Local and global dynamics of multi-resolved polymer chains: Effects of the interactions atoms-beads on the dynamic of the chains.

We present a thorough analysis of the dynamic behaviour of hybrid atomistic/coarse-grained (CG) models of polymer melts. While structural properties are well preserved in a dual-resolved model, we show how the dynamic of the chains can be influenced by the simultaneous presence of atoms and beads. We show that although the polymer chains are long enough to exhibit reptation, the corresponding CG model is unable to capture the expected subdiffusive regimes and seems to still follow the Rouse dynamics. The introduction of atoms in the chain restores the correct dynamic regime, and the dynamics of hybrid systems becomes comparable to that of the atomistic dynamics as the atoms/beads ratio is increased.

Multiscale modelling of heterogeneous fillers in polymer composites: the case of polyisoprene and carbon black.

The dispersion of inorganic particles within polymeric materials is an extensively used method to enhance their mechanical properties. One of the major challenges in the simulation of polymer composites is to model the uneven surface of the fillers which strongly affects the dynamics of the adsorbed polymers and consequently the macroscopic mechanical properties of the final composite. Here we propose a new multiscale approach that, using experimental adsorption data, constructs the filler surface to statistically reproduce the surface defects. We use this approach to analyse the structure and dynamics of highly entangled polyisoprene melt in contact with different realistic carbon black samples. We show that the presence of the heterogeneous surface has a negligible influence on the structure of the polymer chains but a major effect on their dynamics and the surface wettability.

Cyclic urinary leukopoietic activity in gray collie dogs.

The urinary activities for bone marrow colony formation were measured on consecutive 24-hour urine samples from two gray collie dogs with cyclic neutropenia and from two normal collies. The activity varied cyclically in the gray collies with a peak activity developing during the neutropenic phase, which antecedes the return of blood neutrophils. The activity fell to undetectable levels after the blood neutrophil counts returned to the normal range. The urine of normal dogs showed no activity. Since the dogs with cyclic neutropenia have been shown to have periodic hematopoiesis, these data suggest a regulatory hormonal role for the substance measured by this assay.

[Folic acid and congenital malformation: scientific evidence and public health strategies]. / Acido folico e difetti congeniti: evidenze scientifiche e strategie di sanità pubblica.

In Italy at least 3% of babies are born with some congenital malformation. The intake of folic acid (FA) prior to conception and during the early stages of pregnancy plays an important role in preventing neural tube defects, severe anomalies of brain embryogenesis, and other malformations such as cardiac and urinary tract anomalies, oro-facial clefts and limb reduction defects. The Italian Network for Folic Acid Promotion, coordinated by the National Center on Rare Diseases of the Italian National Institute of Health, has elaborated and diffused a recommendation for the periconceptional FA supplementation: "Women of child-bearing age, are recommended to consume 0,4 mg/day of FA, to reduce the risk of congenital defects. The intake of folic acid should start at least one month before the conception and should continue for the first quarter of pregnancy". This paper discusses various strategies in order to promote FA intake during periconceptional period. Food fortification, adopted in several countries such as USA, has raised concerns about the risk of an excessive FA intake which may lead to adverse effect such as tumour promotion. Currently, periconceptional supplementation and healthy dietary habits promotion appear to be the most effective strategies.

Computational characterisation of dried and hydrated graphene oxide membranes.

A multi-step molecular dynamics procedure was developed to construct fully flexible atomistic models of graphene oxide (GO) membranes. The method of preparation replicates the experimental synthesis of the material; i.e. the flow-directed self-assembly of individual flakes onto a substrate or filter. A total of 180 GO membrane models were prepared with water contents varying between 0 and 20%, providing an insight into changes in the membrane's interlayer distance with swelling. Membranes with 15% water content have an average interlayer distance (0.80 nm), bulk density (1.77 g cm-3) and tensile modulus (18.1 GPa) in excellent agreement with the experimental literature, demonstrating that air-dried membranes have 15% water content. The models reveal the intrinsic structural heterogeneity and complex morphology of GO membranes. This feature has previously been unaccounted for in both experimental interpretations and GO nanopore models, which often use pre-defined and idealised 2D geometries. Completely dried membranes have considerable free pore volume. This observation explains the modest change in interlayer distance (0.02 nm) as the membrane's water content is increased from 0% to 10% compared to a much more significant change (0.12 nm) as the water content is increased from 10% to 20%. Combined with this new understanding of membrane swelling, the availability of such representative models opens the possibility of the molecular-level design of GO membranes for a variety of applications, such as gaseous and aqueous separations.

Intestinal lymphangiectasia: a protein-losing enteropathy with hypogammaglobulinemia, lymphocytopenia and impaired homograft rejection.

Intestinal lymphangiectasia is a disease characterized by dilated intestinal lymphatics, protein-losing enteropathy, hypoalbuminemia, and edema. The immunologic status of 18 patients with intestinal lymphangiectasia was studied. Concentrations of IgG, IgA, and IgM were measured by immune precipitation and metabolism of these three immunoglobulins was studied using purified radioiodinated proteins. The serum concentration and total body pool of each immunoglobin were greatly reduced. The fraction of the intravascular protein pool catabolized per day was increased to 34% for IgG, 59% for IgA, and 66% for IgM; these are in contrast with control values of 7%, 28%, and 17%, respectively. Synthetic rates of the immunoglobulins were normal or slightly increased. Primary circulating antibody response was tested in five patients with Vi and tularemia antigens. Titers elicited in patients with the Vi antigen were significantly lower than those seen in a control group, whereas no difference was seen between patient and control responses to the tularemia antigen. Lymphocytopenia was noted in patients with intestinal lymphangiectasia. The mean circulating lymphocyte count was 710 +/- 340/mm(3) in contrast to 2500 +/- 600/mm(3) in controls. Cellular hypersensitivity was studied with skin tests and skin grafts. 91% of normal individuals reacted to at least one of the four skin test antigens: purified protein derivative, mumps, Trichophyton, and Candida albicans; in contrast, only 17% of patients with intestinal lymphangiectasia had a positive reaction. Each of three patients tested with dinitrochlorobenzene had a negative reaction. Finally, all four patients who received skin homografts have retained these grafts for at least 12 months. The immunological disorders in patients with intestinal lymphangiectasia appear to result from loss of immunoglobulins and lymphocytes into the gastrointestinal tract secondary to disorders of lymphatic channels. Lymphocyte depletion then leads to skin anergy and impaired homograft rejection.

Cryptorchidism and hypospadias in the Sicilian district of Ragusa and the use of pesticides.

The aim of the study was to explore the role of environmental exposures to pesticides in the birth prevalence of hypospadias and cryptorchidism, in the 12 agricultural municipalities of Ragusa Sicily. Data on the birth prevalence of the two birth defects were obtained from the local pediatric services for the period 1998-2002. Municipalities were ranked according to the degree of "pesticide impact" on the basis of three quantitative criteria of intensity of agricultural activities of the population. We found a significantly higher birth prevalence of hypospadias with increasing "pesticide impact" (trend test, P=0.003). The association with cryptorchidism was not statistically significant, but when the two birth defects were pooled together, the linear trend was significant (trend test, P=0.001).

Cancer treatment and age: patient perspectives.

BACKGROUND: Despite some evidence that age does not meaningfully influence the efficacy or toxicity of cancer treatment, older patients tend to receive less comprehensive cancer therapies. PURPOSE: We conducted a population-based study to evaluate the selection of cancer treatment among the elderly. METHODS: Between September 1 and November 30, 1990, we interviewed by telephone a sample of 628 female Wisconsin residents recently diagnosed with breast (507) or colorectal (121) cancer. The women, aged 20-74 at the time of diagnosis, were identified through Wisconsin's statewide tumor registry. The approximately 30-minute long telephone interview, part of a larger study of cancer etiology, included questions on treatment history, physician specialty, and reasons for the selection of specific therapies. Analyses compared the proportion of subjects with various treatment characteristics according to age (< 65 and > or = 65 years). In evaluating the effect of age on selected therapies, we adjusted summary proportions for stage of disease using the indirect method. The Mantel-Haenszel chi square statistic was used to evaluate statistical significance of the differences in proportions. RESULTS: After adjusting for stage of disease at diagnosis, substantial variation was observed in cancer treatment according to age for both breast and colorectal cancer. Older women (> or = 65 years) with breast cancer were less likely than younger women (< 65 years) to have received conservative surgery, radiation, and adjuvant therapy. Older women were, in fact, more likely than younger women to accept mastectomy (P = .03). Consultation with a medical or radiation oncologist was less common among older than younger patients (57% versus 73%). Older women were also less likely to have alternative therapies presented to them (19% versus 31%). While older patients were less likely to have been offered adjuvant treatments, like chemotherapy (P < .01), they were also more likely than younger women to reject these treatments when offered (P = .01). These differences were observed in both breast and colorectal cancer patients. Regardless of age, the most common reasons for not selecting treatments were physicians' recommendations and the desire for more comprehensive treatment. Concern about side effects, however, was more frequently reported by older women (P = .07). CONCLUSION AND IMPLICATION: Patients' ages influence the choice of treatment. Physicians offer older women with cancer different treatments from those offered to younger women and are less likely to recommend specialist consultation. Physicians' advice and description of toxicity may influence patients' selection of treatment. However, older patients' concerns about the consequences of cancer treatment may also influence treatment choice.

In vitro induction of human skin ornithine decarboxylase by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate.

A method was developed for the in vitro induction by 12-O-tetradecanoylphorbol-13-acetate (TPA) of ornithine decarboxylase (ODC) activity in human skin punch biopsy samples. Addition of TPA to 1 ml serum-free minimum essential medium containing a single 3-mm human skin punch biopsy sample obtained from a surgical specimen resulted in an induction of ODC activity with a peak activity at 5 hours after TPA addition. In vitro induction of human epidermal ODC activity was dependent on the TPA concentration in the medium; about a twofold increase in ODC activity was observed 6 hours after the addition of 0.1 microM TPA, and about a fivefold increase in ODC activity was observed with 1 microM TPA. TPA also caused about a fivefold to sixfold increase in ODC activity in 3-mm skin punch biopsy samples from healthy volunteers. Human skin punch biopsy samples remained responsive to TPA induction of ODC activity even when stored in serum-free medium at 4 degrees C for 24 hours. A similar degree of induction of ODC activity by TPA was observed whether whole unfractionated human epidermis or a soluble epidermal extract was used for ODC assays. Increased ODC activity was the result of the increase in enzymatically active ODC protein, quantitated by a [3H]difluoromethylornithine-binding assay. Thus human skin, like mouse skin, is responsive to TPA for ODC induction.

Randomized phase II-III trial of combination beta and gamma interferons and etoposide and cisplatin in inoperable non-small cell cancer of the lung.

We observed major responses in two patients with adenocarcinoma of the lung who had received a combination of interferon (IFN)-beta and IFN-gamma, immediately followed by chemotherapy. To verify these observations, we initiated a prospective randomized phase II-III trial of etoposide and cisplatin, with or without IFN-beta and IFN-gamma, in patients with inoperable non-small cell lung cancer. Thirty-seven patients were randomized to receive either two cycles of chemotherapy or 6 weeks of IFN-beta plus IFN-gamma followed by two cycles of chemotherapy. Chemotherapy consisted of 60 mg of cisplatin/m2 on day 1 and 120 mg of etoposide/m2 on days 4, 6, and 8, repeated every 21 days. Patients who were randomized to the IFN plus chemotherapy arm received 200 micrograms of IFN-gamma and 30 x 10(6) U of IFN-beta three times per week for 6 weeks, followed by two cycles of chemotherapy. Three of 18 (17%) eligible patients in the chemotherapy arm and two of 18 (11%) patients in the combination arm had partial responses. All responses occurred while patients were receiving chemotherapy. Median survival was 190 days for the chemotherapy arm and 246 days in the combined modality arm, as estimated from Kaplan-Meier curves (P = .35). We observed no significant difference in subjective toxic effects between the two arms. We observed more hematologic toxicity during chemotherapy on the combined modality arm (P = .02). We conclude that pretreatment with IFN-beta and IFN-gamma does not enhance the efficacy of etoposide and cisplatin in this disease. Although the combined modality arm is relatively well tolerated, it does result in more chemotherapy-associated toxic effects. This study also exemplifies a hybrid phase II-III trial design, which is useful in allowing phase II results to be quickly incorporated into a phase III trial.

Effects of tamoxifen therapy on lipid and lipoprotein levels in postmenopausal patients with node-negative breast cancer.

We conducted a 2-year, randomized, double-blind, placebo-controlled toxicity trial of therapy with tamoxifen (10 mg twice a day) in 140 postmenopausal women with a history of breast cancer and histologically negative axillary lymph nodes. These women had been treated with surgery with or without radiotherapy. At a 3-month evaluation, tamoxifen-treated women showed a significant decrease in fasting plasma levels of total cholesterol and low-density lipoprotein (LDL) cholesterol, which persisted at 6- and 12-month evaluations. During the first 12 months, plasma triglyceride levels increased; small but significant decreases in high-density lipoprotein cholesterol (HDL) were observed in tamoxifen-treated women, but ratios of total cholesterol to HDL cholesterol and of LDL to HDL cholesterol changed favorably. While data relating lipid/lipoprotein profiles and cardiovascular disease are limited in women, current evidence suggests that total cholesterol and possibly low-density lipoprotein cholesterol are risk factors. We conclude that during the first 12 months of treatment, tamoxifen exerts a favorable effect on the lipid profile in postmenopausal women with early stage breast cancer.

Randomized phase I chemoprevention dose-seeking study of alpha-difluoromethylornithine.

BACKGROUND: alpha-Difluoromethylornithine (DFMO) is an irreversible inhibitor of ornithine decarboxylase (ODC), the key enzyme in mammalian polyamine biosynthesis. Levels of ODC are closely related to tumor promotion, and inhibition of ODC is associated with suppression of tumor development in laboratory animals. DFMO has shown a dose-response effect in tumor inhibition in mice. PURPOSE: A randomized phase I study of DFMO was conducted to determine the lowest daily oral dose that can achieve at least 50% inhibition of ODC activity induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in human skin, with minimal clinical toxicity (grade 1 or lower; Eastern Cooperative Oncology Group [ECOG]). METHODS: Cancer patients entered in steps 1 and 2 of the study had been treated and had no clinical evidence of cancer. In step 1, 13 patients received 0.125, 0.25, 0.5, or 0.75 g/m2 DFMO four times a day. In step 2, 13 patients received 0.125 or 0.25 g/m2 four times a day or 0.5 or 1.0 g/m2 every day. The 26 patients treated in steps 1 and 2 (range, < 1-6 months) had colon, prostate, or bladder cancer. In step 3, six cancer-free subjects at risk for colorectal cancer received 0.5 g/m2 every day for 5-12 months. To evaluate the effectiveness of DFMO in reducing TPA-induced ODC activity, we calculated the percent change from pretreatment ODC levels in skin biopsy specimens and the percentage of subjects with at least a 50% reduction in ODC levels. RESULTS: In step 1 of the study, treatment-limiting audiotoxicity was observed at the three highest doses. Because the only dose with no major toxic effects in step 2 was 0.5 g/m2 every day, that dose was administered in step 3, with no major toxic effects. Seven subjects treated with 0.5 g/m2 every day had pretreatment ODC levels in the normal range; five averaged a reduction in ODC activity of at least 50%. DFMO had linear pharmacokinetics over the entire dose range. When 0.5 g/m2 was given every day, the peak plasma concentration was 47.1 +/- 5.1 microM at 3-4 hours (monthly mean +/- SE, 14.5 +/- 5.2 microM); half-life was 3.5 hours; and area under the curve for plasma concentration x time for a single dose of DFMO was 311 +/- 39 microM x hour. CONCLUSIONS: These data support phase II chemoprevention studies with DFMO given at a dose of 0.5 g/m2 every day. IMPLICATIONS: Studies investigating prevention of cancers with DFMO are under consideration.

Tumor biology and clinical trials: the Richard and Hinda Rosenthal Foundation Award Lecture.

Laboratory research is often described as basic and clinical research, prognostic or empirical. In this address, the point is made that research may be clinical or laboratory. Good clinical research may give important biological answers. Breast cancer clinical trials are decribed in terms of their biological interpretation. A list of significant biological questions that need answering are presented.

Cancer biology and cancer cures: reflections of a clinical investigator: presidential address.

Basic biological principles in cancer biology can be learned from laboratory experiments as well as the clinic. The clinical investigator may be able to uncover cancer biology and clinical cures, an exciting possibility. Clinical trials can and should be designed to discover biological principles as well as to test one option of surgery or drug combination versus another. During the past 20 years, a variety of clinical research programs in patients with myeloma, chronic myelogenous leukemia, lymphoma, and breast cancer have led to the discovery of important biological principles. These include contributions leading to the origin of myeloid and lymphoid cells in the marrow, the discovery of immunoglobulin D myeloma, the development of effective combination chemotherapy in Hodgkin's disease, and the concept of adjuvant therapy in breast cancer. These studies also have led to improved or new therapy for these diseases. Future research and cancer cures will undoubtedly be facilitated by close collaboration between the clinical and the laboratory investigator.

Van der Waals pressure and its effect on trapped interlayer molecules.

Van der Waals assembly of two-dimensional crystals continue attract intense interest due to the prospect of designing novel materials with on-demand properties. One of the unique features of this technology is the possibility of trapping molecules between two-dimensional crystals. The trapped molecules are predicted to experience pressures as high as 1 GPa. Here we report measurements of this interfacial pressure by capturing pressure-sensitive molecules and studying their structural and conformational changes. Pressures of 1.2±0.3 GPa are found using Raman spectrometry for molecular layers of 1-nm in thickness. We further show that this pressure can induce chemical reactions, and several trapped salts are found to react with water at room temperature, leading to two-dimensional crystals of the corresponding oxides. This pressure and its effect should be taken into account in studies of van der Waals heterostructures and can also be exploited to modify materials confined at the atomic interfaces.

Developing a postgraduate medical oncology training program in Taipei, Taiwan, Republic of China.

Because cancer is the number one cause of mortality in Taiwan, a governmental decision was made to develop an experiment in medical oncology education using a United States-style training program in medical oncology in three Taipei, Taiwan, university hospitals. In the past, trainees from developing countries came to the United States or other foreign countries to receive specialty training. In doing so, the training did not necessarily prepare the individuals with skills to treat the indigenous cancers, nor did they work with other related specialists or support staff such as nursing and pharmacy, so important to providing good cancer care. This program involved 13 fellows with significant laboratory experience working with American faculty on-site. The major benefits of this model for oncology training are that the trainees developed important interdisciplinary relationships with local staff at each of the hospitals; they were involved in the treatment of the major cancer diseases of Taiwan such as nasopharyngeal, hepatocellular, and cervical cancers as well as breast, lung, and colon cancers; and they completed a certification process involving written and oral tests by two senior American oncologist examiners. Oncology services have been established at each of the hospitals and most of the fellows have expressed an interest or made arrangements to come to the United States to get additional research experience.

Inhibition of phorbol ester--induced human epidermal ornithine decarboxylase activity by oral compounds: a possible role in human chemoprevention studies.

Extensive animal data have suggested that, in some systems, the induction of ornithine decarboxylase (ODC) is an essential, although not sufficient, aspect of tumor promotion and that compounds that inhibit ODC can inhibit tumor formation. Using fasting human volunteers, we report that human epidermal and dermal ODC are consistently induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in a manner similar to that seen in mouse skin. There is a marked intersubject variation in TPA-induced epidermal ODC activity levels. Orally administered compounds significantly inhibited TPA-caused human epidermal ODC induction. These data may be useful in the further development of drugs, doses, and dose schedules for use in human cancer chemoprevention studies.

Fundamental dilemmas of the randomized clinical trial process: results of a survey of the 1,737 Eastern Cooperative Oncology Group investigators.

PURPOSE: We studied oncologists' attitudes and behavior with regard to their participation in randomized clinical trials. METHODS: We surveyed the 1,737 physician members of the Eastern Cooperative Oncology Group (ECOG) using the Physician Orientation Profile (POP), a self-administered mailed questionnaire. A response rate of 86% was achieved (1,485 of 1,737); each physician's actual patient accrual was recorded. RESULTS: All respondents indicated that they had a systematic pattern of patient preselection for entry onto trials beyond the formal inclusion/exclusion trial criteria. Eighty-nine percent stated that improving patient quality of life rather than prolonging survival was more personally satisfying. Sixty-two percent did not enter a single patient during the 12-month period following the survey, while 10% entered 80% of all patients during that time. Physicians overestimated their accrual rate by a factor of 6. Eighty-three percent defined randomization and adherence to trial protocol as a serious challenge to their ability to make individualized treatment decisions. CONCLUSION: This study raises questions regarding the following: (1) the perceived generalizability of trial findings, (2) the role of end points other than survival for clinical trials, (3) the consequences of physician overestimation of patient accrual, and (4) the impact of randomized trials on the behavior of clinicians. Further investigation into these critical issues will provide meaningful recommendations to enhance the future design, implementation, and conduct of randomized clinical trials in cancer.

Adjuvant CMFP versus CMFP plus tamoxifen versus observation alone in postmenopausal, node-positive breast cancer patients: three-year results of an Eastern Cooperative Oncology Group study.

After mastectomy, 265 postmenopausal patients with node-positive breast cancer were stratified according to pathologic nodal status and estrogen-receptor (ER) status and randomized to receive either 12 cycles of cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone (CMFP), or CMFP plus tamoxifen (CMFPT), or observation alone. Patients entered the study between March 1978 and July 1981. Cox regression analysis indicated that, compared to observation alone, chemotherapy (CMFP and CMFPT groups combined) led to a significant reduction in relapses by the end of the first year of study in every examined prognostic subgroup. However, after the first year the relapse-free survival curves of all treatment groups tended to merge, so that by three years 52% of the observation group and 51% of the chemotherapy groups remained disease free. Chemotherapy continued to show a significantly superior relapse-free survival rate for three years only in the subgroup of patients with ER-negative tumors (the subgroup with the largest relapse-free survival advantage at one year). The addition of tamoxifen produced no benefit or harm in any prognostic subcategory examined. ER status was prognostically important for predicting early relapse only in those patients not receiving chemotherapy, due to the greater effectiveness of this chemotherapy to prevent early relapse in the ER-negative subgroup. Treatment has had no early effect on survival. As breast cancer continues to recur even after ten or more years, later relapse patterns may alter these results.

Randomized comparison of three adriamycin regimens for metastatic soft tissue sarcomas.

This study addressed two major questions regarding therapeutic use of Adriamycin ([Adr] Adria Laboratories, Columbus, OH) in adult soft tissue sarcomas: the influence of dosing schedule and the value of adding imidazole carboxamide (DTIC) to Adr. Patients with objectively measurable metastatic soft tissue sarcomas were randomized to Adr 70 mg/m2 intravenously (IV) day 1 and every 3 weeks (94 patients); Adr 20 mg/m2 IV day 1, 2, and 3, and 15 mg/m2 IV day 8 and weekly thereafter (89 patients); and Adr 60 mg/m2 IV day 1 and DTIC 250 mg/m2 days 1 to 5, repeated every 3 weeks (92 patients). The regimens using Adr as a single agent resulted in an equivalent response frequency (18% and 16%) and survival (median, 8.0 and 8.4 months). DTIC significantly increased (P less than .02) the overall response frequency of Adr to 30%. However, DTIC did not influence survival (median, 8.0 months) or increase the number of complete responses. The toxicities of the two single-agent regimens differed: Adr weekly resulted in more stomatitis (P = .09) and less hematologic toxicity (P less than .05). DTIC resulted in substantially increased toxicity, primarily gastrointestinal (P less than .002); overall, 98% of patients receiving Adr-DTIC experienced moderate or worse toxicity. To decrease the potential for error in interpretation of treatment results, histopathological confirmation of diagnosis was undertaken by a panel of reference pathologists; pathology slides were submitted on 97% of entered patients. The on-study clinical diagnosis was affirmed in 199 of 316 patients (63%) with a final review. In 23% of patients, the panel agreed with the diagnosis of soft tissue sarcoma, but not with the type. In 14%, the panel concluded that a diagnosis of mesenchymal malignancy could not be affirmed. Final treatment results were based on the 275 pathologically confirmed, eligible patients. The most common histological subtype entered was leiomyosarcoma (99 patients). The response to Adr-DTIC of this subtype was higher (44%) than that of any other subtype. However, this difference alone was not responsible for the overall superiority of the combination. This confirmed that the combination of DTIC plus Adr adds to the response rate of Adr alone in soft tissue sarcomas. Whether the increased response frequency, without an impact on survival, is worth the significantly greater toxicity remains a subjective judgement that must be made within the context of the individual patient.