Outcomes of ab interno trabeculectomy with the trabectome by degree of angle opening.

AimTo analyse ab interno trabeculectomy (AIT) with the trabectome and combined phacoemulsification with AIT (phaco-AIT) by Shaffer angle grade (SG).MethodsProspective study of AIT and phaco-AIT with narrow angles of SG≤2 versus open angles ≥3. Outcomes included intraocular pressure (IOP), medications, complications, secondary surgery and success (IOP <21 mm Hg and >20% reduction without further surgery). Exclusion criteria were missing preoperative data and <1 year follow-up.ResultsOf 671 included cases, at 1 year AIT SG≤2 (n=43) had an IOP reduction of 42% from 27.3±7.4 to 15.7±3.0 mm Hg (p<0.01) versus AIT SG≥3 (n=271) with an IOP reduction of 37% from 26.1±7.8 to 16.4±3.9 mm Hg (p<0.01). In phaco-AIT with SG≤2 (n=48), IOP was reduced 24% from 20.7±7.0 to 15.7±3.6 mm Hg (p<0.01) versus phaco-AIT with SG≥3 (n=309) with an IOP reduction of 25% from 22.6±6.4 to 17.0±3.4 mm Hg (p<0.01). There was no difference between SG≤2 and SG≥3 in reduction of IOP or medications, complications, secondary surgery and success rates (p>0.05).ConclusionsSG≤2 is not associated with worse outcomes in AIT or phaco-AIT

Human Immunodeficiency Virus Infection in Young Adults: Treatment of Substance Use Disorders as a Priority Component of HIV Prevention, Care and Treatment in Low and Middle Income Countries

Young adults comprise roughly one-quarter of the global population and are at the developmental stage where personal life goals are formulated and personal independence is obtained. It is also the time of sexual debut and exposure to illicit drug and alcohol use. Thus, young adulthood is a time of high-risk for HIV transmission due to drug and alcohol use in the context of sexual activity. Social-networking, gender norms, economic, educational, familial, personal identity and development factors, among others, play a role in illicit drug and alcohol use and HIV infection in young adults. It is estimated that young adults account for 42% of new HIV infections globally, and that 4 million young adults living with HIV reside in sub-Saharan Africa. In Central Asia, Eastern Europe and the United States key populations are important subpopulations of young adults at high-risk for living with HIV. Subpopulations of young adults, particularly key populations, consume illicit drugs and alcohol with high-risk sexual and injection activity, thereby establishing connections between substance use/injection drug use/substance use disorders and HIV infection. Globally, interventions that comprise evidence-based prevention, care and treatment of substance use disorders targeting young adults and prioritizing treatment of substance use disorders as part of HIV care and treatment are vital to reduce the transmission of HIV infection and promote good clinical outcomes for young adults at-risk for and living with HIV

Virtual embedded librarianship for information literacy teaching.

This paper, reports on the planning and preliminary results of an action research project undertaken for the redesign of an online distance learning information literacy (IL) module on the basis of virtual 'embedded librarianship'. The research project, which followed an action research design, brought together the IL module coordinator and an Academic Liaison Librarian, working at different institutions to collaboratively redesign the assessment and teaching of the module. Data were collected via a qualitative analysis of students' work and a series of open-ended questions addressed to students on the value of the approach followed. Students reacted positively to the embedded librarianship design and engaged constructively in situated learning. Challenges included time-zones differences, the contribution level of students and lack of confidence. The paper puts emphasis on educating future information professionals as embedded information literacy partners, promoting the development of transferable skills and a collaborative/sharing online working ethos

Clinical relevance of biomarkers of oxidative stress

SIGNIFICANCE Oxidative stress is considered to be an important component of various diseases. A vast number of methods have been developed and used in virtually all diseases to measure the extent and nature of oxidative stress, ranging from oxidation of DNA to proteins, lipids, and free amino acids. Recent Advances: An increased understanding of the biology behind diseases and redox biology has led to more specific and sensitive tools to measure oxidative stress markers, which are very diverse and sometimes very low in abundance. CRITICAL ISSUES The literature is very heterogeneous. It is often difficult to draw general conclusions on the significance of oxidative stress biomarkers, as only in a limited proportion of diseases have a range of different biomarkers been used, and different biomarkers have been used to study different diseases. In addition, biomarkers are often measured using nonspecific methods, while specific methodologies are often too sophisticated or laborious for routine clinical use. FUTURE DIRECTIONS Several markers of oxidative stress still represent a viable biomarker opportunity for clinical use. However, positive findings with currently used biomarkers still need to be validated in larger sample sizes and compared with current clinical standards to establish them as clinical diagnostics. It is important to realize that oxidative stress is a nuanced phenomenon that is difficult to characterize, and one biomarker is not necessarily better than others. The vast diversity in oxidative stress between diseases and conditions has to be taken into account when selecting the most appropriate biomarker. Antioxid. Redox Signal. 00, 000-000

Cytokine-associated drug toxicity in human hepatocytes is associated signaling network dysregulation

Refer to Web version on PubMed Central for supplementary material.Idiosyncratic drug hepatotoxicity is a major problem in pharmaceutical development due to poor prediction capability of standard preclinical toxicity assessments and limited knowledge of its underlying mechanisms. Findings in animal models have shown that adverse effects of numerous drugs with idiosyncratic hepatotoxicity in humans can be reproduced in the presence of coincident inflammatory cytokine signaling. Following these observations, we have recently developed an in vitro drug/inflammatory cytokine co-treatment approach that can reproduce clinical drug hepatotoxicity signatures—particularly for idiosyncratic drugs—in cultured primary human hepatocytes. These observations have suggested that drug-induced stresses may interact with cytokine signaling to induce hepatic cytotoxicity, but the hepatocyte signaling mechanisms governing these interactions are poorly understood. Here, we collect high-throughput phosphoprotein signaling and cytotoxicity measurements in cultured hepatocytes, from multiple human donors, treated with combinations of hepatotoxic drugs (e.g. trovafloxacin, clarithromycin) and cytokines (tumor necrosis factor-α, interferon-γ, interleukin-1α, and interleukin-6). We demonstrate, through orthogonal partial least-squares regression (OPLSR) modeling of these signal-response data, that drug/cytokine hepatic cytotoxicity is integratively controlled by four key signaling pathways: Akt, p70 S6 kinase, MEK–ERK, and p38–HSP27. This modeling predicted, and experimental studies confirmed, that the MEK–ERK and p38–HSP27 pathways contribute pro-death signaling influences in drug/cytokine hepatic cytotoxicity synergy. Further, our four-pathway OPLSR model produced successful prediction of drug/cytokine hepatic cytotoxicities across different human donors, even though signaling and cytotoxicity responses were both highly donor-specific. Our findings highlight the critical role of kinase signaling in drug/cytokine hepatic cytotoxicity synergies and reveal that hepatic cytotoxicity responses are governed by multi-pathway signaling network balance.Pfizer Inc.Institute for Collaborative BiotechnologiesMIT Center for Cell Decision ProcessesNational Institute of Mental Health (U.S.) (grant P50-GM68762)Massachusetts Institute of Technology. Biotechnology Process Engineering CenterMassachusetts Institute of Technology. Center for Environmental Health SciencesNational Institute of Mental Health (U.S.) (grant U19ES011399)Whitaker Foundatio

Modulation of Hepatic Amyloid Precursor Protein and Lipoprotein Receptor-Related Protein 1 by Chronic Alcohol Intake: Potential Link Between Liver Steatosis and Amyloid-β

Heavy alcohol consumption is a known risk factor for various forms of dementia and the development of Alzheimer’s disease (AD). In this work, we investigated how intragastric alcohol feeding may alter the liver-to-brain axis to induce and/or promote AD pathology. Four weeks of intragastric alcohol feeding to mice, which causes significant fatty liver (steatosis) and liver injury, caused no changes in AD pathology markers in the brain [amyloid precursor protein (APP), presenilin], except for a decrease in microglial cell number in the cortex of the brain. Interestingly, the decline in microglial numbers correlated with serum alanine transaminase (ALT) levels, suggesting a potential link between liver injury and microglial loss in the brain. Intragastric alcohol feeding significantly affected two hepatic proteins important in amyloid-beta (Aβ) processing by the liver: 1) alcohol feeding downregulated lipoprotein receptor-related protein 1 (LRP1, ∼46%), the major receptor in the liver that removes Aβ from blood and peripheral organs, and 2) alcohol significantly upregulated APP (∼2-fold), a potentially important source of Aβ in the periphery and brain. The decrease in hepatic LRP1 and increase in hepatic APP likely switches the liver from being a remover or low producer of Aβ to an important source of Aβ in the periphery, which can impact the brain. The downregulation of LRP1 and upregulation of APP in the liver was observed in the first week of intragastric alcohol feeding, and also occurred in other alcohol feeding models (NIAAA binge alcohol model and intragastric alcohol feeding to rats). Modulation of hepatic LRP1 and APP does not seem alcohol-specific, as ob/ob mice with significant steatosis also had declines in LRP1 and increases in APP expression in the liver. These findings suggest that liver steatosis rather than alcohol-induced liver injury is likely responsible for regulation of hepatic LRP1 and APP. Both obesity and alcohol intake have been linked to AD and our data suggests that liver steatosis associated with these two conditions modulates hepatic LRP1 and APP to disrupt Aβ processing by the liver to promote AD

Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity

Idiosyncratic drug hepatotoxicity represents a major problem in drug development due to inadequacy of current preclinical screening assays, but recently established rodent models utilizing bacterial LPS co-administration to induce an inflammatory background have successfully reproduced idiosyncratic hepatotoxicity signatures for certain drugs. However, the low-throughput nature of these models renders them problematic for employment as preclinical screening assays. Here, we present an analogous, but high-throughput, in vitro approach in which drugs are administered to a variety of cell types (primary human and rat hepatocytes and the human HepG2 cell line) across a landscape of inflammatory contexts containing LPS and cytokines TNF, IFNγ, IL-1α, and IL-6. Using this assay, we observed drug–cytokine hepatotoxicity synergies for multiple idiosyncratic hepatotoxicants (ranitidine, trovafloxacin, nefazodone, nimesulide, clarithromycin, and telithromycin) but not for their corresponding non-toxic control compounds (famotidine, levofloxacin, buspirone, and aspirin). A larger compendium of drug–cytokine mix hepatotoxicity data demonstrated that hepatotoxicity synergies were largely potentiated by TNF, IL-1α, and LPS within the context of multi-cytokine mixes. Then, we screened 90 drugs for cytokine synergy in human hepatocytes and found that a significantly larger fraction of the idiosyncratic hepatotoxicants (19%) synergized with a single cytokine mix than did the non-hepatotoxic drugs (3%). Finally, we used an information theoretic approach to ascertain especially informative subsets of cytokine treatments for most highly effective construction of regression models for drug- and cytokine mix-induced hepatotoxicities across these cell systems. Our results suggest that this drug–cytokine co-treatment approach could provide a useful preclinical tool for investigating inflammation-associated idiosyncratic drug hepatotoxicity.Pfizer Inc.Institute for Collaborative BiotechnologiesMIT Center for Cell Decision ProcessesNational Institute of Mental Health (U.S.) (grant P50-GM68762)National Institute of Mental Health (U.S.) (grant T32-GM008334)Massachusetts Institute of Technology. Biotechnology Process Engineering CenterMassachusetts Institute of Technology. Center for Environmental Health SciencesNational Institute of Mental Health (U.S.) (grant U19ES011399)Whitaker Foundatio

Increasing follow-up questionnaire response rates in a randomized controlled trial of telehealth for depression: three embedded controlled studies

Background: Attrition is problematic in trials, and may be exacerbated in longer studies, telehealth trials and participants with depression – three features of The Healthlines Study. Advance notification, including a photograph and using action-oriented email subject lines might increase response rates, but require further investigation. We examined the effectiveness of these interventions in three embedded Healthlines studies. Methods: Based in different trial sites, participants with depression were alternately allocated to be pre-called or not ahead of the 8-month follow-up questionnaire (Study 1), randomized to receive a research team photograph or not with their 12-month questionnaire (Study 2), and randomized to receive an action-oriented (‘ACTION REQUIRED’) or standard (‘Questionnaire reminder’) 12-month email reminder (Study 3). Participants could complete online or postal questionnaires, and received up to five questionnaire reminders. The primary outcome was completion of the Patient Health Questionnaire (PHQ-9). Secondary outcome measures were the number of reminders and time to questionnaire completion. Results: Of a total of 609 Healthlines depression participants, 190, 251 and 231 participants were included in Studies 1–3 (intervention: 95, 126 and 115), respectively. Outcome completion was ≥90 % across studies, with no differences between trial arms (Study 1: OR 0.38, 95 % CI 0.07–2.10; Study 2: OR 0.84, 95 % CI 0.26–2.66; Study 3: OR 0.53 95 % CI 0.19–1.49). Pre-called participants were less likely to require a reminder (48.4 % vs 62.1 %, OR 0.41, 95 % CI 0.21–0.78), required fewer reminders (adjusted difference in means −0.67, 95 % CI −1.13 to −0.20), and completed follow-up quicker (median 8 vs 15 days, HR 1.35, 95 % CI 1.00–1.82) than control subjects. There were no significant between-group differences in Studies 2 or 3. Conclusions: Eventual response rates in this trial were high, with no further improvement from these interventions. While the photograph and email interventions were ineffective, pre-calling participants reduced time to completion. This strategy might be helpful when the timing of study completion is important. Researchers perceived a substantial benefit from the reduction in reminders with pre-calling, despite no overall decrease in net effort after accounting for pre-notification