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Effects of injection site and flow rate on the distribution of injected solutions in an extracorporeal membrane oxygenation circuit.

The effects of injection site and flow rates on drug distribution within an extracorporeal membrane oxygenation (ECMO) circuit were studied. Two commercially available reservoirs (30 mL and 50 mL) were connected to a closed ECMO circuit that did not include the membrane oxygenator and heater. The circuit was filled with 150-170 mL of a 9.5% dextran solution in deionized, distilled water with a viscosity approximating that of blood. Flow rates of the circulating solution were set at 75 mL/min and 375 mL/min. Bordeaux red dye was injected into an ECMO circuit at prereservoir, postreservoir, and intrareservoir sites, and samples were obtained from these sites for analysis. Gentamicin was also injected at the prereservoir site, with samples obtained from the reservoir, reservoir tubing, and the prereservoir and postreservoir sites. Postreservoir dye injections resulted in complete mixing at any flow rate. Prereservoir injections at flow rates less than 250 mL/min resulted in incomplete mixing of dye, whereas intrareservoir injections resulted in incomplete mixing at any flow rate. Gentamicin injection was also affected by flow rate, resulting in higher concentrations within the reservoir and reservoir tubing. In patients on ECMO, drug distribution may be substantially altered if drugs are given as a bolus at prereservoir or intrareservoir sites. Efforts should be made to select injection sites that will provide safe and therapeutic drug delivery while minimizing the effects of the ECMO circuit on drug distribution.

Critical Care

Does a needleless injection system reduce anxiety in children receiving intramuscular injections?

Previous studies have shown that needle injections are very stressful for children. This study examined if a needleless injection system would be associated with lower anxiety levels in children by comparing children's responses to a traditional needle injection to their responses to the Biojector, a needleless system. Seventy-four sixth-grade students of two public middle schools, all scheduled to receive the Hepatitis B vaccine, were enrolled. The study used a cross-over design. The children's anxiety levels were measured both before and after each of the two types of injections using the Spielberger State Trait Anxiety Index for Children (STAIC). Data analysis found no significant difference in levels of anxiety associated with the Biojector injections when compared with anxiety levels associated with needle injections. When asked to choose the injection method for their third injection, however, students showed a preference for the Biojector (61%), which indicated a trend towards significance (p = .08).

Anxiety

The effect of dose, route, number of injections and the use of adjuvant on the clearance of and immune response to, haemocyanin following injection into brown trout (Salmo trutta).

The primary and secondary immune responses were investigated in trout injected with haemocyanin (HCN) intramuscularly (IM) or intraperitoneally (IP), with or without adjuvant. HCN was detected in the blood 30 min after injection and clearance times varied after one injection from 8 to 56 days. Fish given two and three injections cleared the antigen faster. Precipitins against HCN were first detected 21 to 30 days after injection and were still present on Day 56. However, antibodies detectable by indirect haemagglutination (IHA) and complement fixation (CFA) were initially demonstrated 7 to 21 days after a single injection and highest titres were reached between 33 and 56 days according to the experimental protocol. In fish given two injections, maximum titres were reached between Days 42 and 56 (IM), and Days 50 and 56 (IP). With three injections, maximum CFA and IHA values occurred on Days 62 and 66 respectively in the case of IP, and on Days 103 and 106 respectively with IM. Overall, higher titres were found with IHA than by CFA.

Animals

Changes in the injecting risk behaviour of injecting drug users in London, 1990-1993.

OBJECTIVE: To describe changes in the injecting risk behaviour of injecting drug users (IDU) in London between 1990 and 1993. DESIGN: Injecting risk behaviour was measured over 4 years (1990-1993) in a serial point HIV prevalence study of 2062 IDU recruited in both drug treatment and non-treatment community-based settings within greater London. The study used a structured questionnaire and common sampling and interview strategy developed by a World Health Organization technical group and implemented in 13 cities. METHODS: Log-linear models were used to assess patterns of change over years and of differences in injecting risk behaviour, including syringe sharing and syringe hygiene between 1990 and 1993. The log likelihood chi 2 statistic, G2, was used to test statistical significance. Changes in the mean values were assessed first using parametric tests assuming normality and the results were compared with Kruskal-Wallis (non-parametric) tests. Pearsons chi 2 was used to measure differences in frequency of sharing occasions and partner selectivity. RESULTS: An overall reduction in injecting risk behaviour was observed during the first 2 years of this study, including a decline in syringe sharing (both accepting and passing on used syringes), the number of sharing partners and the frequency of sharing occasions. Most sharers restricted sharing to sexual partners and close friends. The majority of sharers reported always cleaning injecting equipment. Main source of sterile equipment was pharmacies and syringe exchanges. Indirect sharing (of spoons, filters, and by front- or backloading) was reported. Since 1991 there has been a stabilization in risk behaviour. CONCLUSIONS: The data indicate that IDU in London have made positive reductions in risk behaviour. Levels of syringe sharing were substantially lower than those reported up to 1987 before AIDS awareness and the introduction of HIV prevention measures. The majority did not share syringes or confined their sharing to close friends and sexual partners, and if shared, cleaned their syringes. Continuation of indirect sharing indicates the need for more detailed prevention messages. While the initial decline in syringe-sharing rates may be attributed to the wide availability of sterile injecting equipment and other preventive measures, it may now be necessary to look beyond current intervention initiatives to develop interventions which seek to change the social etiquette of sharing and move towards the long-term maintenance of low levels of injecting risk behaviour.

Adult

A multicentred phase III comparative clinical trial of Mesigyna, Cyclofem and Injectable No. 1 given by intramuscular injection to Chinese women. II. The comparison of bleeding patterns.

Between 1988 and 1992, a randomized phase III clinical trial was conducted in China to compare three monthly injectable contraceptives: Mesigyna, Cyclofem and Injectable No. 1. This paper presents a detailed analysis of the menstrual diaries provided by 5098 (89%) of the subjects. In total, 902, 903 and 913 diaries were analyzed to compare bleeding patterns induced by Mesigyna, Cyclofem and Injectable No. 1. The first withdrawal bleeding usually occurs 14-20 days after the first injection for all three of these preparations. Thereafter, 50% of Mesigyna users had precisely 3 bleeding/spotting episodes every 90 days, 50% of Cyclofem users had 2-3 and 50% of Injectable No. 1 users had 3-4 episodes every 90 days. Relative to users of Mesigyna or Cyclofem, Injectable No. 1 users had 2-3 more bleeding/spotting days, and a shorter length of bleeding/spotting-free intervals in each period. 63.7%, 41.4% and 60.6% of subjects using Mesigyna, Cyclofem and Injectable No. 1, respectively, had bleeding patterns similar to their untreated patterns in the first 90-day period. The percentages increased to 82.2% 67.8% and 75.0% in the fourth 90-day period. A total of 1815 diaries for Mesigyna and 1802 for Cyclofem were analyzed for more in depth comparison of these two methods. The number of bleeding/spotting days over four periods showed little difference between the two group, but there were more spotting days and there was greater individual variability among Cyclofem users.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent

Influence of concentration and injection volume on the bioavailability of subcutaneous growth hormone: comparison of administration by ordinary syringe and by injection pen.

In order to study whether the bioavailability of subcutaneously injected growth hormone (GH) is dependent on the concentration/volume injected, the relative GH bioavailability was evaluated in 14 GH-deficient patients. In a cross-over study the patients received, in random order two separate subcutaneous GH injections (Norditropin) 4 IU administered by means of an ordinary syringe (4 IU ml) and an injection pen with cartridge (Nordiject 24) (12 IU/ml). Blood samples were drawn over a 14 hr period and assayed for serum concentrations of GH and IGF-I. The mean value (+/- S.D.) of the relative absorption fraction (Fpen/sy) was 1.09 +/- 0.39. Mean values of Cmax were 8.6 ng/ml +/- 4.8 and 8.3 ng/ml +/- 7.5 for syringe and pen respectively. Corresponding values for Tmax were 311 min. +/- 131 for syringe and 309 min. +/- 104 for pen. Although a considerable interindividual variation was seen, the relative absorption fraction did not differ significantly from 1 (2 P = 0.78). Further there was no significant difference in neither Cmax (2 P = 0.39) nor Tmax (2 P = 0.55). IGF-I serum profiles tended to be higher following syringe compared to pen injection (2 P = 0.054). On the basis of this study we conclude that in this dosage regimen. GH bioavailability following pen injection equals that of injection by syringe (i.e. no effect of a three fold increase/decrease in GH concentration/volume respectively).

Adult

Prolongation of cardiac allograft survival by intraportal injection of donor antigens--differential mechanisms according to the timing of injection.

Recently, we reported that intraportal (IP) injection of donor spleen cells (SPCs) before transplantation as well as at the time of transplantation significantly prolongs cardiac allograft survival in rats (7). Long-term establishment of chimerism induced by intraportal administration of SPCs could be a part of this prolongation. In this study, we examined the effect of irradiation of SPCs as a source of donor antigens on cardiac allograft survival. Experiments were carried out using DA (RT1a) as the donor and BUF (RT1b) as the recipient strain. Fifty million irradiated or nonirradiated SPCs were injected either intravenously (i.v.) or intraportally (i.p.) on day -10 or day 0, the day of cardiac allografting. Untreated animals rejected allografts within a mean survival time (MST) of 7.2 +/- 0.8 days (n = 5). Injection (i.p.) of SPCs on both day -10 (n = 4) and day 0 (n = 6) induced significant prolongation of MST over the control (19.0 +/- 4.7, 14.2 +/- 2.1 days; p < 0.001 vs. control), while i.v. injection of SPCs on either day -10 (n = 4) or day 0 (n = 4) failed to do so (9.2 +/- 1.0, 8.5 +/- 0.6 days). Significant prolongation was still observed when irradiated SPCs were injected on day -10 (n = 4; MST: 19.0 +/- 5.4 days, p < 0.002 vs. control), but not when injected on day 0 (n = 5; MST: 9.4 +/- 2.1 days). These data suggest that the immunosuppressive effect of i.p. injection of donor SPCs could be induced by differential mechanisms according to the timing of inoculation of donor antigens.

Animals

Hemodynamic effects of calcium chloride injection following cardiopulmonary bypass: response to bolus injection and continuous infusion.

To determine the hemodynamic effects of intravenous injection of calcium chloride, 26 patients were studied immediately after termination of extracorporeal circulation. Eighteen patients (Group A) had injection of a single bolus of CaCl2; in the other 8 patients (Group B), the bolus injection was followed by infusion of CaCl2 at a rate of 1.5 mg/kg/min for 10 minutes. Myocardial contractile element velocity (Vpm), aortic blood flow, electrocardiograms, and left ventricular, systemic arterial, pulmonary arterial, and left atrial pressures were recorded continuously. The baseline ionized calcium level after bypass was 3.6 +/- 0.6 mg/100 ml (normal range, 3.9 to 4.5 mg/100 ml); this increased to 5.4 +/- 0.5 mg/100 ml 1 minute after CaCl2 injection. The ionized calcium level was 4.7 +/- 0.6 mg/100 ml 6 minutes after CaCl2 injection in Group A, and was 5.9 +/- 0.2 mg/100 ml and 6.4 +/- 0.2 mg/100 ml at 6 and 10 minutes, respectively, in Group B. There was significant early hemodynamic improvement after CaCl2 injection, including increases in Vpm (p less than 0.001), cardiac index (p less than 0.001), mean blood pressure (p less than 0.01), and stroke volume index (p less than 0.001). A similar pattern of hemodynamic response was observed in both groups. Approximately 1 minute after CaCl2 injection, cardiac index returned to control level, Vpm and mean blood pressure remained elevated, and heart rate declined (p less than 0.01). Systemic vascular resistance gradually increased and was significantly elevated (p less than 0.05) in Group B at 3 minutes and in Group A at 6 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult

The Blood-Injection Symptom Scale (BISS): assessing a structure of phobic symptoms elicited by blood and injections.

Assessments for blood-injury-injection phobia measure feared stimuli and overt behaviours, but they have not systematically addressed the symptoms of fear and faintness. The Blood-Injection Symptom Scale (BISS) was developed to overcome this omission. An exploratory factor analysis grouped symptoms triggered by blood and injections into three internally consistent factors (faintness, anxiety and tension). A confirmatory factor analysis replicated the factor structure in a new sample. To test the construct validity of the BISS, an attempt was made to reproduce Ost's (1992, Journal of Abnormal Psychology, 101, 68-74) finding that fear was stronger among people with concerns about injections, while faintness was stronger among people with concerns about blood. A community sample of 80 individuals with concerns (i.e. fear or fainting) about blood or injections completed the BISS. Controlling faintness, individuals with concerns about injections reported more fear than people with concerns about blood. In contrast, controlling for fear, the latter reported more symptoms of faintness. These data suggest that the BISS generates stable and internally consistent subscales useful in the measurement of symptoms elicited by blood and injections.

Adult

Influence of diet or intrarectal bile acid injections on colon epithelial cell proliferation in rats previously injected with 1,2-dimethylhydrazine.

The effects of varying colon bile acid concentrations on rat colon epithelial cell proliferation were studied. Bile acid concentrations were altered by intrarectally injecting either deoxycholic or lithocholic acid for 4 weeks or by increasing the dietary fat or fiber (wheat bran, agar, or carrageenan) intake for 4 weeks. 1,2-Dimethylhydrazine (DMH) was s.c. injected into half of the rats 1 week before treatments began. Colon epithelial cell proliferation was measured by [3H]thymidine autoradiography of colon crypts. Rats injected with DMH had more DNA-synthesizing cells per crypt. Neither bile acid injection nor any of the diets altered the number of DNA-synthesizing cells per crypt. DMH injections, deoxycholic and lithocholic acid intrarectal injections, and dietary agar and wheat bran all increased the total number of cells per crypt. High fat diets and dietary carrageenan did not affect cell number. All diets containing fiber lowered total fecal bile acid concentrations, but increasing the fat content of the diet did not affect them. These results indicate that the bile acid injections and dietary agar and wheat bran induce a slight hyperplasia in the colon.

Animals

Children's ratings of dental injection and treatment pain, and the influence of the time taken to administer the injection.

Three hundred and eight children aged 3-16 years (mean age 10.2), who were undergoing routine dental treatment, recorded on visual analogue scales their ratings of pain associated with injection and treatment. The injection pain scores were examined for their relationship to age, gender, time taken to administer the injection and injection type. The treatment pain scores were compared between groups who had teeth either extracted or restored, and between groups assessed by the operator as having total or partial anaesthesia. A significant inverse correlation was found between subjective injection pain and injection duration. The difference in treatment pain scores was significant between groups assessed by the operator as having total or partial anaesthesia. Inferior dental nerve blocks were rated significantly more painful than buccal infiltrations. Age, gender, and the operative procedure performed had no statistically significant relationship to the injection pain scores or treatment pain scores. The visual analogue pain scale was found to be unsuitable for use by children under 7 years of age.

Administration, Buccal

The variability of the absorption of subcutaneously injected insulin: effect of injection technique and relation with brittleness.

A comparison has been made of insulin absorption rate and its variability in healthy subjects (n = 12), matched Type 1 diabetic patients (n = 12), and brittle Type 1 diabetic patients (n = 13) after subcutaneous injection with a standardized injection technique. In each individual 8 U of iodinated neutral human soluble insulin were injected twice, at the fat-muscle boundary. Disappearance of radioactivity was measured for 8 h. Differences in absorption rate could not be demonstrated (T50 207 +/- 30 (+/- SD), 224 +/- 73 and 217 +/- 80 min in the three groups, respectively). Intra-individual variance was similar in the three groups (intra-individual SD of T50 14 +/- 9, 10 +/- 6 and 12 +/- 10%, respectively). Injection with the skinfold technique each patient usually employed, did not alter mean absorption rate or its variability significantly (T50 179 +/- 52 min; intra-individual SD 12 +/- 8%). In a group of Type 1 diabetic patients (n = 26) the absorption rate after deep injection was compared with that after superficial injection. No differences were found (T50 207 +/- 66 vs 236 +/- 66 min). In some of these patients (n = 10) plasma free insulin and glucose concentrations were measured. The increase in free insulin concentrations was significantly different only at some time-points, but insulin curves and plasma glucose concentrations did not differ significantly. Thus neither insulin absorption nor its variability differ between healthy subjects and diabetic patients, between deep and superficial subcutaneous injection, or between stable and brittle diabetic patients.

Absorption

Effects of atropine, injected into a lateral cerebral ventricle of the rabbit, on fevers due to intravenous leucocyte pyrogen and hypothalamic and intraventricular injections of prostaglandin E1.

1. Cholinergic synapses in the hypothalamus may transmit information in those thermoregulatory pathways which function to raise body temperature. The effect of atropine, administered intracranially, on the febrile response to intravenous leucocyte pyrogen or intracranial prostaglandin E1 was therefore examined in conscious rabbits. 2. In rabbits exposed to a thermoneutral environment, micro-injections of PGE1, into the anterior hypothalamus, intraventricular injections of PGE1, and intravenous injection so leucocyte pyrogen all caused fever accompanied by vasoconstriction in the ears and reduced respiratory rate. Intraventricular injection of 200 mug atropine during such fevers attenuated their development. This was due to the activation of heat loss mechanisms through vasodilatation in the ears and an increase in the frequency of respiration. This suggests a similarity in the pattern of neuronal activity evoked by PGE1 and leucocyte pyrogen, at least at the site(s) where atropine directly or indirectly exerted its effect and in the efferent pathways from this site. 3. In rabbits exposed to a cold environment, intraventricular injection of PGE1 caused fever through the activation of shivering accompanied by increased O2 consumption. Intraventricular injection of atropine during the development of fever caused an inhibition of shivering accompanied by increased O2 consumption. Intraventricular injection of atropine during the development of fever caused an inhibition of shievering and a decrease in O2 consumption so that temperature ceased to rise and returned to normal. 4. During fever, reversal by atropine of the increased heat conservation of rabbits in a neutral environment, and of their increased heat production in a cold environment adds further support to the concept that cholinergic synapses provide an important link in central temperature-rasising pathways.

Animals

Is sclerosant injection mandatory after an epinephrine injection for arrest of peptic ulcer haemorrhage? A prospective, randomised, comparative study.

A prospective, randomised, comparative study was performed to assess the need for a pure alcohol injection after an epinephrine injection in the arrest of active peptic ulcer bleeding. Sixty four patients with active ulcer bleeding were enrolled in the study. The two groups (epinephrine and epinephrine plus pure alcohol) were matched for sex, age, site of bleed, endoscopic findings, shock, haemoglobin, and concomitant illness at randomisation. The volume of injected epinephrine in the epinephrine and the epinephrine plus pure alcohol groups mean (SD) was 6.0 (3.0) ml and 5.5 (3.0) ml respectively (p > 0.05). The volume of injected pure alcohol in the epinephrine plus pure alcohol group was 1.9 (1.1) ml. Bleeding was initially controlled in 31 (97%) of the epinephrine group and all of the epinephrine plus pure alcohol group. Rebleeding occurred in 11 (36%) of the epinephrine group and in five (16%) of the epinephrine plus pure alcohol group (p > 0.05). Rebleeding was successfully controlled in some patients with treatment by a second injection. Other patients had heat probe thermocoagulation or surgery. Ultimate haemostatic rates were 69% (22/32) and 88% (28/32) for the epinephrine and the epinephrine plus pure alcohol groups respectively (p > 0.05). The epinephrine plus pure alcohol group achieved a better haemostatic effect for spurting haemorrhage (9/10 v 5/11, p < 0.05). The need for emergency operations and blood transfusions were comparable in both groups. The stay in hospital were less in the epinephrine plus pure alcohol group (mean 4.3 v 7.1, p < 0.05). It is concluded that pure alcohol injection after an epinephrine injection can improve the haemostatic rate in patients with spurting haemorrhage and shorten the hospital stay for patients with active bleeding.

Combined Modality Therapy

Comparison of ketorolac tromethamine with other injectable nonsteroidal anti-inflammatory drugs for pain-on-injection and muscle damage in the rat.

The local tolerance of ketorolac tromethamine (Toradol, Syntex) was compared with that of four other injectable nonsteroidal anti-inflammatory drugs (NSAIDs) (diclofenac sodium, piroxicam, ketoprofen, and metamizol magnesium) in the rat paw-lick/muscle irritation assay as described previously. All drugs were tested at concentrations approved for clinical use. After subplantar (footpad) injection, ketorolac produced virtually no pain-on-injection as assessed by the number of paw-lick/lift responses during a 15 min observation period. The other NSAIDs produced slight to moderate paw-lick/lift responses. Redness and swelling at the injection site were less severe for ketorolac than for the other NSAIDs. After intramuscular (i.m.) injection, all of the NSAIDs produced some degree of muscle damage, as assessed histopathologically 24 h after injection. The lesions, consisting primarily of muscle degeneration, were less severe for ketorolac than for the other NSAIDs. Ketorolac and metamizol produced the smallest elevations in serum creatine kinase, as measured 2 h after i.m. dosing, not significantly different from isotonic saline. Overall, ketorolac was better tolerated in the assay than the other injectable NSAIDs, thereby suggesting the possibility of improved local tolerance on clinical use.

Animals

The absorption of subcutaneously injected short-acting soluble insulin: influence of injection technique and concentration.

The effect of injection technique on the absorption of subcutaneously injected short-acting insulin [125I-labeled Actrapid (MC), Novo, Copenhagen, Denmark] was investigated in insulin-dependent diabetic patients. In one side of the abdomen insulin was given with a fixed standard technique. In the other side of the abdomen the temperature of the injected insulin, the depth of injection, and the duration of injection were varied. Furthermore, we compared the absorption of U40 and U100 insulin by giving either 8 U of the two insulins or 0.1 ml of both insulins simultaneously to the patients in either side of the abdomen. With regard to the injection technique the only significant finding was a faster absorption rate with deep (12 mm) than with superficial (3 mm) injection. The absorption of U100 insulin was significantly slower than of U40 insulin, when given in the same amount (8 U) as well as in the same volume (0.1 ml).

Absorption

Neurological dysfunction after intrathecal injection of dynorphin A (1-13) in the rat. I. Injection procedures modify pharmacological responses.

In rats, the spinal subarachnoid injection of the kappa opioid agonist Dynorphin A (Dyn A)(1-13) and the delta opioid receptor antagonist ICI 174864 produced dose-related flaccid paralysis of hindlimbs and tail that were influenced appreciably by injection procedures. When injected through indwelling intrathecal (i.t.) catheters terminating at L1 to L2, both peptides were significantly more potent producing paralysis 1 day, rather than 10 to 14 days, after i.t. catheterization. Other rats received direct subarachnoid injections of these peptides through 30-gauge needles placed in the L4 to L5 intervertebral space. In naive, uncatheterized and acutely catheterized rats, direct intervertebral injection of these peptides, as well as D-Ala2-Dyn A (1-13) amide (a metabolically stable analog of Dyn A (1-13), produced hindlimb paralysis with potencies comparable to those recorded after injections through acutely implanted catheters. In contrast, chronically catheterized rats showed significantly reduced responsivity to direct intervertebral injections of all three of these peptides. Loss of hindlimb motor function was associated with loss of nociceptive responsiveness. Elevations in tail-flick latencies were only seen with doses of Dyn A (1-13) which produced motor dysfunction, and were not blocked or reversed by high doses of the opioid antagonist naloxone. These results indicate that: 1) indwelling i.t. catheters induce spinal cord alterations which complicate their experimental usefulness, 2) Dyn A (1-13) does not alter responsiveness to thermal nociceptive stimuli through opioid mechanism and 3) Dyn A (1-13) causes parallel disruptions of spinal cord motor and nociceptive function.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals

Reducing the risk of unsafe injections in immunization programmes: financial and operational implications of various injection technologies.

The unsafe use and disposal of injection equipment continues to put patients, health care workers, and the general community at risk of infections such as hepatitis B virus and human immunodeficiency virus. Although the potential for unsafe injection practices varies substantially with the type of equipment that is used, technology alone cannot totally eliminate the risk. A knowledge of the cost, practicality and, most importantly, the potential for misuse, is critical for selecting the most appropriate injection equipment for each immunization setting. Four types of injection equipment are currently available for administering vaccines: sterilizable needles and syringes; standard disposable needles and syringes; autodestruct needles and syringes; and jet injectors. In general, the cost per injection is lowest with sterilizable equipment and highest with autodestruct. However, only autodestruct syringes virtually eliminate the risk of unsafe injection practices. Owing to differences in cost and programme factors, in some settings it may be appropriate to use a combination of equipment. For example, autodestruct syringes may be used in areas where it is difficult to ensure adequate supervision, while in medium-sized, fixed-site clinics with safe injection practices, sterilizable equipment will be the most cost-effective.

Algorithms