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Selective nontreatment of handicapped newborns: a critical essay.

The neonatal intensive care unit is the site of some of the most dramatic technology, complex decision-making and costly activity in the current range of medical institutions. Thus, the decisions made there are particularly visible, and of concern to a society which has increasingly scrutinized and challenged medical practices. Questions of marginal utility and cost-benefit relationships are becoming increasingly prominent. These concerns are heightened by the social and political tensions over issues of the time of initiation of life, quality of life, and assurances of equity for those less well off or handicapped from birth. Robert Weir's book, Selective Nontreatment of Handicapped Newborns, successfully summarizes the current dilemmas and identifies areas of uncertainty and lack of knowledge which cloud the decision-making processes. The book reviews the positions of the major protagonists of the last several years; inevitably, their positions will undergo continuous evolution in response to new data and vigorous political and public policy activity. Weir appropriately identifies the difficulty in arriving at an accurate prognosis as an important and prominent problem in decision-making about defective newborns. The population of surviving, compromised newborns is relatively unfamiliar and their problems remain largely unstudied. Weir's discussion of the desirability of the establishment of Infant Care Review Committees in those institutions which care for defective and handicapped newborns thoughtfully concludes that such committees are, on the balance, desirable. As experience accumulates with Infant Care Review Committees, they should serve the positive purpose of generating open discussion of legitimate disagreements. These committees will provide a forum in which decision-makers can disclose uncertainty, consider alternatives, and receive counsel.(ABSTRACT TRUNCATED AT 250 WORDS)

Persons with Disabilities↗

Using PBPK modeling and comprehensive realism methodology for the quantitative cancer risk assessment of butadiene.

The National Academy of Sciences and many others have noted the need for quantitative health risk assessment methodology that goes beyond a simple screening analysis based on upper bounds on risk. The Academy recommended adoption of methodologies which provide a higher-tier analysis based on realistic estimates of risk which reflect more of the available biological information. In recent years, scientists have challenged the assumption of low-dose linearity and other default assumptions in cancer risk assessment. These challenges have stimulated the continued evolution of quantitative risk assessment methodologies, because effective risk management requires accurate characterizations of uncertainty and greater utilization of cost-benefit analyses for decision making. "Comprehensive Realism" is an emerging quantitative weight-of-evidence based risk assessment methodology for both cancer and noncancer health effects which utilizes probability distributions and decision analysis techniques to reflect more of the available human and animal dose-response data. The current state of knowledge about the relative plausibility of alternative dose-response analyses is also addressed in this approach. The framework discussed here should lead to a higher-tier assessment of butadiene.

Butadienes↗

Robotic-enhanced totally endoscopic mitral valve repair and ablative therapy.

PURPOSE: The aim of this article was to assess the feasibility of totally closed robotic mitral valve repair and ablative therapy. DESCRIPTION: Two patients with mitral valve disease and permanent atrial fibrillation underwent the combined procedure using the da Vinci robotic system (Intuitive Surgical, Sunnyvale, CA). Radiofrequency ablation was performed using the Cardioblate XL unipolar pen (Medtronic Inc, Minneapolis, MN). One patient underwent mitral commissurotomy and the other commissurotomy and Reed annuloplasty. EVALUATION: There were no procedure-related complications. Sinus rhythm was established in both patients after the operation, and transesophageal echocardiography revealed competent mitral valves without residual gradients. CONCLUSIONS: Robotic-enhanced mitral valve repair and ablation proved feasible in both patients with good clinical outcome. The described combined method may find broader application in a selected group of patients with the continuing evolution in technology.

Atrial Fibrillation↗

Antibacterial drug discovery--then, now and the genomics future.

Drug discovery research in the area of infectious diseases, in particular that dealing with antibacterial/antibiotic susceptibility and resistance, is in a process of continuing evolution. Steeped in the history of the highly successful intervention with chemotherapeutic agents to treat human infections, the emergence of drug-resistant pathogens worldwide presents a serious unmet medical need, if not a pending catastrophe. Research in both academia and industry over the past 30 years using molecular biology, genetics and more recently--bacterial genomics--has assembled key enabling technologies to increase productivity and success rates in the discovery and development of novel antibacterial agents. However genomics is not limited only to antibacterial target selection but provides the opportunity to further understand key interactions in the use of antibacterial compounds as therapeutic agents (such as resistance emergence, susceptibility, efflux, interactions between compound and pathogen, etc.). Genomics also offers the potential for insights into: bacterial niche adaptation, host susceptibility, treatment regimens, antibiotic resistance, pharmacokinetics (e.g., host metabolism differences), safety and the microbial genesis of chronic diseases (e.g., gastric ulceration).

Anti-Bacterial Agents↗

Old and new perspectives in the management of high-risk, locally advanced or recurrent, and metastatic vulvar cancer.

During the last decades there has been a continuing evolution in the surgical approach of squamous cell carcinoma of the vulva that has been traditionally treated with radical vulvectomy and bilateral inguinal-femoral lymphadenectomy. Patients with T1 tumour are usually treated with radical local excision, if the lesion is unifocal and the remainder of the vulva is normal. Patients with T1a disease have no risk of groin metastases and do not need lymphadenectomy, whereas those with T1b disease need ipsilateral inguinal-femoral lymphadenectomy if the lesion is lateral, and bilateral lymphadenectomy if the lesion is midline. Modifications of the surgical technique of deep femoral lymphadenectomy and the mapping of sentinel node can offer new interesting therapeutic perspectives. Postoperative adjuvant pelvic and groin irradiation is warranted for patients with two or more or macroscopically involved groin nodes. Locally advanced squamous cell carcinoma of the vulva has been long surgically treated with en-block radical vulvectomy and bilateral inguinal-femoral lymphadenectomy plus partial resection of urethra, vagina or anum, or by exenteration, with severe postsurgical complications, poor quality of life, and unsatisfactory survival rates. 5-Fluorouracil [5-FU] or 5-FU- and cisplatin-based chemotherapy concurrent with irradiation followed by tailored surgery represents an attractive therapeutic option for advanced disease, planned to avoid such ultra-radical surgical procedures and, hopefully, to improve patient outcome. Chemotherapy has also been used in neoadjuvant setting, with contrasting and generally unsatisfactory results, and in palliative treatment of patients with distant metastases. Surgery is the primary treatment also for vulvar malignancies other than squamous cell carcinoma, whereas the clinical usefulness of adjuvant irradiation or chemotherapy is still to be defined. Primary chemoradiation can be also used for advanced carcinoma of the Bartholin gland or for advanced adenocarcinoma associated with extramammary Paget's disease. The drugs used for chemotherapy of metastatic melanomas or sarcomas of the vulva are the same employed for the melanomas or sarcomas developed in other sites.

Combined Modality Therapy↗

Governmentality, discourse and space in the New Zealand health care system, 1991-2003.

This paper considers recent health care reform in New Zealand in the context of the continuing evolution of the 'neoliberal project'. It advocates the adoption of a Foucauldian governmentality approach to analysis as a productive way to extricate the changing understandings of space within evolving New Zealand health discourses. We analyse two policy documents released 9 years apart which, when examined together, encapsulate the changing discourses of the health care system in the 1990s. We note that through the 1990s the central governing rationality has shifted from competition towards cooperation in health care delivery. While place was held to be subservient to the market at the beginning of the decade, health care has been increasingly re-territorialised through 'community' and its associated constructions.

Health Care Reform↗

Antibiotic resistance in outpatient urinary isolates: final results from the North American Urinary Tract Infection Collaborative Alliance (NAUTICA).

The goal of the North American Urinary Tract Infection Collaborative Alliance (NAUTICA) study was to determine antibiotic susceptibility to commonly used agents for urinary tract infections against outpatient urinary isolates obtained in various geographic regions in the USA and Canada. Forty-one medical centres (30 from the USA and 11 from Canada) participated, with each centre submitting up to 50 consecutive outpatient midstream urine isolates. Isolates were identified to species level by the standard protocol of each laboratory. Susceptibility testing was determined using the National Committee for Clinical Laboratory Standards (NCCLS) microdilution method. Resistance breakpoints used were those published by the NCCLS, including: ampicillin (resistant > or = 32 microg/mL), sulphamethoxazole/trimethoprim (SMX/TMP) (resistant > or = 4 microg/mL), nitrofurantoin (resistant > or = 128 microg/mL), ciprofloxacin (resistant > or = 4 microg/mL) and levofloxacin (resistant > or = 8 microg/mL). Of the 1990 isolates collected, 75.1% (1494) were collected from the USA and 24.9% (496) were collected from Canada. The mean age of the patients was 48.3 years (range 1 month to 99 years), and 79.5% and 20.5% of isolates were obtained from women and men, respectively. The most common organisms were Escherichia coli (57.5%), Klebsiella pneumoniae (12.4%), Enterococcus spp. (6.6%), Proteus mirabilis (5.4%), Pseudomonas aeruginosa (2.9%), Citrobacter spp. (2.7%), Staphylococcus aureus (2.2%), Enterobacter cloacae (1.9%), coagulase-negative staphylococci (1.3%), Staphylococcus saprophyticus (1.2%), Klebsiella spp. (1.2%), Enterobacter aerogenes (1.1%) and Streptococcus agalactiae (1.0%). Among all 1990 isolates, 45.9% were resistant to ampicillin, 20.4% to SMX/TMP, 14.3% to nitrofurantoin, 9.7% to ciprofloxacin and 8.1% to levofloxacin. Fluoroquinolone resistance was highest in patients > or = 65 years of age. For the 1142 E. coli isolates, resistance rates were: ampicillin 37.7%, SMX/TMP 21.3%, ciprofloxacin 5.5%, levofloxacin 5.1% and nitrofurantoin 1.1%. For all 1990 isolates and for the 1142 E. coli only, resistance rates were significantly higher in US compared with Canadian medical centres. This study reports higher rates of antibiotic resistance in US versus Canadian outpatient urinary isolates and demonstrates the continuing evolution of resistance to antimicrobial agents.

Adolescent↗

Antibiotic resistance in Escherichia coli outpatient urinary isolates: final results from the North American Urinary Tract Infection Collaborative Alliance (NAUTICA).

The North American Urinary Tract Infection Collaborative Alliance (NAUTICA) study determined the antibiotic susceptibility to commonly used agents for urinary tract infections of outpatient Escherichia coli urinary isolates obtained from various geographic regions in the USA and Canada. NAUTICA involved 40 medical centres (30 from the USA and 10 from Canada). From April 2003 to June 2004 inclusive, each centre submitted up to 50 consecutive outpatient midstream urine isolates. All isolates were identified to species level by each laboratory's existing protocol. Susceptibility testing was determined using the Clinical and Laboratory Standards Institute (CLSI) microdilution method. Ampicillin (resistant>or=32 microg/mL), sulphamethoxazole/trimethoprim (SMX/TMP) (resistant>or=4 microg/mL), nitrofurantoin (resistant>or=128 microg/mL), ciprofloxacin (resistant>or=4 microg/mL) and levofloxacin (resistant>or=8 microg/mL) resistance breakpoints used were those published by the CLSI. Of the 1142 E. coli collected, 75.5% (862) were collected from the USA and 280 (24.5%) were from Canada. Patient demographics revealed a mean age of 48.1 years (range, 2 months to 99 years), with female patients representing 79.4% of patients and males representing 20.6%. Overall, resistance to ampicillin was 37.7%, followed by SMX/TMP (21.3%), nitrofurantoin (1.1%), ciprofloxacin (5.5%) and levofloxacin (5.1%). Resistance rates for all antimicrobials were higher in US medical centres compared with Canadian centres (P<0.05). Fluoroquinolone resistance was highest in patients>or=65 years of age (P<0.05). Resistance rates demonstrated considerable geographic variability both in the USA and Canada. This study reports higher rates of antibiotic resistance in US versus Canadian outpatient urinary isolates of E. coli and demonstrates the continuing evolution of resistance to antimicrobial agents.

Adolescent↗

Glatiramer acetate (GA) therapy induces a focused, oligoclonal CD8+ T-cell repertoire in multiple sclerosis.

We have demonstrated that GA therapy induces a differential upregulation of GA-specific, cytotoxic/suppressor CD8+ T-cell responses in MS patients. We utilized a novel combination of flow sorting and anchored PCR to analyze the evolving clonal composition of GA-specific CD4+ and CD8+ T-cells. TCRbeta chain analysis revealed the development of an oligoclonal GA-specific CD8+ repertoire with persistence of dominant clones over long periods. Interestingly, some sequences resembled published oligoclonal CD8+ TCR sequences from MS lesions. In contrast, GA-specific CD4+ responses were polyclonal and showed continual evolution of their repertoire. This clonotypic and functional analysis provides mechanistic insights into GA therapy.

Adult↗

Antibacterial research and development in the 21(st) Century--an industry perspective of the challenges.

The continued evolution of resistance to antibiotics has led to wide ranging consultation at National and International levels as to how to address this issue. In addition to attempting to limit the spread of resistance there is growing consensus that a cornerstone requirement is the development of new antibiotics to help redress the balance of resistance versus available antibiotics. The availability of new technologies such as genomics has opened up new approaches for antibacterial research. It would appear that from an industry perspective, the research and development of antibiotics should be an attractive option. However, this is not the current perception at the majority of large pharmaceutical companies. In addition, the perceived failure of new technologies to create another golden age of new antibacterial classes has led many companies to prioritise other areas of research and, in some cases, to exit antibacterial research. In response, a plethora of small biotech companies have emerged with an interest in antibacterial discovery and large pharmaceutical companies may look to these as a source of development candidates although, to date, these have contributed a very low number of truly novel antibiotic lead compounds. As a reaction to these changes several initiatives are ongoing to examine ways to incentivise antibacterial research and development and ensure a healthy pipeline of compounds in the 21st Century.

Anti-Bacterial Agents↗

Medical management of acid-peptic disorders of the stomach.

In the past 30 years, medicine has witnessed an unprecedented evolution in acid-peptic disorder management, fueled by major advances in our understanding of the physiology of acid secretion and the gastric mucosal barrier. The other pivotal development in understanding these disorders has been the recognition of Helicobacter pylori's role in the pathophysiology of peptic ulcer disease,chronic gastritis, and even gastric malignancy. This evolution continues as H pylori wanes in significance, and medicine is challenged by treating iatrogenic conditions brought on by ulcerogenic anti-inflammatory drugs. Following a description of the relevant physiology and biochemistry of gastric acid secretion and the gastric mucosal barrier, this article describes the current medicinal arsenal available to treat acid-peptic disorders of the stomach.

Anti-Ulcer Agents↗

How can toxicogenomics inform risk assessment?

Technologies that generate information about the genome are being used to explore changes in gene expression and related proteins following exposure to chemicals. Conceptually, this information allows a greater understanding of genomic level mRNA expression (transcriptomics), cell and tissue protein expression (proteomics) and information about metabolite profiles (metabonomics). Having a greater understanding of this information alongside, empirical toxicological reference data provide for the continued evolution in our ability to understand toxicological modes of action, thereby providing a more scientific basis for extrapolation of toxicological information from animals to humans. Toxicogenomics also provides specific opportunities for improvements at different stages of the risk assessment process such as the development of new predictive models for identifying human health hazards and the identification of more precise molecular biomarkers of exposure. One possibility is that molecular fingerprinting in vivo or in vitro can be used to categorize chemicals and mixtures of chemicals into different mode of action groups. As there is indication that molecular signals differ at dose levels, it is hoped that toxicogenomic information can also contribute to the understanding and interpretation of effects seen with low dose exposure. Several gene polymorphisms have already been identified which play a role in the differing intra-species response to chemicals thus providing explanation for the observed differences in effects. It is therefore likely that a better understanding of genomic expression will enable a greater insight into the factors behind the observed variability in susceptibility to chemical exposure that can be seen in human populations.

Genomics↗

What can we expect from prophylactic implantable defibrillators?

Death due to ventricular tachyarrhythmia (VT) remains an important public health problem; patients with prior myocardial infarction (MI) constitute the largest identifiable population for prophylactic interventions. Targeting of progressively higher-risk subgroups of post-MI survivors carries inevitable tradeoffs with respect to the global impact of interventions on overall mortality. Therapy with aspirin, beta blockers, and angiotensin-converting enzyme (ACE) inhibitors comprise the benchmark against which all additional interventions, including implantable defibrillators, must be measured. Initial enthusiasm for empiric amiodarone therapy has been tempered by the limited benefit demonstrated in recent randomized trials. Trials of other class III antiarrhythmic drugs, including both d,l-sotalol and d-sotalol, have also failed to demonstrate survival benefit. The Multicenter Automatic Defibrillator Implantation Trial (MADIT) demonstrated significantly improved survival associated with defibrillators in a small subgroup of post-MI survivors with a high short-term risk of death. The ultimate number and optimal criteria for selection of patients who may benefit from prophylactic defibrillator therapy after MI will undergo continued evolution as new data from current and ongoing trials become available.

Amiodarone↗

Timing of treatment for nonneutropenic patients colonized with Candida.

There has been a continuing evolution of the clinical spectrum of Candida infection in nonneutropenic patients. With better understanding of the predisposing factors for fungemia in critically ill patients, interest now centers on indications for early therapy, prior to the progression of colonization to fungemia. Recent prospective trials have identified persistence of Candida species in repetitive cultures of various sites as an essential if not necessary precursor for fungemia. Treatment for patients requiring prolonged intensive-care-unit residence and demonstrating colonization with Candida is suggested, based on the frequency with which such patients progress to fungemia. The efficacy of such treatment is undocumented, and clinical trials of various regimens of polyene or azole antifungals is needed.

Antifungal Agents↗

Duplex ultrasound insertion of inferior vena cava filters in multitrauma patients.

BACKGROUND: Techniques for placement of inferior vena cava (IVC) filters have undergone continued evolution from open surgical exposure of the venous insertion site to percutaneous insertion in most cases today. However, the required transport either to an operating room or interventional suite can be complex and potentially hazardous for the multiply injured trauma patient who may require ventilator support, controlled intravenous infusions, or skeletal immobilization. Increased experience with color-flow duplex scanning for routine IVC imaging and portability of ultrasound equipment have suggested the usefulness of duplex-guided IVC filter insertion (DGFI) in critically ill trauma and intensive care unit (ICU) patients. METHODS: A total of 25 multitrauma/ICU patients were considered for DGIF. Screening color-flow duplex scans were performed on all patients, and obesity or bowel gas prevented ultrasound imaging in 2 cases, leaving 23 patients suitable for DGFI. In each case, the IVC was imaged in the transverse and longitudinal planes. The right renal artery was identified as it passed posterior to the IVC and was used as a landmark of the infrarenal segment of the IVC. All procedures were performed at the bedside in a monitored ICU setting using percutaneous placement of titanium Greenfield filters. Duplex scanning after insertion was used to document proper placement, and circumferential engagement of the filter struts in the IVC wall. An abdominal radiograph was also obtained in each case to confirm proper filter location. Duplex ultrasound imaging was repeated within 1 week of insertion to assess IVC and insertion site patency. RESULTS: DGFI was successful in all cases. The filter was deployed at a suprarenal level in one case, as was recognized at the time of postprocedural scanning. Three patients died as a result of their injuries but there were no pulmonary embolism deaths. Repeat duplex scanning was obtained in 17 patients, and revealed no case of IVC or insertion site thrombosis. CONCLUSIONS: Vena caval interruption can be safely performed under ultrasound guidance in a monitored, ICU environment. In selected multiply injured trauma patients, this will reduce the risk, complexity and cost of transport for these critically ill patients. DGFI also reduces procedural costs compared with an operating room or interventional suite, and eliminates intravenous contrast exposure. Preprocedural scanning is essential to identify patients suitable for DGFI, and careful attention must be paid to the known ultrasonographic anatomical landmarks.

Adult↗

What is the best treatment for patients with acute type B aortic dissections--medical, surgical, or endovascular stent-grafting?

BACKGROUND: Controversy continues regarding treatment for patients with acute type B aortic dissection. METHODS: One hundred eighty-nine patients with acute type B aortic dissection managed over a 36-year period were analyzed retrospectively for three outcome endpoints: survival; freedom from reoperation, and freedom from late aortic-related complications or late death. Risk factors for death were identified using a multivariable Cox proportional hazards model. Then to account for patient selection bias, heterogeneity of the population, and continuous evolution in techniques, propensity score analysis was used to identify risk-matched cohorts (quintiles I and II) in which the results of medical (n = 111) or surgical (n = 31) therapy were compared more comprehensively. RESULTS: The two main determinants of death were shock (hazard ratio [HR] = 14.5, 95% confidence level [CL] 4.7, 44.5; p < 0.001) and visceral ischemia (HR = 10.9, 95% CL 3.9, 30.3; p < 0.001). Arch involvement, rupture, stroke, previous sternotomy, and coronary or lung disease roughly doubled the hazard. Female sex was also a significant but weaker independent predictor of death. Actuarial survival estimates for all patients were 71%, 60%, 35%, and 17% at 1, 5, 10, and 15 years, respectively, and were similar for the medical and surgical patients. The Marfan syndrome predicted reoperation and late aortic complications or late death. In a separate analysis of the 142 patients in quintiles I and II, survival, freedom from reoperation, as well as freedom from late aortic complications or death were almost identical in the medical and surgical subsets. CONCLUSIONS: The poor long-term prognosis of patients with acute type B aortic dissection is determined primarily by dissection-related and patient-specific risk factors, which are not readily modifiable. Whether the outlook in the future will be improved using stent-grafts remains to be determined.

Acute Disease↗

Robotic mitral valve repair: experience with the da Vinci system.

BACKGROUND: As part of a Food and Drug Administration trial, mitral repairs were performed in 38 patients using the robotic da Vinci surgical system (Intuitive Surgical, Inc, Mountain View, CA). Prospectively, we evaluated safety and efficacy in performing both simple and complex mitral repairs. METHODS: Eligible patients had nonischemic moderate to severe mitral insufficiency. Operative techniques included peripheral cardiopulmonary perfusion, a 4- to 5-cm mini-thoracotomy, transthoracic aortic occlusion, and antegrade blood cardioplegia. Transesophageal echocardiograms were done intraoperatively with three-dimensional reconstructions. Successful repairs were defined as mild or less residual regurgitation. RESULTS: Enhanced three-dimensional visualization of mitral leaflets and the subvalvar apparatus allowed safe, dexterous intracardiac tissue manipulation. All patients had successful valve repairs including quadrangular resections, sliding plasties, and edge-to-edge approximations, as well as both chordal transfers and replacements. There were no operative deaths, strokes, or device-related complications. One patient required valve replacement for hemolysis and 1 was reexplored for bleeding. There were no incisional conversions. Both robotic repair and total operating times decreased significantly from 1.9 +/- 0.1 and 5.1 +/- 0.1 hours (mean +/- standard error of the mean) for the first 19 patients to 1.5 +/- 0.1 (p = 0.002) and 4.4 +/- 0.1 hours (p = 0.04) for the last 19 operations, respectively. Total hospital length of stay for patients was 3.8 +/- 0.6 days. Of all patients, 31 (82%) had a 4-day or less length of stay. Seven patients (18%) had stays between 5 and 9 days (6.4 +/- 1.0). CONCLUSIONS: This study shows that the da Vinci surgical system (Intuitive Surgical, Inc) has few limitations in performing complex valve repairs. Articulated wrist-like instruments and three-dimensional visualization enabled precise tissue telemanipulation. Future robotic design advances and adjunctive suture technologies may promote continuing evolution of robotic cardiac operations.

Cardiac Surgical Procedures↗

Introduction of the pill and its impact.

Introduction of the birth control pill in the United States in 1960 marked the end of a relatively short period of time (< 10 years) to intentionally produce an oral contraceptive, and the beginning of a relatively long period of controversy surrounding the use of the pill. Availability of the pill had an impact on various aspects of social life, including women's health, fertility trends, laws and policies, religion, interpersonal relationships and family roles, feminist issues, and gender relations, as well as sexual practices among both adults and adolescents. The pill proved to be highly effective from the outset. Although safety issues developed with the earlier formulations, continued evolution of pill hormones and doses has resulted in a greatly improved and safe oral contraceptive. A broad range of noncontraceptive health benefits also is associated with the pill. These health effects are significant, as they include protection against potentially fatal diseases, including ovarian and endometrial cancers, as well as against other conditions that are associated with substantial morbidity and potential hospitalization and associated costs. The popularity of the pill has remained high, with rates of use in the past 30 years in the United States ranging from one-quarter to almost one-third of women using contraception. Almost 40 years after its introduction, the pill's contraceptive efficacy is proven, its improved safety has been established, and the focus has shifted from supposed health risks to documented and real health benefits.

Contraception↗