In 12 long-standing insulin-dependent diabetics with background diabetic retinopathy their 100-hu... more In 12 long-standing insulin-dependent diabetics with background diabetic retinopathy their 100-hue colour vision scores were positively related to the degree of retinopathy and negatively to fasting blood glucose levels. However, the 100-hue calour vision scores and types were not significantly different from those of normal subjects matched for age, sex, and social class.
OBJECTIVE— We sought to report the 6-year incidence of proteinuria and associated risk factors in... more OBJECTIVE— We sought to report the 6-year incidence of proteinuria and associated risk factors in African Americans with type 1 diabetes. RESEARCH DESIGN AND METHODS— African Americans (n = 483) with type 1 diabetes were reexamined in a 6-year follow-up study. Proteinuria and creatinuria were measured in 4-h timed urine specimens obtained at initial and follow-up visits. Other evaluations included a structured clinical interview, ocular examination, masked grading of seven stereoscopic fundus photographs, blood pressure measurements, blood assays, and administration of the Beck Depression Inventory (BDI). RESULTS— Over the 6-year period, 117 (42.9%) of the 473 patients at risk developed “any” proteinuria, defined as either microalbuminuria (26.0%) or overt (16.9%) proteinuria; 87 (23.5%) progressed from micro- or no albuminuria to overt proteinuria and 39 (8.7%) to end-stage renal disease; and 40 (20.6%) regressed. Peak incidence of any proteinuria occurred for patients who were 10–...
We examined hypothalamic-pituitary-adrenal (HPA) axis function in insulin-dependent diabetic outp... more We examined hypothalamic-pituitary-adrenal (HPA) axis function in insulin-dependent diabetic outpatients (N = 22) and age-, sex-, and weight-matched normal controls (N = 22). The evaluation included measurements of 9:00 AM fasting plasma cortisol and cortisol-binding globulin (CBG) levels, 24-hour urinary free cortisol (UFC) excretion, and plasma corticotropin and cortisol responses to intravenously administered ovine corticotropin-releasing hormone ([CRH] 1 microgram/kg given as a bolus at 8:00 PM). Diabetic patients had significantly elevated 9:00 AM plasma cortisol levels (mean +/- SE, 300.7 +/- 99.3 v 237.3 +/- 99.3 nmol/L, P < .04), higher 24-hour UFC excretion (313.2 +/- 112.6 v 244.2 +/- 69.3 nmol/24 h, P < .02), and greater cortisol responses to CRH infusion (time-integrated values: 49,408.2 +/- 11,289.8 v 40,217.9 +/- 7,228.6 nmol/L.120 min, P < .004; peak cortisol values: 529.7 +/- 107.6 v 438.7 +/- 77.3 nmol/L, P < .002) than controls. UFC excretion values were positively correlated with both 5-year averaged hemoglobin A1c level (P = .03) and total number of insulin units administered per day (P = .03). These results suggest that insulin-dependent diabetic outpatients have mild chronic hypercortisolism, which might influence the control of the disease and play a role in the development of its chronic complications.
A 40-year-old women with a 17-year-history of glaucomatocyclitic crises in 1 eye developed idiopa... more A 40-year-old women with a 17-year-history of glaucomatocyclitic crises in 1 eye developed idiopathic foveal subretinal neovascularization in the other eye. The subretinal neovascular membrane spontaneously regressed over a 2-month period, and useful reading vision was subsequently maintained for more than 6 years. This favorable outcome is discussed in relation to the previously reported cases of idiopathic macular subretinal neovascularization.
AIMS/BACKGROUND--While the retinal lesions of sickle cell retinopathy have been well documented, ... more AIMS/BACKGROUND--While the retinal lesions of sickle cell retinopathy have been well documented, their pathogenesis remains unclear. The purpose of this study was (1) to compare macular blood flow velocity in patients with sickle cell disease and controls, and (2) to determine in sickle cell patients the relation between macular blood flow velocity and red blood cell density. METHODS--Macular blood flow
The Farnsworth-Munsell 100-hue test was used to compare color vision in patients with sickle cell... more The Farnsworth-Munsell 100-hue test was used to compare color vision in patients with sickle cell anemia, 20/20 visual acuity, and mild to severe peripheral retinopathy, but without posterior retinal vessel involvement, with matched normal controls. Patients with sickle cell anemia had significantly more blue-yellow and mixed color vision defects and significantly higher Farnsworth-Munsell 100-hue scores than did controls. There were no significant associations between color vision defects and the severity of peripheral retinal findings or the diameter of the foveal avascular zone. These results suggest that color vision defects may exist in patients with sickle cell anemia in the absence of ophthalmoscopic retinal changes in the posterior fundus.
Ophtalmologie: organe de la Société française d'ophtalmologie
New methodology to analyze posterior vitreous fluorophotometry (PVF) data is described. Values fo... more New methodology to analyze posterior vitreous fluorophotometry (PVF) data is described. Values for D, fluorescein vitreous diffusion coefficient and P, permeability of the blood retinal barrier (BRB) to fluorescein are obtained. D was found to be significantly greater in diabetic patients with minimal retinopathy compared with either controls or patients with no retinopathy. P values were not significantly different between diabetic patients and controls or between diabetic subgroups, confirming the absence of breakdown of the BRB, as assessed by PVF, in early diabetic retinopathy.
Color vision is known to change with age. We conducted the Farnsworth-Munsell (FM) 100-Hue and th... more Color vision is known to change with age. We conducted the Farnsworth-Munsell (FM) 100-Hue and the Lanthony Desaturated Panel D-15 (DD-15) tests in 115 normal North American subjects aged 5-81 years to obtain age-specific norms for these procedures. For each test, color discrimination was best between the ages of 20 and 50 years. Both increasing age and the occurrence of lens changes were significantly associated with increasing 100-Hue error scores. Age-specific norms for the 100-Hue test were comparable with those obtained by Verriest in a European population, but such norms for the DD-15 test are problematic. Our data indicate somewhat greater variability in the DD-15 than in the 100-Hue test.
A 54-year-old woman with a history of bilateral central retinal vein occlusion, probably due to a... more A 54-year-old woman with a history of bilateral central retinal vein occlusion, probably due to an inflammatory process, developed a hemispheric retinal vein occlusion with cystoid macular edema in her only seeing eye. Five months later, in the absence of improvement in vision and macular edema, she received on two occasions a 2-weekly course of twice daily 100% hyperbaric oxygen. After each course retinal leakage, as assessed by vitreous fluorophotometry, decreased from abnormal to the normal range while visual acuity improved by two lines. The possible implications are discussed.
A new automated analysis procedure was used to evaluate the apparent blood-retinal barrier permea... more A new automated analysis procedure was used to evaluate the apparent blood-retinal barrier permeability (mean +/- SD = 1.31 = 0.31 X 10(-7) cm/s at 60 minutes after intravenous dye administration) and the effective diffusivity (mean +/- SD = 0.88 +/- 0.40 X 10(-5) cm2/s) for fluorescein in the vitreous of 21 normal subjects. The analysis improvements include (1) use of an individualized convolution (spread) function for each eye in comparing simulated and experimental scans, (2) separation of vitreous and chorioretinal fluorescence, and (3) precise determination of vitreous position relative to the retina. The average reproducibility in six subjects was 23% for permeability and 22% for diffusivity based on repeated determinations separated in time by at least a week. Diffusivity values, but not permeability values, significantly associated in comparisons of first and second determinations, suggesting permeability may fluctuate in time while diffusivity remains relatively constant. The fluorescence at 3 mm anterior to the retina (commonly employed as a measure of blood-retinal barrier leakiness) was strongly associated with diffusivity. In contrast, the anticipated association between permeability and 3-mm fluorescence was weak or absent.
We examined plasma levels of fibrinopeptide A, beta-thromboglobulin, and platelet factor 4 in dia... more We examined plasma levels of fibrinopeptide A, beta-thromboglobulin, and platelet factor 4 in diabetic patients. Among diabetic patients (n = 33) plasma levels of fibrinopeptide A, beta-thromboglobulin and platelet factor 4 were significantly higher than in controls (n = 41). In the subgroups of diabetic patients with (1) minimal (n = 13), and (2) moderate-severe (n = 14) retinopathy only plasma fibrinopeptide A levels were significantly higher than in controls. Among the total group of diabetic patients plasma levels of fibrinopeptide A increased significantly with increasing severity of retinopathy. These results suggest that diabetic retinopathy is associated with in vivo activation of blood coagulation factors and that this activation increases with advancing retinopathy.
We used 3-d food-record-keeping techniques to examine nutritional factors in diabetic patients wi... more We used 3-d food-record-keeping techniques to examine nutritional factors in diabetic patients with and without retinopathy. Patients without retinopathy had significantly higher daily intakes of total carbohydrate, water-soluble dietary fibers, insoluble dietary fibers, and glucose than did patients with retinopathy. Also, patients without retinopathy took a significantly lower proportion of their total daily calories as protein.
Seventy-six cases of surgical hepatomegaly were subjected to fine needle aspiration cytology (FNA... more Seventy-six cases of surgical hepatomegaly were subjected to fine needle aspiration cytology (FNAC) for initial diagnosis. Primary malignancies, as suspected clinically with adjunction of other investigative procedures, were 29 cases of whom 25 were confirmed by biopsy or therapy. Secondary deposits in liver were 27 of whom 15 were confirmed by therapy. Inflammatory lesions were 9 of whom 6 were confirmed by therapeutic response with specific therapy. Benign lesions were 10 of whom 5 were confirmed by surgery. Diagnosis of malignancies of liver is rather easier than that of benign lesions like hydatid cysts of liver which were Casoni's test negative; and hepatocellular adenoma, as the aspirate in the former is clear fluid and that of the latter is only normal looking liver cells. Thus, in respect of benign lesions of liver, FNAC diagnosis may be clinched after due consideration to the clinical findings, radiological and ultrasonographic findings and ultimately confirmed by exploration. Thus the fallacy lies in aspiration of normal looking liver cells whereby the histology may prove it to be hepatocellular adenoma, well differentiated hepatocellular carcinoma and secondary deposits where the exact site has not been hit. Ultrasonogram (USG) guidance helps in these cases where the same facility is available. This fallacy can again be avoided, where USG guidance is not available, by imparting due importance to clinical findings, USG findings and also by repeat smear.
An attempt was made to study the histological and histochemical changes as well as immunohistoche... more An attempt was made to study the histological and histochemical changes as well as immunohistochemical changes in desmin expression occurring in four types of clinical myopathies e.g. Chronic ischaemic myopathy due to Buerger's disease (Group I), Carcinomatous myopathy (Group II), Metabolic myopathy (Group III) and Muscular dystrophy (Group IV). The number of cases studied were 16 cases, 15 cases, 4 cases and 5 cases respectively. The study revealed: (i) a combination of normal, degenerated, necrotic and regenerating fibres in different proportions in all the four groups having maximum number of degenerated fibres in Group I and Group IV, relatively more number of regenerating fibres in groups III and absence of necrotic fibres in Group I. (ii) Altered tinctorial property in most of the fibres indicating degenerated and regenerating fibres in all the groups with Masson's trichrome staining against inconstant staining with PTAH appear to be a good indicator for myopathy. (iii) The Desmin expression was week and irregular in most of the cases with most of the fibres probably due to reduction of desmin content probably indicating degenerated fibres, appear to be a good indicator for myopathy. (iv) Chronic ischaemic myopathy showed close resemblance with muscular dystrophy though no typical or distinct distinguishing feature could be identified in these four groups.
The main reinforcing effect of cocaine happens by altering dopaminergic neurotransmission in the ... more The main reinforcing effect of cocaine happens by altering dopaminergic neurotransmission in the brain reward systems. Dopamine is found in high concentrations in the retina in which it plays an important role in color vision. Therefore, we investigated whether cocaine-dependent patients might have impaired color vision. We compared patients recently withdrawn from cocaine (n = 31) with matched normal controls (n = 31) on 2 color vision tests. Cocaine-withdrawn patients had significantly higher error scores than matched controls on the Farnsworth-Munsell 100-hue and Lanthony desaturated D-15 color vision tests. Also, 23 of the 31 cocaine-withdrawn patients had blue-yellow color vision losses on the Farnsworth-Munsell 100-hue test compared with 3 controls (P < .001, chi 2 test) and 15 had blue-yellow color vision loss on the Lanthony desaturated D-15 test compared with 2 controls (P < .001, chi 2 test). These significantly higher test error scores and blue-yellow color vision losses suggest that color vision is impaired in cocaine-withdrawn patients. Color vision testing may be useful in future studies of cocaine-dependent patients.
In 12 long-standing insulin-dependent diabetics with background diabetic retinopathy their 100-hu... more In 12 long-standing insulin-dependent diabetics with background diabetic retinopathy their 100-hue colour vision scores were positively related to the degree of retinopathy and negatively to fasting blood glucose levels. However, the 100-hue calour vision scores and types were not significantly different from those of normal subjects matched for age, sex, and social class.
OBJECTIVE— We sought to report the 6-year incidence of proteinuria and associated risk factors in... more OBJECTIVE— We sought to report the 6-year incidence of proteinuria and associated risk factors in African Americans with type 1 diabetes. RESEARCH DESIGN AND METHODS— African Americans (n = 483) with type 1 diabetes were reexamined in a 6-year follow-up study. Proteinuria and creatinuria were measured in 4-h timed urine specimens obtained at initial and follow-up visits. Other evaluations included a structured clinical interview, ocular examination, masked grading of seven stereoscopic fundus photographs, blood pressure measurements, blood assays, and administration of the Beck Depression Inventory (BDI). RESULTS— Over the 6-year period, 117 (42.9%) of the 473 patients at risk developed “any” proteinuria, defined as either microalbuminuria (26.0%) or overt (16.9%) proteinuria; 87 (23.5%) progressed from micro- or no albuminuria to overt proteinuria and 39 (8.7%) to end-stage renal disease; and 40 (20.6%) regressed. Peak incidence of any proteinuria occurred for patients who were 10–...
We examined hypothalamic-pituitary-adrenal (HPA) axis function in insulin-dependent diabetic outp... more We examined hypothalamic-pituitary-adrenal (HPA) axis function in insulin-dependent diabetic outpatients (N = 22) and age-, sex-, and weight-matched normal controls (N = 22). The evaluation included measurements of 9:00 AM fasting plasma cortisol and cortisol-binding globulin (CBG) levels, 24-hour urinary free cortisol (UFC) excretion, and plasma corticotropin and cortisol responses to intravenously administered ovine corticotropin-releasing hormone ([CRH] 1 microgram/kg given as a bolus at 8:00 PM). Diabetic patients had significantly elevated 9:00 AM plasma cortisol levels (mean +/- SE, 300.7 +/- 99.3 v 237.3 +/- 99.3 nmol/L, P < .04), higher 24-hour UFC excretion (313.2 +/- 112.6 v 244.2 +/- 69.3 nmol/24 h, P < .02), and greater cortisol responses to CRH infusion (time-integrated values: 49,408.2 +/- 11,289.8 v 40,217.9 +/- 7,228.6 nmol/L.120 min, P < .004; peak cortisol values: 529.7 +/- 107.6 v 438.7 +/- 77.3 nmol/L, P < .002) than controls. UFC excretion values were positively correlated with both 5-year averaged hemoglobin A1c level (P = .03) and total number of insulin units administered per day (P = .03). These results suggest that insulin-dependent diabetic outpatients have mild chronic hypercortisolism, which might influence the control of the disease and play a role in the development of its chronic complications.
A 40-year-old women with a 17-year-history of glaucomatocyclitic crises in 1 eye developed idiopa... more A 40-year-old women with a 17-year-history of glaucomatocyclitic crises in 1 eye developed idiopathic foveal subretinal neovascularization in the other eye. The subretinal neovascular membrane spontaneously regressed over a 2-month period, and useful reading vision was subsequently maintained for more than 6 years. This favorable outcome is discussed in relation to the previously reported cases of idiopathic macular subretinal neovascularization.
AIMS/BACKGROUND--While the retinal lesions of sickle cell retinopathy have been well documented, ... more AIMS/BACKGROUND--While the retinal lesions of sickle cell retinopathy have been well documented, their pathogenesis remains unclear. The purpose of this study was (1) to compare macular blood flow velocity in patients with sickle cell disease and controls, and (2) to determine in sickle cell patients the relation between macular blood flow velocity and red blood cell density. METHODS--Macular blood flow
The Farnsworth-Munsell 100-hue test was used to compare color vision in patients with sickle cell... more The Farnsworth-Munsell 100-hue test was used to compare color vision in patients with sickle cell anemia, 20/20 visual acuity, and mild to severe peripheral retinopathy, but without posterior retinal vessel involvement, with matched normal controls. Patients with sickle cell anemia had significantly more blue-yellow and mixed color vision defects and significantly higher Farnsworth-Munsell 100-hue scores than did controls. There were no significant associations between color vision defects and the severity of peripheral retinal findings or the diameter of the foveal avascular zone. These results suggest that color vision defects may exist in patients with sickle cell anemia in the absence of ophthalmoscopic retinal changes in the posterior fundus.
Ophtalmologie: organe de la Société française d'ophtalmologie
New methodology to analyze posterior vitreous fluorophotometry (PVF) data is described. Values fo... more New methodology to analyze posterior vitreous fluorophotometry (PVF) data is described. Values for D, fluorescein vitreous diffusion coefficient and P, permeability of the blood retinal barrier (BRB) to fluorescein are obtained. D was found to be significantly greater in diabetic patients with minimal retinopathy compared with either controls or patients with no retinopathy. P values were not significantly different between diabetic patients and controls or between diabetic subgroups, confirming the absence of breakdown of the BRB, as assessed by PVF, in early diabetic retinopathy.
Color vision is known to change with age. We conducted the Farnsworth-Munsell (FM) 100-Hue and th... more Color vision is known to change with age. We conducted the Farnsworth-Munsell (FM) 100-Hue and the Lanthony Desaturated Panel D-15 (DD-15) tests in 115 normal North American subjects aged 5-81 years to obtain age-specific norms for these procedures. For each test, color discrimination was best between the ages of 20 and 50 years. Both increasing age and the occurrence of lens changes were significantly associated with increasing 100-Hue error scores. Age-specific norms for the 100-Hue test were comparable with those obtained by Verriest in a European population, but such norms for the DD-15 test are problematic. Our data indicate somewhat greater variability in the DD-15 than in the 100-Hue test.
A 54-year-old woman with a history of bilateral central retinal vein occlusion, probably due to a... more A 54-year-old woman with a history of bilateral central retinal vein occlusion, probably due to an inflammatory process, developed a hemispheric retinal vein occlusion with cystoid macular edema in her only seeing eye. Five months later, in the absence of improvement in vision and macular edema, she received on two occasions a 2-weekly course of twice daily 100% hyperbaric oxygen. After each course retinal leakage, as assessed by vitreous fluorophotometry, decreased from abnormal to the normal range while visual acuity improved by two lines. The possible implications are discussed.
A new automated analysis procedure was used to evaluate the apparent blood-retinal barrier permea... more A new automated analysis procedure was used to evaluate the apparent blood-retinal barrier permeability (mean +/- SD = 1.31 = 0.31 X 10(-7) cm/s at 60 minutes after intravenous dye administration) and the effective diffusivity (mean +/- SD = 0.88 +/- 0.40 X 10(-5) cm2/s) for fluorescein in the vitreous of 21 normal subjects. The analysis improvements include (1) use of an individualized convolution (spread) function for each eye in comparing simulated and experimental scans, (2) separation of vitreous and chorioretinal fluorescence, and (3) precise determination of vitreous position relative to the retina. The average reproducibility in six subjects was 23% for permeability and 22% for diffusivity based on repeated determinations separated in time by at least a week. Diffusivity values, but not permeability values, significantly associated in comparisons of first and second determinations, suggesting permeability may fluctuate in time while diffusivity remains relatively constant. The fluorescence at 3 mm anterior to the retina (commonly employed as a measure of blood-retinal barrier leakiness) was strongly associated with diffusivity. In contrast, the anticipated association between permeability and 3-mm fluorescence was weak or absent.
We examined plasma levels of fibrinopeptide A, beta-thromboglobulin, and platelet factor 4 in dia... more We examined plasma levels of fibrinopeptide A, beta-thromboglobulin, and platelet factor 4 in diabetic patients. Among diabetic patients (n = 33) plasma levels of fibrinopeptide A, beta-thromboglobulin and platelet factor 4 were significantly higher than in controls (n = 41). In the subgroups of diabetic patients with (1) minimal (n = 13), and (2) moderate-severe (n = 14) retinopathy only plasma fibrinopeptide A levels were significantly higher than in controls. Among the total group of diabetic patients plasma levels of fibrinopeptide A increased significantly with increasing severity of retinopathy. These results suggest that diabetic retinopathy is associated with in vivo activation of blood coagulation factors and that this activation increases with advancing retinopathy.
We used 3-d food-record-keeping techniques to examine nutritional factors in diabetic patients wi... more We used 3-d food-record-keeping techniques to examine nutritional factors in diabetic patients with and without retinopathy. Patients without retinopathy had significantly higher daily intakes of total carbohydrate, water-soluble dietary fibers, insoluble dietary fibers, and glucose than did patients with retinopathy. Also, patients without retinopathy took a significantly lower proportion of their total daily calories as protein.
Seventy-six cases of surgical hepatomegaly were subjected to fine needle aspiration cytology (FNA... more Seventy-six cases of surgical hepatomegaly were subjected to fine needle aspiration cytology (FNAC) for initial diagnosis. Primary malignancies, as suspected clinically with adjunction of other investigative procedures, were 29 cases of whom 25 were confirmed by biopsy or therapy. Secondary deposits in liver were 27 of whom 15 were confirmed by therapy. Inflammatory lesions were 9 of whom 6 were confirmed by therapeutic response with specific therapy. Benign lesions were 10 of whom 5 were confirmed by surgery. Diagnosis of malignancies of liver is rather easier than that of benign lesions like hydatid cysts of liver which were Casoni's test negative; and hepatocellular adenoma, as the aspirate in the former is clear fluid and that of the latter is only normal looking liver cells. Thus, in respect of benign lesions of liver, FNAC diagnosis may be clinched after due consideration to the clinical findings, radiological and ultrasonographic findings and ultimately confirmed by exploration. Thus the fallacy lies in aspiration of normal looking liver cells whereby the histology may prove it to be hepatocellular adenoma, well differentiated hepatocellular carcinoma and secondary deposits where the exact site has not been hit. Ultrasonogram (USG) guidance helps in these cases where the same facility is available. This fallacy can again be avoided, where USG guidance is not available, by imparting due importance to clinical findings, USG findings and also by repeat smear.
An attempt was made to study the histological and histochemical changes as well as immunohistoche... more An attempt was made to study the histological and histochemical changes as well as immunohistochemical changes in desmin expression occurring in four types of clinical myopathies e.g. Chronic ischaemic myopathy due to Buerger's disease (Group I), Carcinomatous myopathy (Group II), Metabolic myopathy (Group III) and Muscular dystrophy (Group IV). The number of cases studied were 16 cases, 15 cases, 4 cases and 5 cases respectively. The study revealed: (i) a combination of normal, degenerated, necrotic and regenerating fibres in different proportions in all the four groups having maximum number of degenerated fibres in Group I and Group IV, relatively more number of regenerating fibres in groups III and absence of necrotic fibres in Group I. (ii) Altered tinctorial property in most of the fibres indicating degenerated and regenerating fibres in all the groups with Masson's trichrome staining against inconstant staining with PTAH appear to be a good indicator for myopathy. (iii) The Desmin expression was week and irregular in most of the cases with most of the fibres probably due to reduction of desmin content probably indicating degenerated fibres, appear to be a good indicator for myopathy. (iv) Chronic ischaemic myopathy showed close resemblance with muscular dystrophy though no typical or distinct distinguishing feature could be identified in these four groups.
The main reinforcing effect of cocaine happens by altering dopaminergic neurotransmission in the ... more The main reinforcing effect of cocaine happens by altering dopaminergic neurotransmission in the brain reward systems. Dopamine is found in high concentrations in the retina in which it plays an important role in color vision. Therefore, we investigated whether cocaine-dependent patients might have impaired color vision. We compared patients recently withdrawn from cocaine (n = 31) with matched normal controls (n = 31) on 2 color vision tests. Cocaine-withdrawn patients had significantly higher error scores than matched controls on the Farnsworth-Munsell 100-hue and Lanthony desaturated D-15 color vision tests. Also, 23 of the 31 cocaine-withdrawn patients had blue-yellow color vision losses on the Farnsworth-Munsell 100-hue test compared with 3 controls (P < .001, chi 2 test) and 15 had blue-yellow color vision loss on the Lanthony desaturated D-15 test compared with 2 controls (P < .001, chi 2 test). These significantly higher test error scores and blue-yellow color vision losses suggest that color vision is impaired in cocaine-withdrawn patients. Color vision testing may be useful in future studies of cocaine-dependent patients.
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