Effect of training-sample size and classification difficulty on the accuracy of genomic predictors.

Introduction: As part of the MicroArray Quality Control (MAQC)-II project, this analysis examines how the choice of univariate feature-selection methods and classification algorithms may influence the performance of genomic predictors under varying degrees of prediction difficulty represented by three clinically relevant endpoints. Methods: We used gene-expression data from 230 breast cancers (grouped into training and independent validation sets), and we examined 40 predictors (five univariate feature-selection methods combined with eight different classifiers) for each of the three endpoints. Their classification performance was estimated on the training set by using two different resampling methods and compared with the accuracy observed in the independent validation set. Results: A ranking of the three classification problems was obtained, and the performance of 120 models was estimated and assessed on an independent validation set. The bootstrapping estimates were closer to the validation performance than were the cross-validation estimates. The required sample size for each endpoint was estimated, and both gene-level and pathway-level analyses were performed on the obtained models. Conclusions: We showed that genomic predictor accuracy is determined largely by an interplay between sample size and classification difficulty. Variations on univariate feature-selection methods and choice of classification algorithm have only a modest impact on predictor performance, and several statistically equally good predictors can be developed for any given classification problem.

Effect of intermittent hypoxic training on HIF gene expression in human skeletal muscle and leukocytes

Intermittent hypoxic exposure with exercise training is based on the assumption that brief exposure to hypoxia is sufficient to induce beneficial muscular adaptations mediated via hypoxia-inducible transcription factors (HIF). We previously demonstrated (Mounier et al. Med Sci Sports Exerc 38:1410-1417, 2006) that leukocytes respond to hypoxia with a marked inter-individual variability in HIF-1alpha mRNA. This study compared the effects of 3 weeks of intermittent hypoxic training on hif gene expression in both skeletal muscle and leukocytes. Male endurance athletes (n = 19) were divided into an Intermittent Hypoxic Exposure group (IHE) and a Normoxic Training group (NT) with each group following a similar 3-week exercise training program. After training, the amount of HIF-1alpha mRNA in muscle decreased only in IHE group (-24.7%, P < 0.05) whereas it remained unchanged in leukocytes in both groups. The levels of vEGF(121) and vEGF(165) mRNA in skeletal muscle increased significantly after training only in the NT group (+82.5%, P < 0.05 for vEGF(121); +41.2%, P < 0.05 for vEGF(165)). In leukocytes, only the IHE group showed a significant change in vEGF(165) (-28.2%, P < 0.05). The significant decrease in HIF-1alpha mRNA in skeletal muscle after hypoxic training suggests that transcriptional and post-transcriptional regulations of the hif-1alpha gene are different in muscle and leukocytes.

Effects of Intermittent Training on Anaerobic Performance and MCT Transporters in Athletes.

This study examined the effects of intermittent hypoxic training (IHT) on skeletal muscle monocarboxylate lactate transporter (MCT) expression and anaerobic performance in trained athletes. Cyclists were assigned to two interventions, either normoxic (N; n = 8; 150 mmHg PIO2) or hypoxic (H; n = 10; ∼3000 m, 100 mmHg PIO2) over a three week training (5×1 h-1h30.week-1) period. Prior to and after training, an incremental exercise test to exhaustion (EXT) was performed in normoxia together with a 2 min time trial (TT). Biopsy samples from the vastus lateralis were analyzed for MCT1 and MCT4 using immuno-blotting techniques. The peak power output (PPO) increased (p<0.05) after training (7.2% and 6.6% for N and H, respectively), but VO2max showed no significant change. The average power output in the TT improved significantly (7.3% and 6.4% for N and H, respectively). No differences were found in MCT1 and MCT4 protein content, before and after the training in either the N or H group. These results indicate there are no additional benefits of IHT when compared to similar normoxic training. Hence, the addition of the hypoxic stimulus on anaerobic performance or MCT expression after a three-week training period is ineffective.

A comparison of initial antiretroviral therapy in the Swiss HIV Cohort Study and the recommendations of the International AIDS Society-USA.

BACKGROUND: In order to facilitate and improve the use of antiretroviral therapy (ART), international recommendations are released and updated regularly. We aimed to study if adherence to the recommendations is associated with better treatment outcomes in the Swiss HIV Cohort Study (SHCS). METHODS: Initial ART regimens prescribed to participants between 1998 and 2007 were classified according to IAS-USA recommendations. Baseline characteristics of patients who received regimens in violation with these recommendations (violation ART) were compared to other patients. Multivariable logistic and linear regression analyses were performed to identify associations between violation ART and (i) virological suppression and (ii) CD4 cell count increase, after one year. RESULTS: Between 1998 and 2007, 4189 SHCS participants started 241 different ART regimens. A violation ART was started in 5% of patients. Female patients (adjusted odds ratio aOR 1.83, 95%CI 1.28-2.62), those with a high education level (aOR 1.49, 95%CI 1.07-2.06) or a high CD4 count (aOR 1.53, 95%CI 1.02-2.30) were more likely to receive violation ART. The proportion of patients with an undetectable viral load (<400 copies/mL) after one year was significantly lower with violation ART than with recommended regimens (aOR 0.54, 95% CI 0.37-0.80) whereas CD4 count increase after one year of treatment was similar in both groups. CONCLUSIONS: Although more than 240 different initial regimens were prescribed, violations of the IAS-USA recommendations were uncommon. Patients receiving these regimens were less likely to have an undetectable viral load after one year, which strengthens the validity of these recommendations.

Oncology clinicians' defenses and adherence to communication skills training with simulated patients: an exploratory study.

The aim of this exploratory study was to assess the impact of clinicians' defense mechanisms-defined as self-protective psychological mechanisms triggered by the affective load of the encounter with the patient-on adherence to a communication skills training (CST). The population consisted of oncology clinicians (N = 31) who participated in a CST. An interview with simulated cancer patients was recorded prior and 6 months after CST. Defenses were measured before and after CST and correlated with a prototype of an ideally conducted interview based on the criteria of CST-teachers. Clinicians who used more adaptive defense mechanisms showed better adherence to communication skills after CST than clinicians with less adaptive defenses (F(1, 29) = 5.26, p = 0.03, d = 0.42). Improvement in communication skills after CST seems to depend on the initial levels of defenses of the clinician prior to CST. Implications for practice and training are discussed. Communication has been recognized as a central element of cancer care [1]. Ineffective communication may contribute to patients' confusion, uncertainty, and increased difficulty in asking questions, expressing feelings, and understanding information [2, 3], and may also contribute to clinicians' lack of job satisfaction and emotional burnout [4]. Therefore, communication skills trainings (CST) for oncology clinicians have been widely developed over the last decade. These trainings should increase the skills of clinicians to respond to the patient's needs, and enhance an adequate encounter with the patient with efficient exchange of information [5]. While CSTs show a great diversity with regard to their pedagogic approaches [6, 7], the main elements of CST consist of (1) role play between participants, (2) analysis of videotaped interviews with simulated patients, and (3) interactive case discussion provided by participants. As recently stated in a consensus paper [8], CSTs need to be taught in small groups (up to 10-12 participants) and have a minimal duration of at least 3 days in order to be effective. Several systematic reviews evaluated the impact of CST on clinicians' communication skills [9-11]. Effectiveness of CST can be assessed by two main approaches: participant-based and patient-based outcomes. Measures can be self-reported, but, according to Gysels et al. [10], behavioral assessment of patient-physician interviews [12] is the most objective and reliable method for measuring change after training. Based on 22 studies on participants' outcomes, Merckaert et al. [9] reported an increase of communication skills and participants' satisfaction with training and changes in attitudes and beliefs. The evaluation of CST remains a challenging task and variables mediating skills improvement remain unidentified. We recently thus conducted a study evaluating the impact of CST on clinicians' defenses by comparing the evolution of defenses of clinicians participating in CST with defenses of a control group without training [13]. Defenses are unconscious psychological processes which protect from anxiety or distress. Therefore, they contribute to the individual's adaptation to stress [14]. Perry refers to the term "defensive functioning" to indicate the degree of adaptation linked to the use of a range of specific defenses by an individual, ranging from low defensive functioning when he or she tends to use generally less adaptive defenses (such as projection, denial, or acting out) to high defensive functioning when he or she tends to use generally more adaptive defenses (such as altruism, intellectualization, or introspection) [15, 16]. Although several authors have addressed the emotional difficulties of oncology clinicians when facing patients and their need to preserve themselves [7, 17, 18], no research has yet been conducted on the defenses of clinicians. For example, repeated use of less adaptive defenses, such as denial, may allow the clinician to avoid or reduce distress, but it also diminishes his ability to respond to the patient's emotions, to identify and to respond adequately to his needs, and to foster the therapeutic alliance. Results of the above-mentioned study [13] showed two groups of clinicians: one with a higher defensive functioning and one with a lower defensive functioning prior to CST. After the training, a difference in defensive functioning between clinicians who participated in CST and clinicians of the control group was only showed for clinicians with a higher defensive functioning. Some clinicians may therefore be more responsive to CST than others. To further address this issue, the present study aimed to evaluate the relationship between the level of adherence to an "ideally conducted interview", as defined by the teachers of the CST, and the level of the clinician' defensive functioning. We hypothesized that, after CST, clinicians with a higher defensive functioning show a greater adherence to the "ideally conducted interview" than clinicians with a lower defensive functioning.

Gender differences in HIV progression to AIDS and death in industrialized countries: slower disease progression following HIV seroconversion in women.

To evaluate sex differences in human immunodeficiency virus (HIV) disease progression before (pre-1997) and after (1997-2006) introduction of highly active antiretroviral therapy, the authors used data from a collaboration of 23 HIV seroconverter cohort studies from Europe, Australia, and Canada restricted to the 6,923 seroconverters infected through injecting drug use and sex between men and women. Within a competing risk framework, they used Cox proportional hazards models allowing for late entry to evaluate sex differences in time from HIV seroconversion to death, to acquired immunodeficiency syndrome (AIDS), and to each first AIDS-defining disease and death without AIDS. While no significant sex differences were found before 1997, from 1997 onward, women had a lower risk of AIDS (adjusted cumulative relative risk (aCRR) = 0.76, 95% confidence interval (CI): 0.63, 0.90) and death (adjusted hazard ratio = 0.68, 95% CI: 0.56, 0.82) than men did. Compared with men, women also had lower risks of AIDS dementia complex (aCRR = 0.23, 95% CI: 0.07, 0.74), tuberculosis (aCRR = 0.60, 95% CI: 0.39, 0.92), Kaposi's sarcoma (aCRR = 0.27, 95% CI: 0.07, 0.99), lymphomas (aCRR = 0.47, 95% CI: 0.23, 0.96), and death without AIDS (aCRR = 0.74, 95% CI: 0.56, 0.98). Sex differences in HIV disease progression have become larger and statistically significant in the era of highly active antiretroviral therapy, supporting a stronger impact of health interventions among women.

Skeletal muscle mitochondria in the elderly: effects of physical fitness and exercise training.

CONTEXT: Sarcopenia is thought to be associated with mitochondrial (Mito) loss. It is unclear whether the decrease in Mito content is consequent to aging per se or to decreased physical activity. OBJECTIVES: The objective of the study was to examine the influence of fitness on Mito content and function and to assess whether exercise could improve Mito function in older adults. DESIGN AND SUBJECTS: Three distinct studies were conducted: 1) a cross-sectional observation comparing Mito content and fitness in a large heterogeneous cohort of older adults; 2) a case-control study comparing chronically endurance-trained older adults and sedentary (S) subjects matched for age and gender; and 3) a 4-month exercise intervention in S. SETTING: The study was conducted at a university-based clinical research center. OUTCOMES: Mito volume density (MitoVd) was assessed by electron microscopy from vastus lateralis biopsies, electron transport chain proteins by Western blotting, mRNAs for transcription factors involved in M biogenesis by quantitative RT-PCR, and in vivo oxidative capacity (ATPmax) by (31)P-magnetice resonance spectroscopy. Peak oxygen uptake was measured by graded exercise test. RESULTS: Peak oxygen uptake was strongly correlated with MitoVd in 80 60- to 80-year-old adults. Comparison of chronically endurance-trained older adults vs S revealed differences in MitoVd, ATPmax, and some electron transport chain protein complexes. Finally, exercise intervention confirmed that S subjects are able to recover MitoVd, ATPmax, and specific transcription factors. CONCLUSIONS: These data suggest the following: 1) aging per se is not the primary culprit leading to Mito dysfunction; 2) an aerobic exercise program, even at an older age, can ameliorate the loss in skeletal muscle Mito content and may prevent aging muscle comorbidities; and 3) the improvement of Mito function is all about content.

Cellular immune responses and disease control in acute AIDS-associated Kaposi's sarcoma.

Kaposi's sarcoma-associated herpesvirus (KSHV) specific T cell responses and KSHV viremia were analyzed in seven HIV-infected patients with active Kaposi's sarcoma lesions who initiated highly active antiretroviral therapy, and were compared between patients with improved Kaposi's sarcoma and those with progressive Kaposi's sarcoma requiring further systemic chemotherapy. Patients with controlled Kaposi's sarcoma disease demonstrated undetectable Kaposi's sarcoma viremia together with KSHV-specific CD8 T cells secreting interferon-gamma and tumor necrosis factor-alpha, whereas progressors showed increasing viremia with weak or no T-cell responses. These data point toward a potential role of KSHV-specific immunity in the control of AIDS-associated Kaposi's sarcoma.

Not in Education, Employment, or Training status among young Swiss men. Longitudinal associations with mental health and substance use.

PURPOSE: Not in Education, Employment, or Training (NEET) youth are youth disengaged from major social institutions and constitute a worrying concern. However, little is known about this subgroup of vulnerable youth. This study aimed to examine if NEET youth differ from other contemporaries in terms of personality, mental health, and substance use and to provide longitudinal examination of NEET status, testing its stability and prospective pathways with mental health and substance use. METHODS: As part of the Cohort Study on Substance Use Risk Factors, 4,758 young Swiss men in their early 20s answered questions concerning their current professional and educational status, personality, substance use, and symptomatology related to mental health. Descriptive statistics, generalized linear models for cross-sectional comparisons, and cross-lagged panel models for longitudinal associations were computed. RESULTS: NEET youth were 6.1% at baseline and 7.4% at follow-up with 1.4% being NEET at both time points. Comparisons between NEET and non-NEET youth showed significant differences in substance use and depressive symptoms only. Longitudinal associations showed that previous mental health, cannabis use, and daily smoking increased the likelihood of being NEET. Reverse causal paths were nonsignificant. CONCLUSIONS: NEET status seemed to be unlikely and transient among young Swiss men, associated with differences in mental health and substance use but not in personality. Causal paths presented NEET status as a consequence of mental health and substance use rather than a cause. Additionally, this study confirmed that cannabis use and daily smoking are public health problems. Prevention programs need to focus on these vulnerable youth to avoid them being disengaged.

The pattern and Loci of training-induced brain changes in healthy older adults are predicted by the nature of the intervention.

There is enormous interest in designing training methods for reducing cognitive decline in healthy older adults. Because it is impaired with aging, multitasking has often been targeted and has been shown to be malleable with appropriate training. Investigating the effects of cognitive training on functional brain activation might provide critical indication regarding the mechanisms that underlie those positive effects, as well as provide models for selecting appropriate training methods. The few studies that have looked at brain correlates of cognitive training indicate a variable pattern and location of brain changes - a result that might relate to differences in training formats. The goal of this study was to measure the neural substrates as a function of whether divided attentional training programs induced the use of alternative processes or whether it relied on repeated practice. Forty-eight older adults were randomly allocated to one of three training programs. In the SINGLE REPEATED training, participants practiced an alphanumeric equation and a visual detection task, each under focused attention. In the DIVIDED FIXED training, participants practiced combining verification and detection by divided attention, with equal attention allocated to both tasks. In the DIVIDED VARIABLE training, participants completed the task by divided attention, but were taught to vary the attentional priority allocated to each task. Brain activation was measured with fMRI pre- and post-training while completing each task individually and the two tasks combined. The three training programs resulted in markedly different brain changes. Practice on individual tasks in the SINGLE REPEATED training resulted in reduced brain activation whereas DIVIDED VARIABLE training resulted in a larger recruitment of the right superior and middle frontal gyrus, a region that has been involved in multitasking. The type of training is a critical factor in determining the pattern of brain activation.

Medical students' skills and needs for training in breaking bad news.

This study assessed medical students' perception of individual vs. group training in breaking bad news (BBN) and explored training needs in BBN. Master-level students (N = 124) were randomised to group training (GT)-where only one or two students per group conducted a simulated patient (SP) interview, which was discussed collectively with the faculty-or individual training (IT)-where each student conducted an SP interview, which was discussed during individual supervision. Training evaluation was based on questionnaires, and the videotaped interviews were rated using the Roter Interaction Analysis System. Students were globally satisfied with the training. Still, there were noticeable differences between students performing an interview (GT/IT) and students observing interviews (GT). The analysis of the interviews showed significant differences according to scenarios and to gender. Active involvement through SP interviews seems required for students to feel able to reach training objectives. The evaluation of communication skills, revealing a baseline heterogeneity, supports individualised training.

Postmortem circulation: a new model for testing endovascular devices and training clinicians in their use.

The development of new medical devices, such as aortic valves, requires numerous preliminary studies on animals and training of personnel on cadavers before the devices can be used in patients. Postmortem circulation, a technique used for postmortem angiography, allows the vascular system to be reperfused in a way similar to that in living persons. This technique is used for postmortem investigations to visualize the human vascular system and to make vascular diagnoses. Specific material for reperfusing a human body was developed recently. Our aim was to investigate whether postmortem circulation that imitates in vivo conditions allows for the testing of medical materials on cadavers. We did this by delivering an aortic valve using minimally invasive methods. Postmortem circulation was established in eight corpses to recreate an environment as close as possible to in vivo conditions. Mobile fluoroscopy and a percutaneous catheterization technique were used to deliver the material to the correct place. Once the valve was implanted, the heart and primary vessels were extracted to confirm its position. Postmortem circulation proved to be essential in several of the cadavers because it helped the clinicians to deliver the material and improve their implantation techniques. Due to the intravascular circulation, sites with substantial arteriosclerotic stenosis could be bypassed, which would have been impossible without perfusion. Although originally developed for postmortem investigations, this reperfusion technique could be useful for testing new medical devices intended for living patients.

Does 'altitude training' increase exercise performance in elite athletes?

The general practice of altitude training is widely accepted as a means to enhance sport performance despite a lack of rigorous scientific studies. For example, the scientific gold-standard design of a double-blind, placebo-controlled, cross-over trial has never been conducted on altitude training. Given that few studies have utilised appropriate controls, there should be more scepticism concerning the effects of altitude training methodologies. In this brief review we aim to point out weaknesses in theories and methodologies of the various altitude training paradigms and to highlight the few well-designed studies to give athletes, coaches and sports medicine professionals the current scientific state of knowledge on common forms of altitude training. Another aim is to encourage investigators to design well-controlled studies that will enhance our understanding of the mechanisms and potential benefits of altitude training.