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Systemic toxicity of tacrolimus given by various routes and the response to dose reduction.

PURPOSE: To evaluate the long-term systemic toxicity of tacrolimus (FK-506) administered by various routes, and to assess the effect of dose reduction on toxicity. METHODS: The study animals were 120 experimentally naive adult female Wistar rats weighing 200-250 g each. The rats were randomly divided into 10 equal groups (n=12 in each) and treated with tacrolimus administered topically (in drops, 0.3%, q.i.d.), intravitreally (0.5 mg/kg bodyweight/week), intramuscularly (1 mg/kg bodyweight/week), low-dose intravenously (1 mg/kg bodyweight/week) and in high-dose intravenously (2 mg/kg bodyweight/week) for 3 months. The rats in the control groups (one for each different route of administration) were treated with 0.9% NaCl. The blood concentration of tacrolimus, complete blood count and biochemistry parameters were measured each month for the 3-month study period. RESULTS: The rats in the control groups and experimental groups administered topical and intravitreal tacrolimus did not demonstrate any systemic toxic effects. The rats that developed certain toxic effects (hyperglycaemia, hyperkalaemia and nephrotoxicity) in the groups given low-dose or high-dose i.v. tacrolimus responded well to dose reduction. Following dose reduction, blood glucose concentrations decreased from 247.4 +/- 42.3 mg/dL to 189.6 +/- 37.9 mg/dL (P <0.05), and from 237.4 +/- 41.1 mg/dL to 182.3 +/- 22.7 mg/dL (P <0.05) in the low- and high-dose i.v. tacrolimus-treated rats, respectively. The rats that developed impaired hepatic function after high-dose tacrolimus did not respond to dose reduction. Baseline cholesterol concentrations for the intramuscular and low- and high-dose i.v. tacrolimus-treated groups, demonstrated decreases, respectively, from 87.4 +/- 14.0 mg/dL, 86.4 +/- 14.0 mg/dL and 90.4 +/- 14.3 mg/dL to 53.6 +/- 9.8 mg/dL, 52.1 +/- 12.5 mg/dL and 63.5 +/- 11.7 mg/dL by the end of the second month. The differences were found to be statistically significant (P <0.05 for each result). CONCLUSION: Topical or intravitreal administration of tacrolimus seems to be systemically safe whereas parenteral administration can cause some systemic haematological changes such as dose-dependent decreased serum cholesterol concentrations. Dose reduction may prevent such adverse effects.

Administration, Topical↗

Cyclosporine dose reduction in stable renal transplant patients with high C2 level: simplified method of single C2 measurement and individualization of C0 target.

It is recommended that cyclosporine dosing should be based on the whole blood level 2 h after a dose (C2), not the trough level (C0). Initial studies did not however establish the outcome of dosing according to C2 levels in long-term patients previously managed by C0 levels. C0 and C2 were measured in 152 stable patients receiving Neoral therapy, mean 86.9 months after transplantation. This showed that 38 (25%) had C2 levels above a target range of 700-900 microg/l. Higher C2 levels were associated with higher cholesterol levels (P = 0.0058) and higher diastolic blood pressure (P = 0.0163). Cyclosporine dose reduction was undertaken in 32 patients with high C2 levels. For logistical reasons, C2 was not performed regularly, but an individualized C0 level was set for each patient. A 16% reduction in mean cyclosporine dose was achieved, associated with a 28% fall in mean C0, from 212 to 153 microg/l, and a 25% fall in mean C2, from 1075 to 820 microg/l. There was no excess in adverse events in the dose reduction cohort, compared with patients with initial C2 levels <900 microg/l. Over a mean 15 month follow-up period in the dose reduction cohort, there was a 4.4% reduction in mean diastolic blood pressure, from 84.9 (SEM 2.1) to 80.2 (1.9) mmHg, P = 0.023; and a 10.4% reduction in mean cholesterol, from 5.71 (0.27) to 5.11 (0.25), P = 0.005 (patients starting on statin during follow-up excluded). In patients with initial C2 <900 microg/l, blood pressure did not fall and the cholesterol fell by 3.9%, from 5.27 (0.14) to 5.07 (0.15) mmol/l (P = 0.0405). In conclusion, cyclosporine dose reduction was safe in stable long-term renal allograft recipients with high C2 levels. There was an improvement cholesterol levels and a small improvement in blood pressure after cyclosporine dose reduction.

Blood Pressure↗

High-dose of multiple antipsychotics and cognitive function in schizophrenia: the effect of dose-reduction.

We evaluated the effect of antipsychotic dose-reduction on the neurocognitive function of 17 schizophrenic patients (11 male and 6 female, mean age=42.4+/-11.3) who have been taking high-doses of multiple conventional antipsychotics. The mean (+/-SD) of total daily antipsychotic doses (in mg/day, chlorpromazine-equivalent) was 2,253 (+/-668) at baseline, which was reduced to 1,315 (+/-276). Possible changes in neurocognitive function were assessed using Wisconsin card sorting test (WCST) and continuous performance test (CPT). As controls, we examined WCST and CPT in 6 schizophrenic patients (4 male and 2 female, mean age=47.7+/-14.2) who had been taking high-doses of multiple antipsychotics (mean daily antipsychotic dose=1,753+/-165 mg) and declined to change their antipsychotic regimen. In WCST, the mean number of total correct answers significantly increased (53.2+/-16.3 vs. 63.8+/-19.6, P=0.035, Wilcoxon signed rank test); perseverative errors significantly decreased (54.4+/-27.3 vs. 35.4+/-20.1, P=0.013, Wilcoxon signed rank test) after the antipsychotic dose-reduction. In contrast, the control group showed no significant difference between the two WCST performances conducted with a three-month interval. The improvements in WCST performance significantly correlated with the decreases in PANSS negative syndrome score in the subject patients. No significant change was observed in CPT performances in either group. Our preliminary data shows that, in schizophrenic patients taking high-doses of multiple conventional antipsychotics, dose-reduction might lead to improvements in cognitive functions.

Adult↗

[The smart-scan procedure of spiral computed tomography. A new method for dose reduction].

PURPOSE: In this article a new method - the Smart-Scan-Technique - for dose reduction during spiral computed tomography is described. This technique allows a dynamical adaptation of the tube current according to the measured local density structure form and absorption values of the object of interest. Its clinical applicability for dose reduction is investigated. In addition, changes in image quality are evaluated. METHODS: Specially designed, water filled plexiglas-phantoms, an Alderson-Rando phantom, and 20 patients were used to simulate possible measures of patients within the thoracic and abdominal region. For those two regions the dose reduction, the modulation transfer function, and the pixel noise were measured. RESULTS: Depending on patient geometry dose reduction up to 20% could be achieved with the Smart-Scan-Technique. This technique also enabled a decrease of the modulation transfer function and an increase of the pixel noise by 8%. CONCLUSION: Relevant dose reductions can be achieved by applying the Smart-Scan-Technique in spiral computed tomography.

Absorption↗

Clinical outcome after cyclosporine dose reduction based on C2 levels in long-term liver transplant patients.

BACKGROUND: Recent studies suggest that cyclosporine dose adjustment based on C2 levels results in improvement of renal function. This study investigates the effect on renal function after dose reduction based on the C2 levels in long-term liver transplant patients. METHODS: In 60 patients (>1 yr after transplantation), C2 levels were assessed (target 600 ng/mL +/- 20%). Dose reduction was performed when C2 >720 ng/mL. Serum creatinine concentrations were measured and creatinine clearance was calculated. RESULTS: Twenty-three patients (38%) had C2 values >720 ng/mL. After dose reduction, mean cyclosporine dose decreased by 25% (p < 0.01). Mean C2 value decreased by 42% (p < 0.01). Serum creatinine concentrations remained stable. After dose reduction two patients experienced recurrence of PBC, in one patient AIH recurred and rejection was diagnosed in one patient. CONCLUSION: Cyclosporine C2 concentrations above 720 ng/mL are common in long-term liver transplant patients. Dose reduction of 25% did not improve kidney function and was accompanied by immune activation.

Creatinine↗

Dose reduction in spiral CT angiography of thoracic outlet syndrome by anatomically adapted tube current modulation.

The aim of this study was to evaluate dose reduction in spiral CT angiography of the thoracic outlet by on-line tube-current control. Prospectively, 114 patients undergoing spiral CT angiography of the subclavian artery for thoracic outlet arterial syndromes were evaluated with and without tube-current modulation at the same session (scanning parameters for the two successive angiograms, one in the neutral position and one after the postural maneuver): 140 kV; 206 mA; scan time 0.75 s; collimation 3 mm; pitch = 1). The dose reduction system was applied in the neutral position in the first 92 consecutive patients and after postural maneuver in the remaining 22 consecutive patients. Dose reduction and image quality were analyzed in the overall study group (group 1; n = 114). The influence of the arm position was assessed in 44 of the 114 patients (group 2), matched by the transverse diameter of the upper thorax. The mean dose reduction was 33% in group 1 (range 22-40%) and 34% in group 2 (range 26-40%). In group 2 the only difference in image quality was a significantly higher frequency of graininess on low-dose scans compared with reference scans whatever the patient's arm position, graded as minimal in 38 of the 44 patients (86%). When the low-dose technique was applied after postural maneuver in group 2: (a) the mean dose reduction was significantly higher (35 vs 32% in the neutral position; p = 0.006); (b) graininess was less frequent (82 vs 91% in the neutral position); and (c) the percentage of graininess graded as minimal was significantly higher (83 vs 70% in the neutral position; p = 0.2027). On-line tube-current modulation enables dose reduction on high-quality, diagnostic spiral CT angiograms of the thoracic outlet and should be applied during data acquisition in the neutral position and after postural maneuver for optimal use.

Adult↗

The effect of rare earth filtration on patient exposure, dose reduction, and image quality in oral panoramic radiology.

Rare earth intensifying screen material (Gd2O2S:Tb) was added to the standard Al filtration of an oral panoramic x-ray unit, resulting in a beam capable of achieving reductions in patient dose without a loss of image quality. The added rare earth filtration technique resulted in patient dose reductions of 21-56%, depending on anatomic sites, when compared to the conventional Al filtration technique. Films generated from both techniques were measured densitometrically and evaluated by a panel of practicing clinicians. Diagnostically significant differences were minimal. The results indicate that use of rare earth filters in oral panoramic radiography is an effective means of reducing exposures of dental patients to ionizing radiation.

Film Dosimetry↗

Mycophenolate mofetil dose reduction and the risk of acute rejection after renal transplantation.

Mycophenolate mofetil (MMF) significantly decreases acute rejection rates after renal transplantation, but intolerance often occurs, leading to dose reduction. The clinical effect of MMF dose reduction has not been clearly established. This study determined whether MMF dose reduction after renal transplantation was associated with subsequent risk of acute rejection. This retrospective cohort study assessed 213 renal transplant recipients. Cox regression was used to model MMF dose as a time-dependent variable, with time to first acute rejection as the primary outcome. One hundred twenty-six patients (59%) had a total of 176 MMF dose reductions during the study. MMF dose was reduced because of leukopenia (55.1%), gastrointestinal symptoms (22.2%), infection (7.4%), malignancy (1.1%), and unknown reasons (14.2%). The cumulative number of days with the MMF dose reduced below full dose was an independent predictor of acute rejection. The relative risk of rejection increased by 4% for every week that the MMF dose was reduced below full dose. No significant association was observed between the number of days with MMF dropped below full dose and allograft failure. The cumulative number of days with the MMF dose dropped below full dose is a significant predictor of acute rejection after renal transplantation. Clinicians need to be aware of the rejection risk when the MMF dose is reduced and maintain close surveillance on such patients.

Acute Disease↗

Are phantoms useful for predicting the potential of dose reduction in full-field digital mammography?

A phantom study was performed in full-field digital mammography to investigate the opportunity and the magnitude of a possible dose reduction that would leave the image quality above the accepted thresholds associated with some classical phantoms. This preliminary work is intended to lay the groundwork for a future clinical study on the impact of dose reduction on clinical results. Three different mammography phantoms (ACR RMI 156, CIRS 11A and CDMAM 3.4) were imaged by a full-field digital mammography unit (GE Senographe 2000D) at different dose levels. Images were rated by three observers with softcopy reading and scoring methods specific to each phantom. Different types of data analysis were applied to the ACR (American College of Radiology) and the other two phantoms, respectively. With reference to the minimum acceptance score in screen/film accreditation programmes, the ACR phantom showed that about 45% dose reduction could be applied, while keeping the phantom scores above that threshold. A relative comparison was done for CIRS and CDMAM, for which no threshold is defined. CIRS scoring remained close to the reference level down to 40% dose reduction, the inter- and intra-observer variability being the main source of uncertainty. Contrast-detail curves provided by CDMAM overlapped down to 50% dose reduction, at least for object contrast values ranging between 30% and 3%. This multi-phantom study shows the potential of further reducing the dose in full-field digital mammography beyond the current values. A common dose reduction factor around 50% seems acceptable for all phantoms. However, caution is required before extrapolating the results for clinical use, given the limitations of these widely used phantoms, mainly related to their limited dynamic range and uniform background.

Equipment Failure Analysis↗

[Dose distribution in conventional CT and spiral CT and on the topic of dose reduction with spiral CT].

OBJECTIVE: To compare spiral CT with conventional CT with regard to the dose distribution in the irradiated body and to examine when an increase in the table feed in spiral CT leads to a dose reduction compared with conventional CT. METHODS: In order to show the dose distribution, films were exposed in an acrylic phantom. The nominal slice thickness was 5 mm; the slice distance in conventional CT was 5 and 10 mm; the table feed in spiral CT was 5 and 10 mm per rotation (pitch 1 and 2). The integral doses delivered in spiral CT and conventional CT were related to the table feed per rotation or slice distance, respectively, and were compared arithmetically with each other. RESULTS: Spiral CT showed reduced dose fluctuations in axial direction compared with conventional CT. Only in conventional CT with a slice distance of 5 mm did the axial dose distribution show relative dose peaks near the rotation axis. The longer the body region to be examined is, the less table feed is necessary in spiral CT for a dose reduction. From a length of 15 times the slice thickness, a pitch of > 1.1 leads to a reduction of the integral dose compared with conventional CT. CONCLUSIONS: The continuous table feed in spiral CT results in evenly distributed axial dose distributions compared with the discontinuous scanning in conventional CT. The spiral technique can give an important contribution to dose reduction in CT.

Equipment Design↗

[The use of copper and niobium filters in diagnostic x-ray equipment. A comparison of dose reduction, tube loading and picture quality].

A dose-reducing niobium filter for use in diagnostic radiology was introduced in Norway in 1989. The effect of this filter was compared with that of an ordinary copper filter. Either a 0.05 mm niobium filter or a 0.10 mm copper filter was placed into the beam from an X-ray tube. Parallel measurements were made of dose reduction to the patient, image quality and tube loading. The copper filter reduced skin doses more than the niobium filter did, and caused less increase in tube loading. The resulting image quality was considered to be the same. We conclude that a 0.10 mm copper filter is better than a niobium filter in achieving a considerable dose reduction to the patient, and is far less expensive.

Copper↗

Dose reduction in CT by anatomically adapted tube current modulation. II. Phantom measurements.

Theoretical considerations and simulation studies have led to the expectation that patient dose in CT (computed tomography) can be reduced significantly without a concomitant loss in image quality if tube current is modulated according to rotation angle-dependent x-ray attenuation. In this study, the simulation results presented in Part I were validated with phantoms. We used one cylindrical, two oval, and one elliptical phantom, available both as mathematical descriptions and in physical form, to mimic different parts of the human anatomy. Prototype hardware was available to control tube current on a commercial clinical CT scanner. The potential for dose reduction was evaluated for sinusoidal and attenuation-based current modulation for variable modulation amplitudes. Agreement between simulations and measured results was better than within 10%. Dose reduction values of 8%-56% were found depending on the phantom geometry and tube current modulation function. Attenuation-based tube current modulation consistently yielded higher reduction than fixed-shape sinusoidal modulation functions. For the shoulder phantom and 70% modulation amplitude, 44.6% dose reduction was measured as compared to 34.1% for sinusoidal modulation. A maximum of 56% was measured for the shoulder phantom including inserts. Specifying mAs reduction as an estimate for dose reduction proved to be a valid and conservative estimate; measured dose is reduced more strongly than the total mAs product both centrally and on average. First patient studies confirm the results of simulation and phantom studies. We conclude that attenuation-based online tube current control has great potential for reducing patient dose in CT and that it should be made generally available for clinical use.

Air Pollutants, Radioactive↗

Mycophenolate mofetil dose reductions and discontinuations after gastrointestinal complications are associated with renal transplant graft failure.

BACKGROUND: Mycophenolate mofetil (MMF) use in renal transplantation has steadily increased since 1995 because of its ability to lower the risks of rejection and chronic allograft nephropathy. However, significant gastrointestinal (GI) complications may lead to MMF dose reductions and discontinuations. Little is known of the association between MMF dose reductions and discontinuations following GI complications and graft survival. METHODS: Using the United States Renal Data System, we identified 3,675 adult recipients (age >or=18) with a diagnosed GI complication who were prescribed MMF at the time of first GI diagnosis and had Medicare as their primary insurer. MMF doses were ascertained from Medicare payment records. We estimated risk of graft loss associated with MMF dose adjustments after GI diagnosis: dosage unchanged (reference), reduced <50%, reduced >or=50%, and MMF discontinued. Patients were followed until graft loss, death, last recorded immunosuppression prescription, or 3 years posttransplant. RESULTS: Compared to those with no MMF dose reductions or discontinuations, the risk of graft failure increased with MMF doses reduction >or=50% (HR=2.36, 95% CI 1.23-4.54) and those with MMF discontinuation (2.72, CI 1.60-4.64). CONCLUSION: Renal transplant recipients who underwent MMF dose reduction or withdrawal following GI diagnosis are associated with increased risk of graft failure.

Adolescent↗

The impact of cyclosporine dose reduction with or without the addition of rapamycin on functional, molecular, and histological markers of chronic allograft nephropathy.

BACKGROUND: Overexposure to cyclosporine is a risk factor for chronic allograft nephropathy (CAN) and dose reduction has been advocated. The purpose of this study was to determine the impact of adding the non-nephrotoxic immunosuppressant, rapamycin, after cyclosporine dose reduction in renal-allograft recipients with CAN. METHODS: Thirty-one patients with biopsy-confirmed CAN were prospectively randomized to receive a 40% cyclosporine dose reduction with (rapamycin, n=16) or without (control, n=15) the addition of rapamycin 2 mg/day. Renal function and side-effect parameters were assessed. Patients had renal allograft biopsies taken at recruitment and after 6 months. Glomeruli were isolated from these and underwent total mRNA extraction followed by RT-PCR-ELISA to assess transforming growth factor-beta1, collagen III, TIMP-1, TIMP-2, and matrix metalloproteinase-2 expression. Samples were also stained with Sirius red and the percentage interstitial volume fraction quantified by computerized histomorphometric analysis. Data are presented as mean (+/-SD). RESULTS: Patient characteristics and cyclosporine trough levels after dose reduction (rapamycin 68 [+/-21] vs. control 56 [+/-19] ng/mL, P=NS) were similar in both groups. Rapamycin patients had a significant fall in Cr-51 radioisotope glomerular filtration rate (31.6 [+/-8.9] to 27.3 [+/-8.6] mL/min, P<0.01) that was not significant in controls (29.5 [+/-10.4] to 27.0 [+/-8.0] mL/min, P=NS). Transforming growth factor-beta1 expression fell over time in control but remained constant in rapamycin patients. Conversely collagen III expression increased over the 6-month follow-up in rapamycin patients but not in controls. Both had comparable increases in TIMP-1 and matrix metalloproteinase-2 but only rapamycin patients developed a significant increase in TIMP-2. Sirius red-stained interstitial volume fraction fell over the study in controls (15.3-11.2%, P=0.06) but not in rapamycin patients (16.2-16.3%, P=NS). CONCLUSION: Rapamycin (2 mg/day) did not improve functional, molecular, or histological outcome in patients with CAN after cyclosporine dose reduction. Further studies involving larger numbers of patients are necessary to confirm these findings.

Adult↗

Dose reduction in CT by on-line tube current control: principles and validation on phantoms and cadavers.

We investigated approaches to reducing the dose in CT without impairing image quality. Dose can be reduced for non-circular object cross-sections without a significant increase in noise if X-ray tube current is reduced at angular tube positions where the X-ray attenuation by the patients is small. We investigated different schemes of current modulation during tube rotation by simulation and phantom measurements. Both pre-programmed sinusoidal modulation functions and attenuation-based on-line control of the tube current were evaluated. All relevant scan parameters were varied, including constraints such as the maximum modulation amplitude. A circular, an elliptical and two oval water phantoms were used. Results were validated on six cadavers. Dose reduction of 10-45% was obtained both in simulations and in measurements for the different non-circular phantom geometries and current modulation algorithms without an increase in pixel noise values. On-line attenuation-based control yielded higher reductions than modulation by a sinusoidal curve. The maximal dose reduction predicted any simulations could not be achieved due to limits in the modulation amplitude. In cadaver studies, a reduction of typically 20-40% was achieved for the body and about 10% for the head. Variations of our technique are possible; a slight increase in nominal tube current for high-attenuation projections combined with attenuation-based current modulation still yields significant dose reduction, but also a reduction in the structured noise that may obscure diagnostic details. We conclude that a significant reduction in dose can be achieved by tube current modulation without compromising image quality. Attenuation-based on-line control and a modulation amplitude of at least 90% should be employed.

Cadaver↗

Potential of dose reduction after marker placement with full-field digital mammography.

OBJECTIVES: The purpose of our study was to assess the potential for radiation dose reduction in digital postinterventional digital mammograms after marker placement. MATERIALS AND METHODS: One hundred consecutive cases of marker placement (hook-wire localization or postbiopsy clip marker placement), with 200 full-field digital baseline mammograms (craniocaudal and mediolateral), were included in this prospective trial. For the postinterventional digital mammograms, the milliampere seconds were reduced either by 50% or by 75%. Dose-reduced images were evaluated for sufficient image quality to verify the position of the marker. RESULTS: In 193 of 200 cases (96.5%), image quality was sufficient to verify the correct position of the marker. One (1%) case with insufficient image quality occurred in the 50% dose-reduction group and 6 (6%) in the 75% dose-reduction group (P = 0.06). CONCLUSION: Our results indicate that under evaluation of each individual case, a dose reduction of 50% to 75% can be recommended in postinterventional digital mammograms.

Breast Neoplasms↗

A rational approach to dose reduction in CT: individualized scan protocols.

The aim of this study was to demonstrate that dose reduction and constant image quality can be achieved by adjusting X-ray dose to patient size. To establish the relation between patient size, image quality and dose we scanned 19 patients with reduced dose. Image noise was measured. Four radiologists scored image quality subjectively, whereby a higher score meant less image quality. A reference patient diameter was determined for which the dose was just sufficient. Then 22 patients were scanned with the X-ray dose adjusted to their size. Again, image noise was measured and subjective image quality was scored. The dose reduction compared with the standard protocol was calculated. In the first group the measured noise was correlated to the patient diameter (rho=0.78). This correlation is lost in the second group (rho=-0.13). The correlation between patient diameter and subjective image quality scores changes from rho=0.60 (group 1) to rho=-0.69 (group 2). Compared with the standard protocol, the dose was reduced (mean 28%, range 0-76%) in 19 of 22 patients (86%). Dose reduction and constant noise can be achieved when the X-ray dose is adjusted to the patient diameter. With constant image noise the subjective image quality increases with larger patients.

Anthropometry↗

Reducing the dose of antipsychotic medications for those who had been treated with high-dose antipsychotic polypharmacy: an open study of dose reduction for chronic schizophrenia.

Antipsychotic medications are often used at higher than the recommended dose and sometimes in a combination regimen to treat schizophrenia. However, in general, high-dose therapies have been abandoned in recent clinical studies. In this study, dose reduction of antipsychotic medication was implemented for patients with chronic schizophrenia, most of whom (81%) had been treated with an antipsychotic high-dose polypharmacy regimen consisting of more than 1000 mg/day in total amount. The results show that merely reducing the amount of antipsychotic led to favourable outcome in 23 out of 41 cases (56%), with another 13 cases (32%) showing no change. Dose reduction ended in failure in only five subjects (12%). Overall, the amount as well as the number of antipsychotic medications was significantly reduced from 1984 mg to 812 mg per day (reductions of 59% and from 3.6 to 2.2, respectively; both P<0.0001). The Global Assessment of Functioning scale improved from 30.6 to 37.2, which reached significance (P<0.001). Accordingly, the Severity of Illness improved from 4.7 to 4.2, and was also significant (P<0.01). Dose reduction is an encouraging strategy to consider for those patients with schizophrenia who have chronically been treated with high-dose antipsychotic polypharmacy, even if judged unavoidable in the past.

Adolescent↗