It has long been noted that products of microorganisms have clinical activity against hematologic malignancies. Recent advances suggest that Toll-like receptors (TLRs) activated by ligands in the microbial preparations might account for some of this activity, and that defined TLR agonists might improve the clinical efficacy of this approach. A potentially important mechanism of action of TLR agonists is their ability to cause tumor cells to differentiate into a 'tolerized' state in which they become highly sensitive to cytotoxic effector cells and chemotherapeutic drugs. TLR agonists as single agents have strong activity against cutaneous leukemias and lymphomas but are not as effective against systemic disease. A possible reason for this discrepancy is the hypoxic internal tumor microenvironment, which promotes glycolytic metabolism, and the presence of suppressive cytokines, prostaglandins and nucleosides that prevent strong TLR signaling in cancer cells. Accordingly, concomitant use of agents to counter this intrinsic microenvironmental inhibition, together with TLR agonists, may prove to be an effective treatment strategy for the hematologic malignancies.

Spontaneous remissions of acute myeloid leukemia (AML) have been reported in association with infection. Here, we report a case of spontaneous remission of AML in a 47-year-old Saudi Arabian male patient who presented with a few weeks history of recurrent abdominal pain, vomiting and fever. He was diagnosed with acute monocytic leukemia (AML, FAB M5b) and a perforated bowel. He also had Clostridium septicum bacteremia and thus chemotherapy was deferred. He received supportive therapy and intravenous antibiotics. Six weeks later, he achieved spontaneous and complete remission lasting for about 4 months. The remission and relapse were documented by bone marrow examination. Similarly, previous reports of spontaneous remission of AML were short lived and were followed by relapse and progression.

Oncolytic viruses have gained attention as a novel form of cancer treatment. Many viral vectors in use today have been rendered safe by deletion of genes encoding viral structural proteins, thus making them unable to spread beyond the first infected cells. Hence, such replication-deficient constructs may lack efficacy. Here, we analyzed the oncolytic potential of the replication-competent vector VA7-EGFP, based on the avirulent Semliki Forest virus (SFV) strain A7(74), to kill cancer cells in culture as well as to target s.c. human melanoma xenografts in severe combined immunodeficient (SCID) mice. VA7-EGFP was able to infect most cancer cell lines studied, leading to complete lysis of the cells within 72 hours after infection. In SCID mice grafted with A2058 human melanoma, marked regression of the xenografts was observed following a single injection of 10(6) plaque-forming units of virus given either i.p., i.v., or intratumorally. Histologic analysis revealed the presence of virus not only in all treated tumors but also in the brains of the treated mice, causing progressing neuropathology beginning at day 16 after infection. Following initial oncolysis, clusters of viable tumor cells were observed embedded in connective tissue, and at later stages, encapsulated tumor nodules had formed. Infection of melanoma cells from explant cultures of these nodules revealed that a portion of the cells were resistant to virus. To be eligible for use in virotherapy, the ability of avirulent SFV to spread within tumor tissue may have to be improved and the biological safety of the virus may have to be addressed thoroughly in higher animals.

Purpose: Epidemiological studies have found an inverse association between acute infections and cancer development. In this paper, we review the evidence examining this potentially antagonistic relationship. Methods: In addition to a review of the historical literature, we examined the recent epidemiological evidence on the relationship between acute infections and subsequent cancer development in adult life. We also discuss the impact of chronic infections on tumor development and the influence of the immune system in this process. Results: Exposures to febrile infectious childhood diseases were associated with subsequently reduced risks for melanoma, ovary, and multiple cancers combined, significant in the latter two groups. Epidemiological studies on common acute infections in adults and subsequent cancer development found these infections to be associated with reduced risks for meningioma, glioma, melanoma and multiple cancers combined, significantly for the latter three groups. Overall, risk reduction increased with the frequency of infections, with febrile infections affording the greatest protection. In contrast to acute infections, chronic infections can be viewed as resulting from a failed immune response and an increasing number have been associated with an elevated cancer risk. Conclusion: Infections may play a paradoxical role in cancer development with chronic infections often being tumorigenic and acute infections being antagonistic to cancer.

PURPOSE: A best-case series review is an efficient tool with which to screen complex complementary and alternative treatments for cancer as candidates for further study. STUDY DESIGN: The National Cancer Institute and other agencies have adopted the best-case series method to evaluate cancer treatments involving complementary and alternative medicine (CAM) for further study. The authors conducted a best-case series review of the Hufeland Klinik. Established in 1985 in Bad Mergentheim, Germany, this facility treats more than 500 cancer patients per year. Hufeland treatment includes dietary modification, injections, ozone therapy, active fever therapy, psychotherapy, and sometimes hormone therapy and/or low-dose chemotherapy. The goal of the treatment is to prolong survival and to maintain good quality of life. METHODS: The clinic provided summaries of 27 cases in which patients with longer than expected survival had agreed to make their medical records available for review. The review involved pathologic confirmation of disease and radiologic confirmation of complete response (CR) or partial response (PR) not attributable to conventional treatment. RESULTS: Based on the summaries and an exhaustive 2-year search for medical records, slides, and imaging data, 12 of 27 cases were selected for full review, and 5 (3 CRs and 2 PRs) were judged best cases. CONCLUSION: Most patients with common cancers receive conventional treatment before coming to Hufeland, and many are treated with chemotherapy and/or hormonal therapy while there. Hence, only a few could be considered for review. With 5 of 12 patients showing a treatment response, the authors conclude that the Hufeland treatment merits further study. They also recommend the development of criteria with which to evaluate best-case series reviews of complex CAM treatments for patients with advanced cancer.

Until recently, studies on the role of the metabolites of arachidonic acid (AA), eicosanoids in fever have primarily focused on prostaglandins, prostaglandin E2 (PGE2) in particular, derived from the pathway related to cyclooxygenases (COX). COX exists in two known isoforms; a constitutive COX-1, and COX-2, which is inducible upon the action of pyrogens. Data accumulated in our laboratories suggest a thermoregulatory role for two other pathways of arachidonate metabolism; 5-lipoxygenase (5-LOX) and cytochrome P-450 (epoxygenase). We have demonstrated that leukotrienes (LTs; 5-LOX-derived eicosanoids) and various isomers of epoxyeicosatrienoic acids (EETs; epoxygenase-derived eicosanoids) contribute to the process of endogenous antipyresis or cryogenesis, which limits the height of fever. In support of this are several lines of evidence based on both in vivo and in vitro experiments. 1) Intracerebroventricular (icv) injections of LTC4 at nanomolar concentrations cause a dose-dependent decrease of body temperature (Tb) in mice. 2) Lipopolysaccharide (LPS)-induced anapyrexia in mice is preceded and accompanied by elevation in hypothalamic cysteinyl-LT (CysLT) production. 3) The inhibitor of LT synthesis MK-886 suppresses both of these processes. 4) EETs as well as inducers of the epoxygenase attenuate, whereas inhibitors of epoxygenase enhance the LPS-induced fever in rats. 5) One of the isomers of EET, 11,12-EET, in in vitro studies inhibited both the generation of PGE2 and IL-6 in monocytes stimulated with LPS. These results, together with a well-established pyrogenic role of PGE2, indicate that AA cascade may be regarded as an endogenous system to regulate the temperature response upon disease. COX, 5-LOX, and epoxygenase products may act at the level of hypothalamus as proximal mediators of, respectively, fever (PGE2) or cryogenesis (CysLTs and EETs), or indirectly by influencing the other endogenous cryogens and pyrogens.

Immunotherapy using both active and passive approaches is increasingly being used as a modality to treat human cancer. The last decade has seen a tremendous burst of activity in antigen discovery in cancer, and many new targets have now been identified for both monoclonal antibody therapy and active immunization. In addition, advances have been made in our understanding of the immune response against cancer and how new vaccine vectors, such as poxviruses, alphaviruses and bacterial vectors, can be used to overcome some of the traditional hurdles (e.g. self-tolerance and immune suppression in cancer patients) that have hindered the generation of effective antitumor immune responses. Improvements in genomics technology in the area of DNA microarrays and differential display and subtractive hybridization together with a new wave of mass spectrometry-based proteomics tools, as well as more sensitive assays to validate the immunoreactivity of new antigens, have all accelerated the rate of new antigen discovery in cancer. This rapid progress should initiate a major paradigm shift in how we treat cancer within the next 10 years, where, instead of being a novelty, the combination of targeted T cell-based vaccines and antiangiogenesis therapies will be routinely combined with traditional chemotherapy. The successful combination of these approaches will change the face of cancer from a relatively acute, life-threatening disease to a manageable chronic disorder with long survival times.

Background: Chronic hepatitis C virus (HCV) infection is a significant public health problem, with a worldwide prevalence of approximately 170 million. The standard of care for chronic HCV, a combination of alpha-interferon (IFN) and ribavirin, is only 50% effective, has serious side effects, and can be prohibitively expensive for low-income countries with a high prevalence of HCV. Many patients use natural products, including those who are not eligible for IFN/ribavirin, cannot afford treatment, or fail to respond to IFN. Methods: Extensive literature searches were conducted in order to identify clinical trials and reviews of natural products used for treatment of chronic HCV. This review focuses on the composition, pharmacology and results of clinical trials of three natural products: Oxymatrine, TJ-108/schisandra/Gomisin A and lactoferrin. Results: Several laboratory and human studies have been performed to evalaute these alternative treatments, but many of these studies are small, uncontrolled and have other important design flaws. While they do offer some safety and efficacy data, none of these studies is conclusive. Conclusion: Further research is needed on the effectiveness of these natural products for treatment of chronic HCV, including their preparation and standardization.

OBJECTIVE: To systematically review the literature on the ability of low-dose (LD) and ultra-low-dose (ULD) toxin exposure to prevent and treat biological and chemical threats. METHODS: Laboratory research articles on protection or treatment from LD or ULD exposure for the 13 high-risk chemical and biological warfare threats were collected and systematically evaluated for quantity and scientific quality using pre-defined methodological criteria. RESULTS: Over 2600 articles were screened. Only five studies met the inclusion criteria examining stimulation and protective effects of LD- or ULD-exposures to the 13 pre-identified biological and chemical agents. The quality evaluation (QE) of these studies was above average with a mean QE score of 70.6% of maximum. Two articles of fair to good quality reported both protective and treatment efficacy from exposure of animals or humans to LD- and ULD-exposures to toxins of risk in biochemical warfare. CONCLUSION: There is little research on agents of biological and chemical warfare investigating the possible use of LD- and ULD-toxins for protection and treatment. The existing literature is generally of good quality and indicates that rapid induction of protective tolerance is a feasible but under-investigated approach to bioterrorist or biowarfare defense. In our opinion, further research into the role of induced protection with LD- and ULD-toxic agents is needed.

BACKGROUND: While a number of reviews of homeopathic clinical trials have been done, all have used methods dependent on allopathic diagnostic classifications foreign to homeopathic practice. In addition, no review has used established and validated quality criteria allowing direct comparison of the allopathic and homeopathic literature. METHODS: In a systematic review, we compared the quality of clinical-trial research in homeopathy to a sample of research on conventional therapies using a validated and system-neutral approach. All clinical trials on homeopathic treatments with parallel treatment groups published between 1945-1995 in English were selected. All were evaluated with an established set of 33 validity criteria previously validated on a broad range of health interventions across differing medical systems. Criteria covered statistical conclusion, internal, construct and external validity. Reliability of criteria application is greater than 0.95. RESULTS: 59 studies met the inclusion criteria. Of these, 79% were from peer-reviewed journals, 29% used a placebo control, 51% used random assignment, and 86% failed to consider potentially confounding variables. The main validity problems were in measurement where 96% did not report the proportion of subjects screened, and 64% did not report attrition rate. 17% of subjects dropped out in studies where this was reported. There was practically no replication of or overlap in the conditions studied and most studies were relatively small and done at a single-site. Compared to research on conventional therapies the overall quality of studies in homeopathy was worse and only slightly improved in more recent years. CONCLUSIONS: Clinical homeopathic research is clearly in its infancy with most studies using poor sampling and measurement techniques, few subjects, single sites and no replication. Many of these problems are correctable even within a "holistic" paradigm given sufficient research expertise, support and methods.

Complementary and alternative medicine (CAM) is an area of great public interest and activity, both nationally and worldwide. Many alternative medical practices have existed for hundreds, even thousands of years. Patients and professionals are turning to CAM for a variety of reasons. Most have tried conventional medicine for a particular (usually chronic) medical condition and have found the results inadequate. Some are concerned over the side effects of conventional therapies. Some are seeking out a more "holistic" orientation in health care where they can address body, mind, and spirit. A continuing challenge will be how to address CAM services that are based on time, practitioner-patient interactions, and self-care, using modern standards of evidence, education, licensing, and reimbursement. For most CAM therapies, there is insufficient research to say definitively that it works and CAM research is especially limited in the area of cancer. Given that situation, the questions (but not answers) facing the medical practitioner are clear-cut. Should the practitioner await the definitive results of formal Phase III randomized clinical trials, or should the practitioner rely on limited data, seeking out evidence that makes physiological sense and small trials that seem to offer some benefit to the patient? When and at what point do you discourage, permit, or recommend an available alternative therapy? The answers are not simple. There may be differences of opinion and values among the patient, the practitioner, and the organizations that pay for a therapy. CAM areas should be approached with every patient who enters the office recognizing that there are precautions to consider when patients are using, or plan to use, such therapies. This paper presents a broad survey of what complementary and alternative medicine is from the perspectives of both the public as user and the conventional medical practitioner, as well as provides examples of issues pertinent to understanding and evaluating research in CAM. The past is back and the future will involve integration of modern and ancient ways.

Reduced bone density and osteoporosis are significant health problems and contributors to disability and mortality among older women and men. Therefore the decline of bone mineral content (BMC) and bone mineral density (BMD) are aspects of ageing with great medical and social significance. In recent years a low body weight was declared to be an important risk factor for the development of osteoporosis. In the present study the impact of weight status, defined by the categories of the WHO, on BMC of the whole body and BMD of the proximal femur end, determined by dual energy x-ray absorptiometry (DEXA), were studied in 77 female and 62 male probands aged between 60 and 92 years (x = 71.7 yrs). With increasing weight status (BMI categories), BMC and BMD increased significantly (p < 0.001). This was true of both sexes. Even moderate overweight women and men (BMI 25.0-29.99) showed a significantly higher bone density than their normal weight counterparts (BMI < 25.0). In the present study a marked positive impact of body weight on bone density of old-aged women and men could be shown.

OBJECTIVE: We wished to determine third-year medical students' opinions and knowledge related to complementary and alternative medicine (CAM) in a school with no formal or elective course on the subject. STUDY DESIGN: A questionnaire was offered to third-year medical students during their 8-week rotation on obstetrics and gynecology. RESULTS: Most students had been exposed to CAM therapies, knew that the majority of the American public was using CAM, believed that some CAM interventions were useful, and did not believe CAM therapies were a threat to public health. Most students had insufficient knowledge or understanding of the safety or lack of it for 10 of the more common CAM modalities. Most respondents thought these interventions were useful, but would not refer the patient nor dissuade her from using them. There were no significant differences in responses between men and women or related to the time in the year of the clerkship. CONCLUSION: Medical students in this school self-identified an interest about the clinical usefulness of 10 CAM modalities, but did not have sufficient knowledge about the safety for 10 of the more common CAM modalities. Including CAM topics in the medical school curriculum would better prepare physicians to respond to patient inquiries about CAM and thereby to fulfill their role as patient advocates.

OBJECTIVES: In the present study the associations between bone density of the proximal femur end and weight status, fat distribution patterns (FDI) and body composition parameters i.e. amount of body fat and lean body mass were tested in a sample of old aged women and men. METHODS: In 77 healthy women ranging in age from 60 to 92 years (x=71.8 years) and 62 healthy men ranging in age from 60 to 86 years (x=71.5 years) the bone mineral density (BMD of the proximal femur end and the body composition parameters absolute fat mass, relative fat mass, lean body mass and bone mineral content were estimated by dual energy X-ray absorptiometry. Additionally, the weight status (body mass index, BMI) and the FDI were calculated. The bone density of the proximal femur end was correlated with the absolute fat mass and the lean body mass as well as with the BMI and the FDI. RESULTS: BMD correlated in females significantly positively with parameters of body composition, in males no significant correlations between fat mass (absolute and relative) and BMD as well as BMD/stature was found. Furthermore, it was shown that the weight status (BMI; r(2)=0.13, P<0.0003 in males and r(2)=0.27, P<0.000 in females), and the lean body mass (r(2)=0.21, P<0.001 in males, r(2)=0.36, P<0.004 in females) were associated significantly positively with the BMD of the proximal femur end in both sexes. The absolute fat mass had a significant impact on BMD in the female subsample only (r(2)=0.24, P<0.000). CONCLUSIONS: A lower weight status and a low amount of lean body mass, indicating not only lack of biomechanical forces of the proximal femur end, but also a lack of physical activity can be assumed to be associated increased bone loss and the development of osteoporosis in both sexes. An association between low amount of fat tissue and decreased BMD was especially found in women and may be due to the reduced conversion rates from androgens to estrogens in a low amount of fat tissue.

The phenomenon of spontaneous regression and remission from cancer has been observed by many physicians and was described in hundreds of publications. However, suggestive clues on cause or trigger are sparse and not substantiated by much experimental evidence. In this review, literature is surveyed and summarised and possible causes are discussed. At least in a larger fraction of cases a hefty feverish infection is linked with spontaneous regression in time and is investigated as putative trigger. Epidemiological and immunological evidence is put into perspective. An online forum to discuss the possible application of fever therapy in the future can be accessed at http://bioinfo.tg.fh-giessen.de/fever-and-cancer.

It is generally observed that countries with heavy infectious burden show lower cancer incidence as compared to more affluent nations. With the emerging paradigm on microbial heat shock proteins (hsps) as molecular link between infections and autoimmune diseases, we posit a new hypothesis, the "mimotope-hormesis", on the immunologic impact of infections on regional cancer prevention. According to this, assaults of infection during early adulthood could fortify the immune system to evoke more potent defenses against late-onset diseases, such as cancer, via autoimmunity. Interestingly, both experimental and clinical data support the beneficial role of autoimmunity in long-term cancer survivors. We illustrate this by a comprehensive in silico mimotope (epitope mimicry) analysis of human infectious pathogens against mortalin (mthsp70/PB74/GRP75), a type of hsp70 protein involved in control of cell proliferation, immortalization and tumorigenesis.

Nitric oxide (NO) is a neurotransmitter which plays a powerful role in the immune system: it kills bacteria, and, it also destroys the tumor cells. Specifically, immune system stimuli gamma interferon and lipopolysaccharide transmit signals to a macrophage nucleus causing the production of nitric oxide synthase, the enzyme that converts arginine to NO. The NO thus produced not only destroys bacteria but also attacks the tumor cells by inhibiting the energy-producing Krebs cycle, electron transport activity and DNA synthesis. People in developing countries who survive repeated childhood infections must be inferred to have robust microphage/NO systems and thus, also, a strong immunity against cancer--thence the low incidence of cancers in these countries. However, those unfortunate few in these countries who do develop cancer, despite a robust microphage/NO system, must be presumed to have a markedly virulent tumor development micro-environment (e.g., activation of tumor promotion genes, inactivation of tumor suppression genes, multiple mutations, etc.) that escapes even the particularly alert immune surveillance--thence the earlier (by about a decade) death by cancer in those countries. Thus the NO hypothesis put forward here simultaneously provides a mechanistic causation for (i) low cancer incidence in countries subjected to heavy infectious burdens, and (ii) the earlier occurrence (by about a decade) of major cancers in those countries when the immune surveillance, despite its robustness, fails to destroy the incipient formation of cancer cells.

Two phenomena, one of which relates to the area of human reproduction and the other to the frequency, distribution, and control of disease in a population have emerged in the previous century and continue intensively to develop nowadays. Both these phenomena are directly related to the changes which are occurring in the incidence and prevalence of malignant tumours, as well as to mortality from them and to the opportunities for cancer control. The first of these phenomena has been denominated as the demographic, and the second as the epidemiological transition. The commonly accepted definition of the demographic transition is currently applied to designate a sustainable change in the type of population reproduction, when an initial and abrupt acceleration of population growth is replaced by its rapid deceleration with a subsequent stabilization of a population and a sharp change in its age structure. Demographic transition develops in a brief historical space of time and has the character of a global process. Population ageing and disequilibrium between the younger and older generations are the most important consequences of the demographic transition, and must inevitably influence the strategy and implementation of national cancer control programs. As life expectancy increases, so does the certainty that people will become more and more prone to diseases that are more common among older age groups, i.e. noncommunicable diseases and cancer in particular, rather than being affected by epidemics of infectious diseases. This situation is known as the epidemiological transition and reflects spectacular shifts in the pattern and causes of death and morbidity that have taken place in the vast majority of countries over the previous century. Epidemiological transition results in accession by poor countries to the problems of the rich, and leads to the "double burden" of disease in countries whose economies are undergoing transition, because of the still continuing burden of endemic infectious diseases. Russia is entering the final stages both of the demographic and the epidemiological transition, a period when numerous reasons, increasing demands on the systems of social protection and public health are inevitable. During the years 1992 to 2001, cancer incidence increased from 271.8 up to 313.9 per 100,000 population, i.e. a growth of over 16% and an annual rate of growth of 1.7%. According to the global estimates provided by the International Agency for Research on Cancer the number of new cancer cases in the year 2000 exceeded 10 million, and the number of deaths from cancer reached 6.2 million. The annual growth rate of global cancer incidence during the last 25-30 years was higher than the global population growth rate. Analysis of data available from population based cancer registries in Russia and abroad confirms the conclusion that cancer is mainly the fate of people belonging to the older age groups. Given the levels of exposure to specific carcinogens and genetic predisposition factors, the incidence of cancer should be considered as an exponential function of age. The unfeasibility of attempts to change, in the foreseeable future, the rate and trend of demographic transition and demographic ageing, in particular, is obvious. It would therefore be more feasible to envisage their probable consequences and to adapt the limited resources of national health and social support services to the needs of cancer control, which will significantly increase in the near future.

The recovery of the human character and purpose of life with consciousness-based medicine seems to be able to induce spontaneous remissions in several diseases. On two different occasions, we observed breast tumors reduced to less than half their original diameters (clinically judged) during a holistic session, when working with the patients in accordance with the holistic process theory of healing, the life mission theory, and the theory of human character. One tumor was histologically diagnosed as malign breast cancer prior to the session, while the other was under examination. As both patients had the affected regions of the breast surgically removed immediately after the session, we are unable to determine if they were actually healed by the holistic treatment. We find it extremely interesting that the size of a tumor can be reduced dramatically within a few hours of holistic treatment, when the patient is highly motivated for personal development. The reduction of tumor size is in accordance with the holistic view that many types of cancer are caused by emotional and existential disturbances. From a holistic perspective, cancer can be understood as a simple disturbance of the cells, arising from the tissue holding on to a trauma with strong emotional content. This is called "a blockage", where the function of the cells is changed from their original function in the tissue to a function of holding emotions. The reduction of the tumor in the two cases happened when old painful emotions were identified in the tissues, in and around the tumor, and processed into understanding; when the patients finally did let go of negative beliefs and attitudes that had kept the feeling(s) repressed to that part of the body, the tumor first softened and then disappeared, presumably by apoptosis. We believe that the consciousness-based/holistic medical toolbox has a serious additional offer to cancer patients, and we will therefore strongly encourage the scientific society to explore these new possibilities. Our holistic medical research meets both ethical dilemmas and practical difficulties, as it obviously is important for the research in induced spontaneous remissions that surgery and chemotherapy is not used before it is absolutely necessary. On the other hand, is it important for the patient"s survival that they receive any well-documented treatment as soon as possible. An additional aspect for the patient who is able to cure her own cancer is that she is much less likely to get cancer again and much better prepared to deal with other diseases and challenges in life. Knowing that one can fight even cancer gives a strong belief in life and the need to improve quality of life. The high incidence of secondary cancers and the physical and emotional wounds from the biomedical treatment seem to justify a focus on prevention and additional holistic treatment modules. To support the patient in learning the mastery of coherence of body and life, using the crisis of cancer to recover the human character and the purpose of life, seems turning a personal potential disaster into the greatest gift of all. When it comes down to it, life is not just about surviving; what is more important is to live fully, to learn from the great challenges of life, and to obtain the optimal quality of life while being here.

OBJECTIVE: The risk of serious bacterial infection (SBI) in febrile infants who are classified as low risk (LR) or high risk (HR) by the Rochester criteria has been established. LR infants average a 1.4% occurrence of SBI, whereas HR infants have an occurrence of 21%. The occurrence of SBI in Rochester LR or HR infants with confirmed viral infections is unknown. The objective of this study was to determine the occurrence of SBI in Rochester LR and HR infants with and without viral infections. METHODS: All febrile infants who were 90 days or younger and evaluated at Primary Children's Medical Center between December 1996 and June 2002 were eligible. Infants were classified as Rochester LR or HR, and discharge diagnoses were collected. Viral testing for enteroviruses, respiratory viruses, rotavirus, and herpesvirus was performed as indicated by study protocol, clinical presentation, and season of the year. Results of all bacterial cultures were reviewed. RESULTS: Of 1779 infants enrolled, 1385 (78%) had some form of viral diagnostic testing and 491 (35%) had 1 or more viruses identified. By the Rochester criteria, 456 (33%) infants were classified as LR and 922 (67%) infants as HR. For infants with viral infections, the occurrence of SBI was significantly lower than in infants without a viral infection (4.2% vs 12.3%). Rochester HR virus-positive (HR+) infants had significantly fewer bacterial infections than HR virus-negative (HR-) infants (5.5% vs 16.7%). When compared with HR- infants, HR+ infants were less likely to have bacteremia, urinary tract infection, or soft tissue infections, and HR+ infants had a similar occurrence of bacteremia as LR infants (0.92% vs 1.97%). CONCLUSIONS: Febrile infants with confirmed viral infections are at lower risk for SBI than those in whom a viral infection is not identified. Viral diagnostic data can positively contribute to the management of febrile infants, especially those who are classified as HR.

OBJECTIVES: To update an earlier published report reviewing the effectiveness and cost-effectiveness of liquid-based cytology (LBC). DATA SOURCES: Electronic bibliographic databases, relevant articles, sponsor submissions and various health services research-related resources. REVIEW METHODS: The selected data were reviewed and assessed with respect to the quality of the evidence. Pooled estimates of the parameters of interest were derived from the original and the updated studies. Meta-analyses were undertaken where appropriate. The mathematical model developed for the original rapid review of LBC was adapted to synthesise the updated data to estimate costs, survival and quality-adjusted survival of patients tested using LBC and using Papanicolaou (Pap) smear testing. Cost data from published sources were incorporated into the above model to allow economic, as well as clinical, implications of treatment to be assessed. The primary incremental cost-effectiveness ratio is the cost per life year gained (LYG), although estimates of the cost per quality-adjusted life-year (QALY) gained are also presented. A sensitivity analysis was undertaken to identify the key parameters that determine the cost-effectiveness of the treatments, with the objective of identifying how robust the results of the economic analysis are, given the current level of evidence. RESULTS: From the evidence available, it is likely that the LBC technique will reduce the number of false-negative test results. Modelling analyses undertaken as part of this study indicate that this would reduce the incidence of invasive cancer. There is now more evidence to support improvements emanating from the use of LBC screening in terms of a reduced number of unsatisfactory specimens and a decrease in the time needed to obtain the smear samples. The estimated annual gross cost of consumables and operating equipment, and other one-off conversion costs associated with introducing the new technique, will be between GBP17 and GBP38 million in England and Wales, depending on the LBC system and the configuration of the service. Analyses based on models of disease natural history, conducted in this study, showed that conventional Pap smear screening was extendedly dominated by LBC (LBC was always more cost-effective than conventional Pap smear testing over the same screening interval). Comparing LBC across alternative screening intervals gave a cost-effectiveness of under GBP10,000 per LYG when screening was undertaken every 3 years. The cost-effectiveness results were relatively stable under most conditions, although if screening outcomes such as borderline results and colposcopy are assumed to induce even small amounts of disutility then LBC screening at 5-yearly intervals may be the most cost-effective option. CONCLUSIONS: This updated analysis provides more certainty with regard to the potential cost-effectiveness of LBC compared with conventional Pap smear testing. However, there is uncertainty regarding the relative effectiveness (and cost-effectiveness) of the two main LBC techniques. Further research in the area of utility assessment may be worthwhile and possibly a full cost-effectiveness study of LBC based on a trial of its introduction in a low-prevalence population, although the results of the modelling analysis provide a robust argument that LBC is a cost-effective alternative to conventional cervical cancer screening. A randomised comparison of the two main techniques may also be useful.