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Donor safety is essential in living donor liver transplantation. In this study we assessed the association among perioperative factors, liver dysfunction, and complications in 251 consecutives right hepatectomies for living donation.Retrospectively collected data from a prospectively assembled cohort of 251 consecutive living donors who underwent right hepatectomy between 1999 and 2020 were evaluated.Median age was 36 years; 54% were men. There was a statistically significant relationship between standardized liver volume by body surface area and the volumes calculated by imaging, weighting, and volume displacement. (rEarly postoperative hepatic dysfunction is associated with the development of post-live liver donor complications. A thoughtful balancing of preoperative risk factors for postoperative hepatic dysfunction may indeed and by association reduce postoperative complications.

Simultaneous liver-kidney transplantation (SLKT) is increasingly common in the United States. However, little is known about the renal-related outcomes following SLKT, which are essential to maximize the health of these allografts. We examined the factors impacting renal function following SLKT. This is an observational multicenter cohort study from the US Multicenter SLKT Consortium consisting of recipients of SLKT aged ≥18years of transplantations performed between February 2002 and June 2017 at 6 large US centers in 6 different United Network for Organ Sharing regions. The primary outcome was incident post-SLKT stage 4-5 chronic kidney disease (CKD) defined as

The burden of early hospitalization (within 6 months) following simultaneous liver-kidney transplant (SLKT) is not known. We examined risk factors associated with early hospitalization after SLKT and their impact on patient mortality conditional on 6-month survival. We used data from the US Multicenter SLKT Consortium cohort study of all adult SLKT recipients between 2002 and 2017 who were discharged alive following SLKT. We used Poisson regression to model rates of early hospitalizations after SLKT. Cox regression was used to identify risk factors associated with mortality conditional on survival at 6 months after SLKT. Median age (N = 549) was 57.7 years (interquartile range [IQR], 50.6-63.9) with 63% males and 76% Whites; 33% had hepatitis C virus, 20% had non-alcohol-associated fatty liver disease, 23% alcohol-associated liver disease, and 24% other etiologies. Median body mass index (BMI) and Model for End-Stage Liver Disease-sodium scores were 27.2 kg/m

Background Various reports suggested that pre-existing medical illnesses, including hypertension and other demographic, clinical, and laboratory factors, could pose an increased risk of disease severity and mortality among COVID-19 patients. This study aimed to assess the relation of hypertension and other factors to the severity of COVID-19 pneumonia in patients discharged from Eka Kotebe Hospital in June-September, 2020. Methods This is a single-center case-control study of 265 adult patients discharged alive or dead, 75 with a course of severe COVID-19 for the cases arm and 190 with the non-severe disease for the control arm. Three age and sex-matched controls were selected randomly for each patient on the case arm. Chi-square, multivariable binary logistic regression, and odds ratio (OR) with a 95% confidence interval was used to assess the association between the various factors and the severity of the disease. A p-value of Results Of the 265 study participants, 80% were male. The median age was 43 IQR(36–60) years. Both arms had similar demographic characteristics. Hypertension was strongly associated with the severity of COVID-19 pneumonia based on effect outcome adjustment (AOR = 2.93, 95% CI 1.489, 5.783, p-value = 0.002), similarly, having diabetes mellitus (AOR = 3.17, 95% CI 1.374, 7.313, p-value Conclusions Hypertension was associated with the severity of COVID-19 pneumonia, and so were diabetes mellitus, chronic cardiac disease, and an increase in pulse rate.

Mortality among patients with COVID-19 and respiratory failure is high and there are no known lower airway biomarkers that predict clinical outcome. We investigated whether bacterial respiratory infections and viral load were associated with poor clinical outcome and host immune tone. We obtained bacterial and fungal culture data from 589 critically ill subjects with COVID-19 requiring mechanical ventilation. On a subset of the subjects that underwent bronchoscopy, we also quantified SARS-CoV-2 viral load, analyzed the microbiome of the lower airways by metagenome and metatranscriptome analyses and profiled the host immune response. We found that isolation of a hospital-acquired respiratory pathogen was not associated with fatal outcome. However, poor clinical outcome was associated with enrichment of the lower airway microbiota with an oral commensal (Mycoplasma salivarium), while high SARS-CoV-2 viral burden, poor anti-SARS-CoV-2 antibody response, together with a unique host transcriptome profile of the lower airways were most predictive of mortality. Collectively, these data support the hypothesis that 1) the extent of viral infectivity drives mortality in severe COVID-19, and therefore 2) clinical management strategies targeting viral replication and host responses to SARS-CoV-2 should be prioritized.

In lung cancer, enrichment of the lower airway microbiota with oral commensals commonly occurs, and ex vivo models support that some of these bacteria can trigger host transcriptomic signatures associated with carcinogenesis. Here, we show that this lower airway dysbiotic signature was more prevalent in the stage IIIB–IV tumor–node–metastasis lung cancer group and is associated with poor prognosis, as shown by decreased survival among subjects with early-stage disease (I–IIIA) and worse tumor progression as measured by RECIST scores among subjects with stage IIIB–IV disease. In addition, this lower airway microbiota signature was associated with upregulation of the IL17, PI3K, MAPK, and ERK pathways in airway transcriptome, and we identified Veillonella parvula as the most abundant taxon driving this association. In a KP lung cancer model, lower airway dysbiosis with V. parvula led to decreased survival, increased tumor burden, IL17 inflammatory phenotype, and activation of checkpoint inhibitor markers. Significance: Multiple lines of investigation have shown that the gut microbiota affects host immune response to immunotherapy in cancer. Here, we support that the local airway microbiota modulates the host immune tone in lung cancer, affecting tumor progression and prognosis. See related commentary by Zitvogel and Kroemer, p. 224. This article is highlighted in the In This Issue feature, p. 211

Background We examined cytokine immune response profiles among contacts to tuberculosis patients to identify immunologic and epidemiologic correlates of tuberculosis. Methods We prospectively enrolled 1272 contacts of culture-confirmed pulmonary tuberculosis patients at 9 United States and Canadian sites. Epidemiologic characteristics were recorded. Blood was collected and stimulated with Mycobacterium tuberculosis culture filtrate protein, and tumor necrosis factor (TNF-α), interferon gamma (IFN-γ), and interleukin 10 (IL-10) concentrations were determined using immunoassays. Results Of 1272 contacts, 41 (3.2%) were diagnosed with tuberculosis before or < 30 days after blood collection (co-prevalent tuberculosis) and 19 (1.5%) during subsequent four-year follow-up (incident tuberculosis). Compared with contacts without tuberculosis, those with co-prevalent tuberculosis had higher median baseline TNF-α and IFN-γ concentrations (in pg/mL, TNF-α 129 versus 71, P P P the median were associated with co-prevalent tuberculosis (P P = .03) and smoking (P Conclusions Cytokine concentrations and epidemiologic factors at the time of contact investigation may predict co-prevalent and incident tuberculosis.

Objective To characterize patients with coronavirus disease 2019 (covid-19) in a large New York City medical center and describe their clinical course across the emergency department, hospital wards, and intensive care units. Design Retrospective manual medical record review. Setting NewYork-Presbyterian/Columbia University Irving Medical Center, a quaternary care academic medical center in New York City. Participants The first 1000 consecutive patients with a positive result on the reverse transcriptase polymerase chain reaction assay for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who presented to the emergency department or were admitted to hospital between 1 March and 5 April 2020. Patient data were manually abstracted from electronic medical records. Main outcome measures Characterization of patients, including demographics, presenting symptoms, comorbidities on presentation, hospital course, time to intubation, complications, mortality, and disposition. Results Of the first 1000 patients, 150 presented to the emergency department, 614 were admitted to hospital (not intensive care units), and 236 were admitted or transferred to intensive care units. The most common presenting symptoms were cough (732/1000), fever (728/1000), and dyspnea (631/1000). Patients in hospital, particularly those treated in intensive care units, often had baseline comorbidities including hypertension, diabetes, and obesity. Patients admitted to intensive care units were older, predominantly male (158/236, 66.9%), and had long lengths of stay (median 23 days, interquartile range 12-32 days); 78.0% (184/236) developed acute kidney injury and 35.2% (83/236) needed dialysis. Only 4.4% (6/136) of patients who required mechanical ventilation were first intubated more than 14 days after symptom onset. Time to intubation from symptom onset had a bimodal distribution, with modes at three to four days, and at nine days. As of 30 April, 90 patients remained in hospital and 211 had died in hospital. Conclusions Patients admitted to hospital with covid-19 at this medical center faced major morbidity and mortality, with high rates of acute kidney injury and inpatient dialysis, prolonged intubations, and a bimodal distribution of time to intubation from symptom onset.

Background Ambulatory based treatment of tuberculosis has been recently introduced in Kazakhstan. We sought to assess the attitudes of the general population, TB patients and their household members towards ambulatory TB treatment and identify how knowledge of TB is associated with these attitudes. Methods New pulmonary TB cases and their household and community controls were recruited from three regions of Kazakhstan in 2012–2014. 1083 participants completed audio computer-assisted self interviews to assess their knowledge of TB and attitudes towards ambulatory care. Mixed effects logistic regression models were used to identify factors associated with attitudes toward ambulatory TB treatment. Results The proportion of people who considered ambulatory TB treatment as appropriate was very low (24.9%). Positive attitudes towards ambulatory TB treatment were significantly associated with region of residence, higher level of education, family support and experience with TB. The association between sufficient tuberculosis knowledge and favorable attitude toward ambulatory treatment was stronger among community controls compared to TB patients and their family members. Conclusions This study provides insight into attitudes toward ambulatory TB treatment among different groups and the specific influence of TB knowledge on these attitudes. Our findings can inform the process of integration of new TB treatment strategies and the development of appropriate education and advocacy programs in the general population.

RATIONALE: Data are limited regarding the safety of 12-dose once-weekly isoniazid (H, 900 mg) plus rifapentine (P, 900 mg) (3HP) for latent infection treatment during pregnancy. OBJECTIVES: To assess safety and pregnancy outcomes among pregnant women who were inadvertently exposed to study medications in two latent tuberculosis infection trials (PREVENT TB or iAdhere) evaluating 3HP and 9 months of daily isoniazid (H, 300 mg) (9H). METHODS: Data from reproductive-age (15–51 yr) women who received one or more study dose of 3HP or 9H in either trial were analyzed. Drug exposure during pregnancy occurred if the estimated date of conception was on or before the last dose date. RESULTS: Of 126 pregnancies (125 participants) that occurred during treatment or follow-up, 87 were exposed to study drugs. Among these, fetal loss was reported for 4/31 (13%) and 8/56 (14%), 3HP and 9H, respectively (difference, 13%–14%=−1%; 95% confidence interval = −17% to +18%) and congenital anomalies in 0/20 and 2/41 (5%) live births, 3HP and 9H, respectively (difference, 0% −5% = −5%; 95% confidence interval = −18% to +16%). All fetal losses occurred in pregnancies of less than 20 weeks. Of the total 126 pregnancies, fetal loss was reported in 8/54 (15%) and 9/72 (13%), 3HP and 9H, respectively; and congenital anomalies in 1/37 (3%) and 2/56 (4%) live births, 3HP and 9H, respectively. The overall proportion of fetal loss (17/126 [13%]) and anomalies (3/93 [3%]) were similar to those estimated for the United States, 17% and 3%, respectively. CONCLUSIONS: Among reported pregnancies in these two latent tuberculosis infection trials, there was no unexpected fetal loss or congenital anomalies. These data offer some preliminary reassurance to clinicians and patients in circumstances when these drugs and regimens are the best option in pregnancy or in women of child-bearing potential. This work used the identifying trial registration numbers NCT00023452 and NCT01582711, corresponding to the primary clinical trials PREVENT TB and iAdhere (Tuberculosis Trials Consortium Study 26 and 33).

Rationale: The World Health Organization recommends the use of isoniazid (INH) alone or in combination with rifapentine to treat latent tuberculosis infections. The recent rise of drug-resistant tuberculosis has complicated the choice of treatment regimen for latent tuberculosis infection. Objectives: To evaluate the effects of INH preventive therapy on the contacts of patients with multidrug-resistant tuberculosis. Methods: In a prospective cohort study conducted between September 2009 and August 2012, we identified 4,500 index patients with tuberculosis and 14,044 tuberculosis-exposed household contacts who we followed for 1 year for the occurrence of incident tuberculosis disease. Although Peruvian national guidelines specify that INH preventive therapy should be provided to contacts aged 19 years old or younger, only half this group received INH preventive therapy. Measurements and Main Results: Among 4,216 contacts under 19 years of age, 2,106 contacts (50%) initiated INH preventive therapy at enrollment. The protective effect of INH was more extreme in contacts exposed to drug-sensitive tuberculosis (adjusted hazard ratio, 0.30; 95% confidence interval, 0.18–0.48) and to multidrug-resistant tuberculosis (adjusted hazard ratio, 0.19; 95% confidence interval, 0.05–0.66) compared with those exposed to mono–INH-resistant tuberculosis (adjusted hazard ratio, 0.80; 95% confidence interval, 0.23–2.80). In the second independent study, tuberculosis occurred in none of the 76 household contacts who received INH preventive therapy compared with 3% (8 of 273) of those who did not. Conclusions: Household contacts who received INH preventive therapy had a lower incidence of tuberculosis disease even when they had been exposed to an index patient with multidrug-resistant tuberculosis. INH may have a role in the management of latent multidrug-resistant tuberculosis infection.

BackgroundPatient awareness of asthma severity is important for optimal asthma management. However, there is often a discrepancy between physician assessment of asthma control based on guidelines and patient discernment of control. We compared physician and patient perception of asthma control in a clinic population seen at a tertiary hospital in Addis Ababa, Ethiopia.MethodsIn this cross-sectional study, 182 consecutive patients with a physician diagnosis of asthma seen in Chest Clinic at Tikur Anbessa Specialized Hospital (TASH) between July and December 2015 were studied. Demographics, asthma symptoms, medication use in the past month, and self-perception of asthma control in the past 7 days were obtained from the clinic records. Physician assessed asthma control was based on the GINA asthma symptom control assessment tool. Lung function was measured using a Diagnostic EasyOne Plus model 2001 SN spirometer. The institutional review board approved the study protocol.ResultsOf the 182 subjects, 68.1% were female. The mean age was 52 ± 12 years, and the mean (SD) duration of asthma was 19.4 ± 12.7 years. Forty-four (24.2%) patients had physician determined well-controlled asthma and 138 (75.8%) patients had physician determined partly controlled/uncontrolled asthma. One hundred and fifty-one (83%) patients thought their asthma control was good. However, the degree of concordance between physician evaluation and patient perception of asthma control was low (kappa index = 0.09). On multivariate analysis, self-perceived poor asthma control was associated with any activity limitation due to asthma and inconsistent inhaled corticosteroid use.ConclusionIn our study, the first of its kind in Ethiopia, a high percent of patients with physician determined well-controlled asthma has appropriate perception of their disease state. However, those patients with partly controlled/uncontrolled asthma had poor self-perception of their disease, emphasizing the need for further patient education. These conclusions may be especially useful in the care of asthmatics from other low-income countries.

BACKGROUND Clostridioides difficile infection (CDI) is common after solid organ transplant (SOT) and is associated with high morbidity and mortality. METHODS We assessed incidence, risk factors, and outcomes of CDI among SOT patients at a large multi-organ transplant center. Multivariable logistic regression was used to identify risk factors for initial and recurrent CDI. RESULTS A total of 2622 SOT patients were included. 224 (8.5%) had CDI 1 year post-SOT. The highest incidence of CDI was among pancreas recipients (12.5%) followed by lung (11.7%), liver (11.0%), heart (10.8%), and kidney (5.8%). Median time to CDI was 56 days (range 2-354) post-SOT. About 64% of patients had severe CDI. About 56.3% were treated with metronidazole, 13.8% with oral vancomycin, and 28.6% with both. About 28.6% of patients had recurrent CDI. In multivariable modeling, lung transplant recipient status was the only significant predictor of recurrent CDI (OR 4.97, 95% CI 2.11-11.78, P

Background: More than 75% of the population in Ghana relies on biomass fuels for cooking and heating. Household air pollution (HAP) emitted from the incomplete combustion of these fuels has been associated with adverse health effects including respiratory effects in women that can lead to chronic obstructive pulmonary disease (COPD), a major contributor to global HAP-related mortality. HAP is a modifiable risk factor in the global burden of disease, exposure to which can be reduced. Objective: This study assessed the prevalence of respiratory symptoms, as well as associations between respiratory symptoms and HAP exposure, as measured using continuous personal carbon monoxide (CO), in nonsmoking pregnant women in rural Ghana. Methods: We analyzed current respiratory health symptoms and CO exposures upon enrollment in a subset (n = 840) of the population of pregnant women cooking with biomass fuels and enrolled in the GRAPHS randomized clinical control trial. Personal CO was measured using Lascar continuous monitors. Associations between CO concentrations as well as other sources of pollution exposures and respiratory health symptoms were estimated using logistic regression models. Conclusion: There was a positive association between CO exposure per 1 ppm increase and a composite respiratory symptom score of current cough (lasting >5 days), wheeze and/or dyspnea (OR: 1.2, p = 0.03). CO was also positively associated with wheeze (OR: 1.3, p = 0.05), phlegm (OR: 1.2, p = 0.08) and reported clinic visit for respiratory infection in past 4 weeks (OR: 1.2, p = 0.09). Multivariate models showed significant associations between second-hand tobacco smoke and a composite outcome (OR: 2.1, p 5 days (OR: 3.1, p = 0.01), wheeze (OR: 2.7, p

Background New York City (NYC) reported a higher pneumonia and influenza death rate than the rest of New York State during 2010–2014. Most NYC pneumonia and influenza deaths are attributed to pneumonia caused by infection acquired in the community, and these deaths typically occur in hospitals. Methods We identified hospitalizations of New York State residents aged ≥20 years discharged from New York State hospitals during 2010–2014 with a principal diagnosis of community-setting pneumonia or a secondary diagnosis of community-setting pneumonia if the principal diagnosis was respiratory failure or sepsis. We examined mean annual age-adjusted community-setting pneumonia-associated hospitalization (CSPAH) rates and proportion of CSPAH with in-hospital death, overall and by sociodemographic group, and produced a multivariable negative binomial model to assess hospitalization rate ratios. Results Compared with non-NYC urban, suburban, and rural areas of New York State, NYC had the highest mean annual age-adjusted CSPAH rate at 475.3 per 100,000 population and the highest percentage of CSPAH with in-hospital death at 13.7%. NYC also had the highest proportion of CSPAH patients residing in higher-poverty-level areas. Adjusting for age, sex, and area-based poverty, NYC residents experienced 1.3 (95% confidence interval [CI], 1.2–1.4), non-NYC urban residents 1.4 (95% CI, 1.3–1.6), and suburban residents 1.2 (95% CI, 1.1–1.3) times the rate of CSPAH than rural residents. Conclusions In New York State, NYC as well as other urban areas and suburban areas had higher rates of CSPAH than rural areas. Further research is needed into drivers of CSPAH deaths, which may be associated with poverty.

Correction in: LANCET Volume: 390 Issue: 10103 Pages: 1644-1644 Published: OCT 7 2017 ., Background The scale-up of tobacco control, especially after the adoption of the Framework Convention for Tobacco Control, is a major public health success story. Nonetheless, smoking remains a leading risk for early death and disability worldwide, and therefore continues to require sustained political commitment. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) offers a robust platform through which global, regional, and national progress toward achieving smoking-related targets can be assessed. Methods We synthesised 2818 data sources with spatiotemporal Gaussian process regression and produced estimates of daily smoking prevalence by sex, age group, and year for 195 countries and territories from 1990 to 2015. We analysed 38 risk-outcome pairs to generate estimates of smoking-attributable mortality and disease burden, as measured by disability-adjusted life-years (DALYs). We then performed a cohort analysis of smoking prevalence by birth-year cohort to better understand temporal age patterns in smoking. We also did a decomposition analysis, in which we parsed out changes in all-cause smoking-attributable DALYs due to changes in population growth, population ageing, smoking prevalence, and risk-deleted DALY rates. Finally, we explored results by level of development using the Socio-demographic Index (SDI). Findings Worldwide, the age-standardised prevalence of daily smoking was 25.0% (95% uncertainty interval [UI] 24.2-25.7) for men and 5.4% (5.1-5.7) for women, representing 28.4% (25.8-31.1) and 34.4% (29.4-38.6) reductions, respectively, since 1990. A greater percentage of countries and territories achieved significant annualised rates of decline in smoking prevalence from 1990 to 2005 than in between 2005 and 2015; however, only four countries had significant annualised increases in smoking prevalence between 2005 and 2015 (Congo [Brazzaville] and Azerbaijan for men and Kuwait and Timor-Leste for women). In 2015, 11.5% of global deaths (6.4 million [95% UI 5.7-7.0 million]) were attributable to smoking worldwide, of which 52.2% took place in four countries (China, India, the USA, and Russia). Smoking was ranked among the five leading risk factors by DALYs in 109 countries and territories in 2015, rising from 88 geographies in 1990. In terms of birth cohorts, male smoking prevalence followed similar age patterns across levels of SDI, whereas much more heterogeneity was found in age patterns for female smokers by level of development. While smoking prevalence and risk-deleted DALY rates mostly decreased by sex and SDI quintile, population growth, population ageing, or a combination of both, drove rises in overall smoking-attributable DALYs in low-SDI to middle-SDI geographies between 2005 and 2015. Interpretation The pace of progress in reducing smoking prevalence has been heterogeneous across geographies, development status, and sex, and as highlighted by more recent trends, maintaining past rates of decline should not be taken for granted, especially in women and in low-SDI to middle-SDI countries. Beyond the effect of the tobacco industry and societal mores, a crucial challenge facing tobacco control initiatives is that demographic forces are poised to heighten smoking's global toll, unless progress in preventing initiation and promoting cessation can be substantially accelerated. Greater success in tobacco control is possible but requires effective, comprehensive, and adequately implemented and enforced policies, which might in turn require global and national levels of political commitment beyond what has been achieved during the past 25 years., Bill & Melinda Gates Foundation and Bloomberg Philanthropies.

Early liver transplantation (LT) in European centers reportedly improved survival in patients with severe alcoholic hepatitis (AH) not responding to medical therapy. Our aim was to determine if a strategy of early LT for severe AH could be applied successfully in the United States. We reviewed 111 patients with severe AH at our center from January 2012 to January 2015. The primary end point was mortality at 6 months or early LT, with a secondary end point of alcohol relapse after LT. Survival was compared between those receiving early LT and matched patients who did not. Using a process similar to the European trial, 94 patients with severe AH not responding to medical therapy were evaluated for early LT. Overall, 9 (9.6%) candidates with favorable psychosocial profiles underwent early LT, comprising 3% of all adult LT during the study period. The 6-month survival rate was higher among those receiving early LT compared with matched controls (89% vs 11%, p

Objective Uncontrolled asthma negatively impacts patients, families, and the community. The level of symptom control among asthmatics in Ethiopia has not been well studied. We investigated the level of asthma control and risk factors for poor asthma control in clinic patients seen in the largest public hospital in Ethiopia. Results In this cross-sectional study, we studied all 182 consecutive subjects with a physician diagnosis of asthma who were seen in chest clinic at Tikur Anbessa Specialized Hospital between July and December 2015. Of the 182 subjects, 68.1% were female. The mean age was 52 ± 12 years and the median duration of asthma was 20 ± 12.7 years. One hundred and seventeen subjects (64.3%) had nighttime awakening due to asthma. Fifty-eight (31%) were not using controller medications and 62 (34.6%) had improper inhaler technique. Only 44 (24.2%) subjects had well-controlled asthma. On multivariate analysis, variables associated with uncontrolled asthma included: use of biomass fuel for cooking, longer duration of asthma (> 30 year), incorrect inhalation technique, and asthma exacerbation in the last 12 months. Most asthmatics attending in the largest public hospital in Ethiopia, had uncontrolled asthma. Several risk factors for poor asthma control were identified. Improved asthma control is possible through directed interventions.

Pyrazinamide (PZA) has important sterilizing activity in tuberculosis (TB) chemotherapy. We describe trends, risk factors, and molecular epidemiology associated with PZA-resistant (PZA r ) Mycobacterium tuberculosis in New York City (NYC). From 2001 to 2008, all incident culture-positive TB cases reported by the NYC Department of Health and Mental Hygiene (DOHMH) were genotyped by IS 6110 -based restriction fragment length polymorphism and spoligotype. Multidrug-resistant (MDR) isolates underwent DNA sequencing of resistance-determining regions of pncA , rpoB , katG , and fabG1 . Demographic and clinical information were extracted from the NYC DOHMH TB registry. During this period, PZA r doubled (1.6% to 3.6%) overall, accounting for 44% (70/159) of the MDR population and 1.4% (75/5511) of the non-MDR population. Molecular genotyping revealed strong microbial phylogenetic associations with PZA r . Clustered isolates and those from acid-fast bacillus (AFB) smear-positive cases had 2.7 (95% confidence interval [CI] = 1.71 to 4.36) and 2.0 (95% CI = 1.19 to 3.43) times higher odds of being PZA r , respectively, indicating a strong likelihood of recent transmission. Among the MDR population, PZA r was acquired somewhat more frequently via primary transmission than by independent pathways. Our molecular analysis also revealed that several historic M. tuberculosis strains responsible for MDR TB outbreaks in the early 1990s were continuing to circulate in NYC. We conclude that the increasing incidence of PZA r , with clear microbial risk factors, underscores the importance of routine PZA drug susceptibility testing and M. tuberculosis genotyping for the identification, control, and prevention of increasingly resistant organisms.

Rifapentine has potent activity in mouse models of tuberculosis chemotherapy but its optimal dose and exposure in humans are unknown.We conducted a randomized, partially blinded dose-ranging study to determine tolerability, safety, and antimicrobial activity of daily rifapentine for pulmonary tuberculosis treatment.Adults with sputum smear-positive pulmonary tuberculosis were assigned rifapentine 10, 15, or 20 mg/kg or rifampin 10 mg/kg daily for 8 weeks (intensive phase), with isoniazid, pyrazinamide, and ethambutol. The primary tolerability end point was treatment discontinuation. The primary efficacy end point was negative sputum cultures at completion of intensive phase.A total of 334 participants were enrolled. At completion of intensive phase, cultures on solid media were negative in 81.3% of participants in the rifampin group versus 92.5% (P = 0.097), 89.4% (P = 0.29), and 94.7% (P = 0.049) in the rifapentine 10, 15, and 20 mg/kg groups. Liquid cultures were negative in 56.3% (rifampin group) versus 74.6% (P = 0.042), 69.7% (P = 0.16), and 82.5% (P = 0.004), respectively. Compared with the rifampin group, the proportion negative at the end of intensive phase was higher among rifapentine recipients who had high rifapentine areas under the concentration-time curve. Percentages of participants discontinuing assigned treatment for reasons other than microbiologic ineligibility were similar across groups (rifampin, 8.2%; rifapentine 10, 15, or 20 mg/kg, 3.4, 2.5, and 7.4%, respectively).Daily rifapentine was well-tolerated and safe. High rifapentine exposures were associated with high levels of sputum sterilization at completion of intensive phase. Further studies are warranted to determine if regimens that deliver high rifapentine exposures can shorten treatment duration to less than 6 months. Clinical trial registered with www.clinicaltrials.gov (NCT 00694629).

IFN-γ release assays (IGRAs) are alternatives to tuberculin skin testing (TST) for diagnosis of latent tuberculosis infection. Limited data suggest IGRAs may not perform well for serial testing of healthcare workers (HCWs).Determine the performance characteristics of IGRAs versus TST for serial testing of HCWs.A longitudinal study involving 2,563 HCWs undergoing occupational tuberculosis screening at four healthcare institutions in the United States, where the average tuberculosis case rate ranged from 4 to 9 per 100,000 persons. QuantiFERON-TB Gold In-Tube (QFT-GIT), T-SPOT.TB (T-SPOT), and TST were performed at baseline and every 6 months for 18 months between February 2008 and March 2011.A total of 2,418 HCWs completed baseline testing, which was positive for 125 (5.2%) by TST, 118 (4.9%) by QFT-GIT, and 144 (6.0%) by T-SPOT. A baseline positive TST with negative IGRAs was associated with bacillus Calmette-Guérin (BCG) vaccination (odds ratio: 25.1 [95% confidence interval: 15.5, 40.5] vs. no BCG). Proportions of participants with test conversion during the study period were 138 of 2,263 (6.1%) for QFT-GIT, 177 of 2,137 (8.3%) for T-SPOT, and 21 of 2,293 (0.9%) for TST (P0.001 for QFT-GIT vs. TST and for T-SPOT vs. TST; P = 0.005 for QFT-GIT vs. T-SPOT). Of the QFT-GIT and T-SPOT converters, 81 of 106 (76.4%) and 91 of 118 (77.1%), respectively, were negative when retested 6 months later. There was negative/positive discordance for 15 of 170 (8.8%) participants by QFT-GIT and for 19 of 151 (12.6%) by T-SPOT when blood was drawn 2 weeks later.Most conversions among HCWs in low TB incidence settings appear to be false positives, and these occurred six to nine times more frequently with IGRAs than TST; repeat testing of apparent converters is warranted.

The new Kreek–McHugh–Schluger–Kellogg scale (‘KMSK scale’) is designed to quantify self-exposure to opiates, cocaine, alcohol, and/or tobacco. Each section of the KMSK scale assesses the frequency, amount, and duration of use of a particular substance during the individual's period of greatest consumption. The scale also assesses the mode of use, whether the substance use is current or past, and whether each substance is the substance of choice. The administration time is under 5 min. In an initial validation study of this scale, 100 human subjects were administered the KMSK scale concurrently with the Structured Clinical Interview for DSM-IV (SCID-I DSM-IV version). The sensitivity and specificity were very good for opiates, cocaine, and alcohol use. In addition, the correlations between KMSK scores and the number of SCID-I criteria items met were excellent for opiates and cocaine and good for alcohol use. Nicotine dependence was not assessed in this study as there is no SCID-I nicotine criteria. These preliminary results show that the KMSK scale may have both construct validity similar to that of other established self-report measures and the potential to be an effective screening instrument for the assessment of a lifetime diagnosis of alcohol, opiate, or cocaine dependence.

Rationale: Adults with chronic critical illness (tracheostomy after ≥ 10 d of mechanical ventilation) have a high burden of palliative needs, but little is known about the actual use and potential need of palliative care services for the larger population of older intensive care unit (ICU) survivors discharged to post–acute care facilities. Objectives: To determine whether older ICU survivors discharged to post–acute care facilities have potentially unmet palliative care needs. Methods: We examined electronic records from a 1-year cohort of 228 consecutive adults ≥ 65 years of age who had their first medical-ICU admission in 2009 at a single tertiary-care medical center and survived to discharge to a post–acute care facility (excluding hospice). Use of palliative care services was defined as having received a palliative care consultation. Potential palliative care needs were defined as patient characteristics suggestive of physical or psychological symptom distress or anticipated poor prognosis. We examined the prevalence of potential palliative needs and 6-month mortality. Measurements and Main Results: The median age was 78 years (interquartile range, 71–84 yr), and 54% received mechanical ventilation for a median of 7 days (interquartile range, 3–16 d). Six subjects (2.6%) received a palliative care consultation during the hospitalization. However, 88% had at least one potential palliative care need; 22% had chronic wounds, 37% were discharged on supplemental oxygen, 17% received chaplaincy services, 23% preferred to not be resuscitated, and 8% were designated “comfort care.” The 6-month mortality was 40%. Conclusions: Older ICU survivors from a single center who required postacute facility care had a high burden of palliative care needs and a high 6-month mortality. The in-hospital postcritical acute care period should be targeted for palliative care assessment and intervention.

Pulmonary tuberculosis (PTB) is one of the most common infectious diseases worldwide, and contributes significantly to morbidity and mortality in developing countries. Despite availability of effective treatment, a significant number of patients suffer from permanent lung damage, which predisposes patients to numerous pulmonary complications.To assess chronic sequelae of patients treated for PTB in a chest clinic at Tikur Anbessa Hospital.This was a retrospective, cross-sectional analysis of patients registered in a clinical database at the chest clinic of Tikur Anbessa specialized Hospital between January and December 2013. Patients with a history of pulmonary tuberculosis treatment were identified and included in the analysis.Among all patients having follow-up at the chest clinic of TASH during the study period, 134 (18.5%) presented with chronic pulmonary complications of TB. Seventy two patients (54%) were male, and the mean and median ages were 40 and 37 years, respectively. Of the study population, 83 (61.9%) patients had clinically significant parenchymal scarring and fibrosis, 40 (29.9%) had bronchiectasis, 5(3.7%) had Aspergilloma, 4(3%) had granuloma/calcification, one patient (0.7%) had pleural thickening, and one patient (0.7%) underwent pneumonectomy during the study period.Fibrosis and bronchiectasis were the most common pulmonary complications of tuberculosis among patients encountered at the TASH chest clinic during the study period. This demonstrates the impact of pulmonary tuberculosis is beyond management of active disease.

To determine the safety profile of new hepatitis C virus (HCV) treatments in liver transplant (LT) recipients with recurrent HCV infection.Forty-two patients were identified with recurrent HCV infection that underwent LT at least 12 mo prior to initiating treatment with a Sofosbuvir-based regimen during December 2013-June 2014. Cases were patients who experienced hepatic decompensation and/or serious adverse events (SAE) during or within one month of completing treatment. Controls had no evidence of hepatic decompensation and/or SAE. HIV-infected patients were excluded. Cumulative incidence of decompensation/SAE was calculated using the Kaplan Meier method. Exact logistic regression analysis was used to identify factors associated with the composite outcome.Median age of the 42 patients was 60 years [Interquartile Range (IQR): 56-65 years], 33% (14/42) were female, 21% (9/42) were Hispanic, and 9% (4/42) were Black. The median time from transplant to treatment initiation was 5.4 years (IQR: 2.1-8.8 years). Thirteen patients experienced one or more episodes of hepatic decompensation and/or SAE. Anemia requiring transfusion, the most common event, occurred in 62% (8/13) patients, while 54% (7/13) decompensated. The cumulative incidence of hepatic decompensation/SAE was 31% (95%CI: 16%-41%). Risk factors for decompensation/SAE included lower pre-treatment hemoglobin (OR = 0.61 per g/dL, 95%CI: 0.40-0.88, P0.01), estimated glomerular filtration rate (OR = 0.95 per mL/min per 1.73 m(2), 95%CI: 0.90-0.99, P = 0.01), and higher baseline serum total bilirubin (OR = 2.43 per mg/dL, 95%CI: 1.17-8.65, P0.01). The sustained virological response rate for the cohort of 42 patients was 45%, while it was 31% for cases.Sofosbuvir/ribavirin will continue to be used in the post-transplant population, including those with HCV genotypes 2 and 3. Management of anemia remains an important clinical challenge.

Background Rifapentine administered 5 days per week has potent activity in mouse models of antituberculosis chemotherapy, but efficacy and safety data are limited in humans. We compared the antimicrobial activity and safety of rifapentine vs rifampin during the first 8 weeks of pulmonary tuberculosis treatment. Methods In total, 531 adults with sputum smear-positive pulmonary tuberculosis were randomized to rifapentine 10 mg/kg/dose or rifampin 10 mg/kg/dose, administered 5 days per week for 8 weeks (intensive phase), with isoniazid, pyrazinamide, and ethambutol. Coprimary outcomes were negative sputum culture on liquid and on solid media at completion of intensive phase. Results Negative cultures on solid media occurred in 145 of 174 participants (83.3%) in the rifampin group and 171 of 198 participants (86.4%) in the rifapentine group (difference, 3.0%; 95% confidence interval [CI]: -4.3, 10.5); negative cultures in liquid media occurred in 110 of 169 (65.1%) in the rifampin group and 133 of 196 (67.9%) in the rifapentine group (difference, 2.8%; 95% CI: -6.9, 12.4). Among 529 participants who received study therapy, 40 of 254 participants (15.7%) in the rifampin group and 40 of 275 participants (14.5%) in the rifapentine group prematurely discontinued treatment (P=.79). Conclusions The rifapentine regimen was safe but not significantly more active than a standard rifampin regimen, by the surrogate endpoint of culture status at completion of intensive phase. Assessment of higher exposures to rifapentine for tuberculosis treatment is warranted. Clinical trials registration NCT00694629.

Objective To evaluate the performance of an interferon-γ release assay (IGRA) versus the standard tuberculin skin test (TST) as a screening tool for latent tuberculosis (TB) infection prior to the initiation of anti–tumor necrosis factor therapy in patients with autoimmune inflammatory diseases. Methods This integrated analysis involved screening of patients with rheumatoid arthritis, those with psoriatic arthritis, and those with ankylosing spondylitis from phase III trials of golimumab. The IGRA used to screen for latent TB was the QuantiFERON-TB Gold In-Tube test. Results In this pooled analysis, 2,282 patients underwent both IGRA and TST screening prior to golimumab treatment. Among these patients, 13.8% had at least one test yielding positive findings for latent TB, including 9.4% with positive results by TST, 7.0% with positive results by IGRA, and 2.6% with positive results on both tests. The rate of indeterminate results for TB on IGRA was 1.8%. Agreement between the TST and IGRA results, measured by the kappa coefficient, was 0.22 (95% confidence interval 0.157–0.279; P = 0.021). Among the patients with positive IGRA findings, 36.9% had positive TST findings. Among the patients with positive TST findings, 27.4% had positive IGRA findings. Overall, 781 (34.2%) of the 2,282 patients had previously received the bacillus Calmette-Guerin (BCG) vaccine; among this vaccinated group, the rate of positivity for latent TB by TST was 15.2% (119 of 781), compared to a rate of positivity of 9.1% (71 of 781) by IGRA (P = 0.0002). Among patients who had not received the BCG vaccine, the rate of positivity by TST was 5.0% (62 of 1,248) and the rate of positivity by IGRA was 5.8% (72 of 1,248) (P = 0.3745). When the IGRA was repeated in patients whose results were initially indeterminate, the rate of indeterminate IGRA findings for latent TB was much lower than has been previously reported. Conclusion In the absence of a true gold standard test for latent TB infection, results of this comparison of IGRA and TST in a large cohort of patients with rheumatic diseases suggest that the IGRA provides greater specificity and possibly greater sensitivity than the TST.

Background: Little is known about the actual treatment of patients with chronic obstructive pulmonary disease (COPD), either in the inpatient or outpatient settings. We hypothesized that there are substantial opportunities for improvement in adherence with current guidelines and recommendations. Methods: We reviewed the medical records of all patients hospitalized with acute exacerbation of COPD between January 2005 and December 2006 at 5 New York City hospitals. Results: There were 1285 unique patients with 1653 hospitalizations. Of these 1653, 83% were for patients with a prior history of COPD and 368 (22%) represented repeat admissions during our study period. The majority were treated during their hospitalization with a combination of systemic steroids (85%), bronchodilators (94%) and antibiotics (80%). There were 59 deaths (3.6%). Smoking cessation counseling was offered to 48% of active smokers. Influenza and pneumococcal vaccines were administered to half of eligible patients. On discharge, only 46.0% were prescribed maintenance bronchodilators and 24% were not prescribed any inhaled therapy. Even in the 226 unique patients (17.6%) readmitted at least once during course of the study, on discharge only 44.7% were prescribed maintenance bronchodilators and 23% were not prescribed any regular inhaled therapy. Conclusions: Patients hospitalized with acute exacerbation of COPD generally receive adequate hospital care, but there may be opportunities to improve care pharmacologically and with smoking cessation counseling and vaccination during and after hospitalization.

A substantial proportion of Ashkenazi Jewish (AJ) breast and ovarian cancer families carry one of three founder mutations in BRCA1 (185delAG, 5382InsC) and BRCA2 (6174delT). Non-founder mutations are identified in another 2-4% of such families. The extent to which major genomic rearrangements in BRCA contribute to breast and ovarian cancer in the Ashkenazim is not well understood. We identified AJ individuals with breast and/or ovarian cancer undergoing hereditary breast/ovarian cancer risk assessment since 2006 without evidence of a deleterious mutation on BRCA gene sequencing who were screened for major gene rearrangements in BRCA1 and BRCA2. For each proband, the pre-test probability of identifying a deleterious BRCA mutation was estimated using the Myriad II model. We identified 108 affected individuals who underwent large rearrangement testing (80 breast cancer, 19 ovarian cancer, nine both breast and ovarian cancer). The mean estimated AJ specific pre-test probability of a deleterious mutation in BRCA1 and BRCA2 was 24.7% (range: 4.4-88.9%). No genomic rearrangements were identified in either the entire group or in the 26 subjects with pre-test mutation prevalence estimates exceeding 30%. Major gene rearrangements involving the BRCA1 and BRCA2 genes appear to contribute little to the burden of inherited predisposition to breast and ovarian cancer in the Ashkenazim.

The tuberculin skin test (TST) has a low specificity in the setting of bacille Calmette-Guérin (BCG) vaccination. Interferon-gamma release assays (IGRAs) appear to be more specific but have not been validated in this population under routine clinical conditions. We sought to validate the routine clinical use of the T-SPOT.TB test (Oxford Immunotec; Oxford, UK), an IGRA, in a predominantly foreign-born population with a high rate of BCG vaccination.We compared the TST and the T-SPOT.TB test in 96 subjects at a New York City Department of Health tuberculosis clinic. We aimed to determine which test better predicted being a close contact of a case of active tuberculosis, a surrogate for latent tuberculosis infection.A positive T-SPOT.TB test result was strongly associated with being a close contact of a case of active tuberculosis after adjustment for potential confounders (adjusted odds ratio, 2.9; 95% confidence interval, 1.1 to 7.3; p = 0.03). A positive TST result was associated with being a contact only in subjects without BCG vaccination (p = 0.02). The T-SPOT.TB test was more specific for being a close contact than the TST (p0.001). Specificity in BCG-vaccinated subjects was 3% for the TST compared with 70% for the T-SPOT.TB test (p0.001).The T-SPOT.TB test is superior in routine clinical use to the TST for identifying high-risk individuals among foreign-born populations with high rates of BCG vaccination.

The incidence appears to be increasing., We reviewed medical records of patients without known HIV and with positive cultures for nontuberculous mycobacteria (NTM) isolated during 2000–2003 from 1 large hospital in New York, New York. Overall, 505 patients had positive NTM cultures; 119 (24%) met the criteria for NTM disease. The difference between demographic characteristics of case-patients in our study (66% female, 61% white, and 59% >60 years of age) and those of the base population as determined by regional census data was statistically significant. Estimated incidences for positive cultures, all disease, and respiratory tract disease were 17.7, 2.7, and 2.0 per 100,000 persons, respectively. More patients with rapidly growing mycobacteria (61%), Mycobacterium kansasii (70%), or M. marinum (100%) met criteria for disease than did patients with M. avium complex (MAC) (27%, (p

Background: Little is known about the United States diagnosis and burden of pulmonary embolism (PE) in the emergency department (ED), and their evolution over the past decade. We examined nationally representative data to evaluate factors associated with and trends in ED diagnosis of PE. Methods: We conducted a cross-sectional study using National Hospital Ambulatory Medical Care Survey (NHAMCS) data from January 1, 2001 to December 31, 2010. We identified all ED patient visits where PE was diagnosed and corresponding demographic, hemodynamic, testing and disposition data. Analyses were performed using descriptive statistics and multivariable logistic regression. Results: During the study period 988,000 weighted patient visits with diagnosis of PE were identified. Among patients with an ED visit, the likelihood of having a diagnosis of PE per year increased significantly from 2001 to 2010 (odds ratio [OR] 1.091, 95% confidence interval [CI] 1.034-1.152, P = 0.002 for trend) when adjusted for demographic and hospital information. In contrast, when further adjusted for the use of computed tomography (CT) among patients in the ED, the likelihood of having a diagnosis of PE per year did not change (OR 1.041, 95% CI 0.987-1.097, P = 0.14). Overall, 75.1% of patients seen with a diagnosis of PE were hemodynamically stable; 86% were admitted with an in-hospital death rate under 3%. Conclusions: The proportion of ED visits with a diagnosis of PE increased significantly from 2001 to 2010 and this rise can be attributed in large part to the increased availability and use of CT. Most of these patients were admitted with low in-hospital mortality. Keywords: Pulmonary embolism Emergency department Computed Tomography (CT) pulmonary angiography

Combined cocaine and illicit opiate use is common. This study aimed to test the hypothesis that cocaine dependence in former heroin-addicted patients maintained on methadone treatment is associated with enhanced glucocorticoid negative feedback. Multiple dose dexamethasone suppression tests, using a conventional 2.0 mg dose, and two lower doses, 0.5 mg and 0.125 mg, were performed in 10 methadone-maintained former heroin addicts with ongoing cocaine dependence (C-MM), 10 stabilized methadone-maintained former heroin addicts with no ongoing drug or alcohol use (MM), and 22 normal volunteers (NV). At 9 hours, there was no difference in plasma adrenocorticotropin hormone (ACTH) and/or cortisol levels among groups on the baseline day, as well as after the two lower doses of dexamethasone. At 17 hours, C-MM and MM had significantly lower plasma ACTH and/or cortisol levels than NV. However, C-MM did not significantly differ from MM in their hormonal levels. When the hormonal responses to dexamethasone are expressed as magnitude of lowering from baseline, there was no significant difference at any dose among groups. Therefore, C-MM exhibited a normal glucocorticoid negative feedback in the morning. Using the standard interpretation of dexamethasone suppression testing based on the examination of the actual hormonal levels rather than the difference from baseline condition, C-MM appear to have glucocorticoid effects similar to MM, yet were both greater than NV in the late afternoon. Thus, further studies are needed to know whether altered glucocorticoid negative feedback is related to chronic cocaine exposure, or is the result of former heroin addiction and/or its long-term treatment with methadone.

In humans, mu- and kappa-opioid receptor agonists lower tuberoinfundibular dopamine, which tonically inhibits prolactin release. Serum prolactin is, therefore, a useful biomarker for tuberoinfundibular dopamine. The current study evaluated the unexpected finding that the relative mu- and kappa-opioid receptor selective antagonist nalmefene increases serum prolactin, indicating possible kappa-opioid receptor agonist activity. In all, 33 healthy human volunteers (14 female) with no history of psychiatric or substance use disorders received placebo, nalmefene 3 mg, and nalmefene 10 mg in a double-blind manner. Drugs were administered between 0900 and 1000 on separate days via 2-min intravenous infusion. Serial blood specimens were analyzed for serum levels of prolactin. Additional in vitro studies of nalmefene binding to cloned human kappa-opioid receptors transfected into Chinese hamster ovary cells were performed. Compared to placebo, both doses of nalmefene caused significant elevations in serum prolactin (p

Posttransplantation allograft malignancy of donor origin is a rare complication after liver transplantation. In the case described, subjective fevers and nonspecific abdominal complaints nearly 6 months following cadaveric liver transplantation in a young woman prompted an evaluation which was remarkable for a large central liver mass. A poorly differentiated squamous cell carcinoma was diagnosed, but was unresectable at exploration. The tumor was confined to the liver. Histocompatibility testing using polymerase chain reaction (PCR) amplification techniques identified both donor and recipient HLA alleles. The patient was treated with chemoembolization, systemic chemotherapy and cessation of immunosuppression. Repeat biopsy 2 months later showed the tumor to be completely necrotic. With decompensated liver disease, she was relisted and retransplanted. More than 2 years later she remains disease-free with complete pathological remission. This is the only reported case of squamous cell carcinoma of donor origin arising in a transplanted liver.

The approach to the diagnosis of both active tuberculosis and latent infection has changed very little in the past several decades. For active disease, sputum smears with or without chest radiographs to aid in diagnostic accuracy, form the cornerstone of the diagnostic approach in many high-burden countries. These tests usually are supplemented by cultures when resources permit. The diagnosis of latent infection still relies on the use of the tuberculin skin test using purified protein derivative. The current global tuberculosis epidemic, which features large numbers of patients with human immunodeficiency virus infection and increasing rates of multidrug-resistant tuberculosis, makes accurate and rapid diagnosis of tuberculosis more urgent than ever before. Currently available technologies, most involving techniques of DNA amplification, can substantially improve the accuracy of the diagnosis of tuberculosis, although the use of such assays has been sharply limited because of concerns about cost. However, economic analyses suggest that these assays can be cost effective if they lead to sharp reductions in transmission through earlier treatment of infectious cases.

Dynorphin A1-13, a shortened sequence of the natural peptide dynorphin A1-17, is a primarily kappa-opioid receptor-preferring peptide. Previously, we showed that dynorphin A1-13 administered to normal volunteers causes a prompt dose-dependent elevation in serum prolactin that may reflect a reduction in tuberoinfundibular dopaminergic tone. This study was conducted to determine whether tuberoinfundibular dopaminergic tone is reduced in methadone-maintained patients. Eight former heroin addicts on stable-dose methadone maintenance with no ongoing drug or alcohol abuse or dependence and 15 normal volunteer controls with no history of drug or alcohol dependence received dynorphin A1-13 intravenously at doses of 120 microg/kg and 500 microg/kg. Studies began one hour before methadone dosing to avoid the expected increase in prolactin that coincides with peak plasma levels of methadone. After intravenous dynorphin A1-13, a dose-response increase in serum prolactin, which peaked within 20 min, was observed in both groups. There was no difference in prolactin between the two groups at baseline or following a placebo. The prolactin response to each dose of dynorphin A1-13 was significantly lower in the methadone-maintained volunteers compared with the controls. These results suggest that tuberoinfundibular dopaminergic tone is altered in methadone-maintained subjects. It is unknown whether altered dopaminergic tone existed before opiate addiction, is a result of heroin addiction, or is reflective of methadone maintenance. Whether methadone-maintained subjects also have decreased dopaminergic response to dynorphin and other kappa-opioid receptor ligands in mesolimbic-mesocortical and nigrostriatal dopaminergic systems cannot be determined from this study.

Inherited predisposition to cancer is a major contributor to the breast and ovarian cancer burden among people of Ashkenazi ancestry. Approximately 2.5% of all people of Ashkenazi Jewish descent carry one of three ancient (founder) mutations in BRCA1 or BRCA2 (185delAG or 5382insC in BRCA1 and 6174delT in BRCA2) .1–3 In a recent population based study, 29% of Jewish women with ovarian cancer were shown to carry one of these three founder mutations.4 In a series of 220 high risk Ashkenazi breast cancer families, a founder BRCA mutation was detected in 44%. If ovarian cancer was present in the kindred, 73% of families segregated a founder BRCA mutation.5 Despite the high proportion of hereditary breast and ovarian cancer attributed to founder mutations of BRCA1 or BRCA2 in this population, some Ashkenazi families with histories highly suggestive of an inherited cancer predisposition have been shown to segregate other (non-founder) mutations of BRCA1 6 or BRCA2 .7 Counselling of families considering full sequence BRCA genotyping is complicated by the limited information available regarding the incidence of these non-founder mutations in the Ashkenazi population. We present a series of Ashkenazi Jewish kindreds at hereditary risk for breast and ovarian cancer who do not segregate one of the three Ashkenazi founder mutations and who have undergone full sequencing of the coding regions and flanking intronic regions of BRCA1 and BRCA2 . Using the BRCAPRO algorithm, we have estimated whether the prevalence of non-founder BRCA1 and BRCA2 mutations in a genetic isolate (Ashkenazim) is consistent with the background rate in an admixed population, or if selective or other effects have led to a non-founder mutation rate lower than would be expected. Records of all patients seen by the Clinical Genetics Service at Memorial Sloan-Kettering Cancer Center (MSKCC) from 1.6.95 to …

Study objectives: To assess the restoration of immune responses to tuberculosis, as manifested by secretion of T-helper type 1 cytokines (interferon (IFN)-, interleukin (IL)-12, and IL-2) and T-helper type 2 cytokines (IL-10), in HIV-positive patients who receive antiretroviral therapy (ART). Design: Prospective cohort study. Setting: University hospital. Patients: Ten HIV-positive patients, all naive to ART and all about to start ART for clinical indications, and 11 healthy, HIV-negative control subjects. Interventions: Assessment of T-cell proliferation and cytokine production after administration of ART to patients with HIV infection. Measurements and results: All patients had a negative tuberculin skin test result at baseline and were anergic. Highly active ART reduced the viral load to very low levels in all patients within a short time after starting therapy. Blood samples were drawn every 2 months after starting therapy, and continued for 1 year while the patients continued to receive ART. There were trends toward increased proliferation of peripheral blood mononuclear cells (PBMCs) in response to Mycobacterium tuberculosis-specific stimuli, but these were delayed until several months of ART had elapsed. Similar trends were noted in relation to the secretion of IFN-. Neither PBMC proliferation nor IFN- secretion reached levels seen in healthy control subjects. No consistent trends in IL-2, IL-10, or IL-12 production were noted. Conclusion: ART restores immune responses to M tuberculosis, although this restoration is delayed and does not reach levels seen in healthy, HIV-negative control subjects. These results may explain in part the phenomenon of paradoxic reactions to antituberculosis therapy in patients with HIV infection. A larger study in which patients are followed up for a longer period of time will allow the magnitude and timing of this reconstitution to be more precisely defined. (CHEST 2002; 122:597- 602)

Background Sputum smear-positive tuberculosis (TB) patients have a high risk of transmission and are of great epidemiological and infection control significance. Little is known about the smear-positive populations in high TB burden regions, such as Kazakhstan. The objective of this study is to characterize the smear-positive population in Kazakhstan and identify associated modifiable risk factors. Methods Data on incident TB cases’ (identified between April 2012 and March 2014) socio-demographic, risk behavior, and comorbidity characteristics were collected in four regions of Kazakhstan through structured survey and medical record review. We used multivariable logistic regression to determine factors associated with smear positivity. Results Of the total sample, 193 (34.3%) of the 562 study participants tested smear-positive. In the final adjusted multivariable logistic regression model, sex (adjusted odds ratio (aOR) = 2.0, 95% CI:1.3–3.1, p < 0.01), incarceration (aOR = 3.6, 95% CI:1.2–11.1, p = 0.03), alcohol dependence (aOR = 2.6, 95% CI:1.2–5.7, p = 0.02), diabetes (aOR = 5.0, 95% CI:2.4–10.7, p < 0.01), and physician access (aOR = 2.7, 95% CI:1.3–5.5p < 0.01) were associated with smear-positivity. Conclusions Incarceration, alcohol dependence, diabetes, and physician access are associated with smear positivity among incident TB cases in Kazakhstan. To stem the TB epidemic, screening, treatment and prevention policies should address these factors.

Due to the current regionally based allocation system, some patients list for and are transplanted away from home in regions with shorter waits and higher transplant rates. Of 147 included patients, 120 died waiting and 27 received transplants at outside centers during the study (32.5 months). Those transplanted elsewhere had higher median incomes than patients dying on the waitlist ($84 946 vs. $55 250, p = 0.0001). Those with median incomes$60 244 were more likely to die than those with incomes$60 244 (94% vs. 70%, RR: 1.35, 95% CI: 1.14-1.59). Patients with Medicaid were more likely to die waiting than those with other insurance (100% vs. 77%, RR: 1.30, 95% CI: 1.18-1.44). Our analysis demonstrates that those who died waiting were more likely to have lower incomes and Medicaid compared with those transplanted elsewhere. Even when we controlled for Medicaid status, patients who died waiting had lower incomes compared with those transplanted elsewhere. Increased organ sharing over geographically broader regions, as recommended by the Institute of Medicine in 1999, may reduce incentives for patients to travel to receive a liver and reduce inequities. Current efforts to address this disparity continue to fall short of the Institute of Medicine recommendations, United States Department of Health and Human Services regulations and the Final Rule.

The aim of this study is to analyze the impact of the recipient's disease severity on graft size requirements and outcome in adult-to-adult living donor liver transplantation. A limiting factor in adult-to-adult living donor liver transplantation has been adequacy of graft size. A minimal graft-recipient weight ratio (GRWR) of 0.8% to 1% has been suggested, without taking the recipient's disease into account. Forty adults underwent liver transplantation using left (n = 10; mean weight, 481 +/- 83 g) or right lobes (n = 30; mean weight, 845 +/- 182 g). We recorded graft survival, Child-Turcotte-Pugh score, and occurrence of small-for-size syndrome (poor bile production, prolonged postoperative prothrombin time, and cholestasis without ischemia markers). Small grafts were defined as GRWR of < or =0.85%. Large grafts were defined as GRWR greater than 0.85%. Six patients died within 6 months of transplantation (early patient survival rate, 85%); two patients died late of tumor recurrence. Among transplant recipients with normal liver function or Child's class A, there was no significant difference with the use of small (n = 6) or large (n = 9) grafts (graft survival rates, 83% v 88%, respectively; P =.65). Among patients with Child's class B or C, graft survival rates were 74% in recipients of large grafts (n = 19) and 33% in recipients of small grafts (n = 6; P =.023). Five of 6 patients with Child's class B or C who received small grafts developed small-for-size syndrome; 2 patients died (1 patient after retransplantation) and 3 patients survived (2 patients after retransplantation). Graft function and survival are influenced not only by graft size, but also by pretransplantation disease severity. GRWR as low as 0.6% can be used safely in patients without cirrhosis or in patients with Child's class A. Transplant recipients with Child's class B or C require a GRWR greater than 0.85% to avoid small-for-size syndrome and related complications.

Background Short-term outcomes of liver transplantation are well reported. Little is known, however, about long-term results in liver recipients surviving > or =5 years. We sought to analyze long-term complications in liver recipients surviving > or =5 years after transplant, to assess their medical condition and to compare findings to the general population. Methods We analyzed the chart and database records of all patients (n=139) who underwent liver transplantation at a major transplant center before January 1, 1991. Outcome measures included the presence of diabetes, hypertension, heart, renal or neurological disease, osteoporosis, incidence of de novo malignancy or fracture, or other pathology, body mass index, serum cholesterol and glucose, liver function, blood pressure, frequency of laboratory and clinic follow-up, current pharmacological regimen, and late rejection episodes. Results Ninety-six patients (70%) survived > or =5 years. Compared to numbers expected based on U.S. population rates, transplant recipients had significantly higher overall prevalences of hypertension (standardized prevalence ratio [SPR]=3.07, 95% confidence interval [CI], 2.35-3.93) and diabetes (SPR=5.99, 95% CI, 4.15-8.38), and higher incidences of de novo malignancy (standardized incidence ratio [SIR]=3.94, 95% CI, 2.09-6.73), non-Hodgkin's lymphoma (SIR=28.56, 95% CI, 7.68-73.11), non-melanoma skin cancer (estimated SIR> or =3.16) and fractures in women (SIR=2.05, 95% CI, 1.12-3.43). Forty-one of 87 (47.1%) patients were obese, and 23 patients (27.4%) had elevated serum cholesterol levels (> or =240 mg/dl, 6.22 mmol/L), compared to 33% and 19.5% of U.S. adults, respectively. Prevalences of heart or peptic ulcer disease were not significantly higher. Conclusions Liver transplantation is being performed with excellent 5-year survival. Significant comorbidities exist, however, which appear to be related to long-term immunosuppression.

When tacrolimus side effects persist despite dose reduction, conversion to cyclosporine-based immunosuppression (CyA) is necessary. We characterized tacrolimus side effects that warranted discontinuation of the drug, and outcomes after conversion. Of 388 liver recipients who received tacrolimus as primary immunosuppression, 70 required conversion to CyA. We recorded indication for conversion, whether conversion was early or late after transplantation, tacrolimus dose and trough blood level at conversion, and incidence of rejection after conversion. Conversion was early in 29 patients (41.4%) and late in 41 (58.6%). Indications for early conversion were neurotoxicity (20), (insulin-dependent) diabetes mellitus (IDDM) (5), nephrotoxicity (3), gastrointestinal (GI) toxicity (6), and cardiomyopathy (1), and for late conversion were neurotoxicity (15), IDDM (12), nephrotoxicity (3), GI toxicity (5), hepatotoxicity (6), post-transplant lmphoproliferate disease (PTLD) (2), cardiomyopathy (1), hemolytic anemia (1), and pruritus (1). All early-conversion patients showed improvement/resolution of symptoms. Among late-conversion patients, 37 (90.2%) had improvement/resolution; in 4 (9.8%), adverse effects persisted. The overall rejection rate was 30%. Sixty-two patients (88.6%) are alive with functioning grafts 686 +/- 362 days (range, 154-1433 days) after conversion. When tacrolimus side effects are unresponsive to dose reduction, conversion to CyA can be accomplished safely, with no increased risk of rejection and excellent long-term outcome.

Objective: Mycobacterium avium complex (MAC) is isolated with increasing frequency from respiratory specimens. This study was an attempt to determine the significance of this in human immunodeficiency virus (HIV)-positive and HIV-negative patients.Methods: A retrospective cohort study was conducted at Bellevue Hospital, a large municipal hospital in New York City, including all patients with two or more respiratory tract specimens positive for MAC during the period January 1996 to October 1996.Results: Eighty patients met inclusion criteria. Forty-six were HIV-positive, and 34 were HIV-negative. Age, gender distribution, and race were comparable. Cough was a common complaint in all patients, whereas HIV-positive patients were significantly more likely to have fever (19 vs. 2, P < 0.0001). Abnormal chest radiographs were common in both groups (P > 0.8), although HIV-positive patients were more likely to have diffuse abnormalities (P < 0.0001). Focal radiographic findings were similar for both groups; however, there was a trend toward more lymphadenopathy in the HIV-positive group, though this did not reach statistical significance (P = 0.17). Notably, patients in both groups frequently had an established concurrent pulmonary diagnosis or evidence of disseminated MAC infection. Patients who were HIV-positive had Pneumocystis carinii pneumonia (n = 10), pneumonia (n = 10), and disseminated MAC disease (n = 12); whereas the concurrent disease in HIV-negative patients predominantly was active tuberculosis (n = 13). According to the recent American Thoracic Society-recommended criteria for the diagnosis of pulmonary disease caused by nontuberculous mycobacteria only 7 of 46 HIV-positive patients and 1 of 34 HIV-negative patients met clinical, bacteriologic, and radiographic criteria for pulmonary disease caused by MAC (P = 0.052).Conclusion: Mycobacterium avium complex often is cultured from patients with other lung diseases, and its presence in sputum infrequently signifies true disease, though it is more likely to do so in HIV-positive patients.