Publications by authors named "Alice Tsai"

34 Publications

The impact of EAES Fellowship Programme: a five-year review and evaluation.

Surg Endosc 2021 Jun 8. Epub 2021 Jun 8.

Department of General Surgery, Linköping University Hospital, 581 85, Linköping, Sweden.

Background: The European Association of Endoscopic Surgery (EAES) fellowship programme was established in 2014, allowing nine surgeons annually to obtain experience and skills in minimally invasive surgery (MIS) from specialist centres across the Europe and United States. It aligns with the strategic focus of EAES Education and Training Committee on enabling Learning Mobility opportunities. To assess the impact of the programme, a survey was conducted aiming to evaluate the experience and impact of the programme and receive feedback for improvements.

Methods: A survey using a 5-point Likert scale was used to evaluate clinical, education and research experience. The impact on acquisition of new technical skills, change in clinical practice and ongoing collaboration with the host institute was assessed. The fellows selected between 2014 and 2018 were included. Ratings were analysed in percentage; thematic analysis was applied to the free-text feedbacks using qualitative analysis.

Results: All the fellows had good access to observing in operating theatres and 70.6% were able to assist. 91.2% participated in educational activities and 23.5% were able to contribute through teaching. 44.1% participated in research activities and 41.2% became an author/co-author of a publication from the host. 97.1% of fellows stated that their operative competency had increased, 94.3% gained new surgical skills and 85.7% was able to introduce new techniques in their hospitals. 74.29% agreed that the clinical experience led to a change in their practices. The most commonly suggested improvements were setting realistic target in clinical and research areas, increasing fellowship duration, and maximising theatre assisting opportunities. Nevertheless, 100% of fellows would recommend the fellowship to their peers.

Conclusion: EAES fellowship programme has shown a positive impact on acquiring and adopting new MIS techniques. To further refine the programme, an individualised approach should be adopted to set achievable learning objectives in clinical skills, education and research.
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http://dx.doi.org/10.1007/s00464-021-08525-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186018PMC
June 2021

fMRI findings in MTBI patients with headaches following rTMS.

Sci Rep 2021 05 5;11(1):9573. Epub 2021 May 5.

Anesthesiology, UC San Diego School of Medicine, La Jolla, CA, 92093, USA.

Mild Traumatic Brain Injury (MTBI) patients with persistent headaches are known to have diminished supraspinal modulatory connectivity from their prefrontal cortices. Repetitive transcranial magnetic stimulation (rTMS) is able to alleviate MTBI-related headache (MTBI-HA). This functional magnetic resonance imaging (fMRI) study assessed supraspinal correlates associated with the headache analgesic effect of rTMS at left prefrontal cortex (LPFC), hypothesizing real rTMS would significantly increase modulatory functions at LPFC in comparison to sham treatment. Subjects with MTBI-HA were randomized to receive either real or sham rTMS treatments and subjected to pre- and post-treatment resting state and evoked heat-pain fMRI as described in a prior study. Real rTMS consisted of 2000 pulses delivered at 10 Hz and 80% of the resting motor threshold at left dorsolateral prefrontal cortex, whereas sham treatment was delivered with same figure-of-eight coil turned 180 degrees. Follow-up fMRI was performed one-week post-treatment. All fMRI data was processed using BrainVoyager QX Software. 14 subjects receiving real and 12 subjects receiving sham treatments completed the study. The REAL group demonstrated significant (P < 0.02) decreases in headache frequency and intensity at one week following treatment. fMRI scans in the REAL group showed increased evoked heat pain activity (P < 0.002) and resting functional connectivity (P < 0.0001) at the LPFC after rTMS. Neither this significant analgesic effect nor these fMRI findings were seen in the sham group. Sham treatment was, however, associated with a decrease in resting state activity at the LPFC (P < 0.0001). This study correlates the demonstrated analgesic effect of rTMS in the treatment of MTBI-HA with enhanced supraspinal functional connectivity in the left prefrontal cortex, which is known to be involved in "top-down" pain inhibition along the descending midbrain-thalamic-cingulate pathway. Trial Registration: This study was registered on September 24, 2013, on ClinicalTrials.gov with the identifier: NCT01948947. https://clinicaltrials.gov/ct2/show/NCT01948947 .
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http://dx.doi.org/10.1038/s41598-021-89118-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100290PMC
May 2021

Metastatic Cervical Cancer to the Duodenum: A Learning Point.

Cureus 2021 Mar 14;13(3):e13874. Epub 2021 Mar 14.

General Surgery, Croydon University Hospital, London, GBR.

An elderly woman was admitted to the hospital with generalised abdominal pain and bowel obstruction symptoms in a background of renal cell carcinoma and cervical cancer. Investigations showed a degree of gastric outlet obstruction with mild distension of the small bowel loops with no lead point seen and a raised alkaline phosphatase (ALP). Oesophago-gastroduodenoscopy (OGD) showed a stricture at D1/D2; therefore, an enteric stent was inserted. Biopsies showed metastatic cervical cancer. A few cases of metastatic cervical cancer to the duodenum have been reported. Obstructive bowel symptoms in the background of cervical cancer should raise the possibility of metastases in future practice.
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http://dx.doi.org/10.7759/cureus.13874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042662PMC
March 2021

Physiologically-Based Pharmacokinetic Modeling in Renal and Hepatic Impairment Populations: A Pharmaceutical Industry Perspective.

Clin Pharmacol Ther 2021 08 30;110(2):297-310. Epub 2020 Dec 30.

Department of Drug Disposition, Lilly, Indianapolis, Indiana, USA.

The predictive performance of physiologically-based pharmacokinetics (PBPK) models for pharmacokinetics (PK) in renal impairment (RI) and hepatic impairment (HI) populations was evaluated using clinical data from 29 compounds with 106 organ impairment study arms were collected from 19 member companies of the International Consortium for Innovation and Quality in Pharmaceutical Development. Fifty RI and 56 HI study arms with varying degrees of organ insufficiency along with control populations were evaluated. For RI, the area under the curve (AUC) ratios of RI to healthy control were predicted within twofold of the observed ratios for > 90% (N = 47/50 arms). For HI, > 70% (N = 43/56 arms) of the hepatically impaired to healthy control AUC ratios were predicted within twofold. Inaccuracies, typically overestimation of AUC ratios, occurred more in moderate and severe HI. PBPK predictions can help determine the need and timing of organ impairment study. It may be suitable for predicting the impact of RI on PK of drugs predominantly cleared by metabolism with varying contribution of renal clearance. PBPK modeling may be used to support mild impairment study waivers or clinical study design.
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http://dx.doi.org/10.1002/cpt.2125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359227PMC
August 2021

Big Data-driven personal protective equipment stockpiling framework under Universal Healthcare System for Disease Control and Prevention in the COVID-19 Era.

Infect Control Hosp Epidemiol 2020 Aug 3:1-4. Epub 2020 Aug 3.

Department of Health Policy and Management, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.

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http://dx.doi.org/10.1017/ice.2020.387DOI Listing
August 2020

Physiologically Based Pharmacokinetic Modeling of CFTR Modulation in People with Cystic Fibrosis Transitioning from Mono or Dual Regimens to Triple-Combination Elexacaftor/Tezacaftor/Ivacaftor.

Pulm Ther 2020 Dec 30;6(2):275-286. Epub 2020 Jul 30.

Vertex Pharmaceuticals Incorporated, Boston, MA, USA.

Introduction: The triple-combination (TC) cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen elexacaftor, tezacaftor, and ivacaftor was shown to be safe and efficacious in phase 3 trials of people with cystic fibrosis (pwCF) ≥ 12 years of age with ≥ 1 F508del-CFTR allele. Here, a simulation study predicted ivacaftor, tezacaftor, and elexacaftor exposures and impacts on CFTR modulation following transition from ivacaftor [a cytochrome P450 3A (CYP3A) substrate], lumacaftor (a CYP3A inducer)/ivacaftor, or tezacaftor/ivacaftor to TC.

Methods: Physiologically based pharmacokinetic (PBPK) modeling was used to evaluate plasma exposures during transition from mono- or dual-combination CFTR modulator regimens to TC. PBPK models were parameterized using data from human hepatocytes to account for CYP3A induction by lumacaftor and validated to match clinical data from healthy volunteers and pwCF. Using dosing regimens for pwCF ≥ 12 years of age, simulations were performed for ivacaftor, lumacaftor/ivacaftor, and tezacaftor/ivacaftor dosing for 14 days followed by immediate transition to elexacaftor/tezacaftor/ivacaftor dosing for 14 days. Drug exposures during transitions were compared with respective half-maximal effective concentrations (EC) estimated from efficacy endpoint data from clinical studies.

Results: In simulations of immediate transition from ivacaftor or tezacaftor/ivacaftor to TC, the preceding treatment had no impact on ivacaftor, tezacaftor, or elexacaftor exposures. In simulations of immediate transition from lumacaftor/ivacaftor to TC, ivacaftor exposure decreased to 64% of maximum effective concentration (EC), due to reduction in ivacaftor dose and residual CYP3A4 induction, then returned to 90-95% of maximum EC. Lumacaftor-mediated CYP3A induction resolved within approximately 2 weeks. In all simulations, ivacaftor, tezacaftor, and elexacaftor exposures approached steady state within 2 weeks following transition and, at all times, ivacaftor and ≥ 1 CFTR corrector remained above EC.

Conclusion: PBPK modeling indicates that immediate transition to the elexacaftor/tezacaftor/ivacaftor regimen from an ivacaftor, lumacaftor/ivacaftor, or tezacaftor/ivacaftor regimen results in sustained CFTR modulation in pwCF ≥ 12 years of age.
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http://dx.doi.org/10.1007/s41030-020-00124-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672136PMC
December 2020

Surgical Quality Assurance in COLOR III: Standardization and Competency Assessment in a Randomized Controlled Trial.

Ann Surg 2019 11;270(5):768-774

Department of Surgery and Cancer, Imperial College London, London, United kingdom.

Objective: The aim of this study was to develop an objective and reliable surgical quality assurance system (SQA) for COLOR III, an international multicenter randomized controlled trial (RCT) comparing transanal total mesorectal excision (TaTME) with laparoscopic approach for rectal cancer.

Background Of Summary Data: SQA influences outcome measures in RCTs such as lymph nodes harvest, in-hospital mortality, and locoregional cancer recurrence. However, levels of SQA are variable.

Method: Hierarchical task analysis of TaTME was performed. A 4-round Delphi methodology was applied for standardization of TaTME steps. Semistructured interviews were conducted in round 1 to identify key steps and tasks, which were rated as mandatory, optional, or prohibited in rounds 2 to 4 using questionnaires. Competency assessment tool (CAT) was developed and its content validity was examined by expert surgeons. Twenty unedited videos were assessed to test reliability using generalizability theory.

Results: Eighty-three of 101 surgical tasks identified reached 70% agreement (26 mandatory, 56 optional, and 1 prohibited). An operative guide of standardized TaTME was created. CAT is matrix of 9 steps and 4 performance qualities: exposure, execution, adverse event, and end-product. The overall G-coefficient was 0.883. Inter-rater and interitem reliability were 0.883 and 0.986. To enter COLOR III, 2 unedited TaTME and 1 laparoscopic TME videos were submitted and assessed by 2 independent assessors using CAT.

Conclusion: We described an iterative approach to develop an objective SQA within multicenter RCT. This approach provided standardization, the development of reliable and valid CAT, and the criteria for trial entry and monitoring surgical performance during the trial.
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http://dx.doi.org/10.1097/SLA.0000000000003537DOI Listing
November 2019

Applications of Quantitative Systems Pharmacology in Model-Informed Drug Discovery: Perspective on Impact and Opportunities.

CPT Pharmacometrics Syst Pharmacol 2019 11 25;8(11):777-791. Epub 2019 Oct 25.

Eli Lilly and Company, Indianapolis, Indiana, USA.

Quantitative systems pharmacology (QSP) approaches have been increasingly applied in the pharmaceutical since the landmark white paper published in 2011 by a National Institutes of Health working group brought attention to the discipline. In this perspective, we discuss QSP in the context of other modeling approaches and highlight the impact of QSP across various stages of drug development and therapeutic areas. We discuss challenges to the field as well as future opportunities.
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http://dx.doi.org/10.1002/psp4.12463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6875708PMC
November 2019

The Importance of Increasing Surgeon Participation in Hospital Leadership.

JAMA Surg 2019 04;154(4):281-282

Department of Surgery and Cancer, Imperial College London, London, United Kingdom.

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http://dx.doi.org/10.1001/jamasurg.2018.5080DOI Listing
April 2019

A pathway to developing and testing quality measures aimed at improving adult vaccination rates in the United States.

Vaccine 2019 02 6;37(10):1277-1283. Epub 2019 Feb 6.

Immunization Action Coalition, St. Paul, MN, United States.

Despite recommendations for vaccinating adults and widespread availability of immunization services (e.g., pharmacy venues, workplace wellness clinics), vaccination rates in the United States remain low. The U.S. National Adult Immunization Plan identified the development of quality measures as a priority and key strategy to address low adult vaccination coverage rates. The use of quality measures can provide incentives for increased utilization of preventive services. To address the lack of adult immunization measures, the National Adult and Influenza Immunization Summit, a coalition of adult immunization partners led by the Immunization Action Coalition, Centers for Disease Control and Prevention, and National Vaccine Program Office, spearheaded efforts to (1) identify gaps and priorities in adult immunization quality performance measurement; (2) explore feasibility of data collection on adult immunizations through pilot testing and engaging stakeholders; and (3) develop and test quality measure specifications. This paper outlines the process by which a public-private partnership drove the development of two adult immunization performance measures-an adult immunization status measure for influenza, tetanus and diphtheria (Td) and/or tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap), herpes zoster and pneumococcal vaccines, and a prenatal immunization status measure for influenza and Tdap vaccinations in pregnant women. These measures have recently been added to the 2019 Healthcare Effectiveness Data and Information Set (HEDIS®), a widely used set of performance measures reportable by private health plans.
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http://dx.doi.org/10.1016/j.vaccine.2019.01.044DOI Listing
February 2019

Pain-related white matter tract abnormalities in mild traumatic brain injury patients with persistent headache.

Mol Pain 2018 Jan-Dec;14:1744806918810297. Epub 2018 Oct 16.

2 Veteran Affairs San Diego Healthcare System, CA, USA.

Background: The occurrence of debilitating chronic persistent (24/7) headache after mild traumatic brain injury represents a central neuropathic pain state. Previous studies suggest that this chronic headache state can be attributed to altered supraspinal modulatory functional connectivity in both resting and evoked pain states. Abnormalities in the myelin sheaths along the supraspinal superior longitudinal fasciculus and anterior thalamic radiation are frequently associated with alteration in pain modulation related to functional connectivity deficit with the prefrontal cortex. This study assessed the correlated axonal injury-related white matter tract abnormality underlying these previously observed prefrontal functional connectivity deficits by comparing the fractional anisotropy, axial diffusivity, and radial diffusivity of brain white matter in patients with mild traumatic brain injury-related headache to healthy controls.

Result: Diffusion tensor imaging data from patients ( N = 12, average age ±  SD = 35.0 ± 8.0 years old, 10 male) with mild traumatic brain injury-headache were compared with images acquired from healthy controls. The mild traumatic brain injury cohort demonstrated two areas of significant ( P < 0.01, F value >16, cluster size >50 voxels) white matter tract abnormalities closely related to pain affective and modulatory functions in (1) the left superior longitudinal fasciculus which connects the prefrontal cortices with the parietal cortices and (2) the right anterior thalamic radiation connecting the prefrontal cortices with the anterior cingulate cortex. In addition, a significant ( P < 0.01) decrease in axial diffusivity and increase in radial diffusivity at the superior longitudinal fasciculus cluster were noted in the mild traumatic brain injury cohort.

Conclusion: The identified white matter tract abnormalities may represent a state of Wallerian degeneration which correlates with the functional connectivity deficit in pain modulation and can contribute to the development of the chronic persistent headache in the patients with mild traumatic brain injury.
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http://dx.doi.org/10.1177/1744806918810297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311536PMC
April 2019

Promoting Adult Immunization Using Population-Based Data for a Composite Measure.

Am J Prev Med 2018 10 19;55(4):517-523. Epub 2018 Aug 19.

National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia.

Introduction: A composite adult immunization status measure is currently under consideration for adoption into the Healthcare Effectiveness Data and Information Set. This paper complements the Healthcare Effectiveness Data and Information Set health plan-level measure testing efforts by examining use of survey-based self-reported vaccination data to assess composite adult immunization coverage and identify limitations to using survey data to measure progress.

Methods: The 2015 National Health Interview Survey data were used in 2017 to calculate estimates for a composite of selected vaccines routinely recommended for adults aged ≥19 years, overall and in three age groups: 19-59, 60-64, and ≥65 years for tetanus and diphtheria toxoids (Td); tetanus toxoid; reduced diphtheria toxoid; and tetanus, diphtheria, acellular pertussis vaccine (Tdap); and herpes zoster, pneumococcal, and influenza vaccines.

Results: Composite coverage for adults aged ≥19 years including receipt of Tdap in the past 10 years and influenza vaccination was 11.9%, ranging from 6.3% in adults aged 60-64 years to 13.7% in adults aged 19-59 years. Excluding influenza, composite coverage was 20.7%, ranging from 8.1% (adults aged 60-64 years) to 25.2% (adults aged 19-59 years). In a composite including any Td-containing vaccine in the past 10 years, coverage including influenza vaccination for adults aged ≥19 years was 23.4%, ranging from 12.6% (adults aged 60-64 years) to 25.7% (adults aged 19-59 years). Excluding influenza, composite coverage was 51.4%, ranging from 15.8% (adults aged 60-64 years) to 63.0% (adults aged 19-59 years).

Conclusions: Survey-based vaccination data may under- or over-estimate coverage, but most adults require at least one additional vaccination by any metric. A composite measure provides a single focal point to promote adherence to standards of care.
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http://dx.doi.org/10.1016/j.amepre.2018.04.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422357PMC
October 2018

Preclinical QSP Modeling in the Pharmaceutical Industry: An IQ Consortium Survey Examining the Current Landscape.

CPT Pharmacometrics Syst Pharmacol 2018 03 1;7(3):135-146. Epub 2018 Feb 1.

Pfizer Worldwide Research and Development, San Diego, California, USA.

A cross-industry survey was conducted to assess the landscape of preclinical quantitative systems pharmacology (QSP) modeling within pharmaceutical companies. This article presents the survey results, which provide insights on the current state of preclinical QSP modeling in addition to future opportunities. Our results call attention to the need for an aligned definition and consistent terminology around QSP, yet highlight the broad applicability and benefits preclinical QSP modeling is currently delivering.
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http://dx.doi.org/10.1002/psp4.12282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5869550PMC
March 2018

The Differential Effects of Mindfulness and Distraction on Affect and Body Satisfaction Following Food Consumption.

Front Psychol 2017 27;8:1696. Epub 2017 Sep 27.

Melbourne School of Psychological Sciences, The University of Melbourne, Melbourne, VIC, Australia.

This study investigated whether engaging in mindfulness following food consumption produced changes in affect and body satisfaction, as compared to a control distraction task. The moderating effects of eating pathology and neuroticism were also examined. A total of 110 female university students consumed food and water before engaging in either a mindfulness induction or a control distraction task. Participants completed trait measures of eating pathology and neuroticism at baseline, and measures of state affect and body satisfaction before and after food consumption, and after the induction. Results revealed that consuming food and water reduced positive affect. Unexpectedly, both the mindfulness group and distraction control group experienced similar improvements in negative affect and body satisfaction following the induction. Eating pathology and neuroticism did not moderate the observed changes. These findings suggest that both mindfulness and distraction may contribute to the effectiveness of treatments for disordered eating that incorporate both of these techniques, such as Dialectical Behavior Therapy.
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http://dx.doi.org/10.3389/fpsyg.2017.01696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5623713PMC
September 2017

Left Dorsolateral Prefrontal Cortex rTMS in Alleviating MTBI Related Headaches and Depressive Symptoms.

Neuromodulation 2018 Jun 30;21(4):390-401. Epub 2017 May 30.

Veteran Affairs San Diego Healthcare System, San Diego, CA, USA.

Objective: Persistent mild traumatic brain injury related headache (MTBI-HA) represents a neuropathic pain state. This study tested the hypothesis that repetitive transcranial magnetic stimulation (rTMS) at the left prefrontal cortex can alleviate MTBI-HA and associated neuropsychological dysfunctions.

Methods And Materials: Veterans with MTBI-HA were randomized to receive four sessions of either real (REAL group) or sham (SHAM group) high frequency rTMS delivered at 10 Hz, 80% of resting motor threshold and 2000 pulses per session at >24 and <72 hours apart. Pre-treatment, post-treatment 1-week and 4-week headache and neuropsychological assessments were conducted.

Results: Twenty nine out of forty-four consented subjects completed the study. A two-factor (visit × treatment) repeated measures ANOVA showed a significant (p = 0.002, F = 11.63, df = 1) interaction for the average daily persistent headache intensity with the REAL group exhibiting a significant (p < 0.0001) average reduction (±SD) of 25.3 ± 16.8% and 23.0 ± 17.7% reduction in their numerical rating scale at the one-week and four-week post-treatment assessments in comparison to <1 ± 11.7% and 2.3 ± 14.5% reduction found in the SHAM group. In addition, a significant (p < 0.01) 50% and 57% reduction was found in the prevalence of persistent headache in the REAL group at the one-week and four-week assessments in comparison to 7% and 20% reduction found in the SHAM group. Furthermore, the REAL group demonstrated a significant (p = 0.033) improvement (from 22.3 ± 6.4 at pre-treatment to 19.0 ± 5.0 at post-treatment one-week) in the Hamilton Rating Scale for Depression score, while the SHAM group's score remained largely unchanged (from 25.33 ± 8.43 to 24.64 ± 5.03) in the same time frame. This trend of improvement, although not statistically significant, continues to the post-treatment four-week assessment.

Conclusion: A short-course rTMS at the left DLPFC can alleviate MTBI-HA symptoms and provide a transient mood enhancing benefit. Further studies are required to establish a clinical protocol balancing both treatment efficacy and patient compliance.
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http://dx.doi.org/10.1111/ner.12615DOI Listing
June 2018

Translational pharmacokinetic-pharmacodynamic analysis in the pharmaceutical industry: an IQ Consortium PK-PD Discussion Group perspective.

Drug Discov Today 2017 10 2;22(10):1447-1459. Epub 2017 May 2.

Novartis Institutes for Biomedical Research, Cambridge, MA, USA.

With inadequate efficacy being the primary cause for the attrition of drug candidates in clinical development, the need to better predict clinical efficacy earlier in the drug development process has increased in importance in the pharmaceutical industry. Here, we review current applications of translational pharmacokinetic-pharmacodynamic (PK-PD) modeling of preclinical data in the pharmaceutical industry, including best practices. Preclinical translational PK-PD modeling has been used in many therapeutic areas and has been impactful to drug development. The role of preclinical translational PK-PD modeling in drug discovery and development will continue to evolve and broaden, given that its broad implementation in the pharmaceutical industry is relatively recent and many opportunities still exist for its further application.
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http://dx.doi.org/10.1016/j.drudis.2017.04.015DOI Listing
October 2017

Novel 2-Substituted 7-Azaindole and 7-Azaindazole Analogues as Potential Antiviral Agents for the Treatment of Influenza.

ACS Med Chem Lett 2017 Feb 18;8(2):261-265. Epub 2017 Jan 18.

Vertex Pharmaceuticals Incorporated , 50 Northern Avenue, Boston, Massachusetts 02210, United States.

JNJ-63623872 () is a first-in-class, orally bioavailable compound that offers significant potential for the treatment of pandemic and seasonal influenza. Early lead optimization efforts in our 7-azaindole series focused on 1,3-diaminocyclohexyl amide and urea substitutions on the pyrimidine-7-azaindole motif. In this work, we explored two strategies to eliminate observed aldehyde oxidase (AO)-mediated metabolism at the 2-position of these 7-azaindole analogues. Substitution at the 2-position of the azaindole ring generated somewhat less potent analogues, but reduced AO-mediated metabolism. Incorporation of a ring nitrogen generated 7-azaindazole analogues that were equipotent to the parent 2-H-7-azaindole, but surprisingly, did not appear to improve AO-mediated metabolism. Overall, we identified multiple 2-substituted 7-azaindole analogues with enhanced AO stability and we present data for one such compound () that demonstrate a favorable oral pharmacokinetic profile in rodents. These analogues have the potential to be further developed as anti-influenza agents for the treatment of influenza.
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http://dx.doi.org/10.1021/acsmedchemlett.6b00487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5304303PMC
February 2017

Discovery of Novel, Orally Bioavailable β-Amino Acid Azaindole Inhibitors of Influenza PB2.

ACS Med Chem Lett 2017 Feb 20;8(2):256-260. Epub 2017 Jan 20.

Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.

In our efforts to develop novel small-molecule inhibitors for the treatment of influenza, we utilized molecular modeling and the X-ray crystal structure of the PB2 subunit of the influenza polymerase to optimize a series of acyclic β-amino acid inhibitors, highlighted by compound . Compound showed good oral exposure in both rat and mouse. More importantly, it showed strong potency versus multiple influenza-A strains, including pandemic 2009 H1N1 and avian H5N1 strains and showed a strong efficacy profile in a mouse influenza model even when treatment was initiated 48 h after infection. Compound offers good oral bioavailability with great potential for the treatment of both pandemic and seasonal influenza.
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http://dx.doi.org/10.1021/acsmedchemlett.6b00486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5304291PMC
February 2017

Diminished supraspinal pain modulation in patients with mild traumatic brain injury.

Mol Pain 2016 16;12. Epub 2016 Aug 16.

Veteran Administration San Diego Healthcare System, San Diego, CA, USA Department of Radiology, The University of California, San Diego, CA, USA.

Background: Chronic pain conditions are highly prevalent in patients with mild traumatic brain injury. Supraspinal diffuse axonal injury is known to dissociate brain functional connectivity in these patients. The effect of this dissociated state on supraspinal pain network is largely unknown. A functional magnetic resonance imaging study was conducted to compare the supraspinal pain network in patients with mild traumatic brain injury to the gender and age-matched healthy controls with the hypothesis that the functional connectivities of the medial prefrontal cortices, a supraspinal pain modulatory region to other pain-related sensory discriminatory and affective regions in the mild traumatic brain injury subjects are significantly reduced in comparison to healthy controls.

Results: The mild traumatic brain injury group (N = 15) demonstrated significantly (P < 0.01, cluster threshold > 150 voxels) less activities in the thalamus, pons, anterior cingulate cortex, insula, dorsolateral prefrontal cortex, and medial prefrontal cortices than the healthy control group (N = 15). Granger Causality Analyses (GCA) indicated while the left medial prefrontal cortices of the healthy control group cast a noticeable degree of outward (to affect) causality inference to multiple pain processing related regions, this outward inference pattern was not observed in the mild traumatic brain injury group. On the other hand, only patients' bilateral anterior cingulate cortex received multiple inward (to be affected) causality inferences from regions including the primary and secondary somatosensory cortices and the inferior parietal lobe. Resting state functional connectivity analyses indicated that the medial prefrontal cortices of the mild traumatic brain injury group demonstrated a significantly (P < 0.01, F = 3.6, cluster size > 150 voxels) higher degree of functional connectivity to the inferior parietal lobe, premotor and secondary somatosensory cortex than the controls. Conversely, the anterior cingulate cortex of the healthy group demonstrated significantly (P < 0.01, F = 3.84, cluster size > 150 voxels) less degree of functional connectivities to the inferior parietal lobe and secondary somatosensory cortex than their mild traumatic brain injury counterparts.

Conclusions: In short, the current study demonstrates that patients with mild traumatic brain injury and headaches appear to have an altered state of supraspinal modulatory and affective functions related to pain perception.
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http://dx.doi.org/10.1177/1744806916662661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4989585PMC
February 2018

Unusual case of appendicitis.

BMJ Case Rep 2016 Jun 30;2016. Epub 2016 Jun 30.

Imperial College London, London, UK.

A teenage girl was admitted to the paediatric assessment unit with non-specific abdominal pain that gradually localised to the right iliac fossa (RIF). She remained systemically well; investigations including blood tests, urine sample and abdominal ultrasound were inconclusive. Surgical opinion was sought and the decision was made to perform a diagnostic laparoscopy due to the ongoing pain. Laparoscopy showed no evidence of any significant pathology, and appendicectomy was performed following the routine practice. Numerous pinworms came out while the appendix was resected. The RIF pain resolved and the patient made a full post-operative recovery. A stat dose of mebendazole and amoxicillin were given and the immediate family was also treated. Enterobius vermicularis (pinworm) causes significant morbidity worldwide and has a high prevalence among children in the UK. It can be easily treated and prompt recognition based on clinical symptoms can potentially prevent unnecessary surgery.
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http://dx.doi.org/10.1136/bcr-2016-214944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4932348PMC
June 2016

Repetitive Transcranial Magnetic Stimulation in Managing Mild Traumatic Brain Injury-Related Headaches.

Neuromodulation 2016 Feb 10;19(2):133-41. Epub 2015 Nov 10.

Veteran Administration San Diego Healthcare System, La Jolla, CA, USA.

Objective: Headache is one of the most common debilitating chronic pain conditions in either active or retired military personnel with mild traumatic brain injury (MTBI). This study assessed the effect of repetitive transcranial magnetic stimulation (rTMS) in alleviating MTBI-related headache (MTBI-HA).

Materials And Method: Veterans with MTBI-HA were randomized to receive either real rTMS (REAL group) at 10 hz for a total of 2000 pulses divided into 20 trains with one-sec inter-train interval or sham rTMS (SHAM group) at the left motor cortex (LMC) with brain magnetic resonance imaging neuronavigation guidance. Pretreatment, posttreatment one-week and four-week headache and neuropsychological assessments were conducted.

Result: Thirty veterans were screened and twenty four (21 men and 3 women with average year-old ± SD at 14.3 ± 12.6) subjects' data were analyzed. A two-factor (visit × treatment) repeated measures analysis of variance (RM-ANOVA) indicated a close to significant (p = 0.06) trend of interaction between pretreatment and posttreatment one-week assessment with the intensity of the persistent daily headache decreasing from 5.7 ± 1.9 to 2.2 ± 2.7 and 4.6 ± 1.3 to 3.5 ± 2.0 for the REAL and SHAM groups, respectively. Subsequent analyses indicated REAL group demonstrated a significantly (p = 0.041) higher % of reduction in persistent headache intensity than the SHAM group (56.3 ± 48.2% vs.15.4 ± 43.6%) at the posttreatment one-week assessment and the trend continued to the four-week assessment. Overall, a significantly (p = 0.035) higher percentage of the subjects in the REAL group (58.3%) demonstrated at least a 50% headache intensity reduction at posttreatment one-week assessment compared with the SHAM group (16.6%). The overall composite score of functionally debilitating headache exacerbation is significantly (p = 0.017) reduced in REAL group at the posttreatment four-week assessment in comparison with the SHAM group. No major sustained change in neuropsychological assessments was noted.

Conclusion: The studied rTMS protocol appears to be a clinically feasible and effective treatment option in managing MTBI-HA.
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http://dx.doi.org/10.1111/ner.12364DOI Listing
February 2016

COLOR III: a multicentre randomised clinical trial comparing transanal TME versus laparoscopic TME for mid and low rectal cancer.

Surg Endosc 2016 08 4;30(8):3210-5. Epub 2015 Nov 4.

Department of Surgery, VU University Medical Centre, Postbus 7057, 1007 MB, Amsterdam, The Netherlands.

Introduction: Total mesorectal excision (TME) is an essential component of surgical management of rectal cancer. Both open and laparoscopic TME have been proven to be oncologically safe. However, it remains a challenge to achieve complete TME with clear circumferential resections margin (CRM) with the conventional transabdominal approach, particularly in mid and low rectal tumours. Transanal TME (TaTME) was developed to improve oncological and functional outcomes of patients with mid and low rectal cancer.

Methods: An international, multicentre, superiority, randomised trial was designed to compare TaTME and conventional laparoscopic TME as the surgical treatment of mid and low rectal carcinomas. The primary endpoint is involved CRM. Secondary endpoints include completeness of mesorectum, residual mesorectum, morbidity and mortality, local recurrence, disease-free and overall survival, percentage of sphincter-saving procedures, functional outcome and quality of life. A Quality Assurance Protocol including centralised MRI review, histopathology re-evaluation, standardisation of surgical techniques, and monitoring and assessment of surgical quality will be conducted.

Discussion: The difference in involvement of CRM between the two treatment strategies is thought to be in favour of the TaTME. TaTME is therefore expected to be superior to laparoscopic TME in terms of oncological outcomes in case of mid and low rectal carcinomas.
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http://dx.doi.org/10.1007/s00464-015-4615-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4956704PMC
August 2016

Novel Ranking System for Identifying Efficacious Anti-Influenza Virus PB2 Inhibitors.

Antimicrob Agents Chemother 2015 Oct 13;59(10):6007-16. Epub 2015 Jul 13.

Department of Infectious Diseases, Vertex Pharmaceuticals Inc., Boston, Massachusetts, USA.

Through antigenic drift and shifts, influenza virus infections continue to be an annual cause of morbidity in healthy populations and of death among elderly and at-risk patients. The emergence of highly pathogenic avian influenza viruses such as H5N1 and H7N9 and the rapid spread of the swine-origin H1N1 influenza virus in 2009 demonstrate the continued need for effective therapeutic agents for influenza. While several neuraminidase inhibitors have been developed for the treatment of influenza virus infections, these have shown a limited window for treatment initiation, and resistant variants have been noted in the population. In addition, an older class of antiviral drugs for influenza, the adamantanes, are no longer recommended for treatment due to widespread resistance. There remains a need for new influenza therapeutic agents with improved efficacy as well as an expanded window for the initiation of treatment. Azaindole compounds targeting the influenza A virus PB2 protein and demonstrating excellent in vitro and in vivo properties have been identified. To evaluate the in vivo efficacy of these PB2 inhibitors, we utilized a mouse influenza A virus infection model. In addition to traditional endpoints, i.e., death, morbidity, and body weight loss, we measured lung function using whole-body plethysmography, and we used these data to develop a composite efficacy score that takes compound exposure into account. This model allowed the rapid identification and ranking of molecules relative to each other and to oseltamivir. The ability to identify compounds with enhanced preclinical properties provides an opportunity to develop more-effective treatments for influenza in patients.
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http://dx.doi.org/10.1128/AAC.00781-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4576026PMC
October 2015

Preclinical pharmacokinetic/pharmacodynamic modeling and simulation in the pharmaceutical industry: an IQ consortium survey examining the current landscape.

AAPS J 2015 Mar 29;17(2):462-73. Epub 2015 Jan 29.

Modeling and Simulation, Eisai Inc., 155 Tice Blvd, Woodcliff Lake, NJ, 07677, USA,

The application of modeling and simulation techniques is increasingly common in preclinical stages of the drug discovery and development process. A survey focusing on preclinical pharmacokinetic/pharmacodynamics (PK/PD) analysis was conducted across pharmaceutical companies that are members of the International Consortium for Quality and Innovation in Pharmaceutical Development. Based on survey responses, ~68% of companies use preclinical PK/PD analysis in all therapeutic areas indicating its broad application. An important goal of preclinical PK/PD analysis in all pharmaceutical companies is for the selection/optimization of doses and/or dose regimens, including prediction of human efficacious doses. Oncology was the therapeutic area with the most PK/PD analysis support and where it showed the most impact. Consistent use of more complex systems pharmacology models and hybrid physiologically based pharmacokinetic models with PK/PD components was less common compared to traditional PK/PD models. Preclinical PK/PD analysis is increasingly being included in regulatory submissions with ~73% of companies including these data to some degree. Most companies (~86%) have seen impact of preclinical PK/PD analyses in drug development. Finally, ~59% of pharmaceutical companies have plans to expand their PK/PD modeling groups over the next 2 years indicating continued growth. The growth of preclinical PK/PD modeling groups in pharmaceutical industry is necessary to establish required resources and skills to further expand use of preclinical PK/PD modeling in a meaningful and impactful manner.
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http://dx.doi.org/10.1208/s12248-014-9716-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4365101PMC
March 2015

Preclinical activity of VX-787, a first-in-class, orally bioavailable inhibitor of the influenza virus polymerase PB2 subunit.

Antimicrob Agents Chemother 2015 Mar 29;59(3):1569-82. Epub 2014 Dec 29.

Department of Chemistry, Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA

VX-787 is a novel inhibitor of influenza virus replication that blocks the PB2 cap-snatching activity of the influenza viral polymerase complex. Viral genetics and X-ray crystallography studies provide support for the idea that VX-787 occupies the 7-methyl GTP (m(7)GTP) cap-binding site of PB2. VX-787 binds the cap-binding domain of the PB2 subunit with a KD (dissociation constant) of 24 nM as determined by isothermal titration calorimetry (ITC). The cell-based EC50 (the concentration of compound that ensures 50% cell viability of an uninfected control) for VX-787 is 1.6 nM in a cytopathic effect (CPE) assay, with a similar EC50 in a viral RNA replication assay. VX-787 is active against a diverse panel of influenza A virus strains, including H1N1pdm09 and H5N1 strains, as well as strains with reduced susceptibility to neuraminidase inhibitors (NAIs). VX-787 was highly efficacious in both prophylaxis and treatment models of mouse influenza and was superior to the neuraminidase inhibitor, oseltamivir, including in delayed-start-to-treat experiments, with 100% survival at up to 96 h postinfection and partial survival in groups where the initiation of therapy was delayed up to 120 h postinfection. At different doses, VX-787 showed a 1-log to >5-log reduction in viral load (relative to vehicle controls) in mouse lungs. Overall, these favorable findings validate the PB2 subunit of the viral polymerase as a drug target for influenza therapy and support the continued development of VX-787 as a novel antiviral agent for the treatment of influenza infection.
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http://dx.doi.org/10.1128/AAC.04623-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4325764PMC
March 2015

Discovery of a novel, first-in-class, orally bioavailable azaindole inhibitor (VX-787) of influenza PB2.

J Med Chem 2014 Aug 24;57(15):6668-78. Epub 2014 Jul 24.

Vertex Pharmaceuticals Inc. , 50 Northern Ave, Boston, Massachusetts 02210, United States.

In our effort to develop agents for the treatment of influenza, a phenotypic screening approach utilizing a cell protection assay identified a series of azaindole based inhibitors of the cap-snatching function of the PB2 subunit of the influenza A viral polymerase complex. Using a bDNA viral replication assay (Wagaman, P. C., Leong, M. A., and Simmen, K. A. Development of a novel influenza A antiviral assay. J. Virol. Methods 2002, 105, 105-114) in cells as a direct measure of antiviral activity, we discovered a set of cyclohexyl carboxylic acid analogues, highlighted by VX-787 (2). Compound 2 shows strong potency versus multiple influenza A strains, including pandemic 2009 H1N1 and avian H5N1 flu strains, and shows an efficacy profile in a mouse influenza model even when treatment was administered 48 h after infection. Compound 2 represents a first-in-class, orally bioavailable, novel compound that offers potential for the treatment of both pandemic and seasonal influenza and has a distinct advantage over the current standard of care treatments including potency, efficacy, and extended treatment window.
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http://dx.doi.org/10.1021/jm5007275DOI Listing
August 2014

Contributions of the Global Emerging Infections Surveillance and Response System Network to global health security in 2011.

US Army Med Dep J 2013 Apr-Jun:7-18

Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.

In its 15th year, the Global Emerging Infections Surveillance and Response System (GEIS) continued to make significant contributions to global public health and emerging infectious disease surveillance worldwide. As a division of the US Department of Defense's Armed Forces Health Surveillance Center since 2008, GEIS coordinated a network of surveillance and response activities through collaborations with 33 partners in 76 countries. The GEIS was involved in 73 outbreak responses in fiscal year 2011. Significant laboratory capacity-building initiatives were undertaken with 53 foreign health, agriculture and/or defense ministries, as well as with other US government entities and international institutions, including support for numerous national influenza centers. Equally important, a variety of epidemiologic training endeavors reached over 4,500 individuals in 96 countries. Collectively, these activities enhanced the ability of partner countries and the US military to make decisions about biological threats and design programs to protect global public health as well as global health security.
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August 2013

The U.S. military's Neisseria gonorrhoeae resistance surveillance initiatives in selected populations of five countries.

MSMR 2013 Feb;20(2):25-7

Armed Forces Health Surveillance Center, Silver Spring, Maryland, USA.

Multi-drug resistant Neisseria gonorrhoeae (GC) threatens the successful treatment of gonorrhea. This report presents preliminary findings with regard to the prevalence of laboratory-confirmed GC and the extent of drug-resistance among sample populations in five countries. Between October 2010 and January 2013, 1,694 subjects (54% male; 45% female; 1% unknown) were enrolled and screened for the presence of laboratory-confirmed GC in the United States, Djibouti, Ghana, Kenya, and Peru. Overall, 108 (6%) of enrolled subjects tested positive for GC. Antimicrobial susceptibility testing results were available for 66 GC isolates. Resistance to at least three antibiotics was observed at each overseas site. All isolates tested in Ghana (n=6) were resistant to ciprofloxacin, penicillin, and tetracycline. In Djibouti, preliminary results suggested resistance to penicillin, tetracycline, ciprofloxacin, cefepime, and ceftriaxone. The small sample size and missing data prevent comparative analysis and limit the generalizability of these preliminary findings.
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February 2013
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