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Lung cancer is the leading global cause of cancer-related deaths. Although smoking cessation is the best prevention, 50% of lung cancer diagnoses occur in people who have quit smoking. Research into treatment options for high-risk patients is constrained to rodent models, which are time-consuming, expensive, and require large cohorts. Embedding precision-cut lung slices (PCLS) within an engineered hydrogel and exposing this tissue to vinyl carbamate, a carcinogen from cigarette smoke, creates an in vitro model of lung cancer premalignancy. Hydrogel formulations are selected to promote early lung cancer cellular phenotypes and extend PCLS viability to six weeks. Hydrogel-embedded PCLS are exposed to vinyl carbamate, which induces adenocarcinoma in mice. Analysis of proliferation, gene expression, histology, tissue stiffness, and cellular content after six weeks reveals that vinyl carbamate induces premalignant lesions with a mixed adenoma/squamous phenotype. Putative chemoprevention agents diffuse through the hydrogel and induce tissue-level changes. The design parameters selected using murine tissue are validated with hydrogel-embedded human PCLS and results show increased proliferation and premalignant lesion gene expression patterns. This tissue-engineered model of human lung cancer premalignancy is the foundation for more sophisticated ex vivo models that enable the study of carcinogenesis and chemoprevention strategies., (© 2023 Wiley-VCH GmbH.)

Tissue fibrosis remains a serious health condition with high morbidity and mortality rates. There is a critical need to engineer model systems that better recapitulate the spatial and temporal changes in the fibrotic extracellular microenvironment and enable study of the cellular and molecular alterations that occur during pathogenesis. Here, we present a process for chemically modifying human decellularized extracellular matrix (dECM) and incorporating it into a dynamically tunable hybrid-hydrogel system containing a poly(ethylene glycol)-α methacrylate (PEGαMA) backbone. Following modification and characterization, an off-stoichiometry thiol-ene Michael addition reaction resulted in hybrid-hydrogels with mechanical properties that could be tuned to recapitulate many healthy tissue types. Next, photoinitiated, free-radical homopolymerization of excess α-methacrylates increased crosslinking density and hybrid-hydrogel elastic modulus to mimic a fibrotic microenvironment. The incorporation of dECM into the PEGαMA hydrogel decreased the elastic modulus and, relative to fully synthetic hydrogels, increased the swelling ratio, the average molecular weight between crosslinks, and the mesh size of hybrid-hydrogel networks. These changes were proportional to the amount of dECM incorporated into the network. Dynamic stiffening increased the elastic modulus and decreased the swelling ratio, average molecular weight between crosslinks, and the mesh size of hybrid-hydrogels, as expected. Stiffening also activated human fibroblasts, as measured by increases in average cellular aspect ratio (1.59 ± 0.02 to 2.98 ± 0.20) and expression of α-smooth muscle actin (αSMA). Fibroblasts expressing αSMA increased from 25.8 to 49.1% upon dynamic stiffening, demonstrating that hybrid-hydrogels containing human dECM support investigation of dynamic mechanosensing. These results improve our understanding of the biomolecular networks formed within hybrid-hydrogels: this fully human phototunable hybrid-hydrogel system will enable researchers to control and decouple the biochemical changes that occur during fibrotic pathogenesis from the resulting increases in stiffness to study the dynamic cell-matrix interactions that perpetuate fibrotic diseases.

The lung parenchyma-consisting of gas-filled alveoli, vasculature, and connective tissue-is the site for gas exchange in the lung and plays a critical role in a number of chronic lung diseases. In vitro models of lung parenchyma can, therefore, provide valuable platforms for the study of lung biology in health and disease. Yet modeling such a complex tissue requires integrating multiple components, including biochemical cues from the extracellular environment, geometrically defined multicellular interactions, and dynamic mechanical inputs such as the cyclic stretch of breathing. In this chapter, we provide an overview of the broad spectrum of model systems that have been developed to recapitulate one or more features of lung parenchyma, and some of the scientific advances generated by those models. We discuss the use of both synthetic and naturally derived hydrogel materials, precision-cut lung slices, organoids, and lung-on-a-chip devices, with perspectives on the strengths, weaknesses, and potential future directions of these engineered systems., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease that progressively and irreversibly alters the lung parenchyma, eventually leading to respiratory failure. The study of this disease has been historically challenging due to the myriad of complex processes that contribute to fibrogenesis and the inherent difficulty in accurately recreating the human pulmonary environment in vitro . Here, we describe a poly(ethylene glycol) PEG hydrogel-based three-dimensional model for the co-culture of primary murine pulmonary fibroblasts and alveolar epithelial cells that reproduces the micro-architecture, cell placement, and mechanical properties of healthy and fibrotic lung tissue. Co-cultured cells retained normal levels of viability up to at least three weeks and displayed differentiation patterns observed in vivo during IPF progression. Interrogation of protein and gene expression within this model showed that myofibroblast activation required both extracellular mechanical cues and the presence of alveolar epithelial cells. Differences in gene expression indicated that cellular co-culture induced TGF-β signaling and proliferative gene expression, while microenvironmental stiffness upregulated the expression of genes related to cell-ECM interactions. This biomaterial-based cell culture system serves as a significant step forward in the accurate recapitulation of human lung tissue in vitro and highlights the need to incorporate multiple factors that work together synergistically in vivo into models of lung biology of health and disease.

Background: Numerous resting-state studies on attention deficit hyperactivity disorder (ADHD) have reported aberrant functional connectivity (FC) between the default-mode network (DMN) and the ventral attention/salience network (VA/SN). This finding has commonly been interpreted as an index of poorer DMN regulation associated with symptoms of mind wandering in ADHD literature. However, a competing perspective suggests that dysfunctional organization of the DMN and VA/SN may additionally index increased sensitivity to the external environment. The goal of the current study was to test this latter perspective in relation to auditory distraction by investigating whether ADHD-adults exhibit aberrant FC between DMN, VA/SN, and auditory networks., Methods: Twelve minutes of resting-state fMRI data was collected from two adult groups: ADHD ( n = 17) and controls ( n = 17); from which the FC between predefined regions comprising the DMN, VA/SN, and auditory networks were analyzed., Results: A weaker anticorrelation between the VA/SN and DMN was observed in ADHD. DMN and VA/SN hubs also exhibited aberrant FC with the auditory network in ADHD. Additionally, participants who displayed a stronger anticorrelation between the VA/SN and auditory network at rest, also performed better on a cognitively demanding behavioral task that involved ignoring a distracting auditory stimulus., Conclusion: Results are consistent with the hypothesis that auditory distraction in ADHD is linked to aberrant interactions between DMN, VA/SN, and auditory systems. Our findings support models that implicate dysfunctional organization of the DMN and VA/SN in the disorder and encourage more research into sensory interactions with these major networks., Competing Interests: AC had received speaker’s fees, and/or scientific advisory board compensation from Lundbeck, Indivior, DNE Pharma, and Camurus, all outside the scope of the current project. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Blomberg, Signoret, Danielsson, Perini, Rönnberg and Capusan.)

Idiopathic pulmonary fibrosis is a chronic disease characterized by progressive lung scarring that inhibits gas exchange. Evidence suggests fibroblast-matrix interactions are a prominent driver of disease. However, available preclinical models limit our ability to study these interactions. We present a technique for synthesizing phototunable poly(ethylene glycol) (PEG)-based hybrid-hydrogels comprising healthy or fibrotic decellularized extracellular matrix (dECM) to decouple mechanical properties from composition and elucidate their roles in fibroblast activation. Here, we engineered and characterized phototunable hybrid-hydrogels using molecular techniques such as ninhydrin and Ellman's assays to assess dECM functionalization, and parallel-plate rheology to measure hydrogel mechanical properties. These biomaterials were employed to investigate the activation of fibroblasts from dual-transgenic Col1a1-GFP and αSMA-RFP reporter mice in response to changes in composition and mechanical properties. We show that reacting functionalized dECM from healthy or bleomycin-injured mouse lungs with PEG alpha-methacrylate (αMA) in an off-stoichiometry Michael-addition reaction created soft hydrogels mimicking a healthy lung elastic modulus (4.99 ± 0.98 kPa). Photoinitiated stiffening increased the material modulus to fibrotic values (11.48 ± 1.80 kPa). Percent activation of primary murine fibroblasts expressing Col1a1 and αSMA increased by approximately 40% following dynamic stiffening of both healthy and bleomycin hybrid-hydrogels. There were no significant differences between fibroblast activation on stiffened healthy versus stiffened bleomycin-injured hybrid-hydrogels. Phototunable hybrid-hydrogels provide an important platform for probing cell-matrix interactions and developing a deeper understanding of fibrotic activation in pulmonary fibrosis. Our results suggest that mechanical properties are a more significant contributor to fibroblast activation than biochemical composition within the scope of the hybrid-hydrogel platform evaluated in this study., Supplementary Information: The online version contains supplementary material available at 10.1007/s12195-022-00726-y., Competing Interests: Conflict of interestDr. Magin is an inventor on a pending patent related to the technology described in this manuscript. All remaining authors (KSS, RH, PS, RB, BJS, SEN, BE, and DWHR) have no conflicts of interest to disclose., (© The Author(s) under exclusive licence to Biomedical Engineering Society 2022.)

Cognitive control provides us with the ability to inter alia , regulate the locus of attention and ignore environmental distractions in accordance with our goals. Auditory distraction is a frequently cited symptom in adults with attention deficit hyperactivity disorder (aADHD)-yet few task-based fMRI studies have explored whether deficits in cognitive control (associated with the disorder) impedes on the ability to suppress/compensate for exogenously evoked cortical responses to noise in this population. In the current study, we explored the effects of auditory distraction as function of working memory (WM) load. Participants completed two tasks: an auditory target detection (ATD) task in which the goal was to actively detect salient oddball tones amidst a stream of standard tones in noise, and a visual n -back task consisting of 0-, 1-, and 2-back WM conditions whilst concurrently ignoring the same tonal signal from the ATD task. Results indicated that our sample of young aADHD ( n = 17), compared to typically developed controls ( n = 17), had difficulty attenuating auditory cortical responses to the task-irrelevant sound when WM demands were high (2-back). Heightened auditory activity to task-irrelevant sound was associated with both poorer WM performance and symptomatic inattentiveness. In the ATD task, we observed a significant increase in functional communications between auditory and salience networks in aADHD. Because performance outcomes were on par with controls for this task, we suggest that this increased functional connectivity in aADHD was likely an adaptive mechanism for suboptimal listening conditions. Taken together, our results indicate that aADHD are more susceptible to noise interference when they are engaged in a primary task. The ability to cope with auditory distraction appears to be related to the WM demands of the task and thus the capacity to deploy cognitive control., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Blomberg, Johansson Capusan, Signoret, Danielsson and Rönnberg.)

Under adverse listening conditions, prior linguistic knowledge about the form (i.e., phonology) and meaning (i.e., semantics) help us to predict what an interlocutor is about to say. Previous research has shown that accurate predictions of incoming speech increase speech intelligibility, and that semantic predictions enhance the perceptual clarity of degraded speech even when exact phonological predictions are possible. In addition, working memory (WM) is thought to have specific influence over anticipatory mechanisms by actively maintaining and updating the relevance of predicted vs. unpredicted speech inputs. However, the relative impact on speech processing of deviations from expectations related to form and meaning is incompletely understood. Here, we use MEG to investigate the cortical temporal processing of deviations from the expected form and meaning of final words during sentence processing. Our overall aim was to observe how deviations from the expected form and meaning modulate cortical speech processing under adverse listening conditions and investigate the degree to which this is associated with WM capacity. Results indicated that different types of deviations are processed differently in the auditory N400 and Mismatch Negativity (MMN) components. In particular, MMN was sensitive to the type of deviation (form or meaning) whereas the N400 was sensitive to the magnitude of the deviation rather than its type. WM capacity was associated with the ability to process phonological incoming information and semantic integration., (Copyright © 2020 Signoret, Andersen, Dahlström, Blomberg, Lundqvist, Rudner and Rönnberg.)

Soil salinization is an increasing global threat to economically important agricultural crops such as bread wheat (Triticum aestivum L.). A main regulator of plants' responses to salt stress is WRKY transcription factors, a protein family that binds to DNA and alters the rate of transcription for specific genes. In this study, we identified 297 WRKY genes in the Chinese Spring wheat genome (Ensembl Plants International Wheat Genome Sequencing Consortium (IWGSC)), of which 126 were identified as putative. We classified 297 WRKY genes into three Groups: I, II (a-e) and III based on phylogenetic analysis. Principal component analysis (PCA) of WRKY proteins using physicochemical properties resulted in a very similar clustering as that observed through phylogenetic analysis. The 5` upstream regions (-2 000 bp) of 107 891 sequences from the wheat genome were used to predict WRKY transcription factor binding sites, and from this we identified 31 296 genes with putative WRKY binding motifs using the Find Individual Motif Occurrences (FIMO) tool. Among these predicted genes, 47 genes were expressed during salt stress according to a literature survey. Thus, we provide insight into the structure and diversity of WRKY domains in wheat and a foundation for future studies of DNA-binding specificity and for analysis of the transcriptional regulation of plants' response to different stressors, such as salt stress, as addressed in this study., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Obesity is a risk factor for multiple diseases, including diabetes, cardiovascular disease, and cancer. Within obese adipose tissue, multiple factors contribute to creating a disease-promoting environment, including metabolic dysfunction, inflammation, and fibrosis. Recent evidence points to fibrotic responses, particularly extracellular matrix remodeling, in playing a highly functional role in the pathogenesis of obesity. Fibroblast activation protein plays an essential role in remodeling collagen-rich matrices in the context of fibrosis and cancer. We observed that FAP-null mice have increased weight compared to wild-type controls, and so investigated the role of FAP in regulating diet-induced obesity. Using genetically engineered mouse models and in-vitro cell-derived matrices, we demonstrate that FAP expression by pre-adipocytes restrains adipogenic differentiation. We further show that FAP-mediated matrix remodeling alters lipid metabolism in part by regulating mTOR signaling. The impact of FAP on adipogenic differentiation and mTOR signaling together confers resistance to diet-induced obesity. The critical role of ECM remodeling in regulating obesity offers new potential targets for therapy., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The large body of research that forms the ease of language understanding (ELU) model emphasizes the important contribution of cognitive processes when listening to speech in adverse conditions; however, speech-in-noise (SIN) processing is yet to be thoroughly tested in populations with cognitive deficits. The purpose of the current study was to contribute to the field in this regard by assessing SIN performance in a sample of adolescents with attention deficit hyperactivity disorder (ADHD) and comparing results with age-matched controls. This population was chosen because core symptoms of ADHD include developmental deficits in cognitive control and working memory capacity and because these top-down processes are thought to reach maturity during adolescence in individuals with typical development. The study utilized natural language sentence materials under experimental conditions that manipulated the dependency on cognitive mechanisms in varying degrees. In addition, participants were tested on cognitive capacity measures of complex working memory-span, selective attention, and lexical access. Primary findings were in support of the ELU-model. Age was shown to significantly covary with SIN performance, and after controlling for age, ADHD participants demonstrated greater difficulty than controls with the experimental manipulations. In addition, overall SIN performance was strongly predicted by individual differences in cognitive capacity. Taken together, the results highlight the general disadvantage persons with deficient cognitive capacity have when attending to speech in typically noisy listening environments. Furthermore, the consistently poorer performance observed in the ADHD group suggests that auditory processing tasks designed to tax attention and working memory capacity may prove to be beneficial clinical instruments when diagnosing ADHD.

Fibroblast activation protein (FAP) is a cell-surface serine protease that acts on various hormones and extracellular matrix components. FAP is highly upregulated in a wide variety of cancers, and is often used as a marker for pro-tumorigenic stroma. It has also been proposed as a molecular target of cancer therapies, and, especially in recent years, a great deal of research has gone into design and testing of diverse FAP-targeted treatments. Yet despite this growing field of research, our knowledge of FAP's basic biology and functional roles in various cancers has lagged behind its use as a tumor-stromal marker. In this review, we summarize and analyze recent advances in understanding the functions of FAP in cancer, most notably its prognostic value in various tumor types, cellular effects on various cell types, and potential as a therapeutic target. We highlight outstanding questions in the field, the answers to which could shape preclinical and clinical studies of FAP.

Pancreatic ductal adenocarcinomas (PDAs) are desmoplastic and can undergo epithelial-to-mesenchymal transition to confer metastasis and chemoresistance. Studies have demonstrated that phenotypically and functionally distinct stromal cell populations exist in PDAs. Fibroblast activation protein-expressing (FAP-expressing) cells act to enhance PDA progression, while α-smooth muscle actin myofibroblasts can restrain PDA. Thus, identification of precise molecular targets that mediate the protumorigenic activity of FAP+ cells will guide development of therapy for PDA. Herein, we demonstrate that FAP overexpression in the tumor microenvironment correlates with poor overall and disease-free survival of PDA patients. Genetic deletion of FAP delayed onset of primary tumor and prolonged survival of mice in the KPC mouse model of PDA. While genetic deletion of FAP did not affect primary tumor weight in advanced disease, FAP deficiency increased tumor necrosis and impeded metastasis to multiple organs. Lineage-tracing studies unexpectedly showed that FAP is not only expressed by stromal cells, but can also be detected in a subset of CD90+ mesenchymal PDA cells, representing up to 20% of total intratumoral FAP+ cells. These data suggest that FAP may regulate PDA progression and metastasis in cell-autonomous and/or non-cell-autonomous fashions. Together, these data support pursuing FAP as a therapeutic target in PDA.

Linus Pauling established the conceptual framework for understanding and mimicking enzymes more than six decades ago. The notion that enzymes selectively stabilize the rate-limiting transition state of the catalysed reaction relative to the bound ground state reduces the problem of design to one of molecular recognition. Nevertheless, past attempts to capitalize on this idea, for example by using transition state analogues to elicit antibodies with catalytic activities, have generally failed to deliver true enzymatic rates. The advent of computational design approaches, combined with directed evolution, has provided an opportunity to revisit this problem. Starting from a computationally designed catalyst for the Kemp elimination--a well-studied model system for proton transfer from carbon--we show that an artificial enzyme can be evolved that accelerates an elementary chemical reaction 6 × 10(8)-fold, approaching the exceptional efficiency of highly optimized natural enzymes such as triosephosphate isomerase. A 1.09 Å resolution crystal structure of the evolved enzyme indicates that familiar catalytic strategies such as shape complementarity and precisely placed catalytic groups can be successfully harnessed to afford such high rate accelerations, making us optimistic about the prospects of designing more sophisticated catalysts.

Computational enzyme design has emerged as a promising tool for generating made-to-order biocatalysts. In addition to improving the reliability of the design cycle, current efforts in this area are focusing on expanding the set of catalyzed reactions and investigating the structure and mechanism of individual designs. Although the activities of de novo enzymes are typically low, they can be significantly increased by directed evolution. Analysis of their evolutionary trajectories provides valuable feedback for the design algorithms and can enhance our understanding of natural protein evolution., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Nucleophilic catalysis is a general strategy for accelerating ester and amide hydrolysis. In natural active sites, nucleophilic elements such as catalytic dyads and triads are usually paired with oxyanion holes for substrate activation, but it is difficult to parse out the independent contributions of these elements or to understand how they emerged in the course of evolution. Here we explore the minimal requirements for esterase activity by computationally designing artificial catalysts using catalytic dyads and oxyanion holes. We found much higher success rates using designed oxyanion holes formed by backbone NH groups rather than by side chains or bridging water molecules and obtained four active designs in different scaffolds by combining this motif with a Cys-His dyad. Following active site optimization, the most active of the variants exhibited a catalytic efficiency (k(cat)/K(M)) of 400 M(-1) s(-1) for the cleavage of a p-nitrophenyl ester. Kinetic experiments indicate that the active site cysteines are rapidly acylated as programmed by design, but the subsequent slow hydrolysis of the acyl-enzyme intermediate limits overall catalytic efficiency. Moreover, the Cys-His dyads are not properly formed in crystal structures of the designed enzymes. These results highlight the challenges that computational design must overcome to achieve high levels of activity.

A general approach for the computational design of enzymes to catalyze arbitrary reactions is a goal at the forefront of the field of protein design. Recently, computationally designed enzymes have been produced for three chemical reactions through the synthesis and screening of a large number of variants. Here, we present an iterative approach that has led to the development of the most catalytically efficient computationally designed enzyme for the Kemp elimination to date. Previously established computational techniques were used to generate an initial design, HG-1, which was catalytically inactive. Analysis of HG-1 with molecular dynamics simulations (MD) and X-ray crystallography indicated that the inactivity might be due to bound waters and high flexibility of residues within the active site. This analysis guided changes to our design procedure, moved the design deeper into the interior of the protein, and resulted in an active Kemp eliminase, HG-2. The cocrystal structure of this enzyme with a transition state analog (TSA) revealed that the TSA was bound in the active site, interacted with the intended catalytic base in a catalytically relevant manner, but was flipped relative to the design model. MD analysis of HG-2 led to an additional point mutation, HG-3, that produced a further threefold improvement in activity. This iterative approach to computational enzyme design, including detailed MD and structural analysis of both active and inactive designs, promises a more complete understanding of the underlying principles of enzymatic catalysis and furthers progress toward reliably producing active enzymes.

Several studies have documented that the failure of drivers to attend to the forward roadway for a period lasting longer than 2-3 s is a major cause of highway crashes. Moreover, several studies have demonstrated that novice drivers are more likely to glance away from the roadway than the experienced drivers for extended periods when attempting to do a task inside the vehicle. The present study examines the efficacy of a PC-based training programme (FOrward Concentration and Attention Learning, FOCAL) designed to teach novice drivers not to glance away forthese extended periods of time. A FOCAL-trained group was compared with a placebo-trained group in an on-road test, and the FOCAL-trained group made significantly fewer glances away from the roadway that were more than 2 s than the placebo-trained group. Other measures indicated an advantage for the FOCAL-trained group as well. Statement of relevance: Distracted driving is increasingly a problem, as cell phones, navigation systems, and other in-vehicle devices are introduced into the cabin of the automobile. A training programme is described that has beentested on the open road and can reduce the behaviours that lead to crashes caused by the distracted driving.

All programs assessing attention maintenance inside the vehicle have required eye trackers and either a driving simulator or a specially equipped field vehicle. Ideally, one would like a way to assess attention maintenance that could be implemented on a desktop PC. Additionally, one would like to have a program that could be used to train novice drivers to maintain their attention more safely on the forward roadway. An experiment was run (a) to determine whether a program FOCAL (Focused Concentration and Attention Learning) using a desktop PC could differentiate between the attention maintenance skills of novice and experienced drivers and (b) to determine whether a program that improved the hazard anticipation skills of novice drivers might also improve their attention maintenance skills. FOCAL was able to differentiate between the attention maintenance skills of novice and experienced drivers. However, hazard anticipation training did not improve the attention maintenance skills of the novice drivers.

Mercury is a ubiquitous pollutant that when absorbed is extremely toxic to a wide variety of biochemical processes. Mercury (II) is a strong, "invisible" poison that is rapidly absorbed by tissues of the intestinal tract, kidneys, and liver upon ingestion. In this study, a novel fluorescence-based biosensor is presented that allows for the direct monitoring of the uptake and distribution of the metal under noninvasive in vivo conditions. With the introduction of a cysteine residue at position 205, located in close proximity to the chromophore, the green fluorescent protein (GFP) from Aequorea victoria was converted into a highly specific biosensor for this metal ion. The mutant protein exhibits a dramatic absorbance and fluorescence change upon mercuration at neutral pH. Absorbance and fluorescence properties with respect to the metal concentration exhibit sigmoidal binding behavior with a detection limit in the low nanomolar range. Time-resolved binding studies indicate rapid subsecond binding of the metal to the protein. The crystal structures obtained of mutant eGFP205C indicate a possible access route of the metal into the core of the protein. To our knowledge, this engineered protein is a first example of a biosensor that allows for noninvasive and real-time imaging of mercury uptake in a living cell. A major advantage is that its expression can be genetically controlled in many organisms to enable unprecedented studies of tissue specific mercury uptake.

Evaluating board effectiveness is a highly subjective, individualized, and potentially powerful undertaking if pursued with the proper motivation and with the ownership of the board. In this article, the authors describe one successful approach to board self-evaluation pursued by the Albert Lea Medical Center, Mayo Health System, Minnesota. The authors share evaluation methodology as well as process and outcomes. Recommendations directed toward organizations considering the self-evaluation process are formed around three themes. First, engage your board and have them own the process. Second, engage your board in developing the evaluation methodology. Third, ensure accountability in the board and the senior organization leadership for action on self-assessment outcomes. Finally, the authors discuss board development as a functional responsibility of the board. In that context, they present self-evaluation as one opportunity for a board to tangibly embrace its education and development responsibilities.

The acquisition of private medical practices by large health care systems often results in the transition of the physician from self-employment to salaried employee. In order to be successful, new physicians must be socialized into the new environment, requiring both concrete information and cultural orientation. This Mayo Clinic study of recently hired physicians yielded information about both content and delivery mechanisms that will help in planning an integrated system of orientation experiences.

Health-care organizations have recognized the need to prepare physicians for various leadership and management positions within their own institutions. The demands of a dynamic health-care environment have created increased pressure for institutions to develop a larger cadre of physician leaders and managers among their staff, and this must be done cost-effectively and efficiently. In the past, physicians who wanted more education had to look beyond their practice to fulfill this need. Institutions have begun to create tailor-made programs for their physicians in order to meet the various needs of their staff regarding leadership and management. Herein we describe the educational initiatives undertaken in 1995 and 1996 to provide Mayo physicians with in-house leadership and management programming. A substantial number of institutions are answering the challenge for increased physician expertise in leadership and management through the development of their own in-house programs.

Health-care organizations have recognized the need to prepare physicians for various leadership and management positions within their own institutions. In the past, those who desired further education had to search beyond the boundaries of their practice to fulfill this need. The demands of a dynamic and changing health-care environment have created increased pressure on organizations to develop a larger cadre of physician leaders and managers among their staff and to accomplish this outcome in a cost-effective, efficient manner. This article examines the results from a survey of leading medical institutions on the existence of in-house leadership and management educational programming. It also documents the approaches used by the responding organizations and the content of their course work. Numerous institutions are accepting the challenge for increased physician expertise in leadership and management by developing their own in-house programs. Future directions for Mayo initiatives in succession planning will be obtained from this benchmark survey.

The lumbar and lower thoracic subarachnoid space of 26 human autopsy subjects was studied using rigid endoscopy, spinaloscopy. Fibrous attachments were found between nerve roots and/or nerve roots and the arachnoid membrane at least at one spinal level in 16 subjects. The appearance and density of the structures varied, and caused restriction of nerve root mobility in nine subjects. In three of them, the impeded mobility prevented the nerve root from yielding to the contact and pressure exerted either by the tip of the endoscope or by a spinal needle introduced into the subarachnoid space. In another three subjects, a distinct membranous structure was identified in the posterior midline of the subarachnoid space in the lower thoracic and upper lumbar regions. These findings may possibly be associated with the variation in the extent of subarachnoid block and to the development of isolated nerve root trauma in connection with this procedure.

Belt use among drivers traveling on limited access highways was observed before and after New York's mandatory seat belt use law. The results showed that high-speed drivers had lower belt use rates before the law and increased their belt use less in response to the law. Belt use rates before the law were 25%, 29%, and 28% for the high-, medium-, and low-speed groups as compared with 51%, 64%, and 57%, respectively, after the law. High-speed drivers also had inferior previous driving records, confirming their higher risk of motor vehicle crash involvement.

The lumbar subdural extraarachnoid space was examined by spinaloscopy in 15 autopsy subjects. Special attention was paid to the ease with which the space opened up and also to the extent of view achieved. In ten cases the space opened up with ease, in four cases with difficulty, and in one case it was not possible to establish the subdural space at all. The bevel of an 18-gauge Tuohy needle introduced into the subdural space could be visualized in eight of 13 cases. An epidural catheter was then passed through the Tuohy needle into the subdural space in eight cases and was visualized in six of them. Although care must be exercised in drawing conclusions for clinical epidural anesthesia from autopsy cases, this study confirms the possibility of placing both the bevel of a Tuohy needle and an epidural catheter in the subdural space. The results reemphasize the need for caution suggested by other reports regarding the possibility of subdural puncture in epidural anesthesia and subsequent injection of anesthetic solution into the subdural space.

Percutaneous epiduroscopy was performed in 10 patients with the aim of comparing the lumbar epidural space of the patients with the findings made earlier in autopsy subjects. The patients were scheduled for partial laminectomy for a herniated lumbar disc. A complete examination was possible in eight subjects. The extent of view was very limited. The epidural space opened up only temporarily as air was injected. The dura mater lay very close to the dorsal aspect of the epidural space and was attached to the flaval ligaments by a dorsomedian connective tissue band. The band was identified in all eight subjects and was found to cause a dorsal fold in the dura mater. An epidural catheter was introduced 2-5 cm into the space by midline puncture in four patients and by the paramedian approach in the other four. The catheter was visualized in two patients only when the paramedian approach was used. None of the midline catheters could be seen in the space. In 2 of the 10 subjects a moderate bleeding impaired the view and made complete examination impossible. Smaller bleeding occurred in three other subjects. The partial laminectomy performed one to two interspaces caudad to the level of endoscopy did not reveal any evidence of epidural bleeding in any subject. The postoperative course of all patients was uneventful.