Blood Screening Program Research Articles

Hb Barts's Quantitation in Neonatal Cord Blood Screening Samples

Background: a-thalassaemia is known to be prevalent in the Sultanate of Oman. However, there are no studies on the effects of a-thalassaemia on red cell indices in the new born children from the Sultanate of Oman.Materials & Methods: In a prospective study over a period of 2 years, cord blood samples from 7837 neonates, from the two prominent cities i.e Muscat and Sohar in the Sultanate of Oman, were analyzed for complete blood counts [CBC] and high performance chromatography[HPLC]; as part of ongoing studies related to the national neonatal cord blood screening programme. HPLC was performed on the Biorad Variant II™ using the beta thalassaemia short programme for qualitative assessment and alpha thalassaemia short programme for quantitation of Haemoblobin Barts, which was considered as diagnostic of alpha thalassaemia on the cord blood samples.(Biorad Laboratories, Hercules, CA, USA) The positive samples were then further studied with molecular methods for confirmation by GAP PCR with direct sequencing and Genescan studies on ABI 3100 Genetic Analyzer®. (Applied Biosystems, Foster City, CA, USA)Results: There were 4042 samples(51.58%) with normal HPLC (HbA + HbF). [Table] The remaining 3795 cases(48.42%) were associated elevated Hb Barts, indicative of the presence of a-thalassaemia. Amongst these subjects, 229 cases additionally also had HbS, 28 cases had HbD, 30 cases had HbE, and 3 cases had HbC. Overall, a total of 773 cases (9.86%) showed an abnormal hemoglobin like HbS(429), HbC(6), HbD(73), HbE (60)or beta thalassaemia(206).Reference range for Cord Blood in Ethnic Omani newborn children(Mean ± SD)HbRBCHctMCVMCHMCHCRDWHbAHbF(g/dl)(×1012/L)(%)(fl)(pg)(g/dl)(CV%)%%Normal [A+F]15.38 ±2.044.69 ±0.6850.5 ±7.18107.66 ±7.7533.61±4.0730.98 ±3.4417.01 ±2.1722.88±8.0377.02±8.04a-thal [A+F+Barts]14.79† ±2.95.09† ±0.7749.7† ±7.497.29† ±13.829.74† ±11.830.39† ±3.618.09† ±2.5625.74† ±9.0573.96† ±8.91#Barts <1% N=62515.81 ±1.584.54 ±0.5247.92 ±5.03105.72 ±5.6434 ±2.2733.03 ±1.2316.27 ±1.2423.78 ±8.681.55 ±10.2#Barts 1–3% N=184715.78 ±2.034.74 ±0.6648.25 ±6.99101.57 ±5.4433.38 ±2.6932.71 ±1.1716.25 ±6.4621.14 ±8.184.65 ±9.75#Barts 3–10% N=132314.96 ±2.015.29 ±0.6947.46 ±6.889.87 ±5.3928.47 ±2.131.65 ±1.3917.3 ±1.8224.11 ±8.581.42 ±9.5†Significant (P<0.05) compared with Normal (A+F)#Barts Subgroups classified as per alpha thalassaemia short programme [Manufacturer's instructions]Hb Barts levels between 1–3% and 3–10% were seen amongst 48.68% and 34.87% cases respectively. Genescan studies revealed that 61.23% cases had nondeletional type and 38.77% subjects showed deletional.(-a3.7 ) types of a-thalassaemia.[figure] which were confirmed by GAP PCR for deletional cases whereas in non-deletional cases both a2 and a1 genes were selectively amplified and directly sequenced.Conclusions : The incidence a-thalassaemia in this cohort of neonates was 48.42%. a-thalassaemia gene significantly reduced the MCV, MCH, MCHC, Hct, RBC count and the Hb and increased the RDW in the cord blood samples of neonates screened in this study. There was an excellent correlation between qualitative and quantitative estimation of Hb Barts by the two techniques. Importantly, we did not encounter any case of Hb H disease or hydrops faetalis in this study. [Display omitted]

Test, episode, and programme sensitivities of screening for colorectal cancer as a public health policy in Finland: experimental design

Objectives To report the sensitivities of the faecal occult blood test, screening episode, and screening programme for colorectal cancer and the benefits of applying a randomised design at the implementation...

Newborn screening in the Asia Pacific region

The success of blood spot newborn screening in the USA led to early screening efforts in parts of the Asia Pacific Region in the mid-1960s. While there were early screening leaders in the region, many of the countries with depressed and developing economies are only now beginning organized screening efforts. Four periods of screening growth in the Asia Pacific region were identified. Beginning in the 1960s, blood spot screening began in New Zealand and Australia, followed by Japan and a cord blood screening programme for G6PD deficiency in Singapore. In the 1980s, established programmes added congenital hypothyroidism and new programmes developed in Taiwan, Hong Kong, China (Shanghai), India and Malaysia. Programmes developing in the 1990s built on the experience of others developing more rapidly in Korea, Thailand and the Philippines. In the 2000s, with limited funding support from the International Atomic Energy Agency, there has been screening programme development around detection of congenital hypothyroidism in Indonesia, Mongolia, Sri Lanka, Myanmar and Pakistan. Palau has recently contracted with the Philippine newborn screening programme. There is little information available on newborn screening activities in Nepal, Cambodia, Laos and the other Pacific Island nations, with no organized screening efforts apparent. Since approximately half of the births in the world occur in the Asia Pacific Region, it is important to continue the ongoing implementation and expansion efforts so that these children can attain the same health status as children in more developed parts of the world and their full potential can be realized.

Predictive Value of Red Cell Indices and High Performance Liquid Chromatography in the Diagnosis of Haemoglobinopathies: Interim Results of the National Neonatal Cord Blood Screening Programme.

Objective: The aim of the study was to ascertain the feasibility of cord blood screening to determine the prevalence of haemoglobinopathies by a cost-effective method.Background: High rate of consanguinity and intercousin marraiges are prevalent in the Sultanate of Oman, leading to an increase in haemoglobinopathies, which is of growing importance as knowledge of a population structure can be a unique aid in planning genetic services.Methods: 1864 consecutive cord blood samples were screened by HPLC using Biorad Variant II program between April 2005 & March 2006. Complete blood counts [CBC] were also obtained on Cell Dyn 4000 automated blood cell counter. All samples were then processed to isolate and store mononuclear leukocytes for subsequent molecular diagnostics.Results: We observed a 46.83% incidence of α-thalassaemia, based on significant amounts of Hb Barts on HPLC and low mean cell volume [MCV] & mean cell haemoglobin [MCH] on the CBC.Table :Neonatal Cord Blood Screening - HPLC and CBC data with Red Cell IndicesNormalATTHbSHbDHbEHbC?BTTMean HbF %77.4[7.3]76.4[8.7]89.4[9.4]78.1[1.2]81.1[4.9]80.2[7.8]92.1[2.0]Mean HbA %22.5[7.3]23.6[8.2]14.1[6.0]13.7[9.9]12.7[3.1]13.1[4.5]8.1[2.1]Mean Haemoglobin g/dl15.4[1.8]14.4[1.4]14.7[1.6]14.9[0.7]15.6[1.1]15.2[0.8]13.9[2.5]Mean RBC Count × 1012/L4.5[0.6]5.0[0.6]4.9[0.6]4.5[0.4]4.8[0.4]4.6[0.2]4.0[0.6]Mean MCV fl105.2[5.4]89.9[4.1]95.1[9.1]100.8[7.0]98.1[4.7]99.1[5.6]104.4[9.5]Mean MCH pg34.4[2.1]28.5[1.8]30.7[3.4]33.3[2.7]32.6[3.3]32.9[1.2]34.8[1.0]Mean MCHC g/dL32.7[1.1]31.7[1.3]32.2[1.0]33.1[0.9]33.6[2.1]33.2[1.5]33.3[1.0]Mean RDW %16.1[1.1]17.4[2.1]17.1[2.4]16.1[1.5]17.7[2.4]16.5[1.9]16.1[2.5]Values in parenthesis represent SDFurthermore, the overall incidence of other haemoglobinopathies was 9.39%, with 6.01% incidence of sickle haemoglobin. On HPLC, D-window, E-window and C-window were present in 1.02%, 0.32% and 0.11% of the samples respectively. [Display omitted] Since HPLC cannot diagnose β-thalassemia major at birth, in samples with HbA below 10%, the beta globin gene was directly sequenced including the promoter, all exons and introns in the abnormal samples. [n=36] Additionally, direct sequencing of abnormal samples with HbS,[n=112] HbD,[n=19], HbE[n=6] and HbC[n=2] were also performed to validate the HPLC results.Conclusions: It is emphasized that neonatal cord blood screening is an important the first step in the national strategy towards total management of haemoglobinopathies including early diagnosis, comprehensive clinical care and counseling of the affected families. Between group differences were significant for RBC count, MCV, MCH, MCHC and the red cell distribution width (RDW), which along with Hb Barts, and HPLC results can successfully predict the correct underlying diagnosis.

Global epidemiology of hcv infection

The prevalence of hepatitis C virus (HCV) infection is estimated to be 3% worldwide. Regional variation is related to differences in risk factors, health care practices, economic issues, and societal norms. In recent years, blood screening programs and improved public awareness have led to a reduction in new cases of HCV in western countries. Despite these advances, new infections continue to occur, particularly in the developing world. An understanding of the global epidemiology of HCV provides the basis for generating public health initiatives to address this growing problem.

Changing Epidemiology and Approaches to Therapy for Chagas Disease.

Impressive progress has been made in reducing the incidence of Chagas disease, or American trypanosomiasis, in many countries in which the illness is endemic. This has been achieved through expanded blood screening programs and low-technology vector control. Despite the progress made in reducing the number of new cases, the burden of disability and mortality in the endemic countries is enormous and will continue to be so for many years since a substantial portion of the 16 to 18 million persons already infected will develop chronic symptomatic Chagas disease. Unfortunately, no progress has been made in developing new drugs for Trypanosoma cruzi infection, and nifurtimox and benznidazole, both of which lack efficacy and often cause severe side effects, remain the only options for treatment.

Incidence, diagnostic et pronostic des métastases ovariennes du cancer du sein

Ovarian metastasis are frequently encountered during the course of breast cancer, concerning one woman in five among those suffering from the disease. These secondary ovarian lesions are usually small and bilateral with a non-cystic pattern and are more likely to be from primary infiltrating lobular carcinoma of the breast. Distinction between ovarian metastasis and primary ovarian cancer may sometimes be difficult and require immunohistochemical stains with various monoclonal antibodies. Primary ovarian cancer remains preponderant however, even in a woman with breast cancer. From a clinical point of view, ovarian metastasis are frequently unknown except in case of peritoneal dissemination. Trans-vaginal ultrasonography scan is the best examination when clinical signs give cause to suspect ovarian tumour. Although, systematic ultrasonography screening, as well as blood screening program using CA 125 and CA 15-3, should not be recommended because they lack sensibility and are too expensive. The development of ovarian metastasis during the course of a breast primary carcinoma is a negative prognostic factor with regards to the presence or absence of peritoneal dissemination.

Fecal occult blood and flexible sigmoidoscopy screening for colorectal cancer: modeling the impact on colonoscopy requirements and cancer detection rates.

The aim of this study was to estimate the colonoscopy requirements and the likely impact of fecal occult blood and flexible sigmoidoscopy screening on the detection of colorectal cancer by using previously published data. Fecal occult blood and flexible sigmoidoscopy screening programs were applied to the 2.04 million subjects aged 50-65 years, at a participation rate of 40%. The following strategies were evaluated: Fecal occult blood testing with colonoscopy follow up of all positive tests; flexible sigmoidoscopy with colonoscopy follow up of all adenomatous polyps; and flexible sigmoidoscopy with colonoscopy follow up of all adenomatous polyps > 10 mm in size. The fecal occult blood program detected 5.6% of all colorectal cancer cases at a rate of 2,914 colonoscopies/percentage of detection of colorectal cancer. The flexible sigmoidoscopy program detected 14% of all colorectal cancer cases at a rate of 8,160 colonoscopies/percentage of detection of colorectal cancer. The flexible sigmoidoscopy program with follow up of adenomatous polyps > 10 mm in size detected 13% of all colorectal cancer cases at a rate of 1,230 colonoscopies/percentage of detection of colorectal cancer. Flexible sigmoidoscopy screening followed by colonoscopic follow up of adenomatous polyps > 10 mm in size is the most efficient screening strategy in terms of colonoscopies generated and cases of colorectal cancer detected.

Seroepidemiological Prevalence of Human T-Cell Lymphotropic Virus Type I (HTLV-I) among Healthy Blood Donors in Eastern Saudi Arabia

Seroepidemiological Prevalence of Human T-Cell Lymphotropic Virus Type I (HTLV-I) among Healthy Blood Donors in Eastern Saudi Arabia

Neonatal jaundice in Saudi newborns with G6PD Aures.

Sixty-five of 3261 (2%) Saudi neonates were found to be severely G6PD-deficient during a cord blood screening programme conducted from April to December, 1992. However, at the time of molecular studies, the blood samples were available from only 20 randomly selected children, aged from 1 to 6 years. DNA analyses showed that seven (three boys, four girls) of these 20 (35%) had G6PD Aures (nt 143 T - > C), a variant associated with favism which was recently reported in an Algerian. Twelve carried the G6PD Mediterranean (563 T) mutation, and in one child the mutation remained unidentified. The medical records of these children showed that all who had G6PD Aures, including a premature baby, were jaundiced during the 1st week of life, but only six full-term infants had moderate-to-severe hyperbilirubinaemia. Two of seven babies had seizures and one of these two developed kernicterus, in spite of timely blood transfusion.

Use of Elisa for the Detection of Common Drugs of Abuse in Forensic Whole Blood Samples

The Elisa immunoassay technique was tested on whole blood samples for potential application in forensic toxicology blood screening programs. Kits tested included cocaine and metabolites, cannabinoids, phencyclidine (PCP), amphetamines and opiates. Detection limits were found to be lower using the Elisa technique in comparison to standard enzyme multiplied immunoassay (EMIT®)2 procedures used in Royal Canadian Mounted Police Toxicology sections. In addition to an improvement in sensitivity, it was noted that the procedure itself saved analyst's time in that the extraction steps required for EMIT analysis were eliminated. The technique was found inherently flexible in that the choice of matrix or tissue for analysis could be easily adapted to a simple standard procedure.

Screening and the costs of treating colorectal cancer

The objective of this paper is to compare the hospital costs of treating patients with colorectal cancers detected as a result of a faecal occult blood screening programme with those of patients whose cancers present symptomatically (control group). Patient-specific cost estimates are made, using case records and hospital accounts, for 360 patients over 3 years. Mean treatment costs for the group offered screening and for the control group are calculated to be 3,179 pounds and 2,966 pounds respectively, although the difference between these means is insignificant. Low treatment costs in the case of screen-detected cancers are largely accounted for by polypectomy with no subsequent readmission; in the control group case, they tend to be accounted for by early patient death. For the sample as a whole, the costs of treating very early-, and very late-, stage cancer are significantly lower than those of treating cancers in the intermediate stages. On the basis of trial evidence, the introduction of mass screening for colorectal cancer is unlikely to give rise to substantial economies in the costs of treatment.

Gold ultramicroelectrodes for on‐site monitoring of trace lead

AbstractGold and gold‐coated cylinder microelectrodes are used as stripping‐based microsensors for trace lead. These gold ultramicroelectrodes exhibit a favorable stripping performance, similar to that observed at common mercury ultramicroelectrodes. Such use of “mercury‐free” electrodes greatly facilitates the development of disposable sensors for lead blood screening programs. Potentiometric stripping analysis at these gold ultramicroelectrodes yields reproducible results for parts per billion (μg/L) concentrations of lead, following short preconcentration periods and using static, nondeaerated solutions. Numerous experimental variables have been characterized and optimized. Repetitive assays of 200‐μl sample drops yield a relative standard deviation of 2.2% (n = 20). The application of the gold ultramicroelectrodes for assays of various real samples is demonstrated, and prospects for their use in decentralized testings are discussed.

Effect of aspirin and non-steroidal anti-inflammatory drugs on colorectal adenomas: case-control study of subjects participating in the Nottingham faecal occult blood screening programme.

To examine the relation between the use of aspirin and non-steroidal anti-inflammatory drugs and the presence of asymptomatic colorectal adenomas. Case-control study of subjects participating in a randomised controlled trial of faecal occult blood screening for colorectal cancer. Data on analgesics and other drugs were obtained from a questionnaire which was mainly concerned with diet and was administered by an interviewer. Nottingham. 147 patients with positive results in faecal occult blood tests who were found to have colorectal adenomas (cases), 153 age and sex matched control subjects with negative results in such tests (negative controls), and 176 control subjects with positive results in the tests who were found not to have colorectal adenomas (positive controls). Relative risk of developing colorectal adenomas according to frequency and duration of use of analgesics. Cases reported taking less aspirin and non-steroidal anti-inflammatory drugs than the negative controls, with the estimated relative risk for any use being 0.49 (95% confidence interval 0.3 to 0.8). The inverse association was less strong when cases were compared with the positive controls (0.66 (0.4 to 1.1)). The association was specific for aspirin and non-steroidal anti-inflammatory drugs there being no association with paracetamol or other drugs. Prescribed use of non-steroidal anti-inflammatory drugs for longer than five years was associated with the lowest risk (0.21 (0.1 to 0.8)), although the numbers reporting prolonged prescribed use were small. These findings support the hypothesis that aspirin and non-steroidal anti-inflammatory drug use protects against the development of colorectal neoplasia.

Blood transfusion practices and blood-banking services in a Kenyan hospital

To identify ways to improve the operation of blood-screening programs and to decrease the inappropriate use of blood by evaluating blood-transfusion practices and blood-banking services in a Kenyan hospital. Prospective cohort. The study was conducted in a rural district hospital in western Kenya between September 1990 and July 1991. We collected data on all transfusion requests (blood donation, grouping, HIV screening) and blood recipients (age, sex, diagnosis, and for a 3-month period on the pediatric, maternity, and female wards, admission hemoglobin and outcome). During the 11-month study period, 799 patients received 927 transfusions: 67% were children < 15 years of age, 27% were adult women and 6% were adult men. Transfusions were often delayed due to reliance on patient-recruited donors. Patients who received blood donated on or after the date of request waited longer for transfusion (median, 3 days) than patients who received blood that had been banked and screened before the request (median, 1 day). Patient-recruited donors had a higher HIV-seropositivity rate than volunteer donors (13.4 and 4.6%, respectively; chi 2 test, P < 0.001). Overall, 47% of pediatric transfusions were classified as inappropriate: 23% did not meet the criteria of having hemoglobin < 5.0 g/dl and clinical evidence of respiratory distress, and 27% were transfused 2 or more days after requested. Among adults, 68% received one unit of blood or less. Improved laboratory services, reduction of unnecessary transfusions, and increased recruitment of volunteer donors are critical for improving the appropriate and timely use of blood and reducing transfusion-associated HIV transmission.

Colorectal adenomas and energy intake, body size and physical activity: a case-control study of subjects participating in the Nottingham faecal occult blood screening programme

Most case-control studies of colorectal cancer have shown a positive association with energy intake. In contrast studies which have considered physical activity have found the most active to have a lower risk of colonic cancer and obesity appears to be no more than weakly related to colorectal cancer. We therefore compared energy intake determined by a diet history interview, self-reported height and weight, together with measures of lifetime job activity levels and leisure activity in the year prior to interview in 147 cases with colorectal adenomas and two control groups (a) 153 age-sex matched FOB-negative subjects (b) 176 FOB-positive subjects in whom no adenoma or carcinoma was found. Unconditional logistic regression was used to estimate relative risks (RR) and 95% confidence intervals () adjusted for age, sex and social class. No association with weight or body mass index was found. The only association with physical activity found with both control groups was an inverse association with running or cycling for half an hour continuously at least once a week RR 0.46 (0.2-1.3) compared with control group (a), and RR = 0.32 (0.1-0.8) compared with (b), but few subjects engaged in such activity. There was an inverse association with energy intake (trend chi 2 = 5.3, P < 0.025) in the comparison with control group (a) only, a finding which is consistent with those of two previous studies of asymptomatic adenoma.

The cost of screening for colorectal cancer.

The aim was to make projections of the likely costs and yield resulting from the implementation of a faecal occult blood screening programme for colorectal cancer. Cost and clinical data were derived from the MRC colorectal screening trial currently in progress in Nottingham, UK. The above data were used as the basis for modelling the likely implications were the trial to be reproduced as a screening programme within a "typical" family practitioner committee area. For an average family practitioner committee area with a target population of 75,000 subjects aged 50-74 years, the initial screening round might be expected to detect 85 cancers at a total cost of approximately 250,000 pounds. This represents a cost per cancer detected of 2700 pounds and a cost per person screened of approximately 5 pounds. For subsequent screening rounds, total costs might be expected to fall although average costs are likely to remain approximately constant. The model is successful in generating "order of magnitude" estimates for the costs of implementation of a screening programme for colorectal cancer. As benefit estimates are not yet available, however, no cost-effectiveness analysis can be undertaken at this stage. In general, sensitivity analyses reveal that programme costs are more sensitive to changes in clinical variables, especially detection and compliance rates, than they are to variations in the costs of resource inputs. A screening programme with a more elaborate protocol than that currently employed in the Nottingham trial will entail considerable cost increases.

India: HIV banks

The professional blood donor organizations in Bombay, India, face difficulties, since many donors have become infected with the human immunodeficiency virus (HIV). Professional donors meet more than half of the demand from hospitals for blood. More than 5 million liters of blood are bought every year at an annual cost of more than 29 million pounds. The government suspended the manufacture of blood products, and a blood screening program was launched, yet up to 95% of donated blood is unsafe. In a WHo study, it was disclosed that 80% of Bombay's blood sellers are infected with HIV, and 1/3 of them show signs of AIDS or AIDS-related complex. India is expected to have 250,000 HIV carriers and at least 60,000 cases of AIDS by 1995. Medical organizations like the Indian Health Organization (IHO) and the WHO are educating blood donors and prostitutes about AIDs and are promoting safe sex. An IHO team consisting of a doctor, social worker, and health educator regularly visits the district of Bombay where 200,000 prostitutes ply their trade. Team members distribute literature, organize slide shows, and hand out free condoms to prostitutes and their clients.

Pediatric Acquired Immunodeficiency Syndrome, Poverty, and National Priorities

Human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS), as found in children, represents a microcosm of the problems and failures of this nation's health care system for the poor. EPIDEMIOLOGY When Oleske et al 1 and Rubenstein et al 2 first described the disease in children, it was not evident that AIDS was to become a disease found predominantly in poor children of minority status. But in the years since those first reports appeared, epidemiologic studies have demonstrated that AIDS in children is largely acquired through perinatal transmission from HIV-infected mothers who are or have been involved in intravenous drug use or who have had intercourse with someone involved in the drug culture. About 15% of children with AIDS are hemophiliacs or others who were infected by contaminated blood products before the advent of the national universal HIV blood screening program. Presumably, the number of transfusion-related cases will

A critical analysis of the largest reported mass fecal occult blood screening program in the united states

Fecal occult blood testing for the detection of colon cancer remains controversial. We performed a mass screening program from January 24, 1988, to February 19, 1988, with intensive media promotion, including 121 minutes of televised air time. A total of 5,000 primary practitioners were notified by mail. Hemoccult-II tests were distributed to 156,000 individuals; 55,051 (35%) were returned. Ninety-five percent of the respondents were informed of the program by television. A total of 3,375 persons (6%) tested positive for fecal occult blood; of these, 2,469 (73%) informed the center that they saw their physician to initiate a work-up. Information from physicians regarding work-ups was returned on only 1,356 (55%) patients. Diagnostic tests numbered 2,227 (1.6 tests per patient). However, 5% had no testing, 16% had a repeat Hemoccult only, and 35% had neither a barium enema nor colonoscopy performed. Thirty-six colorectal cancers and 212 polyps were identified. The predictive value (i.e., number of cancers per number of patients who tested positive) increased directly by decade. Thirty-three of 36 patients (92%) with cancer underwent either a barium enema or colonoscopy versus only 185 of 438 (42%) patients with a "negative" work-up. Cancers found were carcinoma in situ in 10 patients (29%), Dukes A in 12 (35%), Dukes B in 4 (12%), and Dukes C in 8 (24%); distant metastases were not found in any participant. Thirty-six percent of the tumors were located in either the right or transverse colon. We conclude that: (1) Screening identified early cancers. All were potentially curable and 64% were limited to the bowel wall. (2) Massive Hemoccult distribution was possible over a short interval, but patient and physician compliance was disturbingly low. (3) Total colonic evaluation is mandatory, since at least 36% of tumors were beyond the reach of the flexible sigmoidoscope. (4) Many work-ups were unnecessary (repeat Hemoccults) or inadequate, indicating a need for physician education.