Maternal and neonatal outcomes associated with illness severity of maternal COVID-19.

BACKGROUND: Several reports demonstrated that perinatal SARS-CoV-2 has significant impact on maternal and neonatal health outcomes. However, the relationship between severity of maternal illness with outcomes remains less clear. METHODS: This is a single-center retrospective cohort study of mother/infant dyads with positive maternal test for SARS-CoV-2 between 14 days prior and 3 days after delivery from 3/30/2020 to 12/28/2021. RESULTS: Among 538 mothers, those with moderate/severe/critical illness were more likely to undergo induction, receive oxygen, mechanical ventilation or ECMO. Mortality was significantly higher among the mothers with severe illness than asymptomatic and those with mild illness (6% vs 0% and 0%, respectively, P < 0.05). Neonates born to mothers with moderate/severe/critical illness were more likely to be preterm with lower birth weight, and to be admitted to the NICU (P < 0.05) but not to be small for gestational age. Mild maternal illness was only associated with NICU admission for isolation precaution and decreased rate of breastfeeding. CONCLUSIONS: Maternal illness severity was significantly associated with prematurity and several adverse maternal and neonatal outcomes.

Peripherally inserted central cathether migration in neonates: Incidence, timing and risk factors.

BACKGROUND: PICC line use is a common practice in neonatal units, but it is associated with various complications. Catheter migration is the most common complication in neonates. Periodic imaging is recommended to monitor the tip position of the PICCs, but the optimal frequency is undetermined. The incidence, timing and risk factors that are associated with PICC migration have not been fully investigated beyond 24 hrs in neonates. The aim of the study was to determine the incidence, timing and risk factors that are associated with peripherally inserted central venous catheter (PICC) migration in neonates. METHODS: This was a single center, retrospective study of 168 PICCs placed in 141 neonates in the neonatal intensive care unit (NICU) between 2015 and 2016. The incidence of catheter migration was determined radiographically at 12-24 hrs and every third day after insertion until it was removed. RESULTS: Overall incidence of PICC migration was 28%and most commonly was detected within the first three days after PICC placement (83%). The incidence of PICC migration was higher in males. The PICC migration was associated with difficulty advancing the PICC at the time of insertion and PICC dressing change. CONCLUSION: Serial evaluation of PICC placement in neonates is required to maintain proper position. Based on our experience in our unit, we recommend periodic imaging at 12-24 hrs and on the third day after PICC placement as most migration occurred within three days after insertion.

Conversion of bacteriorhodopsin into a chloride ion pump.

In the light-driven proton pump bacteriorhodopsin, proton transfer from the retinal Schiff base to aspartate-85 is the crucial reaction of the transport cycle. In halorhodopsin, a light-driven chloride ion pump, the equivalent of residue 85 is threonine. When aspartate-85 was replaced with threonine, the mutated bacteriorhodopsin became a chloride ion pump when expressed in Halobacterium salinarium and, like halorhodopsin, actively transported chloride ions in the direction opposite from the proton pump. Chloride was bound to it, as revealed by large shifts of the absorption maximum of the chromophore, and its photointermediates included a red-shifted state in the millisecond time domain, with its amplitude and decay rate dependent on chloride concentration. Bacteriorhodopsin and halorhodopsin thus share a common transport mechanism, and the interaction of residue 85 with the retinal Schiff base determines the ionic specificity.

Severe intraventricular hemorrhage and withdrawal of support in preterm infants.

OBJECTIVE: The objective of the study was to determine whether withdrawal of support in severe 'intraventricular hemorrhage' (IVH), that is, IVH grade 3 and periventricular hemorrhagic infarction (PVHI), has decreased after publication of studies that show improved prognosis and to examine cranial ultrasonograms, including PVHI territories defined by Bassan. STUDY DESIGN: Retrospective cohort of preterm infants from 23 0/7 to 28 6/7 weeks' gestation in 1993 to 2013. RESULTS: Among the 1755 infants, 1494 had no bleed, germinal matrix hemorrhage (GMH) or IVH grade 2, 137 had grade 3 IVH and 124 had PVHI. The odds of withdrawal of support, adjusted for severity of GMH-IVH and baseline variables, did not decrease after publications showing better prognosis. Among 82 patients who died with PVHI, 76 had life support withdrawn, including 34 without another contributing cause of death. The median number of PVHI territories involved was three. CONCLUSION: Withdrawal of support adjusted for severity of GMH-IVH did not significantly change after publications showing better prognosis.

Mortality among infants with evolving bronchopulmonary dysplasia increases with major surgery and with pulmonary hypertension.

OBJECTIVE: To assess whether mortality in patients with evolving bronchopulmonary dysplasia (BPD, defined as ⩾28 days of oxygen exposure with lung disease) is independently associated with pulmonary arterial hypertension (PAH) and surgery. STUDY DESIGN: Single institution retrospective birth cohort of preterm infants with gestational age (GA) 230/7 to 366/7 weeks, and evolving BPD delivered between 2001 and 2014. Surgery was classified as minor or major using published criteria. Mortality was analyzed by stepwise logistic regression analysis. RESULTS: Among 577 patients with evolving BPD, 33 (6%) died prior to discharge. Mortality decreased with GA (adjusted odds ratio (aOR): 0.69; 95% confidence interval (CI): 0.55, 0.87), birth weight Z-score (aOR: 0.69, 95% CI: 0.47, 0.996) and increased with PAH (aOR: 30, 95% CI: 2.1, 415), major surgery (aOR; 2.8, 95% CI: 1.3, 6.3), and PAH and surgery (aOR: 10.3, 95% CI: 2.5, 42.1). CONCLUSION: Among preterm patients with evolving BPD, PAH and surgery are independently associated with mortality.

Reconciling crystallography and mutagenesis: a synthetic approach to the creation of a comprehensive model for proton pumping by bacteriorhodopsin.

As a result of the number of new high-resolution structures of the pigment and some of its photointermediates, a realistic model for the functioning of bacteriorhodopsin seems to be finally emerging. However, lack of structural information for some of the key functional states, and contradictions between some published structural models, argue for the use of the synthetic approach, one that includes use of data from both crystallographic and mutagenesis studies. The role of mutagenesis in this synthetic approach falls into two categories. First, to provide additional structural information, and second, to test the predictions of structural models by studying mutant phenotypes. This review urges critical comparisons of the structural and mutagenesis data, as there are problems with their selective and indiscriminate use.

The proton transfers in the cytoplasmic domain of bacteriorhodopsin are facilitated by a cluster of interacting residues.

The stepwise internal proton transfer reactions across the membrane, and the release and uptake at the surface, are the elementary steps that together constitute the transport mechanism in a proton pump. Although the proton donor and acceptor residues can be usually identified, the directionality and the energetics of the proton transfer must be determined to a large extent also by interactions of these with neighboring groups. We have examined the roles of residues D96, T46 and R227 in proton transfers during the photocycle of bacteriorhodopsin near its cytoplasmic surface, and in general the relationship between the reprotonation of the Schiff base and the subsequent proton uptake from the cytoplasmic side. The phenotypes of single and double mutants suggest close functional interaction among D96, T46, R227, and probably internal bound water. Measurements of the free energies of activation indicate that mechanistic interpretation of the rates changed by residue replacements is hindered by a general tendency toward lowered activation enthalpies in the mutated proteins. There is less ambiguity in the free energy levels of the photointermediates. It appears from these that the inhibitory and stimulatory influences of T46 and R227, respectively, on D96 as a proton donor compensate one another and ensure the effective reprotonation of the Schiff base. T46 and D96 mediate, in turn, proton uptake at the cytoplasmic surface. Although ultimately this will reprotonate D96, the observation of proton uptake from the bulk in R82Q without reprotonation of the aspartate residue suggests that the direct proton acceptor is not D96. The results thus indicate that the passage of the proton from the surface to the Schiff base is facilitated by multiple residue and water interactions in the cytoplasmic domain.

Transient channel-opening in bacteriorhodopsin: an EPR study.

Active translocation of ions across membranes requires alternating access of the ion binding site inside the pump to the two membrane surfaces. Proton translocation by bacteriorhodopsin (bR), the light-driven proton pump in Halobacterium salinarium, involves this kind of a change in the accessibility of the centrally located retinal Schiff base. This key event in bR's photocycle ensures that proton release occurs to the extracellular side and proton uptake from the cytoplasmic side. To study the role of protein conformational changes in this reprotonation switch, spin labels were attached to pairs of engineered cysteine residues in the cytoplasmic interhelical loops of bR. Light-induced changes in the distance between a spin label on the EF interhelical loop and a label on either the AB or the CD interhelical loop were observed, and the changes were monitored following photoactivation with time-resolved electron paramagnetic resonance (EPR) spectroscopy. Both distances increase transiently by about 5 A during the photocycle. This opening occurs between proton release and uptake, and may be the conformational switch that changes the accessibility of the retinal Schiff base to the cytoplasmic surface after proton release to the extracellular side.

Light-induced rotation of a transmembrane alpha-helix in bacteriorhodopsin.

Spin labeling EPR spectroscopy has been used to characterize light-induced conformational changes of bacteriorhodopsin (bR). Pairs of nitroxide spin labels were attached to engineered cysteine residues at strategic positions near the cytoplasmic ends of transmembrane alpha-helices B, F, and G in order to monitor distance changes upon light activation. The EPR analysis of six doubly labeled bR mutants indicates that the cytoplasmic end of helix F not only tilts outwards, but also rotates counter-clockwise during the photocycle. The direction of the rotation of helix F is the opposite of the clockwise rotation previously reported for bovine rhodopsin. The opposite chirality of the F helix rotation in the two systems is perhaps related to the differences in the cis-trans photoisomerization of the retinal in the two proteins. Using time-resolved EPR, we monitored the rotation of helix F also in real time, and found that the signal from the rotation arises concurrently with the reprotonation of the retinal Schiff base.

Energy coupling in an ion pump. The reprotonation switch of bacteriorhodopsin.

The active site of an ion pump must communicate alternately with the two opposite membrane surfaces. In the light-driven proton pump, bacteriorhodopsin, the retinal Schiff base is first the proton donor to D85 (with access to the extracellular side), and then it becomes the acceptor of the proton of D96 (with access to the cytoplasmic side). This "reprotonation switch" has been associated with a protein conformation change observed during the photocycle. When D85 is replaced with asparagine, the pKa value of the Schiff base is lowered from above 13 to about 9. We determined the direction of the loss or gain of the Schiff base proton in unphotolyzed and in photoexcited D85N, and the D85N/D96N and D85N/D96A double mutants, in order to understand the intrinsic and the induced connectivities of the Schiff base to the two membrane surfaces. The influence of D96 mutations on proton exchange and on acceleration of proton shuttling to the surface by azide indicated that in either case the access of the Schiff base on D85N mutants is to the cytoplasmic side. In the wild-type protein (but with the pKa of the Schiff base lowered by 13-trifluoromethyl retinal substitution) the results suggested that the Schiff base can communicate also with the extracellular side. Raising the pH without illumination of D85N so as to deprotonate the Schiff base caused the same, or nearly the same, change of X-ray scattering as observed when the Schiff base deprotonates during the wild-type photocycle. The results link the charge state of the active site to the global protein conformation and to the connectivity of the Schiff base proton to the membrane surfaces. Their relationship suggests that the conformation of the unphotolyzed wild-type protein is stabilized by coulombic interaction of the Schiff base with its counter-ion. A proton is translocated across the membrane after light-induced transfer of the Schiff base proton to D85, because the protein assumes an alternative conformation that separates the donor from the acceptor and opens new conduction pathways between the active site and the two membrane surfaces.

No seroconversions among steady sex partners of methadone-maintained HIV-1-seropositive injecting drug users in New York City.

OBJECTIVE: To assess the incidence of heterosexual HIV-1 transmission from seropositive methadone-maintained injecting drug users (IDU) to their seronegative, non-IDU steady sex partners. DESIGN: A prospective, longitudinal study. SETTING: HIV-1-seropositive IDU and their HIV-1-seronegative, non-IDU steady sex partners were recruited from six methadone-maintenance clinics in the New York City boroughs of Brooklyn and Manhattan. PATIENTS, PARTICIPANTS: Between December 1988 and October 1991, 60 research participants were recruited [30 methadone-maintained, HIV-1-seropositive IDU (index subjects) and their non-IDU HIV-1-seronegative steady partners]. Baseline and follow-up (every 3-4 months) data included a structured questionnaire and blood testing for HIV infection and CD4+ cell subsets. RESULTS: Demographic characteristics of the 30 steady sex partners were evaluated as follows: sex (22 women, eight men); age (mean, 32 years; range, 21-55 years) and race (African-American, 13; Hispanic, 13; other, 4). The average duration of relationship between index subject and partner at study entry was 7.5 years (range, 4 months to 19.4 years). At entry, 27 of the 30 partners reported no or intermittent use of condoms with the index subject during a typical 12-month period. Follow-up data (median follow-up, 298 days; range, 85-992 days) were available for 22 partners. Of these, 15 reported no or intermittent condom use. For a total study observation time of 23 person-years, there were no seroconversions. The upper 95% confidence interval for the observed seroconversion rate of 0% is 13%. CONCLUSIONS: These results suggest that the likelihood of heterosexual HIV-1 transmission from seropositive methadone-maintained IDU to their seronegative, non-IDU steady sex partners is low.

High levels of corticotropin-releasing hormone immunoactivity in maternal and fetal plasma during pregnancy.

Corticotropin-releasing hormone immunoactivity (CRHi) was measured in the plasma of 31 pregnant women and 6 nonpregnant women as well as in the umbilical cord plasma of 40 term fetuses. CRHi was not detectable (less than 44 pg/ml) in the plasma of 6 nonpregnant women or in 6 women in the first trimester of pregnancy. Mean plasma CRHi rose progressively to 58 +/- 18 and 270 +/- 68 pg/ml during the second and third trimesters, respectively, and again became undetectable within 24 h after delivery. Mean CRHi in 40 umbilical cord plasma samples was 136 +/- 16 pg/ml. Gel filtration of both fetal and maternal plasma showed that the majority of the CRHi eluted in the same position as synthetic human CRH. There was no significant correlation between CRHi and either beta-endorphin or ACTH in umbilical cord plasma, suggesting that this CRHi may not be primarily responsible for the release of beta-endorphin and ACTH into fetal plasma at delivery. A close correlation (r = 0.82) was found between simultaneously obtained maternal and umbilical cord plasma CRHi in 10 maternal-fetal pairs, supporting a common source for this peptide in maternal and fetal circulation. A placental source for fetal and maternal CRHi was suggested by the finding of a higher CRHi concentration in the umbilical vein than in the umbilical artery and by the disappearance of this peptide from maternal plasma after delivery. We conclude that a large amount of CRHi is secreted by the placenta into both the maternal and fetal circulation during pregnancy and suggest that this may be an important modulator of the maternal and fetal hypothalamic-pituitary-adrenal axis during gestation.

The effect of fluconazole on the clinical pharmacokinetics of methadone.

A randomized, double-blinded, placebo-controlled pharmacokinetic and safety trial was conducted to determine the effect of fluconazole on methadone disposition. Volunteers receiving methadone maintenance therapy were randomized to receive either 200 mg/day oral fluconazole (n = 13) or placebo (n = 12). After 14 days there was a 35% average increase in serum methadone area under the curve relative to baseline among patients receiving fluconazole (p = 0.0008). At the same time, mean serum methadone peak and trough concentrations increased by 27% (p = 0.0076) and 48% (p = 0.0023), respectively, and oral clearance of methadone was reduced by 24% (p = 0.0007). In contrast, the pharmacokinetics of methadone were unaltered in the placebo group. Renal clearance of methadone was not significantly affected by fluconazole or placebo therapy. Although exposed to increased concentrations of methadone, patients treated with fluconazole did not exhibit signs or symptoms of significant narcotic overdose.

Endocrine complications of AIDS and drug addiction.

The endocrine and metabolic consequences of illicit drug use and HIV disease are extensive and profound. Both narcotic drug use and AIDS have the capacity to cause clinically significant multiglandular derangements. Admittedly, we were not able to focus as much attention on the less frequently occurring disturbances of calcium, phosphorus, or folate metabolism in HIV disease. Similarly, we reported very little information about the endocrinologic significance of the use of classes of narcotics other than opiates and to a far lesser extent cocaine. Even with these limitations, the spectrum of drug abuse and HIV-related endocrine manifestations discussed previously is quite diverse. Given the pervasive effects of drug abuse on other organ systems, it is not surprising to find expanding interest in the endocrine consequences of narcotic drug use. In fact, the use of these drugs is responsible, in part, for the past and continuing interest in identifying receptors for these agents and similarly structured endogenous ligands. As these investigations proceed, we must appreciate the limitations in translating basic and clinical scientific findings to the clinical setting. Much of the current research does not study street-relevant narcotic doses, does not use research designs involving polydrug use, and does not involve the processes or routes of drug administration used by active narcotic addicts. There is a critical need for more research methods with animal models and clinical study settings that more adequately mimic drug use outside of the laboratory. Our ability to develop appropriate psychopharmaceutical agents to respond to the different faces of drug abuse in the United States will depend on continued progress in the area of neuroendocrinology. With respect to the consequences of HIV disease, the clinical findings of elevated hormonal levels in some endocrine systems are amazing given what one would expect if one postulated direct or indirect destruction by HIV or the opportunistic complications that accompany AIDS. In unraveling this puzzle, careful attention must be given to evaluating the degree to which the clinical or biochemical consequences are due to a direct HIV effect, to an effect of a complicating infection or neoplasm, or to an AIDS-related therapeutic intervention. More work is needed also in obtaining histopathologic information to correlate with the biochemical and clinical derangement. In summary, there is a wealth of information demonstrating a wide spectrum of endocrine/metabolic consequences of drug abuse and AIDS. Still, just as many questions remain unanswered. While the exact biologic mechanisms are unclear, many of the biochemical aberrations have clinical relevance.(ABSTRACT TRUNCATED AT 400 WORDS)

Rates of tuberculosis infection in healthcare workers providing services to HIV-infected populations. Terry Beirn Community Programs for Clinical Research on AIDS.

OBJECTIVE: To assess the prevalence of tuberculosis (TB) or a positive skin test in healthcare workers (HCWs) providing services to human immunodeficiency virus (HIV)-infected individuals and to determine prospectively the incidence of new infections in this population. DESIGN: This prospective cohort study enrolled 1,014 HCWs working with HIV-infected populations from 10 metropolitan areas. Purified protein derivative (PPD) tuberculin skin tests were placed at baseline and every 6 months afterwards on those without a history of TB or a positive PPD. Demographic, occupational, and TB exposure data also were collected. SETTING: Outpatient clinics, hospitals, private practice offices, and drug treatment programs providing HIV-related healthcare and research programs. PARTICIPANTS: A voluntary sample of staff and volunteers from 16 Community Programs for Clinical Research on AIDS units. RESULTS: Factors related to prior TB or a positive skin test at baseline included being foreign-born, increased length of time in health care, living in New York City, or previous bacille Calmette-Guerin vaccination. The rate of PPD conversion was 1.8 per 100 person years of follow-up. No independent relation was found between the amount or type of contact with HIV-infected populations and the risk of TB infection. CONCLUSION: These data provide some reassurance that caring for HIV-infected patients is not related to an increased rate of TB infection among HCWs in these settings.

The validity of the interviewer severity ratings in groups of ASI interviewers with varying training.

AIMS: This study evaluated the hypothesis that the subjective interviewer severity rating (ISR) summary indices of the intake Addiction Severity Index (ASI) of less trained interviewers are less valid than those of more highly trained interviewers. DESIGN: Baseline ASIs from three completed studies whose interviewers varied in degree of initial ASI training and subsequent quality assurance monitoring were examined. Associations between baseline ISRs and three other sets of ASI summary indices not based on interviewer ratings-composite scores, clinical indices and evaluation indices-were compared for three groups of interviewers with varying amounts of training. The assumption underlying these analyses was that more reliable ISRs, found in more trained interviewers, would be more highly associated with the other more objective indices. SETTING: Methadone maintenance patients in the Philadelphia and New York City areas. PARTICIPANTS: Thirty-five interviewers with the most intense training who administered 295 interviews; 10 interviewers with an intermediate level of training who administered 763 interviews; and eight identified (and other unidentified) least trained interviewers who administered a total of 276 interviews. Measurements and methods. Four sets of summary indices from the above ASIs. Both bivariate and multivariate analyses were performed. FINDINGS: The study found that the validity of the validity of ISRs was greater in more trained interviewers. CONCLUSIONS: Greater training and subsequent monitoring of ASI interviewers generally appears to be associated with increased ISR validity.

Buprenorphine maintenance treatment of opiate dependence: a multicenter, randomized clinical trial.

AIMS: To evaluate the safety and efficacy of an 8 mg/day sublingual dose of buprenorphine in the maintenance treatment of heroin addicts by comparison with a 1 mg/day dose over a 16-week treatment period. As a secondary objective, outcomes were determined concurrently for patients treated with two other dose levels. DESIGN: Patients were randomized to four dosage groups and treated double-blind. SETTING: Twelve outpatient opiate maintenance treatment centers throughout the United States. PARTICIPANTS: Two hundred and thirty-nine women and 497 men who met the DSM-III-R criteria for opioid dependence and were seeking treatment. INTERVENTION: Patients received either 1, 4, 8 or 16 mg/day of buprenorphine and were treated in the usual clinical context, including a 1-hour weekly clinical counseling session. MEASUREMENT: Retention in treatment, illicit opioid use as determined by urine toxicology, opioid craving and global ratings by patient and staff. Safety outcome measures were provided by clinical monitoring and by analysis of the reported adverse events. FINDINGS: Outcomes in the 8 mg group were significantly better than in the 1 mg group in all four efficacy domains. No deaths occurred in either group. The 8 mg group did not show an increase in the frequency of adverse events. Most reported adverse effects were those commonly seen in patients treated with opioids. CONCLUSIONS: The findings support the safety and efficacy of buprenorphine and suggest that an adequate dose of buprenorphine will be a useful addition to pharmacotherapy.

Interviewer severity ratings and composite scores of the ASI: a further look.

The psychometric characteristics of the Addiction Severity Index (ASI) interviewer severity ratings (ISRs) and composite scores (CSs) were examined for a newly trained group of interviewers. The interrater reliabilities of seven raters for 9 methadone maintenance (MM) pilot subjects were determined. These were found to be excellent for the CSs, but only moderate for the ISRs. Regression analyses were performed on the data of 407 methadone maintenance patients entering all of the variables in each area as the independent variables and the ISR as the dependent variable. These analyses indicated that, on average, 55-60% of the variance in ISRs was explained. However, while 63% of the variance was explained for the legal scale only 38% of the variance of the drug scale was explained. The subject's rating of either the need for treatment or the seriousness of the problem accounted for the most variance, with the exception of the drug and alcohol areas. The internal consistency of the composite scores was then examined for this sample using Cronbach's standardized alpha statistic. These were found to be generally satisfactory ranging from 0.62 for the drug scale to 0.87 for the alcohol and psychiatric scales. A mean interitem correlation of 0.11 for the drug scale was obtained suggesting relatively low item homogeneity. Finally, correlations between the CSs and ISRs were calculated for each scale. Moderate to high relationships were found (0.53-0.78) with the exception of the correlation for the employment area which was only 0.08. The findings are discussed in terms of the nature of and limitations of the ISRs and CSs.

Methadone-maintenance outcomes for Hispanic and African-American men and women.

Six-month methadone-maintenance response and outcome were examined for African-American and Hispanic men and women in a large urban sample. A consistent pattern of improvement was indicated for both races and genders on the addiction severity index (ASI). There were virtually no statistically significant differences in ASI outcomes between Hispanics and African-Americans and men and women using conventional analysis of variance (ANOVA) procedures. Results from an additional equivalence analysis, however, indicated that baseline to 6-month changes for the different groups were generally not similar enough to consider them equivalent. Urine toxicologies obtained during the 6-month treatment period were also not statistically equivalent by race and gender. Evaluating outcomes by gender and race are discussed, as are the implications of using equivalence tests when examining group differences.

Lack of a pharmacologic interaction between rifabutin and methadone in HIV-infected former injecting drug users.

Rifampin, an agent known to decrease the half-life of methadone, and rifabutin are two rifamycins that are structurally similar and share mechanisms of action. Hence the possibility of a drug-drug interaction between rifabutin and methadone was evaluated in 24 methadone-maintained, former injecting drug users infected with the human immunodeficiency virus. The study was an open-label, drug-drug interaction and safety trial in which patients were followed for 15 days. Each patient received rifabutin 300 mg as a single dose concomitantly with their individualized methadone dosage. No significant differences in methadone peak plasma concentration, time to peak plasma concentration, area under the plasma concentration-time curve, systemic clearance or renal clearance was observed in the presence of rifabutin. Seventy-five percent of the patients reported at least one symptom of narcotic withdrawal during the study, however, these symptoms were mild. A relationship between the development of narcotic withdrawal and methadone systemic exposure could not be established. Concurrent administration of rifabutin and methadone appeared to be safe in human immunodeficiency virus-infected injecting drug users maintained on stable doses of methadone and is not expected to produce any significant changes in the pharmacokinetics of methadone in these patients.