Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach

There is poor agreement on definitions of different phenotypes of preschool wheezing disorders. The present Task Force proposes to use the terms episodic (viral) wheeze to describe children who wheeze intermittently and are well between episodes, and multiple-trigger wheeze for children who wheeze both during and outside discrete episodes. Investigations are only needed when in doubt about the diagnosis. Based on the limited evidence available, inhaled short-acting beta(2)-agonists by metered-dose inhaler/spacer combination are recommended for symptomatic relief. Educating parents regarding causative factors and treatment is useful. Exposure to tobacco smoke should be avoided; allergen avoidance may be considered when sensitisation has been established. Maintenance treatment with inhaled corticosteroids is recommended for multiple-trigger wheeze; benefits are often small. Montelukast is recommended for the treatment of episodic (viral) wheeze and can be started when symptoms of a viral cold develop. Given the large overlap in phenotypes, and the fact that patients can move from one phenotype to another, inhaled corticosteroids and montelukast may be considered on a trial basis in almost any preschool child with recurrent wheeze, but should be discontinued if there is no clear clinical benefit. Large well-designed randomised controlled trials with clear descriptions of patients are needed to improve the present recommendations on the treatment of these common syndromes.

Primary ciliary dyskinesia: a consensus statement on diagnostic and treatment approaches in children

Primary ciliary dyskinesia (PCD) is associated with abnormal ciliary structure and function, which results in retention of mucus and bacteria in the respiratory tract, leading to chronic oto-sino-pulmonary disease, situs abnormalities and abnormal sperm motility. The diagnosis of PCD requires the presence of the characteristic clinical phenotype and either specific ultrastructural ciliary defects identified by transmission electron microscopy or evidence of abnormal ciliary function. Although the management of children affected with PCD remains uncertain and evidence is limited, it remains important to follow-up these patients with an adequate and shared care system in order to prevent future lung damage. This European Respiratory Society consensus statement on the management of children with PCD formulates recommendations regarding diagnostic and therapeutic approaches in order to permit a more accurate approach in these patients. Large well-designed randomised controlled trials, with clear description of patients, are required in order to improve these recommendations on diagnostic and treatment approaches in this disease.

Thromboelastometry for the assessment of coagulation abnormalities in early and established adult sepsis: a prospective cohort study

INTRODUCTION: The inflammatory response to an invading pathogen in sepsis leads to complex alterations in hemostasis by dysregulation of procoagulant and anticoagulant factors. Recent treatment options to correct these abnormalities in patients with sepsis and organ dysfunction have yielded conflicting results. Using thromboelastometry (ROTEM(R)), we assessed the course of hemostatic alterations in patients with sepsis and related these alterations to the severity of organ dysfunction. METHODS: This prospective cohort study included 30 consecutive critically ill patients with sepsis admitted to a 30-bed multidisciplinary intensive care unit (ICU). Hemostasis was analyzed with routine clotting tests as well as thromboelastometry every 12 hours for the first 48 hours, and at discharge from the ICU. Organ dysfunction was quantified using the Sequential Organ Failure Assessment (SOFA) score. RESULTS: Simplified Acute Physiology Score II and SOFA scores at ICU admission were 52 +/- 15 and 9 +/- 4, respectively. During the ICU stay the clotting time decreased from 65 +/- 8 seconds to 57 +/- 5 seconds (P = 0.021) and clot formation time (CFT) from 97 +/- 63 seconds to 63 +/- 31 seconds (P = 0.017), whereas maximal clot firmness (MCF) increased from 62 +/- 11 mm to 67 +/- 9 mm (P = 0.035). Classification by SOFA score revealed that CFT was slower (P = 0.017) and MCF weaker (P = 0.005) in patients with more severe organ failure (SOFA >or= 10, CFT 125 +/- 76 seconds, and MCF 57 +/- 11 mm) as compared with patients who had lower SOFA scores (SOFA <10, CFT 69 +/- 27, and MCF 68 +/- 8). Along with increasing coagulation factor activity, the initially increased International Normalized Ratio (INR) and prolonged activated partial thromboplastin time (aPTT) corrected over time. CONCLUSIONS: Key variables of ROTEM(R) remained within the reference ranges during the phase of critical illness in this cohort of patients with severe sepsis and septic shock without bleeding complications. Improved organ dysfunction upon discharge from the ICU was associated with shortened coagulation time, accelerated clot formation, and increased firmness of the formed blood clot when compared with values on admission. With increased severity of illness, changes of ROTEM(R) variables were more pronounced.

New insights regarding the incidence, presentation and treatment options of aorto-oesophageal fistulation after thoracic endovascular aortic repair: the European Registry of Endovascular Aortic Repair Complications

OBJECTIVES To review the incidence, clinical presentation, definite management and 1-year outcome in patients with aorto-oesophageal fistulation (AOF) following thoracic endovascular aortic repair (TEVAR). METHODS International multicentre registry (European Registry of Endovascular Aortic Repair Complications) between 2001 and 2011 with a total caseload of 2387 TEVAR procedures (17 centres). RESULTS Thirty-six patients with a median age of 69 years (IQR 56-75), 25% females and 9 patients (19%) following previous aortic surgery were identified. The incidence of AOF in the entire cohort after TEVAR in the study period was 1.5%. The primary underlying aortic pathology for TEVAR was atherosclerotic aneurysm formation in 53% of patients and the median time to development of AOF was 90 days (IQR 30-150). Leading clinical symptoms were fever of unknown origin in 29 (81%), haematemesis in 19 (53%) and shock in 8 (22%) patients. Diagnosis could be confirmed via computed tomography in 92% of the cases with the leading sign of a new mediastinal mass in 28 (78%) patients. A conservative approach resulted in a 100% 1-year mortality, and 1-year survival for an oesophageal stenting-only approach was 17%. Survival after isolated oesophagectomy was 43%. The highest 1-year survival rate (46%) could be achieved via an aggressive treatment including radical oesophagectomy and aortic replacement [relative risk increase 1.73 95% confidence interval (CI) 1.03-2.92]. The survival advantage of this aggressive treatment modality could be confirmed in bootstrap analysis (95% CI 1.11-3.33). CONCLUSIONS The development of AOF is a rare but lethal complication after TEVAR, being associated with the need for emergency TEVAR as well as mediastinal haematoma formation. The only durable and successful approach to cure the disease is radical oesophagectomy and extensive aortic reconstruction. These findings may serve as a decision-making tool for physicians treating these complex patients.

Characteristics and comprehensiveness of adult HIV care and treatment programmes in Asia-Pacific, sub-Saharan Africa and the Americas: results of a site assessment conducted by the International epidemiologic Databases to Evaluate AIDS (IeDEA) Collaboration

INTRODUCTION HIV care and treatment programmes worldwide are transforming as they push to deliver universal access to essential prevention, care and treatment services to persons living with HIV and their communities. The characteristics and capacity of these HIV programmes affect patient outcomes and quality of care. Despite the importance of ensuring optimal outcomes, few studies have addressed the capacity of HIV programmes to deliver comprehensive care. We sought to describe such capacity in HIV programmes in seven regions worldwide. METHODS Staff from 128 sites in 41 countries participating in the International epidemiologic Databases to Evaluate AIDS completed a site survey from 2009 to 2010, including sites in the Asia-Pacific region (n=20), Latin America and the Caribbean (n=7), North America (n=7), Central Africa (n=12), East Africa (n=51), Southern Africa (n=16) and West Africa (n=15). We computed a measure of the comprehensiveness of care based on seven World Health Organization-recommended essential HIV services. RESULTS Most sites reported serving urban (61%; region range (rr): 33-100%) and both adult and paediatric populations (77%; rr: 29-96%). Only 45% of HIV clinics that reported treating children had paediatricians on staff. As for the seven essential services, survey respondents reported that CD4+ cell count testing was available to all but one site, while tuberculosis (TB) screening and community outreach services were available in 80 and 72%, respectively. The remaining four essential services - nutritional support (82%), combination antiretroviral therapy adherence support (88%), prevention of mother-to-child transmission (PMTCT) (94%) and other prevention and clinical management services (97%) - were uniformly available. Approximately half (46%) of sites reported offering all seven services. Newer sites and sites in settings with low rankings on the UN Human Development Index (HDI), especially those in the President's Emergency Plan for AIDS Relief focus countries, tended to offer a more comprehensive array of essential services. HIV care programme characteristics and comprehensiveness varied according to the number of years the site had been in operation and the HDI of the site setting, with more recently established clinics in low-HDI settings reporting a more comprehensive array of available services. Survey respondents frequently identified contact tracing of patients, patient outreach, nutritional counselling, onsite viral load testing, universal TB screening and the provision of isoniazid preventive therapy as unavailable services. CONCLUSIONS This study serves as a baseline for on-going monitoring of the evolution of care delivery over time and lays the groundwork for evaluating HIV treatment outcomes in relation to site capacity for comprehensive care.

Implications of Imaging Criteria for the Management and Treatment of Intraductal Papillary Mucinous Neoplasms - Benign versus Malignant Findings

OBJECTIVES Evaluation of computed tomography (CT) and magnetic resonance imaging (MRI) for differentiation of pancreatic intraductal papillary mucinous neoplasm (IPMN) subtypes based on objective imaging criteria. METHODS Fifty-eight patients with 60 histologically confirmed IPMNs were included in this retrospective study. Eighty-three imaging studies (CT,n = 42; MRI,n = 41) were analysed by three independent blinded observers (O1-O3), using established imaging criteria to assess likelihood of malignancy (-5, very likely benign; 5, very likely malignant) and histological subtype (i.e., low-grade (LGD), moderate-grade (MGD), high-grade dysplasia (HGD), early invasive carcinoma (IPMC), solid carcinoma (CA) arising from IPMN). RESULTS Forty-one benign (LGD IPMN,n = 20; MGD IPMN,n = 21) and 19 malignant (HGD IPMN,n = 3; IPMC,n = 6; solid CA,n = 10) IPMNs located in the main duct (n = 6), branch duct (n = 37), or both (n = 17) were evaluated. Overall accuracy of differentiation between benign and malignant IPMNs was 86/92 % (CT/MRI). Exclusion of overtly malignant cases (solid CA) resulted in overall accuracy of 83/90 % (CT/MRI). The presence of mural nodules and ductal lesion size ≥30 mm were significant indicators of malignancy (p = 0.02 and p < 0.001, respectively). CONCLUSIONS Invasive IPMN can be identified with high confidence and sensitivity using CT and MRI. The diagnostic problem that remains is the accurate radiological differentiation of premalignant and non-invasive subtypes. KEY POINTS • CT and MRI can differentiate benign from malignant forms of IPMN. • Identifying (pre)malignant histological IPMN subtypes by CT and MRI is difficult. • Overall, diagnostic performance with MRI was slightly (not significantly) superior to CT.

Thrombosis during pregnancy: Risks, prevention, and treatment for mother and fetus--harvesting the power of omic technology, biomarkers and in vitro or in vivo models to facilitate the treatment of thrombosis

Maternal thromboembolism and a spectrum of placenta-mediated complications including the pre-eclampsia syndromes, fetal growth restriction, fetal loss, and abruption manifest a shared etiopathogenesis and predisposing risk factors. Furthermore, these maternal and fetal complications are often linked to subsequent maternal health consequences that comprise the metabolic syndrome, namely, thromboembolism, chronic hypertension, and type II diabetes. Traditionally, several lines of evidence have linked vasoconstriction, excessive thrombosis and inflammation, and impaired trophoblast invasion at the uteroplacental interface as hallmark features of the placental complications. "Omic" technologies and biomarker development have been largely based upon advances in vascular biology, improved understanding of the molecular basis and biochemical pathways responsible for the clinically relevant diseases, and increasingly robust large cohort and/or registry based studies. Advances in understanding of innate and adaptive immunity appear to play an important role in several pregnancy complications. Strategies aimed at improving prediction of these pregnancy complications are often incorporating hemodynamic blood flow data using non-invasive imaging technologies of the utero-placental and maternal circulations early in pregnancy. Some evidence suggests that a multiple marker approach will yield the best performing prediction tools, which may then in turn offer the possibility of early intervention to prevent or ameliorate these pregnancy complications. Prediction of maternal cardiovascular and non-cardiovascular consequences following pregnancy represents an important area of future research, which may have significant public health consequences not only for cardiovascular disease, but also for a variety of other disorders, such as autoimmune and neurodegenerative diseases.

The story of HCC in NAFLD: from epidemiology, across pathogenesis, to prevention and treatment.

BACKGROUND & AIMS Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. An increasing number of reports describe HCC in the setting of obesity and diabetes, two major risk factors for non-alcoholic fatty liver disease (NAFLD). The increasing incidence of these conditions and the emerging evidence of HCC in non-cirrhotic NAFLD prioritize a better understanding of NAFLD-related HCC epidemiology and pathogenesis in order to target screening policies and develop preventive-therapeutic strategies. In this review, we focus on the epidemiological impact of this condition, suggesting a possible link between HCC in cryptogenic cirrhosis and NAFLD. Furthermore, we analyse the suggested pathogenic mechanisms and the possible preventive-therapeutic strategies.

Association between ethnicity and treatment status in opioid dependence therapy using methadone and suboxone drugs

Opioids are drugs with opium-like qualities that are either derived from opiates (drugs created from opium, such as morphine or codeine) or chemically produced. In the U.S. opiate abuse and related deaths have been increasing and traditional maintenance treatment has been Methadone with variable success. However, since 2003 synthetic Buprenorphine has been used since it is prescribed daily by physicians in pill form and should improve outcomes. Comparative studies are limited and the effect of ethnicity on treatment outcome is unknown. ^ Data collected at one clinic from December 2005 through May 2009 were used to compare the association between ethnicity and other socioeconomic variables with treatment status, and to identify factors associated with the dropout among participants. Descriptive tables and multiple logistic regression models were used to examine the data on 1,295 total participants. Of the total, 875 participants (68%) were from the Methadone subsample and 420 participants (32%) from the Buprenorphine subsample; only about 15% stayed in treatment. ^ This study showed that with either Methadone or Buprenorphine maintenance therapy, only about 15% participants stay active over 3.5 years. Methadone treated patients that stayed active in treatment were associated with Caucasian ethnicity and were more likely to be employed. With Buprenorphine maintenance treatment only age over 40 years was associated with continuing activity in the program. Further studies that examine the reasons for the high dropout status and the implication of the socioeconomic and ethnic associations found in this data may help to improve treatment outcomes.^

Air Force web-based preventive health assessement alcohol screening effectiveness using the Alcohol Use Disorders Identification Tool (AUDIT)

Alcohol consumption has a long-standing tradition in the United States Air Force (USAF). From squadron bars to officers and enlisted clubs, alcohol has been used in social settings to increase morale and also as a way to help decrease the stress of military operations. Surveys have demonstrated that the USAF has more than double the percentage of heavy drinkers than the US population. More than one-third of the Air Force reports binge drinking in the last month while only six percent of the nation reports the same consumption pattern.^ However, alcohol has a significant harmful health effect if consumed in excess. As part of an overall prevention and treatment program aimed at curbing the harmful effects of alcohol consumption, the USAF uses the Alcohol Use Disorder Identification Test (AUDIT) to screen for high-risk alcohol consumption patterns before alcohol disorder and disability occur. All Air Force active-duty members are required to complete a yearly Preventive Health Assessment questionnaire. Various health topics are included in this questionnaire including nutrition, exercise, tobacco use, family history, mental health and alcohol use. While this questionnaire has been available in a web-based format for several years, mandatory use was not implemented until 2009.^ Although the AUDIT was selected due to its effectiveness in assessing high-risk alcohol consumption in other populations, its effectiveness in the Air Force population had not been studied previously. In order to assess the sensitivity, specificity, and positive predictive value of this screening tool, the Air Force Web-based Preventive Health Assessment alcohol screening results were compared to whether any alcohol-related diagnosis was made from January 1, 2009 to March 31, 2010.^ While the AUDIT has previously been shown to have a high sensitivity and specificity, the Air Force screening values were 27.9% and 93.0% respectively. Positive predictive value was only 4.9%. With the screening statistics found, less than one-third of those having an alcohol disorder will be found with this screening tool and only 1 out of 20 Airmen who require further evaluation actually have an alcohol-related diagnosis.^

Stable isotope record of Cibicidoides spp. from early and middle Miocene sediments

The middle Miocene delta18O increase represents a fundamental change in the ocean-atmosphere system which, like late Pleistocene climates, may be related to deepwater circulation patterns. There has been some debate concerning the early to early middle Miocene deepwater circulation patterns. Specifically, recent discussions have focused on the relative roles of Northern Component Water (NCW) production and warm, saline deep water originating in the eastern Tethys. Our time series and time slice reconstructions indicate that NCW and Tethyan outflow water, two relatively warm deepwater masses, were produced from ~20 to 16 Ma. NCW was produced again from 12.5 to 10.5 Ma. Another feature of the early and middle Miocene oceans was the presence of a high delta13C intermediate water mass in the southern hemisphere, which apparently originated in the Southern Ocean. Miocene climates appear to be related directly to deepwater circulation changes. Deep-waters warmed in the early Miocene by ~3°C (?20 to 16 Ma) and cooled by a similar amount during the middle Miocene delta18O increase (14.8 to 12.6 Ma), corresponding to the increase (?20 Ma) and subsequent decrease (~16 Ma) in the production of NCW and Tethyan outflow water. Large (>0.6 per mil), relatively rapid (~0.5 m.y.) delta18O increases in both benthic and planktonic foraminifera (i.e., the Mi zones of Miller et al. (1991a) and Wright and Miller (1992a)) were superimposed in the long-term deepwater temperature changes; they are interpreted as reflecting continental ice growth events. Seven of these m.y. glacial/interglacial cycles have been recognized in the early to middle Miocene. Two of these glacial/interglacial cycles (Mi3 and Mi4) combined with a 2° to 3°C decrease in deepwater temperatures to produce the middle Miocene delta18O shift.

Evolution and treatment of vitamin B12 deficiency as a risk factor for (cognitive and functional) neurodegenerative diseases in institutionalized elderly = Evolución y tratamiento de la deficiencia de vitamina B12 como factor de riesgo de enfermedades neurodegenerativas (cognitivas y funcionales) en las personas mayores institucionalizadas.

Prevalence of vitamin B12 deficiency is very common in elderly people and can reach values as high as 40.5% of the population. It can be the result of the interaction among several factors. Vitamin B12 deficiencies have been associated with neurological, cognitive deterioration, haematological abnormalities and cardiovascular diseases that have an important influence on the health of the elderly and their quality of life. It is necessary to approach the problems arisen from the lack of data relative to them. The main objective of this thesis was to analyse the evolution of vitamin B12 status and related parameters, lipid and haematological profiles and their relationship to health risk factors, and to functional and cognitive status over one year and to determine the effect of an oral supplementation of 500 μg of cyanocobalamin for a short period of 28 days. An additional objective was to analyze the possible effects of medicine intakes on vitamin B status. Three studies were performed: a) a one year longitudinal follow-up with four measure points; b) an intervention study providing an oral liquid supplement of 500 μg of cyanocobalamin for a 28 days period; and c) analysis of the possible effect of medication intake on vitamin B status using the ATC classification of medicines. The participants for these studies were recruited from nursing homes for the elderly in the Region of Madrid. Sixty elders (mean age 84 _ 7y, 19 men and 41 women) were recruited for Study I and 64 elders (mean age 82 _ 7y, 24 men and 40 women) for Study II. For Study III, baseline data from the initially recruited participants of the first two studies were used. An informed consent was obtained from all participants or their mentors. The studies were approved by the Ethical Committee of the University of Granada. Blood samples were obtained at each examination date and were analyzed for serum cobalamin, holoTC, serum and RBC folate and total homocysteine according to laboratory standard procedures. The haematological parameters analyzed were haematocrit, haemoglobin and MCV. For the lipid profile TG, total cholesterol, LDL- and HDLcholesterol were analyzed. Anthropometric measures (BMI, skinfolds [triceps and subscapular], waist girth and waist to hip ratio), functional tests (hand grip, arm and leg strength tests, static balance) and MMSE were obtained or administered by trained personal. The vitamin B12 supplement of Study II was administered with breakfast and the medication intake was taken from the residents’ anamnesis. Data were analyzed by parametric and non-parametric statistics depending on the obtained data. Comparisons were done using the appropriate ANOVAs or non-parametric tests. Pearsons’ partial correlations with the variable “time” as control were used to define the association of the analyzed parameters. XIII The results showed that: A) Over one year, in relationship to vitamin B status, serum cobalamin decreased, serum folate and mean corpuscular volumen increased significantly and total homocysteine concentrations were stable. Regarding blood lipid profile, triglycerides increased and HDL-cholesterol decreased significantly. Regarding selected anthropometric measurements, waist circumference increased significantly. No significant changes were observed for the rest of parameters. B) Prevalence of hyperhomocysteinemia was high in the elderly studied, ranging from 60% to 90 % over the year depending on the cut-off used for the classification. LDL-cholesterol values were high, especially among women, and showed a tendency to increase over the year. Results of the balance test showed a deficiency and a tendency to decrease; this indicates that the population studied is at high risk for falls. Lower extremity muscular function was deficient and showed a tendency to decrease. A highly significant relationship was observed between the skinfold of the triceps and blood lipid profile. C) Low cobalamin concentrations correlated significantly with low MMSE scores in the elderly studied. No correlations were observed between vitamin B12 status and functional parameters. D) Regarding vitamin B12 status, holo-transcobalamin seems to be more sensitive for diagnosis; 5-10% of the elderly had a deficiency using serum cobalamin as a criterion, and 45-52% had a deficiency when using serum holotranscobalamin as a criterion. E) 500 μg of cyanocobalamin administered orally during 28 days significantly improved vitamin B12 status and significantly decreased total homocysteine concentrations in institutionalized elderly. No effect of the intervention was observed on functional and cognitive parameters. F) The relative change (%) of improvement of vitamin B12 status was higher when using serum holo-transcobalamin as a criterion than serum cobalamin. G) Antiaenemic drug intake normalized cobalamin, urologic drugs and corticosteroids serum folate, and psychoanaleptics holo-transcobalamin levels. Drugs treating pulmonary obstruction increased total homocysteine concentration significantly. H) The daily mean drug intake was 5.1. Fiftynine percent of the elderly took medication belonging to 5 or more different ATC groups. The most prevalent were psycholeptic (53%), antiacid (53%) and antithrombotic (47%) drugs.

Malignant spinal cord compression: prospective study of delays in referral and treatment

Objectives: To examine the delay in presentation, diagnosis, and treatment of malignant spinal cord compression and to define the effect of this delay on motor and bladder function at the time of treatment.

Opposing early and late effects of insulin-like growth factor I on differentiation and the cell cycle regulatory retinoblastoma protein in skeletal myoblasts.

The mechanisms by which insulin-like growth factors (IGFs) can be both mitogenic and differentiation-promoting in skeletal myoblasts are unclear because these two processes are believed to be mutually exclusive in this tissue. The phosphorylation state of the ubiquitous nuclear retinoblastoma protein (Rb) plays an important role in determining whether myoblasts proliferate or differentiate: Phosphorylated Rb promotes mitogenesis, whereas un- (or hypo-) phosphorylated Rb promotes cell cycle exit and differentiation. We hypothesized that IGFs might affect the fate of myoblasts by regulating the phosphorylation of Rb. Although long-term IGF treatment is known to stimulate differentiation, we find that IGFs act initially to inhibit differentiation and are exclusively mitogenic. These early effects of IGFs are associated with maintenance of Rb phosphorylation typical of proliferating cells; upregulation of the gene expression of cyclin-dependent kinase 4 and cyclin D1, components of a holoenzyme that plays a principal role in mediating Rb phosphorylation; and marked inhibition of the gene expression of myogenin, a member of the MyoD family of skeletal muscle-specific transcription factors that is essential in muscle differentiation. We also find that IGF-induced inhibition of differentiation occurs through a process that is independent of its mitogenic effects. We demonstrate, thus, that IGFs regulate Rb phosphorylation and cyclin D1 and cyclin-dependent kinase 4 gene expression; together with their biphasic effects on myogenin expression, these results suggest a mechanism by which IGFs are initially mitogenic and subsequently differentiation-promoting in skeletal muscle.

Examining the Alliance-Outcome Relationship: Reverse Causation, Third Variables, and Treatment Phase Artifacts

Psychotherapy research reveals consistent associations between therapeutic alliance and treatment outcomes in the youth and adult literatures. Despite these consistent findings, prospective associations are not sufficient to support the claim that the alliance is a change mechanism in psychotherapy. The current study examined the direction of effect of the alliance- outcome relationship, the contribution of early symptom change in treatment to the development of therapeutic alliance, and the potential for pretreatment interpersonal functioning characteristics to be third variables that account for the association between alliance and outcome. Participants were adolescents with depression and a history of interpersonal trauma that presented to a community mental health center for treatment. Findings demonstrated that a more positive therapeutic alliance predicted greater subsequent symptom improvement, even after removing symptom change occurring before the measurement of alliance. Results also suggested that early change only slightly contributed to alliance development. Finally, though pretreatment interpersonal functioning was related to the first session alliance, these pretreatment client characteristics were not related to later alliance or symptom change. Overall, results provided some support for therapeutic alliance as a mechanism of change in psychotherapy. Methodological and clinical issues are discussed.