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Dynamic relationship of cycle length to reentrant circuit geometry and to the slow conduction zone during ventricular tachycardia.

BACKGROUND: Knowledge of cycle-to-cycle changes in isthmus geometry is of potential importance for radiofrequency catheter ablation to stop reentrant ventricular tachycardia. It was hypothesized that isthmus geometry often undergoes continuous evolution throughout reentry and that cycle-length variability measurements could be used to segment reentry into distinct phases and to predict changes in isthmus geometry. METHODS AND RESULTS: A canine infarct model of reentrant ventricular tachycardia in the epicardial border zone with a figure 8 pattern of conduction was used for analysis (25 monomorphic reentry episodes, 20 experiments). Tachycardias were segmented, on the basis of cycle-length variations, into 2 to 3 distinct phases corresponding to onset, maintenance, and spontaneous termination, when it occurred (6/25 episodes). Trends of linear cycle-length change occurred throughout the maintenance phase in all tachycardias. For each trend, quantitative geometric parameters of the isthmus were measured, and the following linear relationships were established. During a trend, the slow conduction zone activation interval and tachycardia cycle length increased, while isthmus length decreased. When isthmus length decreased, isthmus width decreased at its narrowed portion. Larger decreases in isthmus length corresponded to higher rates of linear cycle-length prolongation. Also, greater cycle-length variability tended to prolong tachycardia. CONCLUSIONS: Cycle-length alterations occur throughout reentry in this canine model and are predictive of isthmus geometry changes. Because similar reentry dynamics, which affect catheter ablation efficacy, have been observed clinically, estimation of changes in geometry during electrophysiological study may help target ablation sites.

Animals↗

Role and results of surgery in acute type B aortic dissection: insights from the International Registry of Acute Aortic Dissection (IRAD).

BACKGROUND: The clinical profiles and outcomes of patients treated surgically for acute type B aortic dissection (ABAD) are often reported for those in small series or for those cared for at a single institution over a long time period, during which a continuous evolution in techniques has occurred. Accordingly, we sought to evaluate the clinical features and surgical results of patients enrolled in the International Registry of Acute Aortic Dissection by identifying primary factors that influenced surgical outcome and estimating average surgical mortality for ABAD in the current era. METHODS AND RESULTS: A comprehensive analysis of 290 clinical variables and their relation to surgical outcomes for 82 patients who required surgery for ABAD (from a population of 1256 patients; mean+/-SD age, 60.6+/-15.0 years; 82.9% male) and who were enrolled in the International Registry of Acute Aortic Dissection was performed. The overall in-hospital mortality was 29.3%. Factors associated with increased surgical mortality based on univariate analysis were preoperative coma or altered consciousness, partial thrombosis of the false lumen, evidence of periaortic hematoma on diagnostic imaging, descending aortic diameter >6 cm, right ventricle dysfunction at surgery, and shorter time from the onset of symptoms to surgery. Factors associated with favorable outcomes included radiating pain, normotension at surgery (systolic blood pressure 100 to 149 mm Hg), and reduced hypothermic circulatory arrest time. The 2 independent predictors of surgical mortality were age >70 years (odds ratio, 4.32; 95% confidence interval, 1.30 to 14.34) and preoperative shock/hypotension (odds ratio, 6.05; 95% confidence interval, 1.12 to 32.49). CONCLUSIONS: The present study provides insights into current-day clinical profiles and surgical outcomes of ABAD. Knowledge about different preoperative clinical conditions may help surgeons in making treatment decisions among these high-risk patients.

Acute Disease↗

Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America.

BACKGROUND: Despite advances in medical, surgical, and critical care interventions, infective endocarditis remains a disease that is associated with considerable morbidity and mortality. The continuing evolution of antimicrobial resistance among common pathogens that cause infective endocarditis creates additional therapeutic issues for physicians to manage in this potentially life-threatening illness. METHODS AND RESULTS: This work represents the third iteration of an infective endocarditis "treatment" document developed by the American Heart Association under the auspices of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease of the Young. It updates recommendations for diagnosis, treatment, and management of complications of infective endocarditis. A multidisciplinary committee of experts drafted this document to assist physicians in the evolving care of patients with infective endocarditis in the new millennium. This extensive document is accompanied by an executive summary that covers the key points of the diagnosis, antimicrobial therapy, and management of infective endocarditis. For the first time, an evidence-based scoring system that is used by the American College of Cardiology and the American Heart Association was applied to treatment recommendations. Tables also have been included that provide input on the use of echocardiography during diagnosis and treatment of infective endocarditis, evaluation and treatment of culture-negative endocarditis, and short-term and long-term management of patients during and after completion of antimicrobial treatment. To assist physicians who care for children, pediatric dosing was added to each treatment regimen. CONCLUSIONS: The recommendations outlined in this update should assist physicians in all aspects of patient care in the diagnosis, medical and surgical treatment, and follow-up of infective endocarditis, as well as management of associated complications. Clinical variability and complexity in infective endocarditis, however, dictate that these guidelines be used to support and not supplant physician-directed decisions in individual patient management.

Ambulatory Care↗

Psychoanalytic contributions to psychiatric nosology: forms of masochistic behavior.

This paper summarizes the major strengths and weaknesses of current psychiatric nosology, and then discusses various forms of masochistic behavior as one illustration of how psychoanalysis can contribute to the continuing evolution of psychiatric nosology. Masochistic behavior is separated into behavior in which there is a predominantly conscious link between pleasure and pain, and behavior in which that link is predominantly unconscious. Both categories are further separated into normal and pathological forms. The current diagnostic category of dysthymic disorder is then discussed, with consideration given to the contribution that psychoanalysis can make toward the clarification and delineation of this heterogeneous diagnostic category.

Depressive Disorder↗

Quality management in mental health. II. Managing risk of dangerousness.

In 1995 R. L. Coleman and D. E. K. Hunter described a quality management approach that produced measurable improvements in quality of care in a state-operated psychiatric hospital. Continued evolution of this approach has subsequently enabled the development and implementation of effective processes for managing risk of dangerousness among patients throughout the hospital. Supported by management principles that promote hospital-wide quality improvement, clinicians and managers produced an environment that was conducive to promoting quality. The hospital-wide quality improvement context involved integrating multiple activities designed to promote quality of care, including significant collaborations with other health care organizations. The hospital's mission as an acute care psychiatric facility has required that it focus on assessing and managing risk of dangerousness in a systematic manner. This was done through developing and utilizing a predictive risk assessment instrument and indicators for managerial oversight. This was accomplished in these steps. First, clinical leaders rated potential criteria according to estimates of their ability to predict dangerousness behavior and reviewed their estimates in relation to clinical findings. Second (and concurrently), clinicians and managers implemented procedures to monitor clinical risk and performance. Finally, outcome data were reviewed. They suggested that this approach was effective in reducing risk of dangerous behavior among patients on all psychiatric wards.

Dangerous Behavior↗

Palliative care and hospice: one approach.

The establishment of the first department of pain medicine and palliative care in a medical center in the United States is a significant marker in the development and impact of the palliative care movement. The integration of Jacob Perlow Hospice into this department is a milestone in the continued evolution of the hospice movement in the United States, and suggests that an interrelationship and interdependence between palliative care and hospice is one of the characteristics of change for the future.

Hospices↗

Integrating palliative care: a postmodern perspective.

Hospice and palliative care philosophy is becoming increasingly incorporated into medical practice, education, and research. However, this process of integration may be hindered by continued adherence to several perceived conceptual dichotomies: natural and medicalized death, research and clinical care, and acceptance and denial of dying. These dichotomies were perhaps essential for the initial development of palliative care but could undermine the continuing evolution of care for the terminally ill. In this article, the authors deconstruct these dichotomies and advocate for a fully integrated model of palliative care.

Attitude of Health Personnel↗

Characterization of rotaviruses causing diarrhoea in Vietnamese children.

Faecal samples from 123 children admitted to the Centre for Tropical Diseases in Ho Chi Minh city, Vietnam, with acute watery diarrhoea were screened by negative-stain electron microscopy for viral enteropathogens. In addition to the 48 children who were found to be infected with rotavirus only, one had both rotavirus and astrovirus, two had adenovirus 40/41, and one had astrovirus only. The rotaviruses were subjected to molecular analysis by electropherotyping, G- and P-genotyping (by reverse-transcriptase PCR), and amplicon sequencing. By use of newly designed PCR primers, all 49 isolates could be G-genotyped and all but one P-genotyped. Novel variants of G1-G1*--were the most commonly detected G-genotype and such variants of P[8]-P[8*]--were the second commonest P-genotype. The P[8*] and G1* amplicons were, respectively, only 92%-93.4% and 88.1%-89% similar to the corresponding sequences from the prototype P[8] G1 rotavirus, Wa. Several unusual P- and G-genotype combinations were detected. Four (8%) of the children investigated were each found to be co-infected with two different rotaviruses. These data add to our knowledge of the continuing evolution and diversity of human rotaviruses, and should help in the rational design of vaccines.

Adenoviridae↗

Dynamic in vivo imaging and cell tracking using a histone fluorescent protein fusion in mice.

BACKGROUND: Advances in optical imaging modalities and the continued evolution of genetically-encoded fluorescent proteins are coming together to facilitate the study of cell behavior at high resolution in living organisms. As a result, imaging using autofluorescent protein reporters is gaining popularity in mouse transgenic and targeted mutagenesis applications. RESULTS: We have used embryonic stem cell-mediated transgenesis to label cells at sub-cellular resolution in vivo, and to evaluate fusion of a human histone protein to green fluorescent protein for ubiquitous fluorescent labeling of nucleosomes in mice. To this end we have generated embryonic stem cells and a corresponding strain of mice that is viable and fertile and exhibits widespread chromatin-localized reporter expression. High levels of transgene expression are maintained in a constitutive manner. Viability and fertility of homozygous transgenic animals demonstrates that this reporter is developmentally neutral and does not interfere with mitosis or meiosis. CONCLUSIONS: Using various optical imaging modalities including wide-field, spinning disc confocal, and laser scanning confocal and multiphoton excitation microscopy, we can identify cells in various stages of the cell cycle. We can identify cells in interphase, cells undergoing mitosis or cell death. We demonstrate that this histone fusion reporter allows the direct visualization of active chromatin in situ. Since this reporter segments three-dimensional space, it permits the visualization of individual cells within a population, and so facilitates tracking cell position over time. It is therefore attractive for use in multidimensional studies of in vivo cell behavior and cell fate.

Animals↗

Perioperative management of pediatric surgical patients with diabetes mellitus.

UNLABELLED: Pediatric patients with diabetes are managed with increasingly complex regimens. To optimally manage these patients during the perioperative period, pediatric anesthesiologists must carefully consider the pathophysiology of the disease, patient-specific methods of treatment, status of glycemic control, and the type of surgery proposed. Important pediatric issues, including body size, pubertal development, and ability to tolerate nil per os status, must be considered. To keep pace with the array of options for treating diabetes in children, the perioperative plan should be developed in consultation with a pediatric endocrinologist. We present an algorithm that was developed at Children's Hospital Boston for the management of pediatric patients with either type 1 or type 2 diabetes mellitus presenting for surgery and general anesthesia. This collaborative effort between the pediatric anesthesia and endocrine services represents one example of a standardized approach to these patients that should facilitate care and improve management. Differences from previously published recommendations are highlighted, as are expected changes caused by the continued evolution of pediatric diabetes care. IMPLICATIONS: The evolution of diabetes care for children has made the management of perioperative blood glucose levels a greater challenge for pediatric anesthesiologists. A standardized algorithm for the perioperative management of pediatric patients with type 1 or type 2 diabetes mellitus os presented.

Child↗

Selection for vocational/general professional training--the Dundee undergraduate experience.

Vocational training has been mandatory within the dental profession since 1993 but, despite this, there is continued disquiet surrounding the application process. This paper collates and summarizes the experiences of applicants from one dental school, to inform debate and assist in the continued evolution of the process of application for vocational training.

Education, Dental↗

Passive infusion of an S2-Stem broadly neutralizing antibody protects against SARS-CoV-2 infection and lower airway inflammation in rhesus macaques.

The continued evolution of SARS-CoV-2 variants capable of subverting vaccine and infection-induced immunity suggests the advantage of a broadly protective vaccine against betacoronaviruses (β-CoVs). Recent studies have isolated monoclonal antibodies (mAbs) from SARS-CoV-2 recovered-vaccinated donors capable of neutralizing many variants of SARS-CoV-2 and other β-CoVs. Many of these mAbs target the conserved S2 stem region of the SARS-CoV-2 spike protein, rather than the receptor binding domain contained within S1 primarily targeted by current SARS-CoV-2 vaccines. One of these S2-directed mAbs, CC40.8, has demonstrated protective efficacy in small animal models against SARS-CoV-2 challenge. As the next step in the pre-clinical testing of S2-directed antibodies as a strategy to protect from SARS-CoV-2 infection, we evaluated the in vivo efficacy of CC40.8 in a clinically relevant non-human primate model by conducting passive antibody transfer to rhesus macaques (RM) followed by SARS-CoV-2 challenge. CC40.8 mAb was intravenously infused at 10mg/kg, 1mg/kg, or 0.1 mg/kg into groups (n = 6) of RM, alongside one group that received a control antibody (PGT121). Viral loads in the lower airway were significantly reduced in animals receiving higher doses of CC40.8. We observed a significant reduction in inflammatory cytokines and macrophages within the lower airway of animals infused with 10mg/kg and 1mg/kg doses of CC40.8. Viral genome sequencing demonstrated a lack of escape mutations in the CC40.8 epitope. Collectively, these data demonstrate the protective efficiency of broadly neutralizing S2-targeting antibodies against SARS-CoV-2 infection within the lower airway while providing critical preclinical work necessary for the development of pan-β-CoV vaccines.

Animals↗

Experimental models of Parkinson's disease: from the static to the dynamic.

The experimental models of Parkinson's disease (PD) available today can be divided into two categories according to the mode of action of the compound used: transient pharmacological impairment of dopaminergic transmission along the nigrostriatal pathway or selective destruction by a neurotoxic agent of the dopaminergic neurons of the substantia nigra pars compacta. The present article looks at the relative merits of each model, the clinical symptoms and neuronal impairment it induces, and the contribution it could make to the development of a truly dynamic model. It is becoming more and more clear that there is an urgent need for a chronic model integrating all the clinical features of PD including resting tremor, and reproducing the gradual but continuous nigral degeneration observed in the human pathology. Discrepancies have been reported several times between results obtained in classic animal models and those described in PD, and it would seem probable that such contradictions can be ascribed to the fact that animal models do not, as yet, reproduce the continuous evolution of the human disease. Dynamic experimental models which come closer to the progressive neurodegeneration and gradual intensification of motor disability so characteristic of human PD will enable us to investigate crucial aspects of the disease, such as compensatory mechanisms and dyskinesia.

Animals↗

The human genome project: a historical perspective.

Efforts in genomics over the last decade have created a stream of opportunities for drug discovery. High-throughput DNA sequencing has forced a re-definition of the paradigm for identification and validation of targets for drug development. One purpose of this review is to delineate the different approaches to sequence data generation and to establish their various uses for the definition of gene function. There still remain crucial dilemmas for the pharmaceutical industry. The multitude of potential targets can each absorb enormous validation costs and the vast majority are likely to prove academically interesting but useless for drug development. An additional dimension arises from the importance of sequence variation between different individuals. These differences can determine response to therapy and must inform both the drug development process and healthcare delivery. This presents great challenges and opportunities for drug companies, their customers and society as a whole. I will review the technological aspects in some detail and give my view of the legal and social aspects. The field of bioinformatics is at the core of functional and pharmacogenomics and advances will depend on the continuing evolution of tools to interpret data. For the most part this evolution is reviewed in the context of specific application areas rather than as a discrete field, in recognition of its all-pervasive effects.

Animals↗

Development of ligand-targeted liposomes for cancer therapy.

The continued evolution of targeted liposomal therapeutics has resulted in new agents with remarkable antitumour efficacy and relatively mild toxicity profiles. A careful selection of the ligand is necessary to reduce immunogenicity, retain extended circulation lifetimes, target tumour-specific cell surface epitopes, and induce internalisation and subsequent release of the therapeutic substance from the liposome. Methods for assembling targeted liposomes, including a novel micellar insertion technology, for incorporation of targeting molecules that efficiently transforms a non-targeted liposomal therapeutic to a targeted one, greatly assist the translation of targeted liposome technology into the clinic. Targeting strategies with liposomes directed at solid tumours and vascular targets are discussed. The authors believe the development of ligand-targeted liposomes is now in the advanced stage and offers unique and important advantages among other targeted therapies. Anti-HER2 immunoliposomal doxorubicin is awaiting Phase I clinical trials, the results of which should provide new insights into the promise of ligand-targeted liposomal therapies.

Animals↗

Rural healthy people 2010--evolving interactive practice.

The objectives of the Rural Healthy People 2010 project are to employ a survey of state and local rural health leaders to identify rural health priorities, to synthesize available research and other publications on these priorities, to identify and describe models for practice employed by rural communities to address these priorities, and to disseminate this information to rural communities. We describe these priorities; the content of Rural Healthy People 2010 products, methods, and target audiences; and the continuing evolution of the program. Rural Healthy People 2010 encourages rural support of Healthy People 2010 goals and invites state and local rural health leaders to share their successful models with others.

Health Status Indicators↗

The Internet as an information source for geriatricians.

Electronic storage of and access to medical data is becoming increasingly common. Advances in computer technology and telecommunications have made it possible to store vast amounts of information in databases and transmit this information rapidly to any place on the globe. At the forefront of this technology is the Internet, a worldwide computer network that links together over 10 million computers in more than 80 countries. The Internet is an unprecedented information resource. There are tens of thousands of computers on the Internet that are freely accessible to the general public. Commercial organisations, academic institutions and government agencies are just some of the entities that can be accessed through the Internet. There are a large number of medical resources at these sites including electronic journals, online databases and search services, teaching materials, and methods for obtaining online continuing medical education credits. The Internet offers a variety of services such as electronic mail, discussion groups and the ability to log on to and run programs on remote computers. The one service, however, that has been responsible for the phenomenal growth of the Internet is the World Wide Web, the primary focus of this article. The World Wide Web allows a user to view documents that contain text, graphics, images, and movie and sound clips. In addition, any of these elements can be linked to other documents or services anywhere on the Internet. This article gives a general overview of the Internet and the medical resources it contains, with an emphasis on material related to geriatrics and aging. The Internet is in a state of continual evolution, and it is likely that dramatic new capabilities will become available in the near future.

Aged↗

Expression systems for the production of recombinant pharmaceuticals.

The new generation of biological products are largely the result of genetic engineering. The qualitative and quantitative demand for recombinant proteins is steadily increasing. Molecular biologists are constantly challenged by the need to improve and optimise the existing expression systems, and also develop novel approaches to face the demands of producing the complex proteins of tomorrow. This continuous evolution is paralleled by growing concerns about the safety of these novel pharmaceuticals, with health authorities setting high standards for certification. One of the strategies used by researchers in this field involves sourcing new genetic elements for incorporation into expression systems by systematically analysing the rich natural diversity of microorganisms and plant-based expression systems. There are, in addition, numerous tools for modifying microorganisms and for re-engineering existing biological pathways or processes to meet the needs of the pharmaceutical industry. The aim of this review is to present the conventional and alternative expression systems, focusing on prokaryotic expression systems and briefly exploring other complementary recombinant protein production systems and their unique features.

Animals↗