A role for Cep70 in centriole amplification in multiciliated cells.

Centriole amplification in multiciliated cells occurs in a pseudo-cell cycle regulated process that typically utilizes a poorly characterized molecularly dense structure called the deuterosome. We identified the centrosomal protein Cep70 as a novel deuterosome-associated protein that forms a complex with other deuterosome proteins, CCDC78 and Deup1. Cep70 dynamically associates with deuterosomes during centriole amplification in the ciliated epithelia of Xenopus embryos. Cep70 is not found in nascent deuterosomes prior to amplification. However, it becomes localized at deuterosomes at the onset of centriole biogenesis and remains there after the completion of centriole amplification. Deuterosome localization requires a conserved C-terminal "Cep70" motif. Depletion of Cep70 using morpholino oligos or CRISPR/Cas9 editing in F0 embryos leads to a severe decrease in centriole formation in both endogenous MCCs, as well as ectopically induced MCCs. Consistent with a decrease in centrioles, endogenous MCCs have defects in the process of radial intercalation. We propose that Cep70 represents a novel regulator of centriole biogenesis in MCCs.

Evaluating Shifts in Perception After a Pilot Trauma Quality Improvement Training Course in Cameroon.

INTRODUCTION: Trauma is a major contributor to the global burden of disease, with low- and middle-income countries (LMICs) being disproportionately affected. Trauma Quality Improvement (QI) initiatives could potentially save an estimated two million lives each year. Successful trauma QI initiatives rely on adequate training and a culture of quality among hospital staff. This study evaluated the effect of a pilot trauma QI training course on participants' perceptions on leadership, medical errors, and the QI process in Cameroon. METHODS: Study participants took part in a three-day, eight-module course training on trauma QI methods and applications. Perceptions on leadership, medical errors, and QI were assessed pre and post-course using a 15-item survey measured on a five-point Likert scale. Median pre- and post-course scores were compared using the Wilcoxon signed-rank test. Knowledge retention and course satisfaction were also evaluated in a post-course survey and evaluation. RESULTS: A majority of the 25 course participants completed pre-course (92%) and post-course (80%) surveys. Participants' perceptions of safety and comfort discussing medical errors at work significantly increased post-course (pre-median = 5, IQR [4-5]; post-median = 5, IQR [5-5]; P = 0.046). The belief that individuals responsible for medical error should be held accountable significantly decreased after the course (pre-median = 3, IQR [2-4]; post-median = 1, IQR [1-2]; P < 0.001). Overall satisfaction with the course was high with median scores ≥4. CONCLUSIONS: These initial results suggest that targeted trauma QI training effectively influences attitudes about QI. Further investigation of the effect of the trauma QI training on hospital staff in larger courses is warranted to assess reproducibility of these findings.

Instilling Resiliency in Surgical Education: The Benefits of Longitudinal Medical Student Learning.

The longitudinal clerkship has been recognized as an innovative, unique model in medical education that demonstrates significantly higher student and preceptor satisfaction with comparable long-term outcomes like performance on standardized examinations. At the center of this model is the student-preceptor relationship, which promotes effective student-directed learning and personal and professional relationships with established faculty mentors. The University of California, San Francisco (UCSF) has two clerkships models: a traditional or "block" model consisting of 2-month sequential clinical rotations in seven core clerkships, and a longitudinal model that integrates parallel out-patient clinical experiences over the entire year with one-on-one faculty preceptors from each core discipline with focused 2-week intensive inpatient rotations. In the setting of the Covid-19 pandemic beginning in Spring of 2020, this arrangement allowed for a natural experiment to evaluate the resiliency of the respective models in the face of unprecedented disruptions in education and healthcare delivery. As described in this perspective, both clerkships required rapid pivots; however, students enrolled in the longitudinal clerkship were more likely to develop stronger relationships with surgical faculty and felt more prepared for making career choices. Medical school curricula may benefit from incorporating longitudinal components, as this model provided flexibility and fostered greater faculty-student mentorship in the setting of disruption to medical education.

Baseline Patient Safety Culture in Cameroon: Setting a Foundation for Trauma Quality Improvement.

BACKGROUND: Trauma quality improvement (QI) has resulted in decreased trauma mortality and morbidity in high-income countries and has the potential to do the same in low- and middle-income countries. Effective implementation of QI programs relies on a foundational culture of patient safety; however, studies on trauma-related patient safety culture in Sub-Saharan Africa remain scarce. This study assesses baseline patient safety culture in Cameroon to best identify opportunities for improvement. MATERIALS AND METHODS: Over a 3-week period, the Hospital Survey on Patient Safety Culture was administered in three hospitals in the Littoral region of Cameroon. Percentages of positive responses (PPRs) were calculated across 42 items in 12 survey dimensions. A mixed-effects logistic regression model was used to summarize dimension-level percentages and confidence intervals. RESULTS: A total of 179 trauma-related hospital personnel were surveyed with an overall response rate of 76.8%. High PPRs indicate favorable patient safety culture. Of the 12 dimensions evaluated by the Hospital Survey on Patient Safety Culture, nine had a PPR below 50%. Dimensions particularly pertinent in the context of QI include Nonpunitive Response to Errors with a PPR of 25.8% and Organization Learning-Continuous Improvement with a PPR of 64.7%. CONCLUSIONS: The present study elucidates an opportunity for the development of trauma patient safety culture in Cameroon. Low PPR for Nonpunitive Response to Errors indicates a need to shift cultural paradigms from ascribing individual blame to addressing systemic shortcomings of patient care. Moving forward, data from this study will inform interventions to cultivate patient safety culture in partnering Cameroonian hospitals.

Changes in E-cadherin rigidity sensing regulate cell adhesion.

Mechanical cues are sensed and transduced by cell adhesion complexes to regulate diverse cell behaviors. Extracellular matrix (ECM) rigidity sensing by integrin adhesions has been well studied, but rigidity sensing by cadherins during cell adhesion is largely unexplored. Using mechanically tunable polyacrylamide (PA) gels functionalized with the extracellular domain of E-cadherin (Ecad-Fc), we showed that E-cadherin-dependent epithelial cell adhesion was sensitive to changes in PA gel elastic modulus that produced striking differences in cell morphology, actin organization, and membrane dynamics. Traction force microscopy (TFM) revealed that cells produced the greatest tractions at the cell periphery, where distinct types of actin-based membrane protrusions formed. Cells responded to substrate rigidity by reorganizing the distribution and size of high-traction-stress regions at the cell periphery. Differences in adhesion and protrusion dynamics were mediated by balancing the activities of specific signaling molecules. Cell adhesion to a 30-kPa Ecad-Fc PA gel required Cdc42- and formin-dependent filopodia formation, whereas adhesion to a 60-kPa Ecad-Fc PA gel induced Arp2/3-dependent lamellipodial protrusions. A quantitative 3D cell-cell adhesion assay and live cell imaging of cell-cell contact formation revealed that inhibition of Cdc42, formin, and Arp2/3 activities blocked the initiation, but not the maintenance of established cell-cell adhesions. These results indicate that the same signaling molecules activated by E-cadherin rigidity sensing on PA gels contribute to actin organization and membrane dynamics during cell-cell adhesion. We hypothesize that a transition in the stiffness of E-cadherin homotypic interactions regulates actin and membrane dynamics during initial stages of cell-cell adhesion.

A phylogenetic method to perform genome-wide association studies in microbes that accounts for population structure and recombination.

Genome-Wide Association Studies (GWAS) in microbial organisms have the potential to vastly improve the way we understand, manage, and treat infectious diseases. Yet, microbial GWAS methods established thus far remain insufficiently able to capitalise on the growing wealth of bacterial and viral genetic sequence data. Facing clonal population structure and homologous recombination, existing GWAS methods struggle to achieve both the precision necessary to reject spurious findings and the power required to detect associations in microbes. In this paper, we introduce a novel phylogenetic approach that has been tailor-made for microbial GWAS, which is applicable to organisms ranging from purely clonal to frequently recombining, and to both binary and continuous phenotypes. Our approach is robust to the confounding effects of both population structure and recombination, while maintaining high statistical power to detect associations. Thorough testing via application to simulated data provides strong support for the power and specificity of our approach and demonstrates the advantages offered over alternative cluster-based and dimension-reduction methods. Two applications to Neisseria meningitidis illustrate the versatility and potential of our method, confirming previously-identified penicillin resistance loci and resulting in the identification of both well-characterised and novel drivers of invasive disease. Our method is implemented as an open-source R package called treeWAS which is freely available at https://github.com/caitiecollins/treeWAS.

Unraveling the drivers of MERS-CoV transmission.

With more than 1,700 laboratory-confirmed infections, Middle East respiratory syndrome coronavirus (MERS-CoV) remains a significant threat for public health. However, the lack of detailed data on modes of transmission from the animal reservoir and between humans means that the drivers of MERS-CoV epidemics remain poorly characterized. Here, we develop a statistical framework to provide a comprehensive analysis of the transmission patterns underlying the 681 MERS-CoV cases detected in the Kingdom of Saudi Arabia (KSA) between January 2013 and July 2014. We assess how infections from the animal reservoir, the different levels of mixing, and heterogeneities in transmission have contributed to the buildup of MERS-CoV epidemics in KSA. We estimate that 12% [95% credible interval (CI): 9%, 15%] of cases were infected from the reservoir, the rest via human-to-human transmission in clusters (60%; CI: 57%, 63%), within (23%; CI: 20%, 27%), or between (5%; CI: 2%, 8%) regions. The reproduction number at the start of a cluster was 0.45 (CI: 0.33, 0.58) on average, but with large SD (0.53; CI: 0.35, 0.78). It was >1 in 12% (CI: 6%, 18%) of clusters but fell by approximately one-half (47% CI: 34%, 63%) its original value after 10 cases on average. The ongoing exposure of humans to MERS-CoV from the reservoir is of major concern, given the continued risk of substantial outbreaks in health care systems. The approach we present allows the study of infectious disease transmission when data linking cases to each other remain limited and uncertain.

An hourly regression model for ultrafine particles in a near-highway urban area.

Estimating ultrafine particle number concentrations (PNC) near highways for exposure assessment in chronic health studies requires models capable of capturing PNC spatial and temporal variations over the course of a full year. The objectives of this work were to describe the relationship between near-highway PNC and potential predictors, and to build and validate hourly log-linear regression models. PNC was measured near Interstate 93 (I-93) in Somerville, MA using a mobile monitoring platform driven for 234 h on 43 days between August 2009 and September 2010. Compared to urban background, PNC levels were consistently elevated within 100-200 m of I-93, with gradients impacted by meteorological and traffic conditions. Temporal and spatial variables including wind speed and direction, temperature, highway traffic, and distance to I-93 and major roads contributed significantly to the full regression model. Cross-validated model R(2) values ranged from 0.38 to 0.47, with higher values achieved (0.43 to 0.53) when short-duration PNC spikes were removed. The model predicts highest PNC near major roads and on cold days with low wind speeds. The model allows estimation of hourly ambient PNC at 20-m resolution in a near-highway neighborhood.

Disparities in Access, Management and Outcomes of Critically Ill Adult Patients with Trauma.

Despite legal protections guaranteeing care for patients with trauma, disparities exist in patient outcomes. We review disparities in patient management and outcomes related to insurance status, race and ethnicity, and gender for patients with trauma in the preadmission, in-hospital, and postdischarge settings. We highlight groups understudied and either underrepresented or unrepresented in national trauma databases-including American Indians/Alaska Natives, non-English preferred patients, and patients with disabilities. We call for more study of these groups and of upstream factors affecting the reviewed demographics to measure and improve outcomes for these vulnerable populations.

Subclavian line infiltration causing neck compartment syndrome and bradycardic arrest: A case report.

Unrecognized central venous catheter (CVC) infiltration is an uncommon but potentially life-threatening complication. For instance, a malpositioned subclavian line can infuse into the mediastinum, pleural cavity, or interstitial space of the neck. We present the case of a 30-year-old male with gunshot wounds to the right chest, resuscitated with an initially functional left subclavian CVC, which later infiltrated into the neck causing compression of the carotid sinus and consequent bradycardic arrest. Return of spontaneous circulation (ROSC) was achieved following intravenous epinephrine, cardiac massage, and emergency neck exploration and cervical fasciotomy. Our case highlights the importance of frequent reassessment of lines, especially those placed during fast-paced, high-intensity clinical situations. We recommend being mindful when using rapid transfusion devices as an interstitial catheter may not mount enough back pressure to trigger the system's alarm before significant tissue damage or compartment syndrome occurs.

Presence of phage-plasmids in multiple serovars of Salmonella enterica.

Evidence is accumulating in the literature that the horizontal spread of antimicrobial resistance (AMR) genes mediated by bacteriophages and bacteriophage-like plasmid (phage-plasmid) elements is much more common than previously envisioned. For instance, we recently identified and characterized a circular P1-like phage-plasmid harbouring a bla CTX-M-15 gene conferring extended-spectrum beta-lactamase (ESBL) resistance in Salmonella enterica serovar Typhi. As the prevalence and epidemiological relevance of such mechanisms has never been systematically assessed in Enterobacterales, in this study we carried out a follow-up retrospective analysis of UK Salmonella isolates previously sequenced as part of routine surveillance protocols between 2016 and 2021. Using a high-throughput bioinformatics pipeline we screened 47 784 isolates for the presence of the P1 lytic replication gene repL, identifying 226 positive isolates from 25 serovars and demonstrating that phage-plasmid elements are more frequent than previously thought. The affinity for phage-plasmids appears highly serovar-dependent, with several serovars being more likely hosts than others; most of the positive isolates (170/226) belonged to S. Typhimurium ST34 and ST19. The phage-plasmids ranged between 85.8 and 98.2 kb in size, with an average length of 92.1 kb; detailed analysis indicated a high amount of diversity in gene content and genomic architecture. In total, 132 phage-plasmids had the p0111 plasmid replication type, and 94 the IncY type; phylogenetic analysis indicated that both horizontal and vertical gene transmission mechanisms are likely to be involved in phage-plasmid propagation. Finally, phage-plasmids were present in isolates that were resistant and non-resistant to antimicrobials. In addition to providing a first comprehensive view of the presence of phage-plasmids in Salmonella, our work highlights the need for a better surveillance and understanding of phage-plasmids as AMR carriers, especially through their characterization with long-read sequencing.

Complete mitochondrial genome of the introduced Indian walking stick Carausius morosus (Lonchodidae, Insecta) from California.

We present the complete mitochondrial genome of Carausius morosus from Salinas, CA. The mitochondrial genome of C. morosus is circular, AT rich (78.1%), and 16,671 bp in length. It consists of 13 protein-coding, 22 transfer RNA, and 2 ribosomal RNA genes and is identical in gene content to Carausius sp.

Preparing for participation in the centers for Medicare and Medicaid Services' bundle care payment initiative-advanced for major bowel surgery.

BACKGROUND: As healthcare costs rise, there is an increasing emphasis on alternative payment models to improve care efficiency. The bundled payment represents an alternative reimbursement model gaining popularity within the surgical sphere. We aimed to assess where the largest opportunities for care improvement lay and how best to identify patients at high risk of suffering costly complications. METHODS: We utilized itemized CMS claims data for a retrospective cohort of patients between 2014 and 2016 who met inclusion criteria for the Major Bowel Bundled Payment Program and performed a cost analysis to identify opportunities for improved care efficiency. Based on the results of this cost analysis, we identified readmissions as a target for improvement. We then assessed whether the American College of Surgeons' National Surgical Quality Improvement Program surgical risk calculator (ACS NSQIP SRC) could accurately identify patients within our bundled payment population who were at high risk of readmission using a logistic regression model. RESULTS: Our study cohort included 252 patients. Readmissions accounted for 12.8% of the average total care episode cost with a coefficient of variation of 2.72, thereby representing the most substantial, non-fixed cost for our bundled payment patients. Patients readmitted within their 90-day care episode were 2.53 times more likely to be high-cost (>$60,000) than patients not readmitted. However, the ACS NSQIP SRC did not accurately predict patients at high risk of readmission within the first 30 days with an AUROC of 0.58. CONCLUSIONS: Our study highlights the importance of reducing readmissions as a central component of improving care for bowel surgery bundled payment patients. Preventing such readmissions requires accurate identification of patients at high risk of readmission; however, current risk prediction models lack the adaptability necessary for this task.

Building a ciliated epithelium: Transcriptional regulation and radial intercalation of multiciliated cells.

The epidermis of the Xenopus embryo has emerged as a powerful tool for studying the development of a ciliated epithelium. Interspersed throughout the epithelium are multiciliated cells (MCCs) with 100+ motile cilia that beat in a coordinated manner to generate fluid flow over the surface of the cell. MCCs are essential for various developmental processes and, furthermore, ciliary dysfunction is associated with numerous pathologies. Therefore, understanding the cellular mechanisms involved in establishing a ciliated epithelium are of particular interest. MCCs originate in the inner epithelial layer of Xenopus skin, where Notch signaling plays a critical role in determining which progenitors will adopt a ciliated cell fate. Then, activation of various transcriptional regulators, such as GemC1 and MCIDAS, initiate the MCC transcriptional program, resulting in centriole amplification and the formation of motile cilia. Following specification and differentiation, MCCs undergo the process of radial intercalation, where cells apically migrate from the inner layer to the outer epithelial layer. This process involves the cooperation of various cytoskeletal networks, activation of various signaling molecules, and changes in cell-ECM and cell-cell adhesion. Coordination of these cellular processes is required for complete incorporation into the outer epithelial layer and generation of a functional ciliated epithelium. Here, we highlight recent advances made in understanding the transcriptional cascades required for MCC specification and differentiation and the coordination of cellular processes that facilitate radial intercalation. Proper regulation of these signaling pathways and processes are the foundation for developing a ciliated epithelium.

Stress and the Surgical Resident in the COVID-19 Pandemic.

OBJECTIVE: The COVID-19 pandemic has drastically transformed the healthcare community and medical education across the United States. The aim of this study was to evaluate the impact of COVID-19 on the surgical resident training experience, assess possible sources of stress or anxiety among surgery residents, and examine how patterns of anxiety vary by resident rank. DESIGN: We developed and disseminated a survey, which included the Generalized Anxiety Disorder 7-Item Scale (GAD-7), to all general and integrated plastic surgery residents in their clinical years of training at the University of California, San Francisco. Statistical analysis of the survey responses was performed using the Kruskal-Wallis or Wilcoxon rank sum test. Post-hoc analysis was performed using the Bonferroni-corrected Dunn test. Survey data were combined with aggregated duty hour information and operative case numbers from select hospitals for March and April of 2019 (historical baseline) and 2020. RESULTS: The overall survey response rate was 73.7% (n = 73). With an estimated operative volume reduction of 63.3% for general surgery cases, over 90% of residents expressed concern about the decline in operative exposure. While the senior residents tended to work more shifts, they were not more likely to have higher risk perception scores for contracting COVID-19 nor higher anxiety levels about the possibility of contracting COVID-19. They were, however, significantly more likely to have high GAD-7 scores (≥ 10) when compared to interns (z = -2.82, p-adj = 0.014). Overall, residents were more concerned about the general health of loved ones than about their own risk of contracting COVID-19 (U = 3897.5, p < 0.01). CONCLUSIONS: While the work-related experiences of residents varied across a number of factors during the pandemic, residents tended to report similar sources of anxiety. Moving forward, surgical residency training programs will need to develop ways to optimize available surgical experiences and address the unique resident anxieties that an infectious pandemic presents.

Emergency general surgery utilization and disparities during COVID-19: an interrupted time-series analysis.

OBJECTIVE: We aimed to compare general surgery emergency (GSE) volume, demographics and disease severity before and during COVID-19. BACKGROUND: Presentations to the emergency department (ED) for GSEs fell during the early COVID-19 pandemic. Barriers to accessing care may be heightened, especially for vulnerable populations, and patients delaying care raises public health concerns. METHODS: We included adult patients with ED presentations for potential GSEs at a single quaternary-care hospital from January 2018 to August 2020. To compare GSE volumes in total and by subgroup, an interrupted time-series analysis was performed using the March shelter-in-place order as the start of the COVID-19 period. Bivariate analysis was used to compare demographics and disease severity. RESULTS: 3255 patients (28/week) presented with potential GSEs before COVID-19, while 546 (23/week) presented during COVID-19. When shelter-in-place started, presentations fell by 8.7/week (31%) from the previous week (p<0.001), driven by decreases in peritonitis (ß=-2.76, p=0.017) and gallbladder disease (ß=-2.91, p=0.016). During COVID-19, patients were younger (54 vs 57, p=0.001), more often privately insured (44% vs 38%, p=0.044), and fewer required interpreters (12% vs 15%, p<0.001). Fewer patients presented with sepsis during the pandemic (15% vs 20%, p=0.009) and the average severity of illness decreased (p<0.001). Length of stay was shorter during the COVID-19 period (3.91 vs 5.50 days, p<0.001). CONCLUSIONS: GSE volumes and severity fell during the pandemic. Patients presenting during the pandemic were less likely to be elderly, publicly insured and have limited English proficiency, potentially exacerbating underlying health disparities and highlighting the need to improve care access for these patients. LEVEL OF EVIDENCE: III.

Tubulin acetylation promotes penetrative capacity of cells undergoing radial intercalation.

Post-translational modification of tubulin provides differential functions to microtubule networks. Here, we address the role of tubulin acetylation on the penetrative capacity of cells undergoing radial intercalation, which is the process by which cells move apically, insert between outer cells, and join an epithelium. There are opposing forces that regulate intercalation, namely, the restrictive forces of the epithelial barrier versus the penetrative forces of the intercalating cell. Positively and negatively modulating tubulin acetylation in intercalating cells alters the developmental timing such that cells with more acetylation penetrate faster. We find that intercalating cells preferentially penetrate higher-order vertices rather than the more prevalent tricellular vertices. Differential timing in the ability of cells to penetrate different vertices reveals that lower-order vertices represent more restrictive sites of insertion. We shift the accessibility of intercalating cells toward more restrictive junctions by increasing tubulin acetylation, and we provide a geometric-based mathematical model that describes our results.

Centriole Number and the Accumulation of Microtubules Modulate the Timing of Apical Insertion during Radial Intercalation.

Centrioles are microtubule (MT)-based structures that provide important functions during cell migration, cell division, and cell signaling [1]. Modulating centriole number in 3D cell cultures has been shown to influence protrusive behavior [2-5]. Here, we address in vivo the role of centrioles and the accumulation of MTs on the protrusive behavior required during the initiation of radial intercalation. Radial intercalation is an important developmental process whereby cells undergo polarized movements and interdigitate into a more superficial layer [6, 7]. It is commonly employed during metamorphic events, such as the tissue thinning coupled with expansion or during the introduction of different cell types into an epithelium. During radial intercalation, cells emerge from a basal layer by undergoing a process of apical migration, apical insertion, and expansion [8]. In Xenopus skin, multiciliated cells (MCCs), which contain ∼150 centrioles, and ionocytes (ICs), which contain two centrioles, differentiate during the same developmental window, but MCCs complete intercalation prior to ICs. Here, we utilize this difference in timing to create a quantifiable assay for insertion and find that the timing of insertion is modulated by changes in centriole number and the accumulation of acetylated MTs. Additionally, centrioles align between the nucleus and the leading edge creating an axis of migration with apically oriented (+) ends. Using the MT (-) end protein CAMSAP1 fused to the apically positioned Par6 protein, we have artificially reversed the orientation of MTs and find that the accumulation of MTs in either orientation is sufficient to promote apical insertion.

Reflections on the Complexity of Surgical Site Infection Prevention and Detection from an Organizational Lens.

Background: Within the United States, surgical site infections (SSIs) have now become the most common hospital-acquired infection and impact 2%-5% of all surgical patients. It is estimated that approximately 60% of SSIs could be prevented through improved adherence to pre-existing practice guidelines. Methods: The myriad of contributing factors leading to SSIs highlights the need for a multi-faceted approach. Although collaboration and coordination among providers and patients represents a requirement of any sustainable solution, it also creates a space and possible role for innovative technologies and mobile applications utilizing patient-generated health data (PGHD). Results: Upon analysis of hospital practice, we have identified substantial variability in documentation, peri-operative care, and post-discharge instruction with regard to SSI prevention and incision care techniques. This variability is further exacerbated by a loss of information within each transition of patient care. As a result, a patient's risk of SSI often becomes dictated by their provider's preferred (and sometimes arbitrary) peri-operative practices and their own initiative in following poorly explained pre-operative instructions. The quality and efficiency of any subsequent SSI treatment similarly rests on a seemingly inconsistent approach with poor patient instruction for the post-discharge setting. Conclusions: Surgical site infection risk can be mitigated successfully through reliable performance of several evidence-based process measures within the operating room, which are now at the guideline level. However, optimal performance only happens when teams and patients are aligned and truly believe both that the evidence is correct, and that SSIs are preventable. The journey toward this goal will be an iterative process that may take months to years. Although technology can be complementary, it cannot replace human passion for harm prevention.