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Biomedical subjects

J Kjaergaard

Publications and source records attributed to J Kjaergaard.

At least 19 recordsLinked to original sources
PubMed2001

Augmentation versus inhibition: effects of conjunctional OX-40 receptor monoclonal antibody and IL-2 treatment on adoptive immunotherapy of advanced tumor.

Therapeutic efficacy of adoptive immunotherapy of malignancies is proportional to the number of effector T cells transferred. Traditionally, exogenous IL-2 treatment has been used to promote the survival and function of transferred cells. Recently, we described the therapeutic effects of in vivo ligation of the costimulatory receptor, OX-40R, on activated T cells during early tumor growth. In this study, we examined the effects of IL-2 and OX-40R mAb on adoptive immunotherapy of advanced tumors. For treatment of 10-day 3-methylcholanthrene 205 pulmonary metastases, systemic transfer of 50 x 10(6) activated tumor-draining lymph node T cells resulted in >99% reduction of metastatic nodules. With either IL-2 or OX-40R mAb conjunctional treatment, only 20 x 10(6) cells were required. Advanced 10-day 3-methylcholanthrene 205 intracranial tumors could be cured by the transfer of 15 x 10(6) L-selectin(low) T cells derived from draining lymph nodes. In this situation, IL-2 administration inhibited therapeutic effects of the transferred cells. By contrast, 5 x 10(6) T cells were sufficient to cure all mice if OX-40R mAb was administrated. Studies on trafficking of systemically transferred T cells revealed that IL-2, but not OX-40R mAb, impeded tumor infiltration by T cells. Tumor regression required participation of both CD4 and CD8 T cells. Because only CD4 T cells expressed OX-40R at cell transfer, direct CD4 T cell activation is possible. Alternatively, OX-40R might be up-regulated on transferred T cells at the tumor site, rendering them reactive to the mAb. Our study suggests OX-40R mAb to be a reagent of choice to augment T cell adoptive immunotherapy in clinical trials.

Adjuvants, Immunologic↗
PubMed2001

[Incidence of malignant mesothelioma in Denmark and expected number of future cases among men].

INTRODUCTION: The aim was to analyse incidence rates and to predict the future number of cases of malignant mesothelioma in Denmark. METHODS: We analysed the 1912 cases of malignant mesothelioma reported to the Danish Cancer Register, 1943-1993, in order to describe the current incidence rates. The relative risks of synthetic birth cohorts were estimated by a Poisson regression model and used to predict the future number of cases in males. RESULTS: The incidence rate increased to 1.33 per 100,000 person years in men in 1983-1987, and to 0.51 in women in 1973-1977. According to a Poisson regression model, the risk in birth cohorts in males peaked in the 1940-1944 cohort and decreased to 0.57 in the 1950-1954 cohort. The age-specific incidence rate peaked at 246 per 100,000 person years in the age group of 80-84. The future annual number of mesothelioma cases is expected to peak around 2015 with 93 cases in men born before 1955. DISCUSSION: The fit of the model was not ideal, but with careful interpretation of the results we conclude that a further increase in the number of mesothelioma cases can be expected, and the effect of regulating the environmental exposure to asbestos cannot be expected within the next 10-15 years.

Adult↗
PubMed2001

Divergent effects of 4-1BB antibodies on antitumor immunity and on tumor-reactive T-cell generation.

4-1BB is an inducible receptor-like protein expressed rapidly by both CD4 and CD8 T-cells after activation. 4-1BB cross-linking, either by binding to 4-1BBL or by antibody ligation, delivers a costimulatory signal to enhance T-cell activation and proliferation. Previous studies have demonstrated that the administration of 4-1BB monoclonal antibodies (mAbs) induces antitumor immune responses. In the current study using several murine tumors, we examined the systemic effects of 4-1BB mAb on the growth of s.c., intracranial (i.c.), and pulmonary metastases. In addition, the effects of 4-1BB mAb on the generation of antitumor effector T cells were examined. Treatment of 3-day i.c. MCA 205 sarcoma and GL261 glioma with the antibody resulted in prolongation of survival and cure of disease in some mice, whereas only minimal therapeutic effects were observed in established s.c. and pulmonary tumors. No antitumor effects against the poorly immunogenic B16/D5 melanoma were observed. Interestingly, successful treatment of i.c. tumors induced concomitant regression of s.c. tumors. Experiments using severe combined immunodeficient mice and mice depleted of either CD4 or CD8 T cells demonstrated T-cell dependence of the antitumor effects. For generation of effector T cells in the tumor-draining lymph nodes (LNs), administration of 4-1BB mAb had adverse effects, despite the apparent hypertrophy of the LNs. During in vitro activation of tumor-draining LN T cells with anti-CD3 and interleukin 2, the 4-1BB mAb augmented proliferation, resulting in an increase in CD8 T cells. However, they were less therapeutic than not treated LN cells. In adoptive immunotherapy, the coadministration of 4-1BB mAb enhanced the therapeutic efficacy. These results thus demonstrate the limits and potential advantages of 4-1BB antibody interactions with antitumor T cells in vivo and in vitro and suggest that therapeutic interactions of the antibody may be used in a variety of immunotherapeutic approaches.

Animals↗
PubMed2001

Potent effector function of tumor-sensitized L-selectin(low) T cells against subcutaneous tumors requires LFA-1 co-stimulation.

OBJECTIVE: Animal tumor models have demonstrated that adoptive transfer of tumor-draining lymph node (TDLN) T lymphocytes can cure established tumors in many anatomic sites. However, subcutaneous tumors are relatively refractory and have required maximally tolerated doses of cells. The goals of this study were to determine whether a subset of TDLN T lymphocytes varying in expression of the cell adhesion molecule L-selectin (CD62L) had augmented therapeutic efficacy and to determine the co-stimulatory requirements for trafficking and anti-tumor effector function. STUDY DESIGN: TDLNs were recovered from mice bearing progressive MCA 205 fibrosarcomas, and the T lymphocytes were segregated into CD62L(low) and CD62L(high) subsets and activated ex vivo with anti-CD3 mAb and IL-2. Mice bearing established subcutaneous MCA 205 tumors were treated with activated T cell subsets and in some experiments with additional mAb against cell adhesion molecules. RESULTS: Adoptive transfer of as few as 5 x 10(6) activated cells cured mice bearing 3-day subcutaneous MCA 205 tumors initiated with 6 x 10(6) cells, and the tumors demonstrated a dense infiltrate of CD62L(low) cells. In marked contrast, adoptive transfer of 10 times as many T cells derived from the reciprocal CD62L(high) compartment had no effect on tumor growth. The effector function of the CD62L(low) T cells was clearly dependent on co-stimulation through the cell adhesion molecule LFA-1, because anti-LFA-1 mAb completely abrogated the anti-tumor reactivity of the transferred cells against subcutaneous tumors and inhibited tumor infiltration. In contrast, blockade of ICAM-1, VLA-4, or VCAM-1 had no inhibitory effect on the anti-tumor function. CONCLUSION: These studies demonstrate the high therapeutic activity of the CD62L(low) subset of tumor-draining LN T cells against subcutaneous tumors, a relatively refractory site, and confirm the essential role of LFA-1 for effector T cell function. SIGNIFICANCE: Identification of the phenotype and requirements for effector function of T lymphocytes sensitized to tumor antigens has implications for clinical trials of adoptive immunotherapy for head and neck carcinoma using a similar approach.

Adoptive Transfer↗
PubMed2001

Validity and completeness of registration of surgically treated malignant gynaecological diseases in the Danish National Hospital Registry.

BACKGROUND: The increasing tendency to acquire data by linkage to registries not designed for research has introduced a problem into epidemiological research. The data is often crude or possibly incomplete and, in some cases, it has been proposed to use these registries in the routine acquisition of data for existing epidemiological research registries. This study estimates the validity and completeness of the registration of surgically treated malignant gynaecological diseases in the Danish National Hospital Registry 1977-88. METHODS: Completeness was estimated by the method of independent case ascertainment, by comparison with the registration of surgically treated gynaecological cancer cases registered in the Danish Cancer Registry. The validity of the diagnoses was analysed by comparison with the recoding of discharge summaries describing the admission of a 5% random sample. RESULTS: The completeness of registration was 87% overall. Ovarian cancer, cervical cancer and cancer of the uterus were registered with a positive predictive value (PPV) of 89-90%. DISCUSSION: The results of the study emphasise the need to consider the validation of Danish Hospital Registry data before linkage and analysis. In epidemiological cancer research the Danish Cancer Registry is the better alternative when information on malignant tumours is needed.

Denmark↗
PubMed2001

T-cell adoptive therapy of tumors: mechanisms of improved therapeutic performance.

The T cells of many cancer patients are naturally sensitized to tumor-associated antigens (Ag), or they can readily be sensitized with vaccine maneuvers. In melanoma patients, the adoptive transfer of such T cells can often be causally linked to the objective regression of established tumors. So far, few patients have shown sustained clinical benefit from such therapy, but preclinical mouse studies have now clearly delineated the hurdles that must be overcome to render T-cell-based antitumor therapy effective. Contrary to earlier expectations, it is now established that remarkably potent CD4+ and CD8+ pre-effector T cells are naturally sensitized even in mice bearing progressive, weakly immunogenic tumors. However, such T cells often display signal transduction impairments as a consequence of the tumor environment, which limit their acquisition of optimal effector function. Extracorporealization and culture of these tumor-sensitized T cells with appropriate activation stimuli not only restores normal signal transduction, but also confers resolute effector activity that can often sustain tumor rejection upon reinfusion. In mouse studies, the L-selectin(low) fraction of T cells in tumor-draining lymph nodes (TDLN) constitutes the potent pre-effector population and comprises both CD4+ and helper-independent CD8+ T cells. Appropriate in vitro activation confers an apparently unrestricted trafficking capacity to this fraction, and even the ability to proliferate within the tumor bed, leading to unprecedented tumor rejection at anatomic sites (e.g., subcutaneous and intracranial) that were historically refractory to such treatment. Such results underscore the surprising capacity of appropriately activated effector T cells to withstand the immunosuppressive, tolerogenic, and apoptotic influences of the typical tumor environment. Given the increasingly appreciated and critical communications between T cells and host Ag-presenting cells (APC), which cross-present tumor Ag, it is likely that dendritic cell-based vaccine maneuvers that promote sensitization of T1-committed L-selectin(low) antitumor T cells will play an increasingly important role in adoptive therapy strategies.

Animals↗
PubMed2000

Helper-independent, L-selectinlow CD8+ T cells with broad anti-tumor efficacy are naturally sensitized during tumor progression.

We recently reported that the CD4(+) T cell subset with low L-selectin expression (CD62L(low)) in tumor-draining lymph nodes (TDLN) can be culture activated and adoptively transferred to eradicate established pulmonary and intracranial tumors in syngeneic mice, even without coadministration of IL-2. We have extended these studies to characterize the small subset of L-selectin(low) CD8(+) T cells naturally present in TDLN of mice bearing weakly immunogenic tumors. Isolated L-selectin(low) CD8(+) T cells displayed the functional phenotype of helper-independent T cells, and when adoptively transferred could consistently eradicate, like L-selectin(low) CD4(+) T cells, both established pulmonary and intracranial tumors without coadministration of exogenous IL-2. Whereas adoptively transferred L-selectin(low) CD4(+) T cells were more potent on a cell number basis for eradicating 3-day intracranial and s.c. tumors, L-selectin(low) CD8(+) T cells were more potent against advanced (10-day) pulmonary metastases. Although the presence of CD4(+) T cells enhanced generation of L-selectin(low) CD8(+) effector T cells, the latter could also be obtained from CD4 knockout mice or normal mice in vivo depleted of CD4(+) T cells before tumor sensitization. Culture-activated L-selectin(low) CD8(+) T cells did not lyse relevant tumor targets in vitro, but secreted IFN-gamma and GM-CSF when specifically stimulated with relevant tumor preparations. These data indicate that even without specific vaccine maneuvers, progressive tumor growth leads to independent sensitization of both CD4(+) and CD8(+) anti-tumor T cells in TDLN, phenotypically L-selectin(low) at the time of harvest, each of which requires only culture activation to unmask highly potent stand-alone effector function.

Adenocarcinoma↗
PubMed2000

Therapeutic efficacy of OX-40 receptor antibody depends on tumor immunogenicity and anatomic site of tumor growth.

The OX-40 receptor (OX-40R) is a cell surface glycoprotein of the tumor necrosis factor receptor family that is expressed primarily on activated CD4 T cells. Engagement of OX-40R by the OX-40 ligand (OX-40L) is known to costimulate the production of cytokines by activated T lymphocytes and to rescue effector T cells from activation-induced cell death. It was previously reported that in vivo ligation of OX-40R by administration of OX-40L:immunoglobulin fusion protein or OX-40R monoclonal antibody (mAb) resulted in a significant prolongation of survival of tumor-bearing mice in four histologically distinct solid tumors. In this study, we demonstrate that the therapeutic efficacy of OX-40R mAb was influenced by the tumor burden, the intrinsic immunogenicity of the tumor as well as by the histological site of tumor growth. Whereas subdermal and intracranial growth of weakly immunogenic MCA 203 and MCA 205 sarcomas and GL261 glioma were susceptible to the mAb treatment, established pulmonary MCA 205 metastases were refractory to the same regimen of treatment. Furthermore, the mAb administration had no impact on the growth of the poorly immunogenic B16/D5 mela noma. Tumor regression mediated by OX-40R mAb was dependent on the participation of both CD4 and CD8 T cells and as a result of tumor rejection, a long-term tumor-specific immunity was established. Analysis of tumor-infiltrating T cells revealed the presence of a far greater number of OX-40R+ T cells of both CD4 and CD8 phenotypes in the intracranial immunogenic GL261 glioma than that in the poorly immunogenic B16/D5 melanoma. These results suggest that ligation of OX-40R on activated T cells in situ in the tumor may provide a necessary costimulatory signal to augment immune responses leading to tumor regression and immunological memory.

Animals↗
PubMed2000

[The effect of patient-specialist-continuity in a surgical department. Evaluation of seven years of experiences].

From 1990 through 1997 the working schedules for staff surgeons underwent gradual changes. The aim was to comply with patient demands to receive care from few surgeons during hospital care. To evaluate the effect, four controlled or cross sectional studies were conducted. Quality of care was assessed by surgical audit. Patient and surgeon satisfaction was examined with questionnaires and interviews. Changes in costs were evaluated by administrative data. The number of different specialists providing care was reduced by 50%, initially during inpatient care and later also during outpatient care. The patients experienced this change as very satisfying. Hospital stay was reduced, as was time used by specialists on out-of-hours duty. The quality of care did not change neither did the use of diagnostic tests. The specialists appraised the increased individual responsibility in patient care as satisfying. Initiatives should be taken to examine whether other ways of organising work for hospital employed doctors have similar effect.

Attitude of Health Personnel↗
PubMed2000

Biodistribution and tumor localization of lymphokine-activated killer T cells following different routes of administration into tumor-bearing animals.

PURPOSE: The efficiency of adoptive cellular immunotherapy of cancer might depend on the number of effector cells that reach the malignant tissues. In the present study, the biodistribution and tumor localization of ex vivo lymphokine-activated T killer (T-LAK) cells was investigated. METHODS: T-LAK cells were labeled with 125I-dU or the fluorescent dye tetramethylrhodamine isothiocyanate (TRITC) and transferred by intravenous, -cardiac, -portal or -peritoneal injection into normal (C57BL/6) mice or mice with syngeneic day-7 to day-12 B16 melanoma metastases established in various organs. The overall biodistribution of the T-LAK cells was measured by gamma counting and their tumor localization by fluorescence microscopy. RESULTS: At 16 h after intravenous injection, the organ distribution of 125I-dU-labeled T-LAK cells was identical in normal and tumor-bearing animals. Fluorescence microscopy of lung tissue from animals receiving TRITC-labeled T-LAK cells revealed, however, a fivefold higher accumulation of T-LAK cells in lung metastases than in the surrounding normal lung tissue (1174 and 226 cells/mm2 respectively). Some pulmonary metastases were, however, resistant to infiltration. Very few intravenously injected cells redistributed to other organs or to tumors in these, since only 60 and 30 T-LAK cells/mm2 were found within metastases of the adrenal glands and the liver respectively. However, following injection of T-LAK cells via the left ventricle of the heart, a threefold increase (from 60 to 169 cells/mm2) in the number of transferred cells in metastases of the adrenal glands was observed. Moreover, following locoregional administration of T-LAK cells into the portal vein, tenfold higher numbers (from 30 to 400 cells/mm2) were found in hepatic metastases than were observed following intravenous or intracardiac injection. In the liver, a surprisingly large number of intraportally injected T-LAK cells (approx. 1300/mm2) were observed to accumulate in the perivascular spaces of the portal, but not the central veins. Even though some superficial ovarian and liver metastases were separated from the peritoneal cavity by only the peritoneal lining, no localization into these metastases was seen following intraperitoneal injection of the T-LAK cells. While treatment of tumor-bearing animals with T-LAK cells plus IL-2 reduced lung metastases by 76% as compared to treatment with IL-2 alone (P<0.03), no significant reduction of liver metastases was seen. CONCLUSIONS: T-LAK cells are able to localize substantially into tumor metastases in various anatomical locations, but mainly following locoregional injection. This finding might have important implications for the design of future clinical protocols of adoptive immunotherapy based on T cells.

Adrenal Gland Neoplasms↗
PubMed2000

Eradication of Helicobacter pylori compared with long-term acid suppression in duodenal ulcer disease. A randomized trial with 2-year follow-up. The Danish Ulcer Study Group.

BACKGROUND: Trials evaluating long-term management of duodenal ulcer disease have mainly been focused on recurrence of ulcers, disregarding effects on dyspeptic and reflux symptoms. Profound acid inhibition with a proton pump inhibitor is the gold standard therapy in acid-related diseases. We aimed to compare the symptomatic effects of eradication therapy with those of long-term omeprazole treatment in a design with periods both with and without acid inhibition. METHODS: Patients with active duodenal ulcer were randomized either to omeprazole, 20 mg twice daily until healing, followed by omeprazole, 20 mg/ day for 1 year, or to eradication therapy (metronidazole, amoxicillin, and omeprazole for 2 weeks) followed by placebo for 1 year. All patients were followed up passively for an additional year. Clinical controls were performed every 2 months the 1st year (maintenance phase) and every 6 months during the passive follow-up phase. The study was multicentric and double-blind. The primary end-point was discontinuation of treatment, irrespective of reason. RESULTS: Two hundred and seventy-six patients were randomized (139 in the eradication treatment group). In the maintenance phase there were no differences in the reporting of dyspeptic symptoms or in premature withdrawal. In the passive follow-up phase only five patients in the eradication therapy group discontinued owing to relapse of dyspeptic symptoms or ulcer, compared with 51 patients initially randomized to long-term omeprazole. There were no differences in reflux symptoms or in the development of reflux oesophagitis. CONCLUSIONS: Eradication therapy and long-term omeprazole are equally effective in controlling dyspeptic symptoms and reflux in duodenal ulcer patients with healed ulcers. One-quarter of the duodenal ulcer patients who start eradication therapy continue to be symptomatic or fail therapy for other reasons over a 2-year period. Eradication therapy does not increase the risk of reflux in ulcer patients.

Amoxicillin↗
PubMed2000

Incidence rates of malignant mesothelioma in Denmark and predicted future number of cases among men.

OBJECTIVES: This study analyzed the incidence rates of malignant mesothelioma in Denmark in order to predict the future number of cases that will occur among Danish men. METHODS: The 1912 cases of malignant mesothelioma reported to the Danish Cancer registry in 1943-1993 were analyzed in order to describe current incidence rates. By a Poisson regression model the relative risks of synthetic birth cohorts were estimated and used in the prediction of the future number of cases that will occur among Danish men. RESULTS: The incidence rate increased to 1.33 per 100000 person-years in 1983-1987 among men and to 0.51 in 1973-1977 among women. From the Poisson regression model, the risk for birth cohorts of men, relative to the 1940-1944 cohort, peaked in the 1940-1944 cohort and decreased to 0.57 in the 1950-1954 cohort. The age-specific incidence rate peaked at 246 per 100000 person-years in the age group 80-84 years. The future annual number of mesothelioma cases is expected to peak around 2015 with 93 cases among men born before 1955. CONCLUSIONS: The fit of the models was not ideal, but with careful interpretation of the results, it was concluded that a further increase in the number of mesothelioma cases can be expected, and the effect of regulating the environmental exposure to asbestos cannot be expected within the next 10-15 years.

Adult↗
PubMed1999

Infiltration of tumors by systemically transferred tumor-reactive T lymphocytes is required for antitumor efficacy.

The systemic transfer of ex vivo-activated tumor-sensitized T lymphocytes can mediate immunologically specific regression of established tumors. However, it has not been conclusively established whether the infiltration of systemically transferred T cells into metastases is required for their effector function. In this study, T cells from lymph nodes draining the murine fibrosarcoma MCA 205 cells were activated ex vivo with anti-CD3 monoclonal antibody and interleukin-2. During the final 24 h of culture, the T cells were treated with pertussis toxin (PTX) to inhibit signaling through G protein-coupled chemokine receptors required for diapedesis. Systemically transferred PTX-treated cells did not have any therapeutic efficacy against 3-day established pulmonary metastases. This lack of efficacy correlated with their failure to infiltrate the tumor parenchyma. However, PTX-treated cells responded to tumor antigen stimulation with IFN-gamma secretion in vitro. More importantly, PTX-treated effector T cells prevented tumor growth when they were admixed with tumor cells and inoculated s.c. These results demonstrate that systemically transferred tumor-reactive T lymphocytes need to infiltrate the tumor parenchyma through the endothelium to initiate tumor regression, but PTX-sensitive proteins are not required for either antigen recognition or effector functions.

Animals↗
PubMed1999

[Monitoring quality of health care using indicators].

In a modern health care system continuing measurement and monitoring of relevant clinical data comprise the base of documentation for the quality of care. Internationally there has been increasing focus on monitoring and measuring the quality of care using principals from clinical epidemiology, including quality monitoring using clinical indicators. Indicators can be derived with regard to structure, process and outcome. The indicators should be in a form which can be used within the individual department and for comparison between hospitals nationally and internationally. The idea of professional indicators is to be able to track developments over time, as well to be able to respond at relevant times. The work with quality indicators will support continuing work with quality development in the medical specialities as well as giving a possibility for dialogue between politicians, the management system and the medical specialities about priority of resources and the structure of the hospital system, which extend further than the simpler issues of finance, which have been dominating until now.

Denmark↗
PubMed1999

Tumor infiltration by adoptively transferred T cells is independent of immunologic specificity but requires down-regulation of L-selectin expression.

Adoptive immunotherapy with anti-CD3/IL-2 activated tumor-draining lymph node (LN) T cells is capable of eradicating tumor established at various histological sites. Tumor-specific effector lymphocytes have recently been identified to be LN T cells with down-regulated L-selectin (L-selectin-). Using fluorochrome labeling, the present study determined the early trafficking pattern of systemically transferred cells. In mice with 10-day established pulmonary 3-methylcholanthrene (MCA) 205 metastases, accumulation of cells in tumors was evident as early as 2 h after i.v. cell transfer, and, by 24 h, >50-fold higher numbers of cells were seen in metastases than in normal tissues. Similarly, transferred cells selectively infiltrated s.c. tumors, albeit at a lower rate. Analysis of the transferred cells isolated from recipient mice revealed that tumor-infiltrating cells were mostly L-selectin- (>95%). By contrast, only 24% and 58% L-selectin- cells were found in the LN and spleen, respectively. The ability of L-selectin- cells to accumulate at tumor sites was confirmed by the transfer of purified cell populations. Despite this selective tumor infiltration, the trafficking pattern did not reflect antigenetic specificity, and tumor regression occurred only after the transfer of tumor-specific effector cells. These results, thus, suggest that there are two distinct mechanisms operative in successful adoptive immunotherapy. Early infiltration of tumors by transferred cells is dictated by the physiological properties of cells and is independent on their immunologic specificity. Tumor regression, however, requires immunologically specific interactions at the site of tumor.

Adoptive Transfer↗
PubMed1998

[A single physician or a group of specialists in the surgical ward. I: Impact on quality of the care provided by specialists].

The impact on quality of ward care provided by surgeons within two continuity schedules was assessed by explicit and implicit audit. In one schedule one surgeon provided care and in another a staff of surgeons provided care. The study included 214 consecutive inpatients. The study demonstrated that quality of ward care was unaffected by continuity schedule. In the single surgeon continuity schedule, however, nearly twice as many discharge letters were posted within four days (p < 0.001). Likewise, twice as many contained information that the patients had been informed about the diagnosis (p < 0.05). In both continuity schedules about 20% of the patients received inadequate care. Analysis of this finding demonstrated that more patients had been subject to inadequate follow-up in the single surgeon continuity schedule, whereas more patients had been subject to inadequate postoperative observation in the staff continuity schedule. In both schedules an equal number of patients had been subject to incomplete diagnoses and inadequate medical care.

Continuity of Patient Care↗