lucencies and alignment. RESULTS: A total of 17 patients were included in the study; 14 men and 3 women with an average age at the time of surgery of 67.9 years (range 56-80 years). The average follow-up post-operatively was 40.5 months (range 7-78) at the time of this study. The indication for surgery was revision of failed total ankle replacement (TAR) in 16 and revision of failed ankle fusion in 1. An augmented tibia was used in 13, an augmented talus in 13, and both augmented tibia and talus in 9 cases. There were no early surgical complications. One patient required debridement and implant retention for late deep infection. No implants have been revised. The average MOXFQ score improved by 19.3 points at most recent follow-up. The average AOS score improved by 25.2 points. CONCLUSION: The early results of a modular augmented ankle arthroplasty system have shown satisfactory patient outcomes with a low complication and re-operation rate and present another option for patients with larger bone defects. This is a small series, and a larger series with long-term follow-up would be beneficial. LEVELS OF EVIDENCE: Level IV: Case series.

Linking Cardiac Psychology and Cardiovascular Medicine via Self-Determination Theory and Shared Decision-Making.

Despite considerable progress in recent years, research in cardiac psychology is not widely translated into routine practice by clinical cardiologists or clinical health psychologists. Self-determination theory (SDT), which addresses how basic psychological needs of autonomy, competence, and relatedness contribute to the internalization of motivation, may help bridge this research-practice gap through its application to shared decision-making (SDM). This narrative review discusses the following: (a) brief background information on SDT and SDM, (b) the application of SDT to health behavior change and cardiology interventions, and (c) how SDT and SDM may be merged using a dissemination and implementation (D&I) framework. We address barriers to implementing SDM in cardiology, how SDM and SDT address the need for respect of patient autonomy, and how SDT can enhance D&I of SDM interventions through its focus on autonomy, competence, and relatedness and its consideration of other constructs that facilitate the internalization of motivation.

Infection in osteotomy around the knee: Incidence, management and outcomes in a high-volume case series.

PURPOSE: Current evidence around the management of osteotomy-related infection is insufficient to robustly underpin the expert statements formulated by a recent European consensus statement. We present a review of a large case series in a high-volume osteotomy practice to contribute to the understanding of the incidence, management and outcome of infection in this subspecialty area. METHODS: Analyses of two prospectively collected databases for all osteotomy around the knee and infections related to osteotomy were performed, along with a review of hospital readmission data to capture all osteotomy-related infections. Clinical notes were reviewed to assess patient demographics, incidence of infection, how infection was managed and clinical outcome. RESULTS: In a series of 822 osteotomies in 755 patients, there were 21 (2.8%) cases of suspected infection. Twelve (1.6%) were contemporaneously deemed 'superficial' and nine confirmed 'deep' infections (1.2%). Deep infections were all successfully managed with wound debridement, with or without plate removal, depending on union and time from initial surgery. One of these infections was noted during a revision procedure, but no revision was carried out as a direct result of infection, no external fixation was required and no infected nonunions were experienced. CONCLUSION: All of the cases in this series were managed successfully with debridement ± removal of the plate, without the need for revision or external fixation. Any potential signs of infection around an osteotomy, especially in the case of medial high tibial osteotomy, should raise awareness for deep infection and the need for further surgery due to the limited overlying soft tissue cover. This evidence supports the recent European Society of Sports Traumatology, Knee Surgery and Arthroscopy algorithm. LEVEL OF EVIDENCE: Level IV, case series.

Lessons learnt from COVID-19 to reduce mortality and morbidity in the Global South: addressing global vaccine equity for future pandemics.

COVID-19, which killed more than 6 million people, will not be the last pandemic. Vaccines are key to preventing and ending pandemics. Therefore, it is critical to move now, before the next pandemic, towards global vaccine equity with shared goals, intermediate steps and long-term advocacy goals. Scientific integrity, ethical development, transparency, accountability and communication are critical. Countries can draw on lessons learnt from their response to the HIV pandemics, which has been at the vanguard of ensuring equitable access to rights-based services, to create shared goals and engage communities to increase access to and delivery of safe, quality vaccines. Access can be increased by: fostering the spread of mRNA intellectual property (IP) rights, with mRNA vaccine manufacturing on more continents; creating price transparency for vaccines; creating easily understandable, accessible and transparent data on vaccines; creating demand for a new international legal framework that allows IP rights to be waived quickly once a global pandemic is identified; and drawing on scientific expertise from around the world. Delivery can be improved by: creating strong public health systems that can deliver vaccines through the lifespan; creating or strengthening national regulatory agencies and independent national scientific advisory committees for vaccines; disseminating information from reliable, transparent national and subnational surveillance systems; improving global understanding that as more scientific data become available, this may result in changes to public health guidance; prioritising access to vaccines based on scientific criteria during an epidemic; and developing strategies to vaccinate those at highest risk with available vaccines.

Template switching between the leading and lagging strands at replication forks generates inverted copy number variants through hairpin-capped extrachromosomal DNA.

Inherited and germ-line de novo copy number variants (CNVs) are increasingly found to be correlated with human developmental and cancerous phenotypes. Several models for template switching during replication have been proposed to explain the generation of these gross chromosomal rearrangements. We proposed a model of template switching (ODIRA-origin dependent inverted repeat amplification) in which simultaneous ligation of the leading and lagging strands at diverging replication forks could generate segmental inverted triplications through an extrachromosomal inverted circular intermediate. Here, we created a genetic assay using split-ura3 cassettes to trap the proposed inverted intermediate. However, instead of recovering circular inverted intermediates, we found inverted linear chromosomal fragments ending in native telomeres-suggesting that a template switch had occurred at the centromere-proximal fork of a replication bubble. As telomeric inverted hairpin fragments can also be created through double strand breaks we tested whether replication errors or repair of double stranded DNA breaks were the most likely initiating event. The results from CRISPR/Cas9 cleavage experiments and growth in the replication inhibitor hydroxyurea indicate that it is a replication error, not a double stranded break that creates the inverted junctions. Since inverted amplicons of the SUL1 gene occur during long-term growth in sulfate-limited chemostats, we sequenced evolved populations to look for evidence of linear intermediates formed by an error in replication. All of the data are compatible with a two-step version of the ODIRA model in which sequential template switching at short inverted repeats between the leading and lagging strands at a replication fork, followed by integration via homologous recombination, generates inverted interstitial triplications.

Optimization Strategies to Adapt Sheep Breeding Programs to Pasture-Based Production Environments: A Simulation Study.

Strong differences between the selection (indoor fattening) and production environment (pasture fattening) are expected to reduce genetic gain due to possible genotype-by-environment interactions (G × E). To investigate how to adapt a sheep breeding program to a pasture-based production environment, different scenarios were simulated for the German Merino sheep population using the R package Modular Breeding Program Simulator (MoBPS). All relevant selection steps and a multivariate pedigree-based BLUP breeding value estimation were included. The reference scenario included progeny testing at stations to evaluate the fattening performance and carcass traits. It was compared to alternative scenarios varying in the progeny testing scheme for fattening traits (station and/or field). The total merit index (TMI) set pasture-based lamb fattening as a breeding goal, i.e., field fattening traits were weighted. Regarding the TMI, the scenario with progeny testing both in the field and on station led to a significant increase in genetic gain compared with the reference scenario. Regarding fattening traits, genetic gain was significantly increased in the alternative scenarios in which field progeny testing was performed. In the presence of G × E, the study showed that the selection environment should match the production environment (pasture) to avoid losses in genetic gain. As most breeding goals also contain traits not recordable in field testing, the combination of both field and station testing is required to maximize genetic gain.

Neural signals predict information sharing across cultures.

Information sharing influences which messages spread and shape beliefs, behavior, and culture. In a preregistered neuroimaging study conducted in the United States and the Netherlands, we demonstrate replicability, predictive validity, and generalizability of a brain-based prediction model of information sharing. Replicating findings in Scholz et al., Proc. Natl. Acad. Sci. U.S.A. 114, 2881-2886 (2017), self-, social-, and value-related neural signals in a group of individuals tracked the population sharing of US news articles. Preregistered brain-based prediction models trained on Scholz et al. (2017) data proved generalizable to the new data, explaining more variance in population sharing than self-report ratings alone. Neural signals (versus self-reports) more reliably predicted sharing cross-culturally, suggesting that they capture more universal psychological mechanisms underlying sharing behavior. These findings highlight key neurocognitive foundations of sharing, suggest potential target mechanisms for interventions to increase message effectiveness, and advance brain-as-predictor research.

Activity based restorative therapy considerations for children: medical and therapeutic perspectives for the pediatric population.

Well-established scientific evidence demonstrates that activity is essential for the development and repair of the central nervous system, yet traditional rehabilitation approaches target muscles only above the lesion as a means of compensation. Activity-Based Rehabilitation (ABR) represents an evolving paradigm shift in neurorehabilitation targeting activation of the neuromuscular system below the lesion. Based on activity-dependent plasticity, ABR offers high intensity activation of the nervous system to optimize the capacity for recovery, while working to offset the chronic complications that occur as a result of neurologic injury. Treatment focus shifts from compensatory training to promotion of restoration of function with special emphasis on normalizing sensory cues and movement kinematics. ABR in children carries special considerations for a developing nervous system and the focus is not just restoring functions but advancing functions in line with typical development. Application of activity-based interventions includes traditional rehabilitation strategies at higher intensity and frequency than in traditional models, including locomotor training, functional electrical stimulation, massed practice, and task specific training, applied across the continuum of care from early intervention to the chronic condition.

Fluoxetine restrains allergic inflammation by targeting an FcɛRI-ATP positive feedback loop in mast cells.

There is a clinical need for new treatment options addressing allergic disease. Selective serotonin reuptake inhibitors (SSRIs) are a class of antidepressants that have anti-inflammatory properties. We tested the effects of the SSRI fluoxetine on IgE-induced function of mast cells, which are critical effectors of allergic inflammation. We showed that fluoxetine treatment of murine or human mast cells reduced IgE-mediated degranulation, cytokine production, and inflammatory lipid secretion, as well as signaling mediated by the mast cell activator ATP. In a mouse model of systemic anaphylaxis, fluoxetine reduced hypothermia and cytokine production. Fluoxetine was also effective in a model of allergic airway inflammation, where it reduced bronchial responsiveness and inflammation. These data show that fluoxetine suppresses mast cell activation by impeding an FcɛRI-ATP positive feedback loop and support the potential repurposing of this SSRI for use in allergic disease.

Novelty and uncertainty differentially drive exploration across development.

Across the lifespan, individuals frequently choose between exploiting known rewarding options or exploring unknown alternatives. A large body of work has suggested that children may explore more than adults. However, because novelty and reward uncertainty are often correlated, it is unclear how they differentially influence decision-making across development. Here, children, adolescents, and adults (ages 8-27 years, N = 122) completed an adapted version of a recently developed value-guided decision-making task that decouples novelty and uncertainty. In line with prior studies, we found that exploration decreased with increasing age. Critically, participants of all ages demonstrated a similar bias to select choice options with greater novelty, whereas aversion to reward uncertainty increased into adulthood. Computational modeling of participant choices revealed that whereas adolescents and adults demonstrated attenuated uncertainty aversion for more novel choice options, children's choices were not influenced by reward uncertainty.

Contribution of αß T cells to macrophage polarization and MSC recruitment and proliferation on titanium implants.

Physiochemical cues like topography and wettability can impact the inflammatory response and tissue integration after biomaterial implantation. T cells are essential for immunomodulation of innate immune cells and play an important role in the host response to biomaterial implantation. This study aimed to understand how CD4+ and CD8+ T cell subsets, members of the αß T cell family, polarize in response to smooth, rough, or rough-hydrophilic titanium (Ti) implants and whether their presence modulates immune cell crosstalk and mesenchymal stem cell (MSC) recruitment following biomaterial implantation. Post-implantation in mice, we found that CD4+ and CD8+ T cell subsets polarized differentially in response to modified Ti surfaces. Additionally, mice lacking αß T cells had significantly more pro-inflammatory macrophages, fewer anti-inflammatory macrophages, and reduced MSC recruitment in response to modified Ti post-implantation than αß T cell -competent mice. Our results demonstrate that T cell activation plays a significant role during the inflammatory response to implanted biomaterials, contributing to macrophage polarization and MSC recruitment and proliferation, and the absence of αß T cells compromises new bone formation at the implantation site. STATEMENT OF SIGNIFICANCE: T cells are essential for immunomodulation and play an important role in the host response to biomaterial implantation. Our results demonstrate that T cells actively participate during the inflammatory response to implanted biomaterials, controlling macrophage phenotype and recruitment of MSCs to the implantation site.

Modeling Cues May Reduce Sway Following Sit-To-Stand Transfer for People with Parkinson's Disease.

Cues are commonly used to overcome the effects of motor symptoms associated with Parkinson's disease. Little is known about the impact of cues on postural sway during transfers. The objective of this study was to identify if three different types of explicit cues provided during transfers of people with Parkinson's disease results in postural sway more similar to healthy controls. This crossover study had 13 subjects in both the Parkinson's and healthy control groups. All subjects completed three trials of uncued sit to stand transfers. The Parkinson's group additionally completed three trials of sit to stand transfers in three conditions: external attentional focus of reaching to targets, external attentional focus of concurrent modeling, and explicit cue for internal attentional focus. Body worn sensors collected sway data, which was compared between groups with Mann Whitney U tests and between conditions with Friedman's Tests. Sway normalized with modeling but was unchanged in the other conditions. Losses of balance presented with reaching towards targets and cueing for an internal attentional focus. Modeling during sit to stand of people with Parkinson's disease may safely reduce sway more than other common cues.

Inhibiting Isoprenylation Suppresses FcεRI-Mediated Mast Cell Function and Allergic Inflammation.

IgE-mediated mast cell activation is a driving force in allergic disease in need of novel interventions. Statins, long used to lower serum cholesterol, have been shown in multiple large-cohort studies to reduce asthma severity. We previously found that statins inhibit IgE-induced mast cell function, but these effects varied widely among mouse strains and human donors, likely due to the upregulation of the statin target, 3-hydroxy-3-methylgutaryl-CoA reductase. Statin inhibition of mast cell function appeared to be mediated not by cholesterol reduction but by suppressing protein isoprenylation events that use cholesterol pathway intermediates. Therefore, we sought to circumvent statin resistance by targeting isoprenylation. Using genetic depletion of the isoprenylation enzymes farnesyltransferase and geranylgeranyl transferase 1 or their substrate K-Ras, we show a significant reduction in FcεRI-mediated degranulation and cytokine production. Furthermore, similar effects were observed with pharmacological inhibition with the dual farnesyltransferase and geranylgeranyl transferase 1 inhibitor FGTI-2734. Our data indicate that both transferases must be inhibited to reduce mast cell function and that K-Ras is a critical isoprenylation target. Importantly, FGTI-2734 was effective in vivo, suppressing mast cell-dependent anaphylaxis, allergic pulmonary inflammation, and airway hyperresponsiveness. Collectively, these findings suggest that K-Ras is among the isoprenylation substrates critical for FcεRI-induced mast cell function and reveal isoprenylation as a new means of targeting allergic disease.

Neutrophil elastase decreases SARS-CoV-2 spike protein binding to human bronchial epithelia by clipping ACE-2 ectodomain from the epithelial surface.

Patients with cystic fibrosis (CF) have decreased severity of severe acute respiratory syndrome-like coronavirus-2 (SARS-CoV-2) infections, but the underlying cause is unknown. Patients with CF have high levels of neutrophil elastase (NE) in the airway. We examined whether respiratory epithelial angiotensin-converting enzyme 2 (ACE-2), the receptor for the SARS-CoV-2 spike protein, is a proteolytic target of NE. Soluble ACE-2 levels were quantified by ELISA in airway secretions and serum from patients with and without CF, the association between soluble ACE-2 and NE activity levels was evaluated in CF sputum. We determined that NE activity was directly correlated with increased ACE-2 in CF sputum. Additionally, primary human bronchial epithelial (HBE) cells, exposed to NE or control vehicle, were evaluated by Western analysis for the release of cleaved ACE-2 ectodomain fragment into conditioned media, flow cytometry for the loss of cell surface ACE-2, its impact on SARS-CoV-2 spike protein binding. We found that NE treatment released ACE-2 ectodomain fragment from HBE and decreased spike protein binding to HBE. Furthermore, we performed NE treatment of recombinant ACE-2-Fc-tagged protein in vitro to assess whether NE was sufficient to cleave recombinant ACE-2-Fc protein. Proteomic analysis identified specific NE cleavage sites in the ACE-2 ectodomain that would result in loss of the putative N-terminal spike-binding domain. Collectively, data support that NE plays a disruptive role in SARS-CoV-2 infection by catalyzing ACE-2 ectodomain shedding from the airway epithelia. This mechanism may reduce SARS-CoV-2 virus binding to respiratory epithelial cells and decrease the severity of COVID19 infection.

Reduction of neutrophil extracellular traps accelerates inflammatory resolution and increases bone formation on titanium implants.

Neutrophils are the most abundant immune cells in the blood and the first cells to be recruited to the biomaterial implantation site. Neutrophils are fundamental in recruiting mononuclear leukocytes to mount an immune response at the injury site. Neutrophils exert significant pro-inflammatory effects through the release of cytokines and chemokines, degranulation and release of myeloperoxidase (MPO) and neutrophil elastase (NE), and the production of large DNA-based networks called neutrophil extracellular traps (NETs). Neutrophils are initially recruited and activated by cytokines and pathogen- and damage-associated molecular patterns, but little is known about how the physicochemical composition of the biomaterial affects their activation. This study aimed to understand how ablating neutrophil mediators (MPO, NE, NETs) affected macrophage phenotype in vitro and osseointegration in vivo. We discovered that NET formation is a crucial mediator of pro-inflammatory macrophage activation, and inhibition of NET formation significantly suppresses macrophage pro-inflammatory phenotype. Furthermore, reducing NET formation accelerated the inflammatory phase of healing and produced greater bone formation around the implanted biomaterial, suggesting that NETs are essential regulators of biomaterial integration. Our findings emphasize the importance of the neutrophil response to implanted biomaterials and highlight innate immune cells' regulation and amplification signaling during the initiation and resolution of the inflammatory phase of biomaterial integration. STATEMENT OF SIGNIFICANCE: Neutrophils are the most abundant immune cells in blood and are the first to be recruited to the injury/implantation site where they exert significant pro-inflammatory effects. This study aimed to understand how ablating neutrophil mediators affected macrophage phenotype in vitro and bone apposition in vivo. We found that NET formation is a crucial mediator of pro-inflammatory macrophage activation. Reducing NET formation accelerated the inflammatory phase of healing and produced greater appositional bone formation around the implanted biomaterial, suggesting that NETs are essential regulators of biomaterial integration.