MRI findings correlate with difficult dissection during proximal hamstring repair and with postoperative sciatica.

OBJECTIVE: This study examines the correlation between MRI findings and difficult dissection during proximal primary hamstring repair and postoperative sciatica. MATERIALS AND METHODS: A total of 32 cases of surgically repaired hamstring tendon tears that underwent preoperative and postoperative MRI were divided into sciatica (n = 12) and control (n = 20) groups based on the presence or absence of postoperative sciatica. Cases were scored by two blinded musculoskeletal radiologists for imaging features associated with difficult surgical dissection and the development of subsequent sciatica. Intra- and interrater agreements, as well as correlation of MRI findings with symptoms (odds ratio, OR), were calculated. RESULTS: On preoperative MRI, diffuse hamstring muscle edema pattern suggestive of active denervation (OR 9.4-13.6), and greater sciatic perineural scar circumference (OR 1.9-2) and length (OR 1.2-1.3) were significantly correlated with both difficult dissection and postoperative sciatica. Preoperatively, a greater number of tendons torn (OR 3.3), greater tear cross-sectional area (CSA, OR 1.03), and increased nerve T2-weighted signal (OR 3.2) and greater perineural scar thickness (OR 1.7) were also associated with difficult dissection, but not postoperative sciatica. On postoperative MRI, hamstring denervation, sciatic nerve tethering to the hamstring tendon, and development of perineural scar and greater perineural scar extent were all significantly correlated with postoperative sciatica. CONCLUSION: Preoperative hamstring MRI demonstrates findings predictive of difficult sciatic nerve dissection; careful MRI evaluation of the nerve and for the presence and extent of perineural scar is important for preoperative planning. Preoperative and postoperative MRI both depict findings that correlate with postoperative sciatica.

Targeting of lysosomal-bound protein mEAK-7 for cancer therapy.

mEAK-7 (mammalian EAK-7 or MTOR-associated protein, eak-7 homolog), is an evolutionarily conserved lysosomal membrane protein that is highly expressed in several cancer cells. Multiple recent studies have identified mEAK-7 as a positive activator of mTOR (mammalian/mechanistic target of rapamycin) signaling via an alternative mTOR complex, implying that mEAK-7 plays an important role in the promotion of cancer proliferation and migration. In addition, structural analyses investigating interactions between mEAK-7 and V-ATPase, a protein complex responsible for regulating pH homeostasis in cellular compartments, have suggested that mEAK-7 may contribute to V-ATPase-mediated mTORC1 activation. The C-terminal α-helix of mEAK-7 binds to the D and B subunits of the V-ATPase, creating a pincer-like grip around its B subunit. This binding undergoes partial disruption during ATP hydrolysis, potentially enabling other proteins such as mTOR to bind to the α-helix of mEAK-7. mEAK-7 also promotes chemoresistance and radiation resistance by sustaining DNA damage-mediated mTOR signaling through interactions with DNA-PKcs (DNA-dependent protein kinase catalytic subunit). Taken together, these findings indicate that mEAK-7 may be a promising therapeutic target against tumors. However, the precise molecular mechanisms and signal transduction pathways of mEAK-7 in cancer remain largely unknown, motivating the need for further investigation. Here, we summarize the current known roles of mEAK-7 in normal physiology and cancer development by reviewing the latest studies and discuss potential future developments of mEAK-7 in targeted cancer therapy.

Testing the impact of differing behavioural science informed text message content in COVID-19 vaccination invitations on vaccine uptake: A randomised clinical trial.

Behavioural science constructs can be incorporated into messaging strategies to enhance the effectiveness of public health campaigns by increasing the occurrence of desired behaviours. This study investigated the impact of behavioural science-informed text message strategies on COVID-19 vaccination rates in 18-39-year-olds in an area of low uptake in London during the first vaccination offer round in the United Kingdom. This three-armed randomised trial recruited unvaccinated residents of an urban Central London suburb being offered their first vaccination between May and June 2021. Participants were randomised to receive the control (current practice) text message or one of two different behavioural science-informed COVID-19 vaccine invitation strategies. Both intervention strategies contained the phrase "your vaccine is ready and waiting for you", aiming to evoke a sense of ownership, with one strategy also including a pre-alert message. The main outcome measures were vaccination rates at 3 and 8 weeks after message delivery. A total of 88,820 residents were randomly assigned to one of the three trial arms. Each arm had a vaccine uptake rate of 27.2 %, 27.4 % and 27.3 % respectively. The mean age of participants was 28.2 years (SD ± 5.7), the mean index of multiple deprivation was 4.3 (SD ± 2.0) and 50.4 % were women. Vaccine uptake varied by demographics, however there was no significant difference between trial arms (p = 0.872). Delivery was successful for 53.6 % of text messages. Our choice of behavioural science informed messaging strategies did not improve vaccination rates above the rate seen for the current practice message. This likely reflects the wide exposure to public health campaigns during the pandemic, as such text messages nudges were unlikely to alter existing informed decision-making processes. Text message delivery was relatively low, indicating a need for accurate mobile phone number records and multi-modal approaches to reach eligible patients for vaccination. The protocol was registered at clinicaltrials.gov (NCT04895683) on 20/05/2021.

Engineered extracellular matrices facilitate brain organoids from human pluripotent stem cells.

OBJECTIVE: Brain organoids are miniaturized in vitro brain models generated from pluripotent stem cells, which resemble full-sized brain more closely than conventional two-dimensional cell cultures. Although brain organoids mimic the human brain's cell-to-cell network interactions, they generally fail to faithfully recapitulate cell-to-matrix interactions. Here, an engineered framework, called an engineered extracellular matrix (EECM), was developed to provide support and cell-to-matrix interactions to developing brain organoids. METHODS: We generated brain organoids using EECMs comprised of human fibrillar fibronectin supported by a highly porous polymer scaffold. The resultant brain organoids were characterized by immunofluorescence microscopy, transcriptomics, and proteomics of the cerebrospinal fluid (CSF) compartment. RESULTS: The interstitial matrix-mimicking EECM enhanced neurogenesis, glial maturation, and neuronal diversity from human embryonic stem cells versus conventional protein matrix (Matrigel). Additionally, EECMs supported long-term culture, which promoted large-volume organoids containing over 250 µL of CSF. Proteomics analysis of the CSF found it superseded previous brain organoids in protein diversity, as indicated by 280 proteins spanning 500 gene ontology pathways shared with adult CSF. INTERPRETATION: Engineered EECM matrices represent a major advancement in neural engineering as they have the potential to significantly enhance the structural, cellular, and functional diversity that can be achieved in advanced brain models.

Quantification of acceleration as activity counts in ActiGraph wearable.

Digital clinical measures based on data collected by wearable devices have seen rapid growth in both clinical trials and healthcare. The widely-used measures based on wearables are epoch-based physical activity counts using accelerometer data. Even though activity counts have been the backbone of thousands of clinical and epidemiological studies, there are large variations of the algorithms that compute counts and their associated parameters-many of which have often been kept proprietary by device providers. This lack of transparency has hindered comparability between studies using different devices and limited their broader clinical applicability. ActiGraph devices have been the most-used wearable accelerometer devices for over two decades. Recognizing the importance of data transparency, interpretability and interoperability to both research and clinical use, we here describe the detailed counts algorithms of five generations of ActiGraph devices going back to the first AM7164 model, and publish the current counts algorithm in ActiGraph's ActiLife and CentrePoint software as a standalone Python package for research use. We believe that this material will provide a useful resource for the research community, accelerate digital health science and facilitate clinical applications of wearable accelerometry.

Implementing behavioural science informed letter interventions to increase COVID-19 vaccination uptake in uncontactable London residents: a difference-in-difference study in London, UK.

BACKGROUND: The UK COVID-19 vaccination programme began in December, 2020. By February, 2021, eight North West London Clinical Commissioning Groups (CCGs) had the lowest vaccination rates nationally. This study evaluated the impact of behavioural science-informed (BI) letters on vaccination uptake. METHODS: Unvaccinated residents of the Central London CCG who were deemed uncontactable (through text messaging and phone calls) were identified with the whole systems integrated care database. BI letters were sent to residents in the intervention CCG between May and June, 2021. Three neighbouring CCGs in London with similar non-responder data were used as control groups. A linear difference-in-difference analysis was undertaken to assess change in vaccine uptake rate across all four CCGs. Percentage point change was adjusted for selected covariates including ethnicity, age, gender, and index of multiple deprivation (IMD) quintiles. Approval was obtained from the quality improvement and audit office of Imperial College Healthcare NHS Trust (London, UK). FINDINGS: Within the intervention Central London CCG, 10 161 residents received the BI letter. The control CCGs contained 27 383 uncontactable residents. All CCGs showed an increase in vaccination rates in this population. The linear difference-in-difference analysis showed an increase in vaccination uptake in the intervention CCG (relative change 31·9% (95% CI 30·5-33·3; p<0·0001). Residents in IMD quintile 5 (least deprived) showed the largest rate of change (4·1%; p<0·0001). Residents with a mixed or multiple ethnic background were less likely to receive a COVID-19 vaccine (-4·1%, p<0·0001). INTERPRETATION: BI letters improved the rate of vaccine uptake. The percentage point increase of 31·9% equates to 436 additional previously uncontactable residents being vaccinated. Our data highlighted differences in the effect of BI-informed interventions in population subgroups. BI letters are a cost-effective and trusted communication tool, effectively engaging residents where other communication strategies did not work. FUNDING: None.

Conditional deletion of mTOR discloses its essential role in early B-cell development.

Mechanistic target of rapamycin (mTOR) is a serine-threonine kinase and central regulator of cell growth, differentiation, and survival. mTOR is commonly hyperactivated in a diverse number of cancers and critical roles for mTOR in regulating immune cell differentiation and function have been demonstrated. However, there is little work investigating the roles of mTOR in early B-cell development. Here we demonstrate that conditional disruption of mTOR in developing mouse B cells results in reduced pre-B-cell proliferation and survival, as well as a developmental block at the pre-B-cell stage, with a corresponding lack of peripheral B cells. Upon immunization with NP-CGG antigen, mice with Mtor conditional disruption in early B cells lost their ability to form germinal centers and produce specific antibodies. In competitive BM repopulation assays, donor BM cells from conditional knock-out mice were completely impaired in their ability to reconstitute B cells. Our data reveal the essential role of mTOR in early pre-B-cell development and survival.

HPV32-related Heck's disease in a chronic graft-versus-host disease patient with long-term successful KTP laser treatment: A rare case report.

We recently identified and treated a rare case of oral focal epithelial hyperplasia (FEH) in an adult patient with chronic graft-vs-host disease. This is the first report linking KTP laser therapy to successful long-term treatment HPV32 FEH.

Fatty acid oxidation is required for embryonic stem cell survival during metabolic stress.

Metabolic regulation is critical for the maintenance of pluripotency and the survival of embryonic stem cells (ESCs). The transcription factor Tfcp2l1 has emerged as a key factor for the naïve pluripotency of ESCs. Here, we report an unexpected role of Tfcp2l1 in metabolic regulation in ESCs-promoting the survival of ESCs through regulating fatty acid oxidation (FAO) under metabolic stress. Tfcp2l1 directly activates many metabolic genes in ESCs. Deletion of Tfcp2l1 leads to an FAO defect associated with upregulation of glucose uptake, the TCA cycle, and glutamine catabolism. Mechanistically, Tfcp2l1 activates FAO by inducing Cpt1a, a rate-limiting enzyme transporting free fatty acids into the mitochondria. ESCs with defective FAO are sensitive to cell death induced by glycolysis inhibition and glutamine deprivation. Moreover, the Tfcp2l1-Cpt1a-FAO axis promotes the survival of quiescent ESCs and diapause-like blastocysts induced by mTOR inhibition. Thus, our results reveal how ESCs orchestrate pluripotent and metabolic programs to ensure their survival in response to metabolic stress.

MicroRNA-1911-3p targets mEAK-7 to suppress mTOR signaling in human lung cancer cells.

Regulation of mTOR signaling depends on an intricate interplay of post-translational protein modification. Recently, mEAK-7 (mTOR associated protein, eak-7 homolog) was identified as a positive activator of mTOR signaling via an alternative mTOR complex. However, the upstream regulation of mEAK-7 in human cells is not known. Because microRNAs are capable of modulating protein translation of RNA in eukaryotes, we conducted a bioinformatic search for relevant mEAK-7 targeting microRNAs using the Exiqon miRSearch V3.0 algorithm. Based on the score obtained through miRSearch V3.0, the top predicted miRNA (miR-1911-3p) was studied. miR-1911-3p mimics decreased protein levels of both mEAK-7 and mTORC1 downstream effectors p-S6 and p-4E-BP1 in non-small cell lung carcinoma (NSCLC) cell lines H1975 and H1299. miR-1911-3p levels and MEAK7 mRNA/mEAK-7/mTOR signaling levels were negatively correlated between normal lung and NSCLC cells. miR-1911-3p directly interacted with MEAK7 mRNA at the 3'-UTR to negatively regulate mEAK-7 and significantly decreased mTOR localization to the lysosome. Furthermore, miR-1911-3p significantly decreased cell proliferation and migration in both H1975 and H1299 cells. Thus, miR-1911-3p functions as a suppressor of mTOR signaling through the regulation of MEAK7 mRNA translation in human cancer cells.

mEAK-7 Forms an Alternative mTOR Complex with DNA-PKcs in Human Cancer.

MTOR associated protein, eak-7 homolog (mEAK-7), activates mechanistic target of rapamycin (mTOR) signaling in human cells through an alternative mTOR complex to regulate S6K2 and 4E-BP1. However, the role of mEAK-7 in human cancer has not yet been identified. We demonstrate that mEAK-7 and mTOR signaling are strongly elevated in tumor and metastatic lymph nodes of patients with non-small-cell lung carcinoma compared with those of patients with normal lung or lymph tissue. Cancer stem cells, CD44+/CD90+ cells, yield elevated mEAK-7 and activated mTOR signaling. mEAK-7 is required for clonogenic potential and spheroid formation. mEAK-7 associates with DNA-dependent protein kinase catalytic subunit isoform 1 (DNA-PKcs), and this interaction is increased in response to X-ray irradiation to regulate S6K2 signaling. DNA-PKcs pharmacologic inhibition or genetic knockout reduced S6K2, mEAK-7, and mTOR binding with DNA-PKcs, resulting in loss of S6K2 activity and mTOR signaling. Therefore, mEAK-7 forms an alternative mTOR complex with DNA-PKcs to regulate S6K2 in human cancer cells.

Living in immigrant communities does not impact total knee arthroplasty outcomes: experience from a high-volume center in the United States.

BACKGROUND: Community characteristics such as poverty affect total knee arthroplasty (TKA) outcomes. However, it is unknown whether other community factors such as immigrant proportion (IP) also affect outcomes. Our objective was to determine the association of neighborhood IP on preoperative (pre-op) and 2-year postoperative (post-op) Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function after elective TKA. METHODS: Patients in a high volume institutional TKA registry between May 2007 and February 2011 were retrospectively analyzed. Demographics, pre-op and 2-year post-op WOMAC pain and function scores, and geocodable addresses were obtained. Patient-level variables were linked to US Census Bureau census tract data. The effect of patient and neighborhood-level factors on WOMAC scores were analyzed using linear mixed effects models. RESULTS: 3898 TKA patients were analyzed. Pre-op and 2-year post-op WOMAC pain and function scores were between 2.75-4.88 WOMAC points worse in neighborhoods with a high IP (≥ 40%) compared to low IP (< 10%). In multivariable analyses, these differences were not statistically significant. Women had worse pre-op and 2-year post-op WOMAC scores (all p ≤ 0.04), but this difference was not influenced by neighborhood IP (all pinteraction NS). CONCLUSIONS: Patients living in high (≥40%) IP neighborhoods do not have worse pre-op or 2-year post-op pain and function outcomes after TKA compared to those living in low (< 10%) IP neighborhoods. Although sex differences favoring males are notable, these differences are not associated with IP. High neighborhood IP do not appear to affect outcomes after TKA.

Coordinating Tissue Regeneration Through Transforming Growth Factor-ß Activated Kinase 1 Inactivation and Reactivation.

Aberrant wound healing presents as inappropriate or insufficient tissue formation. Using a model of musculoskeletal injury, we demonstrate that loss of transforming growth factor-ß activated kinase 1 (TAK1) signaling reduces inappropriate tissue formation (heterotopic ossification) through reduced cellular differentiation. Upon identifying increased proliferation with loss of TAK1 signaling, we considered a regenerative approach to address insufficient tissue production through coordinated inactivation of TAK1 to promote cellular proliferation, followed by reactivation to elicit differentiation and extracellular matrix production. Although the current regenerative medicine paradigm is centered on the effects of drug treatment ("drug on"), the impact of drug withdrawal ("drug off") implicit in these regimens is unknown. Because current TAK1 inhibitors are unable to phenocopy genetic Tak1 loss, we introduce the dual-inducible COmbinational Sequential Inversion ENgineering (COSIEN) mouse model. The COSIEN mouse model, which allows us to study the response to targeted drug treatment ("drug on") and subsequent withdrawal ("drug off") through genetic modification, was used here to inactivate and reactivate Tak1 with the purpose of augmenting tissue regeneration in a calvarial defect model. Our study reveals the importance of both the "drug on" (Cre-mediated inactivation) and "drug off" (Flp-mediated reactivation) states during regenerative therapy using a mouse model with broad utility to study targeted therapies for disease. Stem Cells 2019;37:766-778.

A toolbox of IgG subclass-switched recombinant monoclonal antibodies for enhanced multiplex immunolabeling of brain.

Generating recombinant monoclonal antibodies (R-mAbs) from mAb-producing hybridomas offers numerous advantages that increase the effectiveness, reproducibility, and transparent reporting of research. We report here the generation of a novel resource in the form of a library of recombinant R-mAbs validated for neuroscience research. We cloned immunoglobulin G (IgG) variable domains from cryopreserved hybridoma cells and input them into an integrated pipeline for expression and validation of functional R-mAbs. To improve efficiency over standard protocols, we eliminated aberrant Sp2/0-Ag14 hybridoma-derived variable light transcripts using restriction enzyme treatment. Further, we engineered a plasmid backbone that allows for switching of the IgG subclasses without altering target binding specificity to generate R-mAbs useful in simultaneous multiplex labeling experiments not previously possible. The method was also employed to rescue IgG variable sequences and generate functional R-mAbs from a non-viable cryopreserved hybridoma. All R-mAb sequences and plasmids will be archived and disseminated from open source suppliers.

Acoustic Tweezing Cytometry Induces Rapid Initiation of Human Embryonic Stem Cell Differentiation.

Mechanical forces play critical roles in influencing human embryonic stem cell (hESC) fate. However, it remains largely uncharacterized how local mechanical forces influence hESC behavior in vitro. Here, we used an ultrasound (US) technique, acoustic tweezing cytometry (ATC), to apply targeted cyclic subcellular forces to hESCs via integrin-bound microbubbles (MBs). We found that ATC-mediated cyclic forces applied for 30 min to hESCs near the edge of a colony induced immediate global responses throughout the colony, suggesting the importance of cell-cell connection in the mechanoresponsiveness of hESCs to ATC-applied forces. ATC application generated increased contractile force, enhanced calcium activity, as well as decreased expression of pluripotency transcription factors Oct4 and Nanog, leading to rapid initiation of hESC differentiation and characteristic epithelial-mesenchymal transition (EMT) events that depend on focal adhesion kinase (FAK) activation and cytoskeleton (CSK) tension. These results reveal a unique, rapid mechanoresponsiveness and community behavior of hESCs to integrin-targeted cyclic forces.

Pharmacokinetics and Skin Tolerability of Intracutaneous Zolmitriptan Delivery in Swine Using Adhesive Dermally Applied Microarray.

Adhesive Dermally Applied Microarray (ADAM) is a new drug-delivery system that uses microprojections (340-µm long) for intracutaneous drug self-administration. We formulated zolmitriptan, a well-accepted and commonly used migraine medication, for administration using ADAM. In vivo studies were conducted in female prepubescent Yorkshire pigs using ADAM 1.9-mg zolmitriptan applied to the inner thigh and left in place for 1 h. Pharmacokinetic studies showed that the ADAM 1.9-mg zolmitriptan was delivered with high efficiency (85%) and high absolute bioavailability (77%). Furthermore, in vivo evaluation showed a rapid systemic absorption with a median Tmax of 15 min. Skin biopsies of the treatment sites showed a mean depth of microprojection penetration of 105.4 ± 3.6 µm. Mass spectrometry imaging showed that the zolmitriptan after 1 h of patch wear time was predominantly localized to the dermis. ADAM zolmitriptan was well tolerated with a transient mild-to-moderate erythema response. The findings in these studies, particularly the rapid zolmitriptan absorption profile after intracutaneous administration, provided validation to advance ADAM zolmitriptan development.

Mammalian EAK-7 activates alternative mTOR signaling to regulate cell proliferation and migration.

Nematode EAK-7 (enhancer-of-akt-1-7) regulates dauer formation and controls life span; however, the function of the human ortholog mammalian EAK-7 (mEAK-7) is unknown. We report that mEAK-7 activates an alternative mechanistic/mammalian target of rapamycin (mTOR) signaling pathway in human cells, in which mEAK-7 interacts with mTOR at the lysosome to facilitate S6K2 activation and 4E-BP1 repression. Despite interacting with mTOR and mammalian lethal with SEC13 protein 8 (mLST8), mEAK-7 does not interact with other mTOR complex 1 (mTORC1) or mTOR complex 2 (mTORC2) components; however, it is essential for mTOR signaling at the lysosome. This phenomenon is distinguished by S6 and 4E-BP1 activity in response to nutrient stimulation. Conventional S6K1 phosphorylation is uncoupled from S6 phosphorylation in response to mEAK-7 knockdown. mEAK-7 recruits mTOR to the lysosome, a crucial compartment for mTOR activation. Loss of mEAK-7 results in a marked decrease in lysosomal localization of mTOR, whereas overexpression of mEAK-7 results in enhanced lysosomal localization of mTOR. Deletion of the carboxyl terminus of mEAK-7 significantly decreases mTOR interaction. mEAK-7 knockdown decreases cell proliferation and migration, whereas overexpression of mEAK-7 enhances these cellular effects. Constitutively activated S6K rescues mTOR signaling in mEAK-7-knocked down cells. Thus, mEAK-7 activates an alternative mTOR signaling pathway through S6K2 and 4E-BP1 to regulate cell proliferation and migration.

Human Growth Hormone Delivery with a Microneedle Transdermal System: Preclinical Formulation, Stability, Delivery and PK of Therapeutically Relevant Doses.

This study evaluated the feasibility of coating formulated recombinant human growth hormone (rhGH) on a titanium microneedle transdermal delivery system, Zosano Pharma (ZP)-hGH, and assessed preclinical patch delivery performance. Formulation rheology and surface activity were assessed by viscometry and contact angle measurement. rhGH liquid formulation was coated onto titanium microneedles by dip-coating and drying. The stability of coated rhGH was determined by size exclusion chromatography-high performance liquid chromatography (SEC-HPLC). Preclinical delivery and pharmacokinetic studies were conducted in female hairless guinea pigs (HGP) using rhGH coated microneedle patches at 0.5 and 1 mg doses and compared to Norditropin® a commercially approved rhGH subcutaneous injection. Studies demonstrated successful rhGH formulation development and coating on microneedle arrays. The ZP-hGH patches remained stable at 40 °C for six months with no significant change in % aggregates. Pharmacokinetic studies showed that the rhGH-coated microneedle patches, delivered with high efficiency and the doses delivered indicated linearity with average Tmax of 30 min. The absolute bioavailability of the microneedle rhGH patches was similar to subcutaneous Norditropin® injections. These results suggest that ZP-transdermal microneedle patch delivery of rhGH is feasible and may offer an effective and patient-friendly alternative to currently marketed rhGH injectables.

Evaluation of drug precipitation of solubility-enhancing liquid formulations using milligram quantities of a new molecular entity (NME).

A precipitation screening method using a 96-well microtiter plate was developed to evaluate in vitro drug precipitation kinetics of liquid formulations for poorly water-soluble compounds, using milligram quantities of compounds and milliliter volumes of biorelevant media. By using this method we identified three formulations showing distinct in vitro precipitation kinetics (fast, slow, and no precipitation) for a model new molecular entity (JNJ-25894934). The in vitro precipitation profiles in simulated intestinal fluid (SIF), fasted state simulated intestinal fluid (FaSSIF), and fed state simulated intestinal fluid (FeSSIF) were compared with those measured by a USP dissolution method, and with in vivo absorption at the fasted and fed states in canine pharmacokinetic (PK) studies. The precipitation kinetics of all three formulations in the initial hours measured by the screening method correlated to those determined by the USP method (R(2) = 0.96). The PK results showed that the fast-precipitation formulation had the lowest bioavailability. However, a similar bioavailability was observed for the slow- and no-precipitation formulations. The oral bioavailability of JNJ-25894934 at the fed state was also significantly higher than that at the fasted state for all three formulations (p < 0.05). In addition, the in vitro precipitation profiles in FeSSIF correlated better with in vivo absorption than those in SIF and FaSSIF.

The benefits of the MOE/MAR implementation: a quantitative approach.

Once the decision was made to implement an electronic medication order entry and medication administration record system at the University Health Network, a significant question soon emerged: How would UHN be able to determine if the project had indeed accomplished its stated objectives of improving patient safety and the medication ordering and processing cycle?