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The International Mouse Phenotyping Consortium (IMPC) systematically produces and phenotypes mouse lines with presumptive null mutations to provide insight into gene function. The IMPC now uses the programmable RNA-guided nuclease Cas9 for its increased capacity and flexibility to efficiently generate null alleles in the C57BL/6N strain. In addition to being a valuable novel and accessible research resource, the production of 3313 knockout mouse lines using comparable protocols provides a rich dataset to analyze experimental and biological variables affecting in vivo gene engineering with Cas9. Mouse line production has two critical steps – generation of founders with the desired allele and germline transmission (GLT) of that allele from founders to offspring. A systematic evaluation of the variables impacting success rates identified gene essentiality as the primary factor influencing successful production of null alleles. Collectively, our findings provide best practice recommendations for using Cas9 to generate alleles in mouse essential genes, many of which are orthologs of genes linked to human disease. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Identify the improvement in diabetes performance measures and population-based clinical outcomes resulting from changes in care management processes (CMP) in primary care practices over 3 years. RESEARCH DESIGN AND METHODS: This repeated cross-sectional study tracked clinical performance measures for all diabetes patients seen in a cohort of 330 primary care practices in 2017 and 2019. Unit of analysis was patient-year with practice-level CMP exposures. Causal inference is based on dynamic changes in individual CMPs between years by practice. We used the Bayesian method to simultaneously estimate a five-outcome model: A1c, systolic and diastolic blood pressure, guideline-based statin use, and Optimal Diabetes Care (ODC). We control for unobserved time-invariant practice characteristics and secular change. We modeled correlation of errors across outcomes. Statistical significance was identified using 99% Bayesian credible intervals (analogous to P < 0.01). RESULTS: Implementation of 18 of 62 CMPs was associated with statistically significant improvements in patient outcomes. Together, these resulted in 12.1% more patients meeting ODC performance measures. Different CMPs affected different outcomes. Three CMPs accounted for 47% of the total ODC improvement, 68% of A1c decrease, 21% of SBP reduction, and 55% of statin use increase: 1) systems for identifying and reminding patients due for testing, 2) after-visit follow-up by a nonclinician, and 3) guideline-based clinician reminders for preventive services during a clinic visit. CONCLUSIONS: Effective quality improvement in primary care focuses on practice redesign that clearly improves diabetes outcomes. Tailoring CMP adoption in primary care provides effective improvement in ODC performance through focused changes in diabetes outcomes. [ABSTRACT FROM AUTHOR]

PURPOSE To learn how the highest-performing primary care practices manage change when implementing improvements to diabetes care delivery. METHODS We ranked a total of 330 primary care practices submitting practice management assessments and diabetes reports to the Understanding Infrastructure Transformation Effects on Diabetes study in 2017 and 2019 by Optimal Diabetes Care performance. We ranked practices from the top quartile by greatest annual improvement to capture dynamic change. Starting with the top performers, we interviewed practice leaders to identify their most effective strategies for managing change. Interview transcripts were qualitatively analyzed to identify change management strategies. Saturation occurred when no new strategies were identified over 2 consecutive interviews. RESULTS Ten of the top 13 practices agreed to interviews. We identified 199 key comments representing 48 key care management concepts. We also categorized concepts into 6 care management themes and 37 strategic approaches. We categorized strategic approaches into 13 distinct change management strategies. The most common strategies identified were (1) standardizing the care process, (2) performance awareness, (3) enhancing care teams, (4) health care organization participation, (5) improving reporting systems, (6) engaging staff and clinicians, (7) accountability for tasks, (8) engaging leadership, and (9) tracking change. Care management themes identified by most practices included proactive care, improving patient relationships, and previsit planning. CONCLUSIONS Top-performing primary care practices identify a similar group of strategies as important for managing change during quality improvement activities. Practices involved in diabetes improvement activities, and perhaps other chronic conditions, should consider adopting these change management strategies. [ABSTRACT FROM AUTHOR]

Genome editing with CRISPR-associated (Cas) proteins holds exceptional promise for "correcting" variants causing genetic disease. To realize this promise, off-target genomic changes cannot occur during the editing process. Here, we use whole genome sequencing to compare the genomes of 50 Cas9-edited founder mice to 28 untreated control mice to assess the occurrence of S. pyogenes Cas9-induced off-target mutagenesis. Computational analysis of whole-genome sequencing data detects 26 unique sequence variants at 23 predicted off-target sites for 18/163 guides used. While computationally detected variants are identified in 30% (15/50) of Cas9 gene-edited founder animals, only 38% (10/26) of the variants in 8/15 founders validate by Sanger sequencing. In vitro assays for Cas9 off-target activity identify only two unpredicted off-target sites present in genome sequencing data. In total, only 4.9% (8/163) of guides tested have detectable off-target activity, a rate of 0.2 Cas9 off-target mutations per founder analyzed. In comparison, we observe ~1,100 unique variants in each mouse regardless of genome exposure to Cas9 indicating off-target variants comprise a small fraction of genetic heterogeneity in Cas9-edited mice. These findings will inform future design and use of Cas9-edited animal models as well as provide context for evaluating off-target potential in genetically diverse patient populations. An analysis of off-target activities for 163 gRNAs in Cas9-edited mice shows that Cas9-induced mutagenesis is rare compared to natural genetic variation. [ABSTRACT FROM AUTHOR]

The goal of systems biology is to gain a network level understanding of how gene interactions influence biological states, and ultimately inform upon human disease. Given the scale and scope of systems biology studies, resource constraints often limit researchers when validating genome-wide phenomena and potentially lead to an incomplete understanding of the underlying mechanisms. Further, prioritization strategies are often biased towards known entities (e.g. previously studied genes/proteins with commercially available reagents), and other technical issues that limit experimental breadth. Here, heterogeneous biological information is modeled as an association graph to which a high-performance minimum dominating set solver is applied to maximize coverage across the graph, and thus increase the breadth of experimentation. First, we tested our model on retrieval of existing gene functional annotations and demonstrated that minimum dominating set returns more diverse terms when compared to other computational methods. Next, we utilized our heterogenous network and minimum dominating set solver to assist in the process of identifying understudied genes to be interrogated by the International Mouse Phenotyping Consortium. Using an unbiased algorithmic strategy, poorly studied genes are prioritized from the remaining thousands of genes yet to be characterized. This method is tunable and extensible with the potential to incorporate additional user-defined prioritizing information. The minimum dominating set approach can be applied to any biological network in order to identify a tractable subset of features to test experimentally or to assist in prioritizing candidate genes associated with human disease. [ABSTRACT FROM AUTHOR]

The generation of a comprehensive catalog of null alleles covering all protein-coding genes is the goal of the International Mouse Phenotyping Consortium. Over the past 20 years, significant progress has been made towards achieving this goal through the combined efforts of many large-scale programs that built an embryonic stem cell resource to generate knockout mice and more recently employed CRISPR/Cas9-based mutagenesis to delete critical regions predicted to result in frameshift mutations, thus, ablating gene function. The IMPC initiative builds on prior and ongoing work by individual research groups creating gene knockouts in the mouse. Here, we analyze the collective efforts focusing on the combined null allele resource resulting from strains developed by the research community and large-scale production programs. Based upon this pooled analysis, we examine the remaining fraction of protein-coding genes focusing on clearly defined mouse–human orthologs as the highest priority for completing the mutant mouse null resource. In summary, we find that there are less than 3400 mouse–human orthologs remaining in the genome without a targeted null allele that can be further prioritized to achieve our overall goal of the complete functional annotation of the protein-coding portion of a mammalian genome. [ABSTRACT FROM AUTHOR]

Objective: To identify the impact of changes surrounding certification as a patient‐centered medical home (PCMH) on outcomes for patients with diabetes. Study Setting: Minnesota legislation established mandatory quality reporting for patients with diabetes and statewide standards for certification as a PCMH. Patient‐level quality reporting data (2008‐2018) were used to study the impact of transition to a PCMH. Study Design: Achievement of Minnesota's optimal diabetes care standard—in aggregate and by component—was modeled for adult patients with Type 1 or Type 2 diabetes as a function of time relative to the year the patient's primary care practice achieved PCMH certification. Patients from uncertified practices were used to control for general trend. Practice‐level random effects captured time‐invariant characteristics of practices and the practices' average patient. Data Collection: Electronic health record data were submitted by 695 Minnesota practices capturing components of the quality standard: blood sugar control, cholesterol control, blood pressure control, nonsmoking status, and use of aspirin. Principal Findings: The first cohort of practices achieving PCMH certification (July 2010‐June 2014) showed statistically insignificant changes in optimal care. The next cohort of practices (July 2014‐June 2018) achieved larger, clinically meaningful increases in quality of care during the time prior to and following certification. Specifically, this second cohort of practices was estimated to achieve a 12.8 percentage‐point improvement (P <.001) in the predicted probability of providing optimal diabetes care over the period spanning 3 years before to 3 years after certification. Conclusions: Our results suggest that the initial cohort of certified practices was already performing at a high level before certification, perhaps requiring little change in their operations to achieve PCMH certification. The second cohort, on the other hand, made meaningful, quality‐improving changes in the years surrounding certification. Differences by cohort may partially explain the inconsistent PCMH impacts found in the literature. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to determine what strategies and factors are most important for high performance in the primary care of patients with diabetes.Methods: We performed a mixed-methods, cross-sectional, observational analysis of interviews and characteristics of primary care clinics in Minnesota and bordering areas. We compared strategies, facilitators, and barriers identified by 31 leaders of 17 clinics in high-, middle-, and low-performance quartiles on a standardized composite measure of diabetes outcomes for 416 of 586 primary care clinics. Semistructured interview data were combined with quantitative data regarding clinic performance and a survey of the presence of care management processes.Results: The interview analysis identified 10 themes providing unique insights into the factors and strategies characterizing the 3 performance groups. The main difference was the degree to which top-performing clinics used patient data to guide proactive and outreach methods to intensify treatment and monitor effect. Top clinics also appeared to view visit-based care management processes as necessary but insufficient, whereas all respondents regarded being part of a large system as mostly helpful.Conclusions: Top-performing clinic approaches to diabetes care differ from lower-performing clinics primarily by emphasizing data-driven proactive outreach to patients to intensify treatment. Although confirmatory studies are needed, clinical leaders should consider the value of this paradigm shift in approach to care. [ABSTRACT FROM AUTHOR]

Objective: The effective redesign of primary care delivery systems to improve diabetes care requires an understanding of which particular components of delivery consistently lead to better clinical outcomes. We identified associations between common systems of care management (SysCMs) and the frequency of meeting standardized performance targets for Optimal Diabetes Care (NQF#0729) in primary care practices.Research Design and Methods: A validated survey of 585 eligible family or general internal medicine practices seeing ≥30 adult patients with diabetes in or near Minnesota during 2017 evaluated the presence of 62 SysCMs. From 419 (72%) practices completing the survey, NQF#0729 was determined in 396 (95%) from electronic health records, including 215,842 patients with type 1 or type 2 diabetes.Results: Three SysCMs were associated with higher rates of meeting performance targets across all practices: 1) a systematic process for shared decision making with patients (P = 0.001), 2) checklists of tests or interventions needed for prevention or monitoring of diabetes (P = 0.002), and 3) physician reminders of guideline-based age-appropriate risk assessments due at the patient visit (P = 0.002). When all three were in place, an additional 10.8% of the population achieved recommended performance measures. In subgroup analysis, 15 additional SysCMs were associated with better care in particular types of practices.Conclusions: Diabetes care outcomes are better in primary care settings that use a patient-centered approach to systematically engage patients in decision making, remind physicians of age-appropriate risk assessments, and provide checklists for recommended diabetes interventions. Practice size and location are important considerations when redesigning delivery systems to improve performance. [ABSTRACT FROM AUTHOR]

Background: The ubiquity of electronic health records (EHR) offers an opportunity to observe trajectories of laboratory results and vital signs over long periods of time. This study assessed the value of risk factor trajectories available in the electronic health record to predict incident type 2 diabetes.Study Design and Methods: Analysis was based on a large 13-year retrospective cohort of 71,545 adult, non-diabetic patients with baseline in 2005 and median follow-up time of 8 years. The trajectories of fasting plasma glucose, lipids, BMI and blood pressure were computed over three time frames (2000-2001, 2002-2003, 2004) before baseline. A novel method, Cumulative Exposure (CE), was developed and evaluated using Cox proportional hazards regression to assess risk of incident type 2 diabetes. We used the Framingham Diabetes Risk Scoring (FDRS) Model as control.Results: The new model outperformed the FDRS Model (.802 vs .660; p-values <2e-16). Cumulative exposure measured over different periods showed that even short episodes of hyperglycemia increase the risk of developing diabetes. Returning to normoglycemia moderates the risk, but does not fully eliminate it. The longer an individual maintains glycemic control after a hyperglycemic episode, the lower the subsequent risk of diabetes.Conclusion: Incorporating risk factor trajectories substantially increases the ability of clinical decision support risk models to predict onset of type 2 diabetes and provides information about how risk changes over time. [ABSTRACT FROM AUTHOR]

Genome editing using the CRISPR/Cas9 RNA-guided endonuclease system has rapidly become a driving force for discovery in modern biomedical research. This simple yet elegant system has been widely used to generate both loss-of-function alleles and precision knock-in mutations using single-stranded donor oligonucleotides. Our CRISPRtools platform supports both of these applications in order to facilitate the use of CRISPR/Cas9. While there are several tools that facilitate CRISPR/Cas9 design and screen for potential off-target sites, the process is typically performed sequentially on single genes, limiting scalability for large-scale programs. Here, the design principle underlying gene ablation is based upon using paired guides flanking a critical region/exon of interest to create deletions. Guide pairs are rank ordered based upon published efficiency scores and off-target analyses, and reported in a concise format for downstream implementation. The exon deletion strategy simplifies characterization of founder animals and is the strategy employed for the majority of knockouts in the mouse. In proof-of-principle experiments, the effectiveness of this approach is demonstrated using microinjection and electroporation to introduce CRISPR/Cas9 components into mouse zygotes to delete critical exons. [ABSTRACT FROM AUTHOR]

Over the past 25 years, new techniques, new discoveries, and new ideas have profoundly impacted our understanding of deuterostome interrelationships and, ultimately, deuterostome evolution. During the late 1980s and early 1990s morphological cladistic analyses made predictions about both taxonomic history and homology, predictions that would be tested independent of the morphological characters themselves with the advent of molecular systematics, the rise of evolutionary developmental biology, and continued exploration of the fossil record. Thanks to these three areas of inquiry, we have gone from scenarios where animals like mobile enteropneust hemichordates and chordates were derived from sessile filter-feeding animals like modern lophophorates, echinoderms, and pterobranch hemichordates, to a new perspective where hemichordates are recognized as the nearest living relative of the echinoderms, and that vagile gill-bearing animals like Cambrian vetulicolians are seen-at least by some-as close to the deuterostome last common ancestor, with both sessility and filter-feeding convergent features of deuterostomes (e.g., echinoderm) and non-deuterostomes (e.g., lophophorates) alike. Although much of the backbone of the new deuterostome phylogeny is supported by multiple independent data sets, as are statements of homology of several different morphological characters, in particular the homology of gill slits across Deuterostomia, nonetheless, the next quarter century of study on this remarkable group of animals promises to be as equally illuminating and exciting as the past quarter century. [ABSTRACT FROM AUTHOR]

The article focuses on the benefits and inequities of improved diabetes care. Topics discussed include maximizing their health requires that we make the most of the ever-growing number of medications and devices that can be used to manage diabetes; and the advent of oral and injectable agents that include glucagon-like peptide 1 (GLP-1) receptor agonists and sodium glucose cotrans porter 2 (SGLT2) inhibitors now supplement an expanding list of reliable basal insulins.

The evolution of specialized cell‐types is a long‐standing interest of biologists, but given the deep time‐scales very difficult to reconstruct or observe. microRNAs have been linked to the evolution of cellular complexity and may inform on specialization. The endothelium is a vertebrate‐specific specialization of the circulatory system that enabled a critical new level of vasoregulation. The evolutionary origin of these endothelial cells is unclear. We hypothesized that Mir‐126, an endothelial cell‐specific microRNA may be informative. We here reconstruct the evolutionary history of Mir‐126. Mir‐126 likely appeared in the last common ancestor of vertebrates and tunicates, which was a species without an endothelium, within an intron of the evolutionary much older EGF Like Domain Multiple (Egfl) locus. Mir‐126 has a complex evolutionary history due to duplications and losses of both the host gene and the microRNA. Taking advantage of the strong evolutionary conservation of the microRNA among Olfactores, and using RNA in situ hybridization, we localized Mir‐126 in the tunicate Ciona robusta. We found exclusive expression of the mature Mir‐126 in granular amebocytes, supporting a long‐proposed scenario that endothelial cells arose from hemoblasts, a type of proto‐endothelial amoebocyte found throughout invertebrates. This observed change of expression of Mir‐126 from proto‐endothelial amoebocytes in the tunicate to endothelial cells in vertebrates is the first direct observation of the evolution of a cell‐type in relation to microRNA expression indicating that microRNAs can be a prerequisite of cell‐type evolution. Research Highlights: Direct observation of cell‐type evolution.High conservation of sequence enables for simple RISH experiment of expression.Mir‐126 follows the evolution of hematopoetic cells to endothelial cells. [ABSTRACT FROM AUTHOR]

Hedgehog (HH) signaling is essential for vertebrate and invertebrate embryogenesis. In Drosophila, feedback upregulation of the HH receptor Patched (PTC; PTCH in vertebrates), is required to restrict HH signaling during development. By contrast, PTCH1 upregulation is dispensable for early HH-dependent patterning in mice. Unique to vertebrates are two additional HH-binding antagonists that are induced by HH signaling, HHIP1 and the PTCH1 homologue PTCH2. Although HHIP1 functions semi-redundantly with PTCH1 to restrict HH signaling in the developing nervous system, a role for PTCH2 remains unresolved. Data presented here define a novel role for PTCH2 as a ciliary localized HH pathway antagonist. While PTCH2 is dispensable for normal ventral neural patterning, combined removal of PTCH2- and PTCH1-feedback antagonism produces a significant expansion of HH-dependent ventral neural progenitors. Strikingly, complete loss of PTCH2-, HHIP1- and PTCH1-feedback inhibition results in ectopic specification of ventral cell fates throughout the neural tube, reflecting constitutive HH pathway activation. Overall, these data reveal an essential role for liganddependent feedback inhibition of vertebrate HH signaling governed collectively by PTCH1, PTCH2 and HHIP1. [ABSTRACT FROM AUTHOR]

The CXCR4 chemokine receptor promotes survival of many different cell types. Here, we describe a previously unsuspected role forCXCR4 as a potent inducer of apoptosis in acute myeloid leukemia (AML) cell lines and a subset of clinical AML samples. We show that SDF-1, the sole ligand for CXCR4, induces the expected migration and ERK activation in the KG1a AML cell line transiently overexpressing CXCR4, but ERK activation did not lead to survival. Instead, SDF-1 treatment led via a CXCR4-dependent mechanism to apoptosis, as evidenced by increased annexin V staining, condensation of chromatin, and cleavage of both procaspase-3 and PARP. This SDF-1-induced death pathway was partially inhibited by hypoxia, which is often found in the bone marrow of AML patients. SDF-1-induced apoptosis was inhibited by dominant negative procaspase-9 but not by inhibition of caspase-8 activation, implicating the intrinsic apoptotic pathway. Further analysis showed that this pathway was activated by multiple mechanisms, including up-regulation of Bak at the level of mRNA and protein, stabilization of the Bak activator Noxa, and down-regulation of antiapoptotic Bcl-XL. Furthermore, adjusting expression levels of Bak, Bcl-XL, or Noxa individually altered the level of apoptosis in AML cells, suggesting that the combined modulation of these family members by SDF-1 coordinates their interplay to produce apoptosis. Thus, rather than mediating survival, SDF-1 may be a means to induce apoptosis of CXCR4-expressing AML cells directly in the SDF-1-rich bone marrow microenvironment if the survival cues of the bone marrow are disrupted. [ABSTRACT FROM AUTHOR]

The article presents a study that explores the goal of the electronic Primary Care Research Network (ePCRN) to enable the development of an electronic infrastructure to support clinical research activities in primary care practice-based research networks (PBRNs). It states that study designs and research processes from various studies were used in the study. Results of the study concluded the importance of the model in providing an important foundation in PBRN research activities.

Mood disorders are more frequent among people with HIV infection than among non-HIV-infected individuals of the same age, socioeconomic status, and HIV risks. They have been associated with worse adherence and clinical outcomes, yet remain underdiagnosed and undertreated in sub-Saharan Africa. We explored the relationship between mood disorders using the 10-item depression scale of the Centers for Epidemiological Studies (CES-D10) and the 22-item Impact of Events Scale-Revised (IES-R) for posttraumatic stress disorder, and a range of demographic and HIV-related variables among 252 consecutive subjects on antiretroviral therapy (ART). The study was conducted in the Genito-Urinary Medicine Clinic of the Medical Research Council's Gambia Unit. These screening tests were positive in 7% and 30%, respectively, of the patients, with higher scores (more depression or more post-traumatic stress) associated with female gender, more advanced WHO clinical stage, and lower Karnofsky Perfomance Scale rating. Higher CES-D10 scores were also seen among those on their second ART regimen. No relationship was seen with age, time on ART, viral load, or CD4 cell count. Compared to an earlier study at the same site in subjects prior to starting ART, the prevalence of depression in those stabilized on ART was dramatically reduced (by 34%, from 41%) while that of PTSD dropped less (by 13%, from 43%). Integrating the CES-D10 or a similar instrument into patient preparation for ART is recommended in order to identify those who may benefit from further mental health investigations, specific therapy, or closer follow-up during early ART. [ABSTRACT FROM AUTHOR]

Objective: The factors associated with the development of immune reconstitution inflammatory syndrome in HIV patients commencing antiretroviral therapy have not been fully elucidated. Using a longitudinal study design, this study addressed whether alteration in the levels of T regulatory cells contributed to the development of IRIS in a West African cohort of HIV-1 and HIV-2 patients. Seventy-one HIV infected patients were prospectively recruited to the study and followed up for six months. The patients were categorized as IRIS or non-IRIS cases following published clinical guidelines. The levels of T regulatory cells were measured using flow cytometry at baseline and all follow-up visits. Baseline cytokine levels of IL-2, IL- 6, IFN-γ, TNF-α, MIP-1β, IL-1, IL-12, IL-13, and IL-10 were measured in all patients. Results: Twenty eight percent of patients (20/71) developed IRIS and were predominantly infected with HIV-1. Patients developing IRIS had lower nadir CD4 T cells at baseline (p = 0.03) and greater CD4 T cell reconstitution (p = 0.01) at six months post-ART. However, the development of IRIS was not influenced by the levels of T regulatory cells. Similarly, baseline cytokine levels did not predict the onset of IRIS. Conclusion: The development of IRIS was not associated with differences in levels of T regulatory cells or baseline proinflammatory cytokines. [ABSTRACT FROM AUTHOR]

The article presents a case study on the electronic Primary Care Research Network (ePCRN) project funded by the U.S. National Institutes of Health which aims to facilitate clinical research using primary care electronic health records (EHRs). It explores the barriers to adoption of the prototype software and identified requirements needed to deliver clinical studies. It concludes that EHRs need to use sophisticated tools to capture and preserve clinical context in coded data and business models.

Previous studies have suggested that there are two signaling pathways leading from ligation of the Fas receptor to induction of apoptosis. Type I signaling involves Fas ligand-induced recruitment of large amounts of FADD (FAS-associated death domain protein) and procaspase 8, leading to direct activation of caspase 3, whereas type II signaling involves Bid-mediated mitochondrial perturbation to amplify a more modest death receptor-initiated signal. The biochemical basis for this dichotomy has previously been unclear. Here we show that type I cells have a longer half-life for Fas message and express higher amounts of cell surface Fas, explaining the increased recruitment of FADD and subsequent signaling. Moreover, we demonstrate that cells with type II Fas signaling (Jurkat or HCT-15) can signal through a type I pathway upon forced receptor overexpression and that shRNA-mediated Fas down- regulation converts cells with type I signaling (A498) to type II signaling. Importantly, the same cells can exhibit type I signaling for Fas and type II signaling for TRAIL (TNF-α- related apoptosis-inducing ligand), indicating that the choice of signaling pathway is related to the specific receptor, not some other cellular feature. Additional experiments revealed that up-regulation of cell surface death receptor 5 levels by treatment with 7- ethyl-10-hydroxy-camptothecin converted TRAIL signaling in HCT116 cells from type II to type I. Collectively, these results suggest that the type I/type II dichotomy reflects differences in cell surface death receptor expression. [ABSTRACT FROM AUTHOR]

The article discusses three discoveries in paleontology to help explain the Cambrian explosion. It relates the importance of microRNAs (miRNAs) in shaping metazoan macroevolution and a solution to the Cambrian conundrum. The new discoveries include the morphological variation in trilobites, the reduce of genetic noise by decreasing genic variation, and the continuous acquisition of miRNAs by the metazoan genomes. A graph that shows the evolutionary acquisition of miRNA family is also included.

OBJECTIVE -- The purpose of this study was to determine whether implementation of a multicomponent organizational intervention can produce significant change in diabetes care and outcomes in community primary care practices. RESEARCH DESIGN AND METHODS -- This was a group-randomized, controlled clinical trial evaluating the practical effectiveness of a multicomponent intervention (TRANSLATE) in 24 practices. The intervention included implementation of an electronic diabetes registry, visit reminders, and patient-specific physician alerts. A site coordinator facilitated previsit planning and a monthly review of performance with a local physician champion. The principle outcomes were the percentage of patients achieving target values for the composite of systolic blood pressure (SBP) < 130 mmHg, LDL cholesterol <100 mg/dl, and A1C <7.0% at baseline and 12 months. Six process measures were also followed. RESULTS -- Over 24 months, 69,965 visits from 8,405 adult patients with type 2 diabetes were recorded from 238 health care providers in 24 practices from 17 health systems. Diabetes process measures increased significantly more in intervention than in control practices, giving net increases as follows: foot examinations 35.0% (P < 0.0.001); annual eye examinations 25.9% (P < 0.001); renal testing 28.5% (P < 0.001); A1C testing 8.1% (P < 0.001); blood pressure monitoring 3.5% (P = 0.05); and LDL testing 8.6% (P < 0.001). Mean A1C adjusted for age, sex, and comorbidity decreased significantly in intervention practices (P < 0.02). At 12 months, intervention practices had significantly greater improvement in achieving recommended clinical values for SBP, A1C, and LDL than control clinics (P = 0.002). CONCLUSIONS -- Introduction of a multicomponent organizational intervention in the primary care setting significantly increases the percentage of type 2 diabetic patients achieving recommended clinical outcomes. [ABSTRACT FROM AUTHOR]

The plant-specific B3 superfamily encompasses well-characterized families, such as the auxin response factor (ARF) family and the LAV family, as well as less well understood families, such as RAV and REM. In Arabidopsis, there are 118 B3 genes, and in rice there are 91 B3 genes. The B3 domain is present in genes from gymnosperms, mosses and green algae, indicating that the B3 domain evolved on the plant lineage before multicellularity. The aim of this review is to phylogenetically characterize the members of the B3 family in Arabidopsis and rice and to review the function of the B3 genes that have been studied to date. [Copyright &y& Elsevier]

The article focuses on the study regarding the poriferan ANTP genes. It has been noted that in order to decide between the two competing hypotheses, primitively simple versus secondarily reduced. Furthermore, it is necessary to distinguish between the gene duplication events that gave rise to the individual paralogy groups versus the speciation events that led to extant demosponges and eumetazoans.

For more than a generation, molecular biology has been used to approach palaeontological problems, and yet only recently have attempts been made to integrate research utilizing the geological and genomic records in uncovering evolutionary history. We codify this approach as Molecular Palaeobiology for which we provide a synthetic framework for studying the interplay among genotype, phenotype and the environment, within the context of deep time. We provide examples of existing studies where molecular and morphological data have been integrated to provide novel insights within each of these variables, and an account of a case study where each variable has been tackled to understand better a single macroevolutionary event: the diversification of metazoan phyla. We show that the promise of this approach extends well beyond research into the evolutionary history of animals and, in particular, we single out plant evolution as the single greatest opportunity waiting to be exploited by molecular palaeobiology. Although most of our examples consider how novel molecular data and techniques have breathed new life into long-standing palaeontological controversies, we argue that this asymmetry in the balance of molecular and morphological evidence is an artefact of the relative ‘newness’ of molecular data. In particular, palaeontological data provide unique and crucial roles in unravelling evolutionary history given that extinct taxa reveal patterns of character evolution invisible to molecular biology. Finally, we argue that palaeobiologists, rather than molecular biologists, are best placed to exploit the opportunity afforded by molecular palaeobiology, though this will require incorporating the techniques and approaches of molecular biology into their skill-set. [ABSTRACT FROM AUTHOR]

Concentrations of P, phytic acid (myo-inositol hexakisphosphate, IP6), and other mineral storage elements were studied in wild-type and low phytic acid (lpa) genotype Js-12-LPA wheat (Triticum aestivum L.) embryos and rest-of-grain fractions. Environmental scanning electron microscopy images revealed a decreased average size and an increased number of aleurone layer globoids in lpa grains compared with the wild type. Energy-dispersive X-ray analyses of unfixed aleurone layer and scutellum cell cytoplasm revealed mainly C, O, P, K, and Mg in both grain types. The starchy endosperm contained virtually no P, K, or Mg, demonstrating no shift of mineral nutrients to that compartment. Scanning transmission electron microscopy – energy-dispersive X-ray analyses of scutellum and aleurone layer globoids in both genotypes revealed that P, K, and Mg were the main mineral nutrients in globoids with low amounts of Ca, Fe, and Zn. Traces of Mn were only in scutellum globoids. Total P was similar between genotypes for the rest-of-grain fractions, which are 97% of grain mass. The main inositol phosphate was IP6, but a small amount of IP5 was present. Both lpa grain fractions exhibited major reductions in IP6 compared with the wild type and a threefold increase in inorganic P. The concentration of K decreased in both fractions, while Ca increased 25% in the Js-12-LPA rest-of-grain compared with the wild type. The lack of large differences in mineral concentration and distribution between the wild type and Js-12-LPA indicates that there is no direct role of localization of IP6 synthesis in mineral distribution. [ABSTRACT FROM AUTHOR]

Many marine invertebrates have a complex life cycle in which the egg develops into an intermediate planktic larval form rather than developing directly to the benthic juvenile stage. Because of the evolutionary and ecological complexity of pelagic-benthic life cycles, the reasons behind the origin of larvae and their subsequent maintenance over geological time are not well understood. Using both a molecular clock and the fossil record, I show that the initial exploitation of the predator-free pelagic realm by lecithotrophic larvae was achieved independently multiple times by the end of the Early Cambrian, and that the convergent evolution of planktotrophy from lecithotrophic ancestors evolved between the latest Cambrian and Middle Ordovician at least four, and possibly as many as eight, times. Both the exploitation of the pelagic realm by nonfeeding larvae and the acquisition of planktotrophy correlate in time with novel modes of benthic predation, including the dramatic rise in the number and type of epifaunal suspension feeders in the Early Ordovician. [ABSTRACT FROM AUTHOR]

The phylogenetic relationships of nine species of freshwater sponges, representing the families Spongillidae, Lubomirskiidae, and Metaniidae, were inferred from analyses of 18S rDNA, cytochrome oxidase subunit I (COI) mtDNA, and internal transcribed spacer 2 (ITS2) rDNA sequences. These species form a strongly supported monophyletic group within the Demospongiae, with the lithistid Vetulina stalactites as the sister taxon. Within the freshwater sponge clade, the basal taxon is not resolved. Depending upon the method of analysis and sequence, the metaniid species, Corvomeyenia sp., or the spongillid species, Trochospongilla pennsylvanica, emerges as the basal species. Among the remaining freshwater sponge species, the spongillids, Spongilla lacustris and Eunapius fragilis, form a sister group to a clade comprised of the spongillid species, Clypeatula cooperensis, Ephydatia fluviatilis, and Ephydatia muelleri, and the lubomirskiid species, Baikalospongia bacillifera and Lubomisrkia baicalensis. C. cooperensis is the sister taxon of E. fluvialitis, and E. muelleri is the sister taxon of ( B. bacillifera+ L. baicalensis). The family Spongillidae and the genus Ephydatia are thus paraphyletic with respect to the lubomirskiid species; Ephydatia is also paraphyletic to C. cooperensis. We suggest that C. cooperensis be transferred to the genus Ephydatia and that the family Lubomirskiidae be subsumed into the Spongillidae. [ABSTRACT FROM AUTHOR]

Molecular clocks have the potential to shed light on the timing of early metazoan divergences, but differing algorithms and calibration points yield conspicuously discordant results. We argue here that competing molecular clock hypotheses should be testable in the fossil record, on the principle that fundamentally new grades of animal organization will have ecosystem-wide impacts. Using a set of seven nuclear-encoded protein sequences, we demonstrate the paraphyly of Porifera and calculate sponge/eumetazoan and cnidarian/bilaterian divergence times by using both distance [minimum evolution (ME)] and maximum likelihood (ML) molecular clocks; ME brackets the appearance of Eumetazoa between 634 and 604 Ma, whereas ML suggests it was between 867 and 748 Ma. Significantly, the ME, but not the ML estimate is coincident with a major regime change in the Proterozoic acritarch record, including: (i) disappearance of low-diversity, evolutionarily static, pre-Ediacaran acanthomorphs; (ii) radiation of the high-diversity, short-lived Doushantuo-pertatataka microbiota; and (ii,) an order-of-magnitude increase in evolutionary turnover rate. We interpret this turnover as a consequence of the novel ecological challenges accompanying the evolution of the eumetazoan nervous system and gut Thus, the more readily preserved microfossil record provides positive evidence for the absence of pre-Ediacaran eumetazoans and strongly supports the veracity, and therefore more general application, of the ME molecular clock. [ABSTRACT FROM AUTHOR]

Purpose: We wanted to describe the emerging role of primary care practice-based in research, quality improvement (QI), and translation of research into practice (TRIP).Methods: We gathered information from the published literature, discussions with PBRN leaders, case examples, and our own personal experience to describe a role for PBRNs that comfortably bridges the gap between research and QI, discovery and application, academicians and practitioners--a role that may lead to the establishment of true learning communities. We provide specific recommendations for network directors, network clinicians, and other potential stakeholders.Results: PBRNs function at the interface between research and QI, an interface called TRIP by some members of the research community. In doing so, PBRNs are helping to clarify the difficulty of applying study findings to everyday care as an inappropriate disconnect between discovery and implementation, research and practice. Participatory models are emerging in which stakeholders agree on their goals; apply their collective knowledge, skills, and resources to accomplish these goals; and use research and QI methods when appropriate.Conclusions: PBRNs appear to be evolving from clinical laboratories into learning communities, proving grounds for generalizable solutions to clinical problems, and engines for improvement of primary care delivery systems. [ABSTRACT FROM AUTHOR]

Because of their importance for proper development of the bilaterian embryo, Hox genes have taken center stage for investigations into the evolution of bilaterian metazoans. Taxonomic surveys of major protostome taxa have shown that Hox genes are also excellent phylogenetic markers, as specific Hox genes are restricted to one of the two great protostome clades, the Lophotrochozoa or the Ecdysozoa, and thus support the phylogenetic relationships as originally deduced by 18S rDNA studies. Deuterostomes are the third major group of bilaterians and consist of three major phyla, the echinoderms, the hemichordates, and the chordates. Most morphological studies have supported Hemichordata + Chordata, whereas molecular studies support Echinodermata + Hemichordata, a clade known as Ambulacraria. To test these competing hypotheses, complete or near complete cDNAs of eight Hox genes and four Parahox genes were isolated from the enteropneust hemichordate Ptychodera flava. Only one copy of each Hox gene was isolated suggesting that the Hox genes of P. flava are arranged in a single cluster. Of particular importance is the isolation of three posterior or Abd-B Hox genes; these genes are only shared with echinoderms, and thus support the monophyly of Ambulacraria. [Copyright &y& Elsevier]

Accurately dating when the first bilaterally symmetrical animals arose is crucial to our understanding of early animal evolution. The earliest unequivocally bilaterian fossils are &ap;555 million years old. In contrast molecular-clock analyses calibrated by using the fossil record of vertebrates estimate that vertebrates split from dipterans (Drosophila) &ap; 900 million years ago (Ma). Nonetheless, comparative genomic analyses suggest that a significant rate difference exists between vertebrates and dipterans, because the percentage difference between the genomes of mosquito and fly is greater than between fish and mouse, even though the vertebrate divergence is almost twice that of the dipteran. Here we show that the dipteran rate of molecular evolution is similar to other invertebrate taxa (echinoderms and bivalve molluscs) but not to vertebrates, which significantly decreased their rate of molecular evolution with respect to invertebrates. Using a data set consisting of the concatenation of seven different amino acid sequences from 23 in- group taxa (giving a total of 11 different invertebrate calibration points scattered throughout the bilaterian tree and across the Phanerozoic) we estimate that the last common ancestor of bilaterians arose somewhere between 573 and 656 Ma, depending on the value assigned to the parameter scaling molecular substitution rate heterogeneity. These results are in accord with the known fossil record and support the view that the Cambrian explosion reflects, in part, the diversification of bilaterian phyla. [ABSTRACT FROM AUTHOR]

Genetic studies using a set of overlapping deletions centered at the piebald locus on distal mouse chromosome 14 have defined a genomic region associated with respiratory distress and lethality at birth. We have isolated and characterized the candidate gene Phr1 that is located within the respiratory distress critical genomic interval. Phr1 is the ortholog of the human Protein Associated with Myc as well as Drosophila highwire and Caenorhabditis elegans regulator of presynaptic morphology 1. Phr1 is expressed in the embryonic and postnatal nervous system. In mice lacking Phr1, the phrenic nerve failed to completely innervate the diaphragm. In addition, nerve terminal morphology was severely disrupted, comparable with the synaptic defects seen in the Drosophila hiw and C. elegans rpm-1 mutants. Although intercostal muscles were completely innervated, they also showed dysmorphic nerve terminals. In addition, sensory neuron terminals in the diaphragm were abnormal. The neuromuscular junctions showed excessive sprouting of nerve terminals, consistent with inadequate presynaptic stimulation of the muscle. On the basis of the abnormal neuronal morphology seen in mice, Drosophila, and C. elegans, we propose that Phr1 plays a conserved role in synaptic development and is a candidate gene for respiratory distress and ventilatory disorders that arise from defective neuronal control of breathing. [ABSTRACT FROM AUTHOR]

Proposes that some of the more conspicuous Ediacaran fossils from the Avalon Peninsula of Newfoundland were biologically similar to members of the Kingdom Fungi. Comparisons between the Ediacaran organisms and extant taxa; Relationship between the fossils and microbial mats; Identification of fungal-specific biomarkers.

Several developmentally important genomic regions map within the piebald deletion complex on distal mouse chromosome 14. We have combined computational gene prediction and comparative sequence analysis to characterize an ∼4.3-Mb segment of the piebald region to identify candidate genes for the phenotypes presented by homozygous deletion mice. As a result we have ordered 13 deletion breakpoints, integrated the sequence with markers from a bacterial artificial chromosome (BAC) physical map, and identified 16 known or predicted genes and >1500 conserved sequence elements (CSEs) across the region. The candidate genes identified include Phr1 (formerly Pam) and Spry2, which are mouse homologs of genes required for development in Drosophila melanogaster. Gene content, order, and position are highly conserved between mouse chromosome 14 and the orthologous region of human chromosome 13. Our studies combining computational gene prediction with genetic and comparative genomic analyses provide insight regarding the functional composition and organization of this defined chromosomal region. [Copyright &y& Elsevier]

Molecular and paleontological data provide independent means of estimating when groups of organisms evolved in the geological past, but neither approach can be considered straightforward. The single most fundamental obstacle to developing an accurate estimate of times of origination from gene sequence data is variation in rates of molecular evolution, both through time and among lineages. Although various techniques have been proposed to circumvent this problem, none unambiguously allow the components of time and rate to be separated. Furthermore, problems of establishing accurate calibration points, correctly rooted phylogenies, and accurate estimates of branch length remain formidable. Conversely, paleontological dates fix only the latest possible time of divergence, and so probabilistic methods are required to set a lower boundary on origination dates. Realistic confidence intervals that take preservational biases into account are only just becoming available. Although molecular and paleontological approaches to dating often agree reasonably well, there are two notable areas of disagreement; when mammal and bird orders originated and when the major phyla originated. The discrepancy in dating bird/mammal ordinal origins probably reflects a global rock-record bias. Paleontological sampling in the Late Cretaceous is still too restricted geographically to draw any firm conclusions about the existence of a pre-Tertiary record for modern orders of bird or mammal from anywhere other than North America. Dating the time of origin of phyla is more complicated, and is confounded by both preservational biases and problems of molecular clock estimation. [ABSTRACT FROM AUTHOR]

SUMMARY Insight into the origin and early evolution of the animal phyla requires an understanding of how animal groups are related to one another. Thus, we set out to explore animal phylogeny by analyzing with maximum parsimony 138 morphological characters from 40 metazoan groups, and 304 18S rDNA sequences, both separately and together. Both types of data agree that arthropods are not closely related to annelids: the former group with nematodes and other molting animals (Ecdysozoa), and the latter group with molluscs and other taxa with spiral cleavage. Furthermore, neither brachiopods nor chaetognaths group with deuterostomes; brachiopods are allied with the molluscs and annelids (Lophotrochozoa), whereas chaetognaths are allied with the ecdysozoans. The major discordance between the two types of data concerns the rooting of the bilaterians, and the bilaterian sister-taxon. Morphology suggests that the root is between deuterostomes and protostomes, with ctenophores the bilaterian sister-group, whereas 18S rDNA suggests that the root is within the Lophotrochozoa with acoel flatworms and gnathostomulids as basal bilaterians, and with cnidarians the bilaterian sister-group. We suggest that this basal position of acoels and gnathostomulids is artifactal because for 1000 replicate phylogenetic analyses with one random sequence as outgroup, the majority root with an acoel flatworm or gnathostomulid as the basal ingroup lineage. When these problematic taxa are eliminated from the matrix, the combined analysis suggests that the root lies between the deuterostomes and protostomes, and Ctenophora is the bilaterian sister-group. We suggest that because chaetognaths and lophophorates, taxa traditionally allied with deuterostomes, occupy basal positions within their respective protostomian clades, deuterostomy most likely represents a suite of characters plesiomorphic for bilaterians. [ABSTRACT FROM AUTHOR]

Describes Clypeatula cooperensis, a genus and species of freshwater sponge from the Rocky Mountains of Montana. Phylogenetic analysis of ribosomal DNA sequences; Morphological and ecological characteristics; Sexual reproduction.

Presents information on a study which assessed Hox complex expression in the indirect development of the polychaete annelid Chaetopterus sp. Preparation of probes; Expression of the Chaetopterus Hox gene complex; Results and discussion.

Deals with the regulatory evolution of bilaterians. Pattern formation in the morphogenesis of adult bilaterian body plans; Embryonic specification; Phylogeny of basal metazoans; Relations between metazoans and bilaterians.

SUMMARY Even though echinoderms are members of the Bilateria, the location of their anterior/posterior axis has remained enigmatic. Here we propose a novel solution to the problem employing three lines of evidence: the expression of a posterior class Hox gene in the coeloms of the nascent adult body plan within the larva; the anatomy of certain early fossil echinoderms; and finally the relation between endoskeletal plate morphology and the associated coelomic tissues. All three lines of evidence converge on the same answer, namely that the location of the adult mouth is anterior, and the anterior/posterior axis runs from the mouth through the adult coelomic compartments. This axis then orients the animal such that there is but a single plane of symmetry dividing the animal into left and right halves. We tentatively hypothesize that this plane of symmetry is positioned along the dorsal/ventral axis. These axis identifications lead to the conclusion that the five ambulacra are not primary body axes, but instead are outgrowths from the central anterior/posterior axis. These identifications also shed insight into several other evolutionary mysteries of various echinoderm clades such as the independent evolution of bilateral symmetry in irregular echinoids, but do not elucidate the underlying mechanisms of the adult coelomic architecture. [ABSTRACT FROM AUTHOR]

PURPOSE To learn whether the COVID-19 pandemic's disruptions and associated reduced health outcomes for people with chronic conditions might have been caused by a decrease in care management processes (CMPs) in primary care clinics. METHODS Longitudinal cohort design with repeated survey-based measures of CMPs from 2017, 2019, and 2021 in 269 primary care clinics in Minnesota. RESULTS There were only small differences in organizational characteristics and no differences in overall CMPs between the 269 clinics analyzed and the 287 that only completed surveys in 1 or 2 years. Overall CMP scores rose by similar amounts (1.6% and 2.1%) from 2017 to 2019 and from 2019 to 2021. In 2021, CMP scores were lower in small medical groups than in large medical groups in 2017 (66.1% vs 78.5%, P <.001), a similar difference to that in 2017. Care management process scores were also lower in clinics in urban areas compared with rural areas (73.9% vs 79.0%, P <.001), but overall scores in all subgroups were higher in 2021 than in 2017. This improvement occurred despite reports from 55% of clinic leaders that the pandemic had been very or extremely disruptive. CONCLUSIONS Although quite disrupted by the pandemic, care management processes for chronic disease care in these resilient primary care clinics actually increased from 2019 to 2021, at least in clinics that were part of large organizations. However, that was not true for clinics from smaller groups and perhaps for other areas of care. [ABSTRACT FROM AUTHOR]

Objective: To learn how high performing primary care practices organized care for patients with diabetes during the initial months of the COVID-19 pandemic. Participants and methods: Semi-structured interviews were conducted between August 10 and December 10, 2020 with 16 leaders from 11 practices that had top quartile performance measures for diabetes outcomes pre-COVID. Each clinic had completed a similar interview and a survey about the existence of care management systems associated with quality outcomes before the pandemic. Transcript analysis utilized a theoretical thematic analysis at the semantic level. Results: The pandemic disrupted the primary care practices' operations and processes considered important for quality prior to the pandemic, particularly clinic reliance on proactive patient care. Safety concerns resulted from the shift to virtual visits, which produced documentation gaps and led practices to reorder their use of proactive patient care processes. Informal interactions with patients also declined. These practices' challenges were mitigated by technical, informational and operational help from the larger organizations of which they were a part. Care management processes had to accommodate both in-person and virtual visits. Conclusion: These high performing practices demonstrated an ability to adapt their use of proactive patient care processes in pursuing quality outcomes for patients with diabetes during the pandemic. Continued clinic transformation and improvements in quality within primary care depend on the ability to restructure the responsibilities of care team members and their interactions with patients. [ABSTRACT FROM AUTHOR]

The BAF chromatin remodeler regulates lineage commitment including cranial neural crest cell (CNCC) specification. Variants in BAF subunits cause Coffin-Siris syndrome (CSS), a congenital disorder characterized by coarse craniofacial features and intellectual disability. Approximately 50% of individuals with CSS harbor variants in one of the mutually exclusive BAF subunits, ARID1A/ARID1B. While Arid1a deletion in mouse neural crest causes severe craniofacial phenotypes, little is known about the role of ARID1A in CNCC specification. Using CSS-patient-derived ARID1A +/− induced pluripotent stem cells to model CNCC specification, we discovered that ARID1A -haploinsufficiency impairs epithelial-to-mesenchymal transition (EMT), a process necessary for CNCC delamination and migration from the neural tube. Furthermore, wild-type ARID1A-BAF regulates enhancers associated with EMT genes. ARID1A-BAF binding at these enhancers is impaired in heterozygotes while binding at promoters is unaffected. At the sequence level, these EMT enhancers contain binding motifs for ZIC2, and ZIC2 binding at these sites is ARID1A-dependent. When excluded from EMT enhancers, ZIC2 relocates to neuronal enhancers, triggering aberrant neuronal gene activation. In mice, deletion of Zic2 impairs NCC delamination, while ZIC2 overexpression in chick embryos at post-migratory neural crest stages elicits ectopic delamination from the neural tube. These findings reveal an essential ARID1A-ZIC2 axis essential for EMT and CNCC delamination. [Display omitted] ARID1A modulates chromatin accessibility at enhancers of genes required for epithelial-to-mesenchymal transition, a process essential for cranial neural crest cell (CNCC) specification. Haploinsufficiency of ARID1A attenuates ZIC2 binding at these enhancers, resulting in impaired CNCC formation with an aberrant neuronal trajectory. This study reveals an ARID1A-ZIC2 axis essential for CNCC specification. [ABSTRACT FROM AUTHOR]

Although previous work suggests that high performing practices focus on proactive patient outreach, the specific care management processes (CMP) that improve diabetes outcomes remain unclear. We evaluated 60 CMP from a state-wide practice survey in 2017 and 2019. Previously validated, the survey included 586 practices in 2017 (71% response, N=415) and 627 practices in 2019 (71% response, N= 445). Electronic health record data for A1c, blood pressure (BP), and lipid management were extracted for all patients with type 1 or type 2 diabetes in the practices. The longitudinal data set included 395 practices providing care to 204,745 patients. We used a longitudinal Bayesian model to correlate CMPs with A1c, systolic/diastolic BP, and probability of taking a statin. Patient outcomes were controlled for age, sex, diabetes type, insurance, comorbidity, community-level race-ethnicity, wealth, education, and income. Practices were controlled for rurality, size, FQHC status, system size, and practice-level random effects. Significance was reduced to <.01 for multiple comparisons. Although 7 CMPs significantly improved the overall diabetes performance measures for an average practice, CMPs affected individual outcomes differently. A1c improved by: 1) implementing a systematic approach to identifying and reminding patients when they were due for testing, and 2) having a nurse or care manager provide after visit follow up. BP was reduced by: 1, 2, and 3) tracking lab tests, 4) using checklists in the practice for required testing, and 5) guideline based reminders for preventive services. Statin use increased by: 5, and 6) screening for substance-abuse, and 7) a formal process for measuring performance. Together, CMPs with a statistically significant impact on performance measures accounted for a drop in average A1c in a practice from 7.39 to 7.25 (P<.01) BP from 127/75 to 121/71 (P<.01) and a 3.9% (P<.01) statin use increase. CMP 1 and 2 exemplify specific proactive patient outreach processes proven to improve diabetes care delivery. Disclosure: K. A. Peterson: Board Member; Self; Treatment.com International Inc. C. Carlin: None. L. Solberg: None. M. Eder: None. Funding: National Institutes of Health (R18DK110732) [ABSTRACT FROM AUTHOR]

Although the primary care office is an important location for integrating new advances in the treatment of diabetes, the current delivery of preventive primary care for patients with diabetes falls short of clinical recommendations. Barriers within the existing health care system, practice structure, and physician and patient support services are among the most commonly cited obstacles to Initiating better preventive care. As public health groups demand greater accountability from the medical system, regulatory efforts focus more scrutiny on systems, clinic practices, and even individual physician practices. Although Improving care delivery effectively and efficiently is difficult, strategies do exist that can increase the likelihood of improving patient outcomes. Successful diabetes initiatives are often characterized by the consensual adoption of an evidence-based treatment plan. Effective physician-oriented interventions include the use of reminder systems, local opinion leaders, and academic detailing. In addition, several national diabetes initiatives are likely to influence primary care practice. New measures of accountability will be widely used to determine the quality of primary diabetes care delivery. [ABSTRACT FROM AUTHOR]

Presents a study which examined the thermodynamics involving the ligand binding and catalysis within the human liver medium-chain acyl-CoA dehydrogenase. Performance of the isothermal calorimetric experiments; Revelation of a comparison between the amino acid sequence of pig liver and human liver medium-chain acyl-CoA dehydrogenases (MCADs); Suggestion of crystallographic data.