Prior abdominal open surgery does not impair outcomes of laparoscopic colorectal surgery: a case-control study in 367 patients.

AIM: This prospective case-matched study was conducted to compare the outcome of laparoscopic colorectal surgery in patients with and without prior abdominal open surgery (PAOS). METHOD: From June 1997 to December 2010, 167 patients with PAOS (including midline, Pfannenstiel, subcostal, right upper quadrant or transverse incision) were manually matched to all identical patients without PAOS from our prospective laparoscopic colorectal surgery database. Matching criteria included age, gender, American Society of Anesthesiology (ASA) score, body mass index, diagnosis and surgical procedure performed. Primary end-points were postoperative 30-day mortality and morbidity. Secondary end-points included operating time, conversion rate and length of stay. RESULTS: A total of 367 patients (167 with PAOS and 200 without PAOS) were included in this study. PAOS was associated with a significantly increased mean operating time (229±66 min vs 216±71 min, P=0.044). The conversion rate was significantly higher in patients with PAOS, compared with patients without PAOS (22%vs 13%, P=0.017). There was one (0.3%) postoperative death. The overall postoperative morbidity rate was similar in both groups (22%vs 19%, P=0.658), including Grade 3 or Grade 4 morbidity, according to Dindo's classification (5%vs 5%, P=0.694). Mean hospital stay showed no difference between both groups (10±7 days vs 9±5 days, P=0.849). CONCLUSION: This large case-control study suggests that PAOS does not affect postoperative outcomes. For this reason, a systematic laparoscopic approach in patients with PAOS, even with midline incision, should be considered in colorectal surgery.

Correlation of haemophagocytosis with clinical criteria of haemophagocytic lymphohistiocytosis and recommendations for bone marrow reporting.

Haemophagocytic lymphohistiocytosis (HLH) is a rare condition resulting from a dysregulated inflammatory response. Currently there are no guidelines on the reporting of haemophagocytosis on bone marrow biopsy (BM) and lack of evidence on correlation between haemophagocytosis with the clinical diagnostic criteria for HLH. We aimed to assess if the amount of haemophagocytosis identified in the BM correlates with HLH-2004 criteria. Secondary aims were to evaluate inter-observer variability in reporting haemophagocytosis, and to formulate recommendations for screening in bone marrow specimens. A retrospective review of bone marrow biopsies from adult patients under investigation for HLH was undertaken independently by two haematopathologists who were blinded to the original biopsy report. The average number of actively haemophagocytic cells in each slide were quantified. Cases with discordance pertaining to the degree of haemophagocytosis were reviewed by both assessors to reach a consensus. Sixty-two specimens from 59 patients were available for assessment. An underlying haematological condition was identified in 34 cases (58%). There was a significant association between the amount of haemophagocytosis identified on the aspirate samples and the number of HLH-2004 criteria met (p<0.0001). In patients where haemophagocytosis was present (n=31), there was a correlation between the amount of haemophagocytosis and ferritin (p=0.041). Based on our review, we have made recommendations for the reporting of BM haemophagocytosis. Our findings indicate that the amount of haemophagocytosis present on BM samples correlates with the number of HLH-2004 criteria. We found marked interobserver variability which we anticipate can be rectified with our recommendations for reporting.

Outer periarteriolar lymphoid sheath arrest and subsequent differentiation of both naive and tolerant immunoglobulin transgenic B cells is determined by B cell receptor occupancy.

T-dependent B cell responses in the spleen are initiated in the outer periarteriolar lymphoid sheath (PALS) and culminate in the generation of proliferative foci and germinal center reactions. By pulsing anti-hen egg lysozyme (HEL) immunoglobulin transgenic (IgTg) B cells with various concentrations of HEL in vitro before adoptive transfer into normal recipients, it was shown that a critical number of B cell receptors (BCRs) must be ligated for B cells to undergo arrest in the outer PALS. T cell help was manipulated independently of the BCR stimulus by incubating B cells expressing the appropriate major histocompatibility complex class II antigen with a peptide recognized by CD4(+) TCR Tg T cells. B cells which either failed to arrest in the outer PALS due to a subthreshold BCR stimulus, or arrested only transiently due to the brevity of the BCR stimulus, underwent an abortive response within the follicles when provided with T cell help. In contrast, naive B cells stimulated by a sustained, suprathreshold concentration of either foreign or self-antigen and given T cell help, proliferated in the outer PALS and then differentiated. Outer PALS arrest was not influenced by the nature of the B cells occupying the follicle, but appeared to be determined solely by the magnitude of BCR stimulation. Thus antigen-pulsed B cells arrested in the outer PALS in an identical manner irrespective of whether the follicles comprised a population of normal B cells with multiple specificities, a monoclonal naive population, or a monoclonal population of tolerant B cells. In addition, tolerant B cells were found to relocate from the follicles to the outer PALS of HEL/anti-HEL double Tg mice in which the concentration of soluble self-antigen had been increased by zinc feeding. Similarly, when anti-HEL Tg mice were crossed with a second HEL Tg strain expressing a higher concentration of soluble HEL, the tolerant anti-HEL Tg B cells were located constitutively in the outer PALS. Thus, subtle variations in antigen concentration resulted in dramatic changes in positioning of B cells within the spleen. A series of mixed bone marrow chimeras in which the effective antigen concentration was inversely related to the number of self-reactive B cells due to absorption of antigen by transgene-encoded membrane and secreted Ig, was used to confirm that alteration in B cell position previously attributed to changes in follicular composition could be explained on the basis of available antigen concentration, rather than the diversity of the repertoire.

Germinal centers without T cells.

Germinal centers are critical for affinity maturation of antibody (Ab) responses. This process allows the production of high-efficiency neutralizing Ab that protects against virus infection and bacterial exotoxins. In germinal centers, responding B cells selectively mutate the genes that encode their receptors for antigen. This process can change Ab affinity and specificity. The mutated cells that produce high-affinity Ab are selected to become Ab-forming or memory B cells, whereas cells that have lost affinity or acquired autoreactivity are eliminated. Normally, T cells are critical for germinal center formation and subsequent B cell selection. Both processes involve engagement of CD40 on B cells by T cells. This report describes how high-affinity B cells can be induced to form large germinal centers in response to (4-hydroxy-3-nitrophenyl) acetyl (NP)-Ficoll in the absence of T cells or signaling through CD40 or CD28. This requires extensive cross-linking of the B cell receptors, and a frequency of antigen-specific B cells of at least 1 in 1,000. These germinal centers abort dramatically at the time when mutated high-affinity B cells are normally selected by T cells. Thus, there is a fail-safe mechanism against autoreactivity, even in the event of thymus-independent germinal center formation.

Generation of splenic follicular structure and B cell movement in tumor necrosis factor-deficient mice.

Secondary lymphoid tissue organogenesis requires tumor necrosis factor (TNF) and lymphotoxin alpha (LTalpha). The role of TNF in B cell positioning and formation of follicular structure was studied by comparing the location of newly produced naive recirculating and antigen-stimulated B cells in TNF-/- and TNF/LTalpha-/- mice. By creating radiation bone marrow chimeras from wild-type and TNF-/- mice, formation of normal splenic B cell follicles was shown to depend on TNF production by radiation-sensitive cells of hemopoietic origin. Reciprocal adoptive transfers of mature B cells between wild-type and knockout mice indicated that normal follicular tropism of recirculating naive B cells occurs independently of TNF derived from the recipient spleen. Moreover, soluble TNF receptor-IgG fusion protein administered in vivo failed to prevent B cell localization to the follicle or the germinal center reaction. Normal T zone tropism was observed when antigen-stimulated B cells were transferred into TNF-/- recipients, but not into TNF/LTalpha-/- recipients. This result appeared to account for the defect in isotype switching observed in intact TNF/LTalpha-/- mice because TNF/LTalpha-/- B cells, when stimulated in vitro, switched isotypes normally. Thus, TNF is necessary for creating the permissive environment for B cell movement and function, but is not itself responsible for these processes.

The fate of self-reactive B cells depends primarily on the degree of antigen receptor engagement and availability of T cell help.

Self-reactive B cells from tolerant double-transgenic (Dbl-Tg) mice coexpressing hen egg lysozyme (HEL) and rearranged anti-HEL immunoglobulin genes have a relatively short life span when compared to normal B cells, irrespective of whether they are exposed to antigen in multivalent membrane-bound form (mHEL-Dbl-Tg mice) or soluble form (sHEL-Dbl-Tg mice). The factors responsible for determining the fate of these B cells after encounter with self-antigen were investigated using a cell-tracking technique in which anti-HEL Ig-Tg spleen cells were labeled with the intracellular dye 5-carboxyfluorescein diacetate-succinimidyl ester (CFSE) and injected either into non-Tg recipients or a variety of HEL-Tg hosts. In non-Tg recipients, HEL-binding B cells persisted in the circulation and could be detected in the follicles of the spleen for at least 5 d. On transfer into either mHEL-Tg or sHEL-Tg hosts, they underwent activation and then rapidly disappeared from the blood and spleen over the next 3 d, consistent with the short life span reported previously. Immunohistology of spleens from sHEL-Tg recipients indicated that the transferred B cells had migrated to the outer margins of the periarteriolar lymphoid sheath (PALS), where they were detectable for 24 h before being lost. The positioning of B cells in the outer PALS depended on a critical threshold of Ig receptor binding corresponding to a serum HEL concentration between 0.5 and 15 ng/ml, but was not restricted to endogenously expressed HEL in that the same migratory pattern was observed after transfer into non-Tg recipients given exogenous (foreign) HEL. Moreover, bone marrow-derived immature Ig-Tg B cells homed to the outer PALS of sHEL-Tg mice and then disappeared at the same rate as mature B cells, indicating that the stage of maturation did not influence the fate of self-reactive B cells in a tolerant environment. On the other hand, HEL-binding B cells transferred into sHEL-Dbl-Tg recipients persisted over the 3-d period of study, apparently due to insufficient availability of antigen, as indicated by the fact that the degree of Ig receptor downregulation on the transferred B cells was much less than in sHEL-Tg recipients. If T cell help was provided to Ig-Tg B cells at the time of transfer into sHEL-Tg recipients in the form of preactivated CD4+ T cells specific for major histocompatibility complex-peptide complexes on the B cell surface, HEL-binding B cells migrated through the outer PALS of the spleen to the follicle, where they formed germinal centers, or to adjacent red pulp, where they formed proliferative foci and secreted significant amounts of anti-HEL antibody. Taken together, these results indicated that the outcome of the interaction between self-antigen and B cells is largely determined by a combination of the degree of receptor engagement and availability of T cell help.

De novo infantile primary antiphospholipid antibody syndrome.

Most autoimmune diseases are rare in infants. Early onset can represent an extreme phenotype arising from strong genetic predisposition relatively independent of environmental influence. Alternatively, neonatal autoimmunity can arise from transplacental passage of maternal pathogenic IgG autoantibodies. Distinguishing between these possible explanations is crucial for determining the prognosis in the specific patient, and has important implications for understanding pathogenesis. We report a case of neonatal thrombotic stroke associated with both cardiolipin and ß2-glycoprotein I antibodies in neonatal serum but absent from cord blood and maternal serum. While the child also carried one prothrombotic allele of factor V (Leiden allele), which may have contributed to the risk of thromboembolic disease, the serological analysis represents unequivocal evidence of de novo neonatal primary phospholipid antibody syndrome.

Epidemiology of primary systemic vasculitis in the Australian Capital Territory and south-eastern New South Wales.

BACKGROUND: The aim of the study was to determine the epidemiology of primary systemic vasculitis in the Australian Capital Territory and the surrounding rural region between 1995 and 2005. METHODS: Cases were ascertained by a medical record search according to international consensus classification criteria. For antineutrophil cytoplasmic antibody-associated vasculitides, ascertainment was corroborated by a search of all positive antineutrophil cytoplasmic antibody serology during the study period. Denominators were obtained from region-specific census data collected during the study period. Prevalence, incidence and patient characteristics for primary systemic vasculitides were determined for two 5-year periods, 1995-1999 and 2000-2004. RESULTS: We identified 41 cases of primary systemic vasculitides (Wegener's granulomatosis (WG), microscopic polyangiitis (MPA), Churg-Strauss syndrome or polyarteritis nodosa) between 1995 and 1999 and 67 between 2000 and 2004, giving prevalences of 95/million (95% confidence interval (CI) 76.9-116.1) and 148/million (95%CI 125.1-173.9), respectively. Annual incidence was similar in both periods (approximately 17/year per million adult population). Disease-specific incidences (per million per year) for each of the two periods were 8.8 and 8.4 for WG, 2.3 and 5.0 for MPA, 2.3 and 2.2 for Churg-Strauss syndrome and 2.3 and 1.1 for polyarteritis nodosa. The rural incidence of MPA was 13.9 (95%CI 7.7-23.5) compared with 1.6 (95%CI 0.2-7.2) in the city and there was a trend towards a higher incidence of WG in rural than urban areas. CONCLUSION: The overall incidence of primary systemic vasculitides is similar to that reported from other developed countries. WG is more common in south-eastern Australia than in southern Europe, whereas MPA is less common. There was a trend towards higher incidence of antineutrophil cytoplasmic antibody-associated vasculitides in rural than urban areas.

Colorectal carcinoma with potentially resectable metastases: factors associated with the failure of curative schedule.

BACKGROUND: The management of patients with colorectal cancer (CRC) and synchronous liver metastases (SLM) depends on the primitive tumor, resectability of the metastatic disseminations and the patient's comorbid condition(s). Considering all patients with potentially resectable primary CRC and SLM, curative resection (R0) will be possible in some patients, although in others surgery will never be performed. The purpose of our study was to identify factors of failure of the curative schedule in these patients. METHODS: We reviewed the data of patients with CRC and SLM between January 2002 and March 2007. Two groups were defined: group R0 when complete metastatic and primary tumor resection was finally achieved after one and more surgical stages and group R2 when curative resection was not possible at the end of the schedule. Clinical, pathologic and outcome data were retrospectively analyzed as well as preoperative management of SLM (chemotherapy, radiofrequency, portal vein embolization). RESULTS: Forty-five patients were included. Curative resection (group R0) was performed in 31 patients (69%) with 48% undergoing major hepatic resection. Mortality of hepatic resection was 0% although it was 9% for primitive tumor. Portal vein embolization was performed preoperatively in eight patients and radiofrequency ablation in 13. Median follow-up was 21 months. Overall survival was 86% at one year and 39% at three years. Survival in group 1 was 97 and 57% at one and three years respectively. Disease-free survival was 87 and 40% at one and three years. Tumor recurrence was noted in 61% of resected patients. At multivariate analysis, number of hepatic metastases superior than three and complicated initial presentation of primitive tumor were found to be significant and predictors of failure of hepatic resection. CONCLUSION: Aggressive management with curative resection of SLM may enable long-term survival. More than three SLM and complicated initial presentation of primitive tumor are factors predictive of failure of the curative schedule.

Profound lymphopenia and bacteraemia.

Bacteraemia often carries a poor prognosis despite prompt antibiotic therapy and is associated with late morbidity and mortality that is difficult to explain. Here, we describe perisistent B- and T- cell lymphopenia in a cohort of patients with Gram-positive and Gram-negative bacteraemia. This suggests previously unrecognized mechanisms of subversion of immunity by pathogens and might explain the comorbidity of blood stream infection with bacteria.

The molecular basis of lymphoid architecture and B cell responses: implications for immunodeficiency and immunopathology.

Immune responses usually take place in secondary lymphoid organs such as spleen and lymph nodes. Most lymphocytes within these organs are in transit, yet lymphoid organ structure is highly organized; T and B cells segregate into separate regions. B cell compartments include naïve cells within follicles, marginal zones and B-1 cells. Interactions between TNF family molecules on hematopoietic cells and their receptors on mesenchymal cells guide the initial phase of lymphoid organogenesis, and regulate chemokine secretion that mediates subsequent T-B cell segregation. Recruitment of B cells into different compartments depends on both the milieu established during organogenesis, and the threshold for B cell receptor signaling, which is modulated by numerous coreceptors. Novel intrafollicular (germinal center) and extrafollicular (plasma cell) compartments are established when B cells respond to antigen. These divergent B cell responses are mediated by different patterns of gene expression, and influenced again by BCR signaling threshold and cellular interactions that depend on normal lymphoid architecture. Aberrant B cell responses are reviewed in the light of these principles taking into account the molecular and architectural aspects of immunopathology. Histological features of immunodeficiency reflect defects of B cell recruitment or differentiation. B cell hyper-reactivity may arise from altered BCR signaling thresholds (autoimmunity), defects in stimuli that guide differentiation in response to antigen (follicular hyperplasia vs plasmacytosis), or defective B cell gene expression. Interestingly, in diseases such as rheumatoid arthritis, Sjogren's syndrome and Hashimoto's thyroiditis lymphoid organogenesis may be recapitulated in non-lymphoid parenchyma, under the influence of molecular interactions similar to those that operate during embryogenesis.

[Contribution of Arantius' ligament to the control of left and middle hepatic veins]. / Apport du ligament veineux (ligament d'Arantius) lors du contrôle de la veine hépatique gauche et du tronc veineux hépatique.

Control of the left hepatic vein or of the common trunk left hepatic vein-middle hepatic vein during a hepatic resection is presumed difficult. This control is facilitated by the knowledge of the Arantius' ligament anatomy. The combined manoeuvre which associates lowering the top of segment I and section-traction of the Arantius' ligament allows exposure of the inferior aspect of the left or middle hepatic veins and allows safe dissection of these veins.

Stress reactivity of the brain noradrenergic system in three rat strains differing in their neuroendocrine and behavioral responses to stress: implications for susceptibility to stress-related neuropsychiatric disorders.

The brain noradrenergic system is activated by stress, modulating the activity of forebrain regions involved in behavioral and neuroendocrine responses to stress. In this study, we characterized brain noradrenergic reactivity to acute immobilization stress in three rat strains that differ in their neuroendocrine stress response: the inbred Lewis (Lew) and Wistar-Kyoto (WKY) rats, and outbred Sprague-Dawley (SD) rats. Noradrenergic reactivity was assessed by measuring tyrosine hydroxylase mRNA expression in locus coeruleus, and norepinephrine release in the lateral bed nucleus of the stria terminalis. Behavioral measures of arousal and acute stress responsivity included locomotion in a novel environment, fear-potentiated startle, and stress-induced reductions in social interaction and open-arm exploration on the elevated-plus maze. Neuroendocrine responses were assessed by plasma adrenocorticotropic hormone. Compared to SD, adrenocorticotropic hormone responses of Lew rats were blunted, whereas those of WKY were enhanced. The behavioral effects of stress were similar in Lew and SD rats, despite baseline differences. Lew had similar elevations of tyrosine hydroxylase mRNA, and initially greater norepinephrine release in the lateral bed nucleus of the stria terminalis during stress, although both noradrenergic responses returned toward baseline more rapidly than in SD rats. WKY rats showed depressed baseline startle and lower baseline exploratory and social behavior than SD. However, unlike the Lew or SD rats, WKY exhibited a lack both of fear potentiation of the startle response and of stress-induced reductions in exploratory and social behavior, indicating attenuated stress responsivity. Acute noradrenergic reactivity to stress, measured by either tyrosine hydroxylase mRNA levels or norepinephrine release, was also attenuated in WKY rats. Thus, reduced arousal and behavioral responsivity in WKY rats may be related to deficient brain noradrenergic reactivity. This deficit may alter their ability to cope with stress, resulting in the exaggerated neuroendocrine responses and increased susceptibility to stress-related pathology exhibited by this strain.

The role of T cells in the regulation of B cell tolerance.

The study of conventional models of B cell tolerance has suggested that self-tolerance is imposed on B cells at an early stage in their development due to a peculiar sensitivity of immature B cells to tolerance induction. While this concept accounts for some aspects of central B cell tolerance, it is inconsistent with recent reports of tolerance induction in mature splenic B cells from immunoglobulin transgenic mice. We present an alternative model, the hierarchical model (Aust. N. Z. J. Med. 25, 761-767, 1995), in which regulation of naive B cell reactivity is a function of antigen signal strength and availability of T cell help, but is independent of B cell maturation stage. In turn, the development of tolerance or memory in the T cell compartment is dependent on a combination of antigen-MHC recognition by T cells and antigen-nonspecific signalling by antigen-presenting cells. Using a transgenic model of T-B collaboration, we have shown that both immature and mature self-reactive B cells can be rescued and induced to secrete auto-antibody if the B cell determinant is linked to a carrier protein bearing a foreign T cell determinant.

p53 mutations in tumors derived from irradiated human thyroid epithelial cells.

A non-tumorigenic human thyroid epithelial cell line (HTori-3) has been transformed into tumorigenic cells by exposure in vitro to alpha particles or gamma-radiation. These transformants were tumorigenic in athymic nude mice and tumors were transplantable into other nude mice. To further characterize processes involved in neoplastic progression, the tumor cell lines derived from these radiation-induced primary tumors were screened for mutations in the p53 tumor suppressor gene. p53 mutation was detected by single-strand conformation polymorphism (SSCP) analysis of exons 5 to 8 inclusive. Mutations detected by SSCP analysis were confirmed by sequencing. Mutations were detected in all four exons analysed, although there was no correlation between dose, LET or mutation position or frequency. Mutations in p53 exons 6 and 7 have been reported in the childhood papillary thyroid carcinomas in Belarus presumably as a result of radioiodine fall-out. Similarly here, p53 mutations are induced experimentally during the development of human thyroid tumors generated by irradiation of a human thyroid epithelial cell line in vitro.

An intestinal epithelial defect conferring ER stress results in inflammation involving both innate and adaptive immunity.

We recently characterized Winnie mice carrying a missense mutation in Muc2, leading to severe endoplasmic reticulum stress in intestinal goblet cells and spontaneous colitis. In this study, we characterized the immune responses due to this intestinal epithelial dysfunction. In Winnie, there was a fourfold increase in activated dendritic cells (DCs; CD11c(+) major histocompatibility complex (MHC) class II(hi)) in the colonic lamina propria accompanied by decreased colonic secretion of an inhibitor of DC activation, thymic stromal lymphopoietin (TSLP). Winnie also displayed a significant increase in mRNA expression of the mucosal T(H)17 signature genes Il17a, IL17f, Tgfb, and Ccr6, particularly in the distal colon. Winnie mesenteric lymph node leukocytes secreted multiple T(H)1, T(H)2, and T(H)17 cytokines on activation, with a large increase in interleukin-17A (IL-17A) progressively with age. A major source of mucosal IL-17A in Winnie was CD4(+) T lymphocytes. Loss of T and B lymphocytes in Rag1(-/-) × Winnie (RaW) crosses did not prevent spontaneous inflammation but did prevent progression with age in the colon but not the cecum. Adoptive transfer of naive T cells into RaW mice caused more rapid and severe colitis than in Rag1(-/-), indicating that the epithelial defect results in an intestinal microenvironment conducive to T-cell activation. Thus, the Winnie primary epithelial defect results in complex multicytokine-mediated colitis involving both innate and adaptive immune components with a prominent IL-23/T(H)17 response, similar to that of human ulcerative colitis.

Nutritional implications of medication use and misuse in elderly.

Factors responsible for an increased risk of drug-nutrient interactions in the elderly are an increased exposure to drug use for chronic health conditions and the greater chance for marginal diets deficient in nutrients. Poor patient compliance and physicians' prescribing patterns further complicate the risk. Several nutrient-drug interactions cause changes in drug efficacy and affect nutritional status. To identify and assess elderly patients at risk, each should be evaluated through socioeconomic, dietary, and clinical parameters. The health-care team must be knowledgeable regarding drug interactions to properly intervene using a multidisciplinary approach. An intervention program could prevent a decline in the elderly's health status, reduce healthcare costs and improve the quality of life.

Microalbuminuria following anaphylaxis with general anaesthesia.

Microalbuminuria is increasingly recognized as a marker of pathologies that cause acute systemic capillary leak. We report a case of an anaphylactic reaction to general anaesthesia involving cardiac arrest. In this case the urinary excretion of albumin following resuscitation suggests that severe anaphylaxis is another condition for which microalbuminuria is a sensitive monitor.

Integrating personal computers into family practice: a comparison of practicing physicians and residents.

A survey was used to assess levels of experience with personal computers and interest in learning personal computer applications among Alabama family practice physicians and residents in 1994. The study compared responses of 272 physicians and 77 residents as well as responses of physicians and residents in a sample of respondents thirty-eight years old or younger, including 77 physicians and 73 residents. Almost 25% of physicians reported never having used a computer, compared to 7.9% of residents. Respondents had learned computer skills through various combinations of methods, with over half of each group claiming to be self-taught through reading and hands-on experience. More than 86% of both groups expressed interest in learning more; interest increased in the population thirty-eight years or younger. Respondents, especially physicians, reported using professional applications less often than personal applications. Overall, there was a high level of interest in learning various practice-related applications; however, a significantly larger proportion of residents reported interest in each type of application than did physicians.