Miracle-dz/UniFAR-FTUs huggingface dataset:
Evolution of resistance to drugs in HIV-1-infected patients failing antiretroviral therapy

Background and objective: The optimal time for changing failing antiretroviral therapy (ART) is not known. It involves balancing the risk of exhausting future treatment options against the risk of developing increased drug resistance. The frequency with which new drug-resistance mutations (DRM) developed and their potential consequences in patients continuing unchanged treatment despite persistent viremia were assessed. Design: A retrospective study of consecutive sequence samples from 106 patients at one institution with viral load (VL) of more than 400 copies/ml, with no change in ART for more than 2 months despite virologic failure. Methods: Two consecutive pol sequences, CD4 cell counts and VL were analyzed to quantify the development of new DRM and to identify changes in immunologic and virologic parameters. Genotypic susceptibility scores (GSS) and viral drug susceptibilities were calculated by a computer program (HIVDB). Poisson log-linear regression models were used to predict the expected number of mutations at the second time point. Results: After a median of 14 months of continued ART, 75% (80 of 106) of patients acquired new DRM and were assigned a significantly lower GSS, potentially limiting the success of future ART. The development of new DRM was proportional to the time between the two sequences and inversely proportional to the number of DRM in the first sequence. However, the development of DRM was not associated with significant changes in CD4 or VL counts. Conclusions: Despite stable levels of CD4 and VL over time, maintaining a failing therapeutic regimen increases drug resistance and may limit future treatment options.
Intrarenal Detection of Nitric Oxide Using Electron Spin Resonance Spectroscopy in Hypertensive Lipopolysaccharide-Treated Rats

The inhibition of nitric oxide (NO) synthesis by chronic administration of NG-nitro-l-arginine methyl ester (l-NAME) in rats is responsible for systemic hypertension. However, the mechanisms involved in this hypertension remain unclear. The effects of chronic l-NAME on kidney and blood NO production were studied in rats in a state of endotoxic shock due to lipopolysaccharide (LPS). A nitric oxide spin trapping technique using electron spin resonance (ESR) spectroscopy has been used to identify and measure the production of NO in the kidney. This method is based on the trapping of nitric oxide by a metal-chelator complex consisting of N-methyl-d-glucamine dithiocarbamate (MGD) and reduced iron (Fe2+) forming a water-soluble NO-FeMGD complex detected by ESR. After LPS injection (14 mg/kg, IV, 6 h before the sacrifice) to rats pretreated with l-NAME (10 mg/kg/d over 14 days), the NO-FeMGD complex was evaluated in the kidney (arbitrary units [AU]/g of kidney) and the density of polynuclear neutrophils was counted by light microscopy. Chronic inhibition of NO synthase by l-NAME, a nonspecific inhibitor, was responsible for a decrease of the NO-FeMGD complex levels in the kidney (24.9 ± 1.6 AU versus 13.8 ± 1.3 AU). LPS administration was responsible for a large increase in both NO-FeMGD complex and neutrophil levels in the kidney of normotensive rats (332.6 ± 12.8 AU versus 24.9 ± 1.6 AU for NO-FeMGD complex and 1.36 ± 0.41 versus 0.11 ± 0.03 for neutrophils). Conversely, LPS administration in hypertensive, l-NAME-pretreated rats was linked to a smaller increase in the NO-FeMGD complex (85.1 ± 7.9 AU versus 332.6 ± 12.8 AU) and a larger increase in glomerular neutrophils (2.48 ± 0.36 versus 1.36 ± 0.41) compared with normotensive rats. These results are in agreement with a direct implication of NO during LPS-and l-NAME-induced kidney injuries.
Competition Between Streptococcus Pneumoniae Strains: Implications for Vaccine-Induced Replacement in Colonization and Disease

Background: Vaccine-induced replacement by nonvaccine serotypes in pneumococcal colonization and disease poses a threat to the long-term effectiveness of pneumococcal vaccination. One of the main drivers for serotype replacement is likely to be the competitive interactions between pneumococcal serotypes. Methods: We used longitudinal datasets of pneumococcal colonization among infants (American Indian and The Gambia) and toddlers (Denmark) to study the strength and mechanism of competition between pneumococcal serotypes. We characterized the strength of competition as the relative reduction in the expected time spent colonized with two serotypes (double colonization) as compared with colonization with no competition. We also assessed the mechanism of competition, that is, whether reduction in double colonization is due to reduced rate of acquisition or enhanced clearance of colonization. The three datasets were analyzed assuming both perfect (100%) and imperfect (50%) sensitivity in detection of double colonization. Results: Each dataset showed strong between-serotype competition, and competition in acquisition was clearly identified. These findings remained in the secondary analysis assuming only 50% sensitivity to detect double colonization. Inferences about enhanced clearance due to competition were susceptible to the assumed sensitivity of detection. Conclusions: Strong competition between pneumococcal serotypes can explain the prompt replacement by the nonvaccine serotypes in vaccinated persons and populations. The main mechanism of between-serotype interaction was identified as competition in acquisition, which suggests that replacement in pneumococcal disease depends largely on propensities of the replacing serotypes to cause disease through acquisition of colonization.
Moderating role of innovation culture in the relationship between organizational learning and innovation performance

Purpose Different studies have analyzed the relationship between organizational learning (OL) and innovation performance (IP). However, the question of how innovation culture (IC) affects the relationship between OL and IP remains unexplored. This study aims to examine the impact of IC on the relationship between OL and various dimensions of IP, including product, process and objective innovation. Design/methodology/approach A research model was developed and performed based on the relevant literature in the field of OL, IC and IP. The hypotheses are tested with the data collected from companies operating in an intensive knowledge-based industry. Findings Based on the results of 625 questionnaires completed by pharmaceutical companies, OL activities and IC can result in product and process innovation. However, this relationship was not supported for the objective innovation. Furthermore, in terms of the moderating role of IC in the relationship between OL and IP dimensions, the results were significant. Practical implications The findings help to gain a better understanding of how organizational commitment by creating a culture for innovation can help to maximize the benefits of continuous OL in product and process innovation. Originality/value Considering the three aspects of IP, it is the first survey of the contribution of OL in firms’ IP with considering the moderating role of IC. The proposed model would enrich the relevant literature and provide us with better understanding how OL contributes to the IP.
Effects of Virtual Reality training on medical students’ learning motivation and competency

Objectives: To determine the need of contemporary immersive approaches (Virtual Reality) in teaching and training at medical sector. The main objective of this study was to explore the effects of text, video and immersive technologies learning methodologies for participants’ learning in public and private medical colleges and universities of Pakistan. Methods: In this quantitative research 87 medical students of 4th year from three public and five private medical colleges and universities participated. A laparoscopy operation was selected in consultation with senior medical consultants for this experiment. The experimental material was arranged in virtual reality, video and text based learning. At completion of each of which, participants completed a questionnaire about learning motivation and learning competency through the different mediums. Results: Statistical t-test was selected for the analysis of this study. By comparing the mean values of virtual reality, video, and text based learning methodologies in medical academics; result of virtual reality is at top of others. All performed model are statistically significant (P=0.000) and results can be applied at all population. Conclusion: Through this research, we contribute to medical students learning methodologies. In medical studies, both theoretical and practical expertise has a vital role, while repetition of hands-on practice can improve young doctors’ professional competency. Virtual reality was found best for medical students in both learning motivation and learning competency. Medical students and educationist may select virtual reality as new learning methodology for curriculum learning.
Predictors of mortality in patients with flail chest: a systematic review

Objective To summarise the risk factors for mortality in patients with flail chest based on available evidence in the literature. Methods A systematic review was completed using articles from PubMed, EMBASE, the Centre for Review and Dissemination database and the Cochrane Library. Additional studies were identified by hand-searching bibliographies, and grey literature was sought by searching abstracts from all relevant Emergency Medicine Conferences. All published and unpublished observational studies were included if they investigated estimates of association between a risk factor and mortality for patients with flail chest. Results This review found seven studies that matched the inclusion criteria, with a total of 944 patients. Patient age of ≥65 years was reported as a predictor of mortality when controlling for injury severity score (ISS) (p<0.02, OR 2.1, 95% CI 1.0 to 4.6). An ISS of ≥31 was reported to be a predictor of mortality in two studies; however, neither controlled for patient age. Pulmonary contusion, bilateral flail chest and hospital length of stay were not consistently found to be associated with mortality. Conclusions The main independent predictors of mortality in patients with flail chest were reported to be increased age and ISS. More data are needed regarding the association of hospital length of stay, presence of pulmonary contusion and bilateral flail chest.
End-of-life decision making for nursing home residents with dementia.

PURPOSE To describe families' decision-making processes, both cognitive and affective, regarding end-of-life treatments for nursing home residents with moderately severe to very severe dementia. DESIGN Naturalistic inquiry provided the framework for this descriptive, qualitative study. METHODS Four focus groups were conducted in selected nursing homes, in the central part of the United States for a qualitative study. Twenty-eight family members of residents with moderately severe to severe dementia shared their decision-making experiences. Open-ended questions were asked in each focus group. Data were analyzed using content analysis. FINDINGS Five themes were identified that describe the context of decision making: emotional effect, insult-to-life story, two faces of death, values and goals regarding end-of-life treatments, and the unrecognized trajectory of dying. Family members made decisions in an emotional climate of overwhelming burden and guilt, because their loved one's life had been robbed of personhood, the changes associated with decline from a dementia-related illness were unrecognized as part of a trajectory of dying, death was both a tragedy and a blessing. CONCLUSIONS Family members had poignant, unresolved emotional needs stemming from their loved one's illness and nursing home placement. Participants were unprepared to make end-of-life treatment decisions and lacked the informational and emotional support of a consistent provider to help with decisions. Family members need assistance in processing difficult and painful emotions, understanding the trajectory of disease, what decisions might impede a natural death, and comfort or palliative care options.
Human hair follicle: reservoir function and selective targeting

Penetration of topically applied compounds may occur via the stratum corneum, skin appendages and hair follicles. The follicular infundibulum increases the surface area, disrupts the epidermal barrier towards the lower parts of the follicle, and serves as a reservoir. Topical delivery of active compounds to specific targets within the skin, especially to distinct hair follicle compartments or cell populations, may help to treat local inflammatory reactions selectively, with reduced systemic side‐effects. Various in vitro and in vivo methods exist for studying the hair follicle structure and follicular penetration pathways. These include cyanoacrylate skin surface stripping, confocal microscopy and cyanoacrylate scalp follicle biopsy. The complex anatomical structure as well as the cyclical activity of the hair follicle must be taken into consideration when designing delivery systems. In addition, delivery into and retention inside the infundibular reservoir are controlled by, for example, molecule or particle size, their polarity and the type of preparation. Preferred penetration depth and storage time must also be considered. Particles with release mechanisms should be preferred; however, the release of drugs from nanoparticles still requires further investigations.
Retinoic Acid Increases Foxp3+ Regulatory T Cells and Inhibits Development of Th17 Cells by Enhancing TGF-β-Driven Smad3 Signaling and Inhibiting IL-6 and IL-23 Receptor Expression1

The de novo generation of Foxp3+ regulatory T (Treg) cells in the peripheral immune compartment and the differentiation of Th17 cells both require TGF-β, and IL-6 and IL-21 are switch factors that drive the development of Th17 cells at the expense of Treg cell generation. The major vitamin A metabolite all-trans retinoic acid (RA) not only enforces the generation of Treg cells but also inhibits the differentiation of Th17 cells. Herein we show that RA enhances TGF-β signaling by increasing the expression and phosphorylation of Smad3, and this results in increased Foxp3 expression even in the presence of IL-6 or IL-21. RA also inhibits the expression of IL-6Rα, IRF-4, and IL-23R and thus inhibits Th17 development. In vitro, RA significantly promotes Treg cell conversion, but in vivo during the development of experimental autoimmune encephalomyelitis it does not increase the frequency of Treg cells in the face of an ongoing inflammation. However, RA suppresses the disease very efficiently by inhibiting proinflammatory T cell responses, especially pathogenic Th17 responses. These data not only identify the signaling mechanisms by which RA can affect both Treg cell and Th17 differentiation, but they also highlight that in vivo during an autoimmune reaction, RA suppresses autoimmunity mainly by inhibiting the generation of effector Th17 cells.
Endothelial Nitric Oxide Synthase in Dorsal Root Ganglia during Chronic Inflammatory Nociception

Nitric oxide (NO) is a gaseous molecule implicated both in vascular tone and nociceptive transmission. The capillary blood supply to the dorsal root ganglia (DRG) is unique because it is highly permeable to several low and high molecular-weight compounds. This anatomical situation leads to a potential role of endothelial nitric oxide synthase (eNOS) in inflammatory nociception, which is not well established. Therefore, we examined the role of eNOS in DRG in a murine chronic inflammatory pain model induced by complete Freund’s adjuvant using L-N5-(1-iminoethyl)ornithine (L-NIO), a potent inhibitor of eNOS activity. Pain state was examined using a behavioral test. The expression of eNOS, platelet endothelial cell adhesion molecule-1 (CD31) and vascular endothelial growth factor (VEGF) was examined by immunofluorescence. In control animals, CD31 was detected in vessels; VEGF was localized both in vessels and neurons while a weak eNOS immunopositivity was detected in both vessels and in neurons. Under inflammatory pain conditions, eNOS, CD31 and VEGF immunopositivity increased. Administration of L-NIO significantly attenuated thermal hyperalgesia by 24 h and decreased eNOS activity and CD31 immunopositivity by 7 days. VEGF was unaffected. Our results show that eNOS plays a nociceptive role in the early phases of inflammation while in the later phases it may be involved in neurotrophic support.
Corrective Exercises Improve Movement Efficiency and Sensorimotor Function but Not Fatigue Sensitivity in Chronic Ankle Instability Patients: A Randomized Controlled Trial.

OBJECTIVE To investigate the effect of corrective exercises on functional movement patterns, sensorimotor function, self-reported function, and fatigue sensitivity in collegiate athletes with chronic ankle instability (CAI). DESIGN A randomized controlled trial. SETTING Laboratory of sports sciences. PARTICIPANTS Forty male volunteers were randomly assigned to the experimental group (age 21.2 ± 1.7 years, height 174.5 ± 6.1 cm, and weight 69.6 ± 6.9 kg) or the control group (age 20.9 ± 1.8 years, height 178.2 ± 6.6 cm, and weight 68.8 ± 8.1 kg). INTERVENTION Participants in the experimental group performed supervised corrective exercises 3 times per week for 8 weeks. Fatigue was induced with a progressive treadmill protocol before and after the 8-week intervention. MAIN OUTCOME MEASURES Outcomes included movement efficiency during 3 squat tasks, static and dynamic postural control, strength of the ankle musculature, joint position sense, and self-reported function with the Foot and Ankle Ability Measure subscales. These outcomes were assessed before and immediately after fatiguing treadmill running both before and after 8-weeks of corrective exercises. RESULTS Significant improvements in movement efficiency, sensorimotor function, and self-reported function were noted in the experimental group relative to the control group (P < 0.001), in a nonfatigued state. However, in a fatigued stated, the experimental intervention only improved static postural control (P = 0.016) relative to the control group. CONCLUSIONS These findings demonstrate that 8-weeks of corrective exercises were effective at enhancing movement efficiency, sensorimotor function, and self-reported function in collegiate athletes with CAI. However, this intervention program has limited abilities at reducing the effects of fatigue.
Client labor: adults with hearing impairment describing their participation in their hearing help-seeking and rehabilitation.

BACKGROUND The uptake and use of hearing aids is low compared to the prevalence of hearing impairment. People who seek help and take part in a hearing aid rehabilitation process participate actively in this process in several ways. PURPOSE In order to gain more knowledge on the challenges of hearing help-seeking and hearing aid use, this qualitative study sought to understand the ways that people with hearing impairment describe themselves as active participants throughout the hearing aid rehabilitation process. RESEARCH DESIGN In this qualitative interview study we examined the hearing rehabilitation process from the perspective of the hearing impaired. In this article we describe how the qualitative interview material was interpreted by a pragmatic qualitative thematic analysis. The analysis described in this article focused on the efforts, initiatives, actions, and participation the study participants described that they had engaged in during their rehabilitation. STUDY SAMPLE Interviews were conducted with people with hearing impairment in Australia, Denmark, the United Kingdom, and the United States. The 34 interview participants were distributed equally between the sites, just as men and women were almost equally represented (56% women). The average age of the participants was 64. All participants had a hearing impairment in at least one ear. The participants were recruited to represent a range of experiences with hearing help-seeking and rehabilitation. DATA COLLECTION AND ANALYSIS With each participant one qualitative semistructured interview ranging between 1 and 2 hr was carried out. The interviews were transcribed verbatim, read through several times, and themes were identified, defined, and reviewed by an iterative process. RESULTS From this thematic focus a concept called "client labor" has emerged. Client labor contains nine subthemes divided into three overarching groups: cognitive labor, emotional labor, and physical labor. The participants' experiences and meaning-making related to these conceptual types of efforts is described. CONCLUSIONS The study findings have implications for the clinical encounter between people with hearing impairment and hearing health-care professionals. We suggest that a patient-centered approach that bears in mind the client's active participation could help toward improving clinical dispensing, fitting, and counseling practices with the end goal to increase hearing aid benefit and satisfaction.
CTL hyporesponsiveness induced by 2,3,7, 8-tetrachlorodibenzo-p-dioxin: role of cytokines and apoptosis.

Studies have shown that blocking B7-mediated costimulation induces T cell tolerance via anergy or apoptosis. Provision of exogenous IL-2 can reverse or prevent the induction of tolerance. We have previously shown that TCDD-induced suppression of the CTL response to allogeneic P815 tumor cells is accompanied by decreased expression of CD86 (B7-2) as well as suppressed IL-2 and IFNgamma production. In the present studies, the role of IL-2 and IFNgamma and the analysis of inappropriate deletion of CD8(+) cells was examined. Administration of IL-2 on days 7-9 relative to the injection of P815 tumor cells dose-dependently increased the CTL activity and the generation of CD8(+) CTL effector cells in TCDD-treated mice. This increased CTL response was not due to recruitment of naive CTL precursors (CTLp), suggesting that a small pool of activated CTLp in TCDD-treated mice could respond to the IL-2. A much larger pool of activated CTLp in control mice was also expanded by IL-2 treatment. In contrast, treatment with IFNgamma during the same time period did not alter CTL activity in control or TCDD-treated mice. To address the possibility that insufficient IL-2 early in the response was responsible for the reduced pool of activated CTLp in TCDD-treated mice, IL-2 was administered on days 1-3 after P815 injection. However, not only did early treatment with IL-2 fail to restore the response in TCDD-treated mice, it suppressed the CTL response of non-TCDD-treated mice. To test whether exposure to TCDD induced apoptosis of activated CD8(+) T cells, phosphatidylserine (PS) expression was measured on various days after P815 tumor challenge. Surprisingly, the percentage of apoptotic CD8(+) T cells was significantly lower in TCDD-treated mice compared to controls throughout the allograft response. Similarly, exposure to TCDD failed to enhance peripheral deletion of Vbeta3(+)CD8(+) T cells after injection of the superantigen Staphylococcal enterotoxin A (SEA). Taken together, the data indicate that TCDD induces an early defect in CTLp activation that is not due to insufficient IL-2 or deletion of CD8(+) cells and may implicate a novel mechanism by which ligands of the Ah receptor disrupt CTL precursor activation.