Influence of anneal atmosphere on ZnO-nanorod photoluminescent and morphological properties with self-powered photodetector performance

OA Monitor ExerciseEPSR

Flexible Manufacturing Facility for Biopharmaceuticals

Monoclonal antibodies (mAbs) have the potential to treat a wide range of diseases. They possess the ability to bind target molecules in a highly specific and effective manner. Recently, great technological advances have been made to enhance the therapeutic effects of these drugs, making treatment cheaper, easier, and more effective while allowing companies to profit significantly. As a Contract Manufacturing Organization (CMO) for these products, we offer the newest technology and many flexible options for producing these proteins. Our facility is designed to produce protein products in Chinese Hamster Ovary (CHO) cells, followed by modification and purification steps. We present the option to cleave smaller antigen binding fragments (Fab) from the mAb product, removing the crystallizable fragment (Fc) which can interfere with the binding specificity of the drug. We also offer the option for polyethylene glycosylation (PEGylation), which has been shown to improve the effectiveness of these drugs. The attachment of a polyethylene glycol (PEG) molecule to the protein enhances its circulation time in the human body so that less frequent doses are needed. To demonstrate the capabilities of this flexible facility, we have modeled the production of an innovative PEGylated anti-TNF-α mAb. Celltech and Pfizer currently have similar products in Phase III clinical trials; and UCB Incorporated’s Cimzia® recently received FDA approval for the first humanized PEGylated anti-TNF-α Fab’ therapeutic protein. Many non- PEGylated TNF-α inhibitor mAbs are currently on the market to treat pathologies including rheumatoid arthritis and Crohn’s disease. PEGylated products have a clear advantage over these drugs. Our facility can produce up to 55 batches of protein product a year for a maximum yield of 993 kg. For economic analysis of this product, sales from the first year of Cimzia® were considered since this product is almost identical to the one being modeled. Producing at 75% of the total design capacity, this facility has a NPV of $1,319,592,100, an IRR of 33.51% and an ROI of 53.0%. This level of production would leave a significant amount of time remaining for other products to be manufactured as well. The additional products that the facility will produce will be mAbs of all forms (i.e. cleaved, uncleaved, PEGylated, non-PEGylated) that are protected under IP for small biotech firms that do not have the capital to build such facilities. Currently, small biotech firms are producing 81 mAbs and are looking to license production for their Phase III molecules. Clearly, this will become a very profitable CMO as we would be able to capture much of this demand. A major threat looming over the mAb market, however, is the production of small molecular inhibitors, which are currently in Phase I and Phase II clinical trials. Such molecules may be able to capture the full market since they would not only have significant delivery advantages over TNF-α inhibitors, which require injection, but also might have an enhanced side effect profile compared with biologics

Effects of the bioturbating marine yabby Trypaea australiensis on sediment properties in sandy sediments receiving mangrove leaf litter

Laboratory mesocosm incubations were undertaken to investigate the influence of burrowing shrimp Trypaea australiensis (marine yabby) on sediment reworking, physical and chemical sediment characteristics and nutrients in sandy sediments receiving mangrove (Avicennia marina) leaf litter. Mesocosms of sieved, natural T. australiensis inhabited sands, were continually flushed with fresh seawater and pre-incubated for 17 days prior to triplicates being assigned to one of four treatments; sandy sediment (S), sediment + yabbies (S+Y), sediment + leaf litter (organic matter; S+OM) and sediment + yabbies + leaf litter (S+Y+OM) and maintained for 55 days. Mangrove leaf litter was added daily to treatments S+OM and S+Y+OM. Luminophores were added to mesocosms to quantify sediment reworking. Sediment samples were collected after the pre-incubation period from a set of triplicate mesocosms to establish initial conditions prior to the imposition of the treatments and from the treatment mesocosms at the conclusion of the 55-day incubation period. Yabbies demonstrated a clear effect on sediment topography and leaf litter burial through burrow creation and maintenance, creating mounds on the sediment surface ranging in diameter from 3.4 to 12 cm. Within S+Y+OM sediments leaf litter was consistently removed from the surface to sub-surface layers with only 7.5% ± 3.6% of the total mass of leaf detritus added to the mesocosms remaining at the surface at the end of the 55-day incubation period. Yabbies significantly decreased sediment wet-bulk density and increased porosity. Additionally, T. australiensis significantly reduced sediment bio-available ammonium (NH4+bio) concentrations and altered the shape of the concentration depth profile in comparison to the non-bioturbated mesocosms, indicating influences on nutrient cycling and sediment-water fluxes. No significant changes for mean apparent biodiffusion coefficients (Db) and mean biotransport coefficients (r), were found between the bioturbated S+Y and S+Y+OM mesocosms. The findings of this study provide further evidence that T. australiensis is a key-species in shallow intertidal systems playing an important role as an ‘ecosystem engineer’ in soft-bottom habitats by significantly altering physical and chemical structures and biogeochemical function

Use of contingency management incentives to improve completion of hepatitis B vaccination in people undergoing treatment for heroin dependence: a cluster randomised trial

Background: Poor adherence to treatment diminishes its individual and public health benefit. Financial incentives, provided on the condition of treatment attendance, could address this problem. Injecting drug users are a high-risk group for hepatitis B virus (HBV) infection and transmission, but adherence to vaccination programmes is poor. We aimed to assess whether contingency management delivered in routine clinical practice increased the completion of HBV vaccination in individuals receiving opioid substitution therapy. Methods: In our cluster randomised controlled trial, we enrolled participants at 12 National Health Service drug treatment services in the UK that provided opioid substitution therapy and nurse-led HBV vaccination with a super-accelerated schedule (vaccination days 0, 7, and 21). Clusters were randomly allocated 1:1:1 to provide vaccination without incentive (treatment as usual), with fixed value contingency management (three £10 vouchers), or escalating value contingency management (£5, £10, and £15 vouchers). Both contingency management schedules rewarded on-time attendance at appointments. The primary outcome was completion of clinically appropriate HBV vaccination within 28 days. We also did sensitivity analyses that examined vaccination completion with full adherence to appointment times and within a 3 month window. The trial is registered with Current Controlled Trials, number ISRCTN72794493. Findings: Between March 16, 2011, and April 26, 2012, we enrolled 210 eligible participants. Compared with six (9%) of 67 participants treated as usual, 35 (45%) of 78 participants in the fixed value contingency management group met the primary outcome measure (odds ratio 12·1, 95% CI 3·7–39·9; p<0·0001), as did 32 (49%) of 65 participants in the escalating value contingency management group (14·0, 4·2–46·2; p<0·0001). These differences remained significant with sensitivity analyses. Interpretation: Modest financial incentives delivered in routine clinical practice significantly improve adherence to, and completion of, HBV vaccination programmes in patients receiving opioid substitution therapy. Achievement of this improvement in routine clinical practice should now prompt actual implementation. Drug treatment providers should employ contingency management to promote adherence to vaccination programmes. The effectiveness of routine use of contingency management to achieve long-term behaviour change remains unknown

The Effects of Heat Acclimatization, Heat Acclimation, and Intermittent Heat Training on Maximal Oxygen Uptake

Maximal oxygen uptake (VO2max) is an important determinant of endurance performance. Heat acclimation/acclimatization (HA/HAz) strategies elicit improvements in endurance performance. When heat exposure is reduced, intermittent heat training (IHT) is potentially beneficial to alleviate HA/HAz adaptation decay, however corresponding VO2max responses are unknown. PURPOSE: To determine the effects of HA/HAz and IHT on VO2max in endurance runners and identify how long VO2max adaptations remain following removal of repeated heat exposure. METHODS: Twenty-seven male endurance runners (mean ± SD; age, 36 ± 12 years; body mass, 73.03 ± 8.97 kg; height, 178.81 ± 6.39 cm; VO2max, 57.48 ± 7.03 ml.kg-1.min-1) completed VO2max and exercise testing at five time points; baseline, pre-HA, post-HA, week 4 of IHT (IHT4), and week 8 of IHT (IHT8). Exercise testing and HA environmental conditions were the same (ambient temperature, 35.42 ± 1.06°C; relative humidity, 46.35 ± 2.48%). Following baseline testing, participants completed HAz, proceeded by 5 days of HA involving exercise to induce hyperthermia (38.50 - 39.50°C) for 60 minutes. Participants were then randomly assigned to one of three IHT groups: once weekly (n = 9), twice weekly (n = 10), or no IHT (n = 8). Differences in VO2max and maximal heart rate at VO2max (HRmax) for baseline, pre-HA, post-HA, IHT4, and IHT8 were analyzed using repeated-measures ANOVAs with Bonferroni corrections post-hoc. RESULTS: No significant VO2max differences were observed between baseline (57.92 ± 6.82 ml.kg-1.min-1), pre-HA (59.65 ± 8.24 ml.kg-1.min-1), and post-HA (59.49 ± 7.18 ml.kg-1.min-1, p = 0.36). No significant group or time effects were identified for VO2max at post-HA, IHT4, and IHT8 (p = 0.67). However, significant HRmax differences were observed between baseline (180 ± 11 beats.min-1), pre-HA (177 ± 10 beats.min-1), and post-HA tests (175 ± 10 beats.min-1, p = 0.01). No significant group or time HRmax differences were shown for post-HA, IHT4, and IHT8 (p = 0.59). CONCLUSION: No changes in VO2max were identified among endurance runners following HA/HAz, potentially due to participants’ high aerobic fitness levels. As IHT maintained VO2max following 8 weeks without repeated heat exposure, it is potentially a beneficial strategy to minimize VO2max adaptation decay in endurance athletes

Patient information leaflets (PILs) for UK randomised controlled trials : a feasibility study exploring whether they contain information to support decision making about trial participation

Peer reviewedPublisher PD

Neurocognitive function in HIV infected patients on antiretroviral therapy

OBJECTIVE To describe factors associated with neurocognitive (NC) function in HIV-positive patients on stable combination antiretroviral therapy. DESIGN We undertook a cross-sectional analysis assessing NC data obtained at baseline in patients entering the Protease-Inhibitor-Monotherapy-Versus-Ongoing-Triple therapy (PIVOT) trial. MAIN OUTCOME MEASURE NC testing comprised of 5 domains. Raw results were z-transformed using standard and demographically adjusted normative datasets (ND). Global z-scores (NPZ-5) were derived from averaging the 5 domains and percentage of subjects with test scores >1 standard deviation (SD) below population means in at least two domains (abnormal Frascati score) calculated. Patient characteristics associated with NC results were assessed using multivariable linear regression. RESULTS Of the 587 patients in PIVOT, 557 had full NC results and were included. 77% were male, 68% Caucasian and 28% of Black ethnicity. Mean (SD) baseline and nadir CD4+ lymphocyte counts were 553(217) and 177(117) cells/µL, respectively, and HIV RNA was <50 copies/mL in all. Median (IQR) NPZ-5 score was -0.5 (-1.2/-0) overall, and -0.3 (-0.7/0.1) and -1.4 (-2/-0.8) in subjects of Caucasian and Black ethnicity, respectively. Abnormal Frascati scores using the standard-ND were observed in 51%, 38%, and 81%, respectively, of subjects overall, Caucasian and Black ethnicity (p<0.001), but in 62% and 69% of Caucasian and Black subjects using demographically adjusted-ND (p = 0.20). In the multivariate analysis, only Black ethnicity was associated with poorer NPZ-5 scores (P<0.001). CONCLUSIONS In this large group of HIV-infected subjects with viral load suppression, ethnicity but not HIV-disease factors is closely associated with NC results. The prevalence of abnormal results is highly dependent on control datasets utilised. TRIAL REGISTRY ClinicalTrials.gov, NCT01230580

NIA-AA Research Framework: Toward a Biological Definition of Alzheimer\u27s Disease

In 2011, the National Institute on Aging and Alzheimer\u27s Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer\u27s disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer\u27s Association to update and unify the 2011 guidelines. This unifying update is labeled a “research framework” because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimer\u27s Association Research Framework, Alzheimer\u27s disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration [AT(N)]. This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six-stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. We appreciate the concern that this biomarker-based research framework has the potential to be misused. Therefore, we emphasize, first, it is premature and inappropriate to use this research framework in general medical practice. Second, this research framework should not be used to restrict alternative approaches to hypothesis testing that do not use biomarkers. There will be situations where biomarkers are not available or requiring them would be counterproductive to the specific research goals (discussed in more detail later in the document). Thus, biomarker-based research should not be considered a template for all research into age-related cognitive impairment and dementia; rather, it should be applied when it is fit for the purpose of the specific research goals of a study. Importantly, this framework should be examined in diverse populations. Although it is possible that β-amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative diseaseamong different disorders that can lead to dementia. We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia. This approach also will enable a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people

Does study duration have opposite effects on recognition and repetition priming?

We investigated whether manipulating the duration for which an item is studied has opposite effects on recognition memory and repetition priming, as has been reported by Voss and Gonsalves (2010). Robust evidence of this would support the idea that distinct explicit and implicit memory systems drive recognition and priming, and would constitute evidence against a single-system model (Berry, Shanks, Speekenbrink, & Henson, 2012). Across seven experiments using study durations ranging from 40 ms to 2250 ms, and two different priming tasks (a classification task in Experiments 1a, 2a, 3a, and 4, and a continuous identification with recognition (CID-R) task in Experiments 1b, 2b, and 3b), we found that although a longer study duration improved subsequent recognition in each experiment, there was either no detectable effect on priming (Experiments 1a, 2a, and 4) or a similar effect to that on recognition, albeit smaller in magnitude (Experiments 1b, 2b, 3a, and 3b). Our findings (1) question whether study duration has opposite effects on recognition and priming, and (2) are robustly consistent with a single-system model of recognition and priming