Publications by authors named "Bruce Wang"

77 Publications

Hierarchical transitions and fractal wrinkling drive bacterial pellicle morphogenesis.

Proc Natl Acad Sci U S A 2021 May;118(20)

Department of Molecular Biology, Princeton University, Princeton, NJ 08544;

Bacterial cells can self-organize into structured communities at fluid-fluid interfaces. These soft, living materials composed of cells and extracellular matrix are called pellicles. Cells residing in pellicles garner group-level survival advantages such as increased antibiotic resistance. The dynamics of pellicle formation and, more generally, how complex morphologies arise from active biomaterials confined at interfaces are not well understood. Here, using as our model organism, a custom-built adaptive stereo microscope, fluorescence imaging, mechanical theory, and simulations, we report a fractal wrinkling morphogenesis program that differs radically from the well-known coalescence of wrinkles into folds that occurs in passive thin films at fluid-fluid interfaces. Four stages occur: growth of founding colonies, onset of primary wrinkles, development of secondary curved ridge instabilities, and finally the emergence of a cascade of finer structures with fractal-like scaling in wavelength. The time evolution of pellicle formation depends on the initial heterogeneity of the film microstructure. Changing the starting bacterial seeding density produces three variations in the sequence of morphogenic stages, which we term the bypass, crystalline, and incomplete modes. Despite these global architectural transitions, individual microcolonies remain spatially segregated, and thus, the community maintains spatial and genetic heterogeneity. Our results suggest that the memory of the original microstructure is critical in setting the morphogenic dynamics of a pellicle as an active biomaterial.
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http://dx.doi.org/10.1073/pnas.2023504118DOI Listing
May 2021

The acute hepatic porphyrias.

Authors:
Bruce Wang

Transl Gastroenterol Hepatol 2021 5;6:24. Epub 2021 Apr 5.

Department of Medicine, University of California San Francisco, San Francisco, CA, USA.

The acute hepatic porphyrias (AHP) are a group of four inherited diseases of heme biosynthesis. They present with similar severe, episodic, acute neurovisceral symptoms due to abnormally elevated levels of porphyrin precursors delta-aminolevulinic acid (ALA). Recently genetic screening indicates that the prevalence of mutation carrier state is more common than previously thought, occurring in 1 in 1,500, though the clinical penetrance of symptomatic AHP is low at ~1%. Symptomatic attacks occur primarily in females during their reproductive years. In an acute porphyria attack, the primary symptom is abdominal pain, due to intestinal dysmotility from autonomic nerve injury. Other manifestations include seizures, weakness and mood changes, point to injury involving peripheral and central nervous system. Due to the non-specific nature of the symptoms and signs in AHP, the diagnosis is often delayed by many years. The diagnosis of AHP depends on biochemical evidence of elevated ALA and PBG levels in urine during symptomatic attacks. Genetic testing is used for confirmation of the gene involved and the exact mutation. Treatment involves administration of heme, which downregulates production of ALA. Long-term management centers on educating genetic carriers on avoiding triggers that increase the risk of acute attacks and screening family members.
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http://dx.doi.org/10.21037/tgh-2020-01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838531PMC
April 2021

Novel treatment options for acute hepatic porphyrias.

Authors:
Bruce Wang

Curr Opin Gastroenterol 2021 May;37(3):194-199

Department of Medicine, University of California, San Francisco, San Francisco, California, USA.

Purpose Of Review: Acute hepatic porphyrias (AHP) are a group of rare diseases that are characterized by episodic acute neurovisceral pain episodes caused by abnormal accumulation of the neurotoxic porphyrin precursor delta-aminolevulinic acid (ALA). Patient with frequent recurrent acute attacks have been difficult to treat and these patients sometimes require liver transplantation. Recent developments in small interfering RNA (siRNA)-based therapy led to the development of an effective prophylactic treatment for patients with frequent recurrent attacks. This review will describe treatment options for AHP and highlight management in light of new treatment option.

Recent Findings: Givosiran is a novel siRNA-based therapy targeted specifically to hepatocytes to inhibit ALA synthase 1, the first and rate-limiting step in heme biosynthesis. Patients with frequent recurrent attacks treated with givosiran had durable normalization of ALA and significantly reduced numbers of acute attacks and need for hemin treatment. The overall safety profile for givosiran was comparable with placebo and the drug was recently approved by the Food and Drug Administration for treatment of AHP patients.

Summary: Givosiran is an effective treatment for prevention of acute porphyria attacks in AHP patients with frequent recurrent attacks.
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http://dx.doi.org/10.1097/MOG.0000000000000734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104969PMC
May 2021

A systematic literature review of economic evaluations of pneumococcal conjugate vaccines in east and southeast Asia (2006-2019).

Expert Rev Vaccines 2021 Mar 22:1-14. Epub 2021 Mar 22.

Health Economics and Outcomes Research, Pfizer Inc, New York, NY, USA.

Introduction: Pneumococcal infections can lead to serious invasive diseases such as meningitis, septicemia and pneumonia, as well as milder but more common illnesses such as sinusitis and otitis media. The World Health Organization (WHO) recommends the inclusion of pneumococcal conjugate vaccines (PCVs) in infant National Immunization Program (NIP) programs worldwide. Decision-makers in Asian countries planning to introduce PCVs in their respective NIP will need a comprehensive evidence of effectiveness of PCVs at the population level and economic evidence including cost-effectiveness.

Areas Covered: A systematic literature review (from 1/1/2016 to 10/11/2019) of PCVs in East and Southeast Asia to understand (1) the contributing factors to cost-effectiveness results of PCVs and (2) whether gaps in evidence exist suggesting why the region may have yet to implement full NIPs.

Expert Opinion: In East and Southeast Asia, vaccination with PCVs was found to significantly reduce the mortality and morbidity of pneumococcal diseases and was cost-effective compared to no vaccination. Study assumptions, specifically vaccine local acquisition, the inclusion or exclusion of indirect effects (serotype replacement and herd effect), cross-protection, and protection against nontypeable and serotype 3, were the main drivers of cost-effectiveness.
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http://dx.doi.org/10.1080/14760584.2021.1894933DOI Listing
March 2021

TBX3 functions as a tumor suppressor downstream of activated CTNNB1 mutants during hepatocarcinogenesis.

J Hepatol 2021 Feb 10. Epub 2021 Feb 10.

Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, San Francisco, CA, USA. Electronic address:

Background & Aims: Gain of function (GOF) mutations in the CTNNB1 gene are one of the most frequent genetic events in hepatocellular carcinoma (HCC). T-box transcription factor 3 (TBX3) is a liver-specific target of the Wnt/β-catenin pathway and thought to be an oncogene mediating activated β-catenin-driven HCC formation.

Methods: We evaluated the expression pattern of TBX3 in human HCC specimens. Tbx3 was conditionally knocked out in murine HCC models by hydrodynamic tail vein injection of Cre together with c-Met and ΔN90-β-catenin (c-Met/β-catenin) in Tbx3 mice. TBX3 was overexpressed in human HCC cell lines to investigate the functions of TBX3 in vitro.

Results: A bimodal expression pattern of TBX3 in human HCC samples was detected: high expression of TBX3 in GOF CTNNB1 HCC and downregulation of TBX3 in non-CTNNB1 mutant tumors. High expression of TBX3 was associated with increased differentiation and decreased expression signatures of tumor growth. Using Tbx3 mice, we found that ablation of Tbx3 significantly accelerates c-Met/β-catenin-driven HCC formation. Moreover, Tbx3(-) HCC demonstrated increased YAP/TAZ activity. The accelerated tumor growth induced by loss of TBX3 in c-Met/β-catenin mouse HCC was successfully prevented by overexpression of LATS2, which inhibited YAP/TAZ activity. In human HCC cell lines, overexpression of TBX3 inhibited HCC cell growth as well as YAP/TAZ activation. A negative correlation between TBX3 and YAP/TAZ target genes was observed in human HCC samples. Mechanistically, phospholipase D1 (PLD1), a known positive regulator of YAP/TAZ, was identified as a novel transcriptional target repressed by TBX3.

Conclusion: Our study suggests that TBX3 is induced by GOF CTNNB1 mutants and suppresses HCC growth by inactivating PLD1, thus leading to the inhibition of YAP/TAZ oncogenes.

Lay Summary: TBX3 is a liver-specific target of the Wnt/β-catenin pathway and thought to be an oncogene in promoting liver cancer development. Herein, we demonstrate that TBX3 is in fact a tumor suppressor gene that restricts liver tumor growth. Strategies which increase TBX3 expression and/or activities may be effective for HCC treatment.
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http://dx.doi.org/10.1016/j.jhep.2021.01.044DOI Listing
February 2021

Pituitary stem cells produce paracrine WNT signals to control the expansion of their descendant progenitor cells.

Elife 2021 Jan 5;10. Epub 2021 Jan 5.

Centre for Craniofacial and Regenerative Biology, King's College London, London, United Kingdom.

In response to physiological demand, the pituitary gland generates new hormone-secreting cells from committed progenitor cells throughout life. It remains unclear to what extent pituitary stem cells (PSCs), which uniquely express SOX2, contribute to pituitary growth and renewal. Moreover, neither the signals that drive proliferation nor their sources have been elucidated. We have used genetic approaches in the mouse, showing that the WNT pathway is essential for proliferation of all lineages in the gland. We reveal that SOX2 stem cells are a key source of WNT ligands. By blocking secretion of WNTs from SOX2 PSCs in vivo, we demonstrate that proliferation of neighbouring committed progenitor cells declines, demonstrating that progenitor multiplication depends on the paracrine WNT secretion from SOX2 PSCs. Our results indicate that stem cells can hold additional roles in tissue expansion and homeostasis, acting as paracrine signalling centres to coordinate the proliferation of neighbouring cells.
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http://dx.doi.org/10.7554/eLife.59142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803373PMC
January 2021

Evidence in the UK Biobank for the underdiagnosis of erythropoietic protoporphyria.

Genet Med 2021 Jan 2;23(1):140-148. Epub 2020 Sep 2.

Deparment of Medicine, Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA, USA.

Purpose: Erythropoietic protoporphyria (EPP), characterized by painful cutaneous photosensitivity, results from pathogenic variants in ferrochelatase (FECH). For 96% of patients, EPP results from coinheriting a rare pathogenic variant in trans of a common hypomorphic variant c.315-48T>C (minor allele frequency 0.05). The estimated prevalence of EPP derived from the number of diagnosed individuals in Europe is 0.00092%, but this may be conservative due to underdiagnosis. No study has estimated EPP prevalence using large genetic data sets.

Methods: Disease-associated FECH variants were identified in the UK Biobank, a data set of 500,953 individuals including 49,960 exome sequences. EPP prevalence was then estimated. The association of FECH variants with EPP-related traits was assessed.

Results: Analysis of pathogenic FECH variants in the UK Biobank provides evidence that EPP prevalence is 0.0059% (95% confidence interval [CI]: 0.0042-0.0076%), 1.7-3.0 times more common than previously thought in the UK. In homozygotes for the common c.315-48T>C FECH variant, there was a novel decrement in both erythrocyte mean corpuscular volume (MCV) and hemoglobin.

Conclusion: The prevalence of EPP has been underestimated secondary to underdiagnosis. The common c.315-48T>C allele is associated with both MCV and hemoglobin, an association that could be important both for those with and without EPP.
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http://dx.doi.org/10.1038/s41436-020-00951-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796935PMC
January 2021

Hepatocellular Carcinoma in Acute Hepatic Porphyrias: Results from the Longitudinal Study of the U.S. Porphyrias Consortium.

Hepatology 2021 May 11;73(5):1736-1746. Epub 2020 Dec 11.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.

Background And Aims: The risk for hepatocellular carcinoma (HCC) is increased in acute hepatic porphyrias (AHP). The aim of this study was to explore the clinicopathologic characteristics, outcomes, and frequency of HCC in patients with AHP in the United States.

Approach And Results: This cross-sectional analysis evaluated patients with HCC in a multicenter, longitudinal study of AHP. Among 327 patients with AHP, 5 (1.5%) were diagnosed with HCC. Of the 5 HCC cases, 4 had acute intermittent porphyria and 1 had variegate porphyria, confirmed by biochemical and/or genetic testing. All patients were white females, with a median age of 27 years (range 21-75) at diagnosis. The median age at HCC diagnosis was 69 years (range 61-74). AHP was asymptomatic in 2 patients; 2 reported sporadic attacks; and 1 reported recurrent attacks (>4 attacks/year). All patients had a single HCC lesion on liver imaging that was 1.8-6.5 centimeters in diameter. Serum alpha fetoprotein levels were below 10 ng/mL in all 4 patients with available results. Four patients underwent liver resection, and 1 was treated with radioembolization. No significant inflammation or fibrosis was found in adjacent liver tissues of 3 patients who underwent liver resection. Two patients developed recurrence of HCC at 22 and 26 months following liver resection. All patients are alive with survival times from HCC diagnosis ranging from 26-153 months.

Conclusion: In this U.S. study, 1.5% of patients with AHP had HCC. HCC in AHP occurred in the absence of cirrhosis, which contrasts with other chronic liver diseases. Patients with AHP, regardless of clinical attacks, should be screened for HCC, beginning at age 50. The pathogenesis of hepatocarcinogenesis in AHP is unknown and needs further investigation.
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http://dx.doi.org/10.1002/hep.31460DOI Listing
May 2021

Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria.

N Engl J Med 2020 06;382(24):2289-2301

From the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York (M.B.); Porphyria Center Sweden, Center for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm (E.S., P.H., D.V.); the Department of Surgical and Medical Sciences for Children and Adults, Internal Medicine Unit, University of Modena and Reggio Emilia, Modena, Italy (P.V.); Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona (P.A.P.); King's College London, King's College Hospital, London (D.C.R., P.E.S.); Klinikum Chemnitz, Chemnitz, Germany (U.S.); the Liver Center and Porphyria Center, University of California, San Francisco, San Francisco (D.M.B., B.W.); the Section on Gastroenterology and Hepatology, Wake Forest University-North Carolina Baptist Medical Center, Winston-Salem (H.L.B.); the Department of Hemostatic Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the University of Texas Medical Branch, Galveston (K.E.A.); the University of Utah, Salt Lake City (C. Parker, J.P.); the University of Michigan, Ann Arbor (S.M.S.); the Department of Medicine, Division of Hematology, University of Washington, Seattle (S.B.K.); the Center for Rare Disease and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan (J.-D.W.); St. Ivan Rilski University Hospital, Sofia, Bulgaria (A.I.); Porphyria Center Rotterdam, Center for Lysosomal and Metabolic Disease, Department of Internal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, the Netherlands (J.G.L.); the Department of Medicine, University Hospital of Helsinki, Helsinki, Finland (R.K.); Stadtspital Triemli, Zentrallabor, Zurich, Switzerland (E.M.); Tottori University School of Medicine, Tottori, Japan (Y.H.); Alnylam Pharmaceuticals, Cambridge, MA (C. Penz, J.C., S.L., J.J.K., M.T.S., P.G., A.V., J.B.K., A.R.S.); and the University of Paris and the Laboratory of Excellence GR-Ex, Paris, and Centre de Référence Maladies Rares Porphyries, Assistance Publique-Hôpitaux de Paris, Colombes - all in France (L.G.).

Background: Up-regulation of hepatic delta-aminolevulinic acid synthase 1 (ALAS1), with resultant accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen, is central to the pathogenesis of acute attacks and chronic symptoms in acute hepatic porphyria. Givosiran, an RNA interference therapy, inhibits ALAS1 expression.

Methods: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned symptomatic patients with acute hepatic porphyria to receive either subcutaneous givosiran (2.5 mg per kilogram of body weight) or placebo monthly for 6 months. The primary end point was the annualized rate of composite porphyria attacks among patients with acute intermittent porphyria, the most common subtype of acute hepatic porphyria. (Composite porphyria attacks resulted in hospitalization, an urgent health care visit, or intravenous administration of hemin at home.) Key secondary end points were levels of ALA and porphobilinogen and the annualized attack rate among patients with acute hepatic porphyria, along with hemin use and daily worst pain scores in patients with acute intermittent porphyria.

Results: A total of 94 patients underwent randomization (48 in the givosiran group and 46 in the placebo group). Among the 89 patients with acute intermittent porphyria, the mean annualized attack rate was 3.2 in the givosiran group and 12.5 in the placebo group, representing a 74% lower rate in the givosiran group (P<0.001); the results were similar among the 94 patients with acute hepatic porphyria. Among the patients with acute intermittent porphyria, givosiran led to lower levels of urinary ALA and porphobilinogen, fewer days of hemin use, and better daily scores for pain than placebo. Key adverse events that were observed more frequently in the givosiran group were elevations in serum aminotransferase levels, changes in serum creatinine levels and the estimated glomerular filtration rate, and injection-site reactions.

Conclusions: Among patients with acute intermittent porphyria, those who received givosiran had a significantly lower rate of porphyria attacks and better results for multiple other disease manifestations than those who received placebo. The increased efficacy was accompanied by a higher frequency of hepatic and renal adverse events. (Funded by Alnylam Pharmaceuticals; ENVISION ClinicalTrials.gov number, NCT03338816.).
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http://dx.doi.org/10.1056/NEJMoa1913147DOI Listing
June 2020

Ly6c non-classical monocytes promote resolution of rhesus rotavirus-mediated perinatal hepatic inflammation.

Sci Rep 2020 04 28;10(1):7165. Epub 2020 Apr 28.

Department of Surgery, University of California, San Francisco, CA, USA.

Perinatal hepatic inflammation can have devastating consequences. Monocytes play an important role in the initiation and resolution of inflammation, and their diverse functions can be attributed to specific cellular subsets: pro-inflammatory or classical monocytes (Ly6c) and pro-reparative or non-classical monocytes (Ly6c). We hypothesized that inherent differences in Ly6c classical monocytes and Ly6c non-classical monocytes determine susceptibility to perinatal hepatic inflammation in late gestation fetuses and neonates. We found an anti-inflammatory transcriptional profile expressed by Ly6c non-classical monocytes, and a physiologic abundance of these cells in the late gestation fetal liver. Unlike neonatal pups, late gestation fetuses proved to be resistant to rhesus rotavirus (RRV) mediated liver inflammation. Furthermore, neonatal pups were rendered resistant to RRV-mediated liver injury when Ly6c non-classical monocytes were expanded. Pharmacologic inhibition of Ly6c non-classical monocytes in this setting restored susceptibility to RRV-mediated disease. These data demonstrate that Ly6c monocytes promote resolution of perinatal liver inflammation in the late gestation fetus, where there is a physiologic expansion of non-classical monocytes, and in the neonatal liver upon experimental expansion of these cells. Therapeutic strategies directed towards enhancing Ly6c non-classical monocyte function may mitigate the detrimental effects of perinatal liver inflammation.
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http://dx.doi.org/10.1038/s41598-020-64158-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188847PMC
April 2020

Understanding the global measurement of willingness to pay in health.

J Mark Access Health Policy 2020 15;8(1):1717030. Epub 2020 Feb 15.

Health Economics, Janssen Pharmaceutical KK, Tokyo, Japan.

: To understand the different methodologies used to elicit willingness to pay for health and the value of a statistical life year through surveys. : A systematic review of the literature was undertaken to identify studies using surveys to estimate either willingness to pay for health or the value of a statistical life year. Each study was reviewed and the study setting, sample size, sample description, survey administration (online or face to face), survey methodology, and results were extracted. The results of the studies were then compared to any published national guidelines of cost-effectiveness thresholds to determine their accuracy. : Eighteen studies were included in the review with 15 classified as willingness to pay and 3 value of a statistical life. The included studies covered Asia (n = 6), Europe (n = 4), the Middle East (n = 1), and North America (n = 5), with one study taking a global perspective. There were substantial differences in both the methodologies and the estimates of both willingness to pay and value of a statistical life between the different studies. : Different methods used to elicit willingness to pay and the value of a statistical life year resulted in a wide range of estimates.
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http://dx.doi.org/10.1080/20016689.2020.1717030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048225PMC
February 2020

mTORC2 Signaling Is Necessary for Timely Liver Regeneration after Partial Hepatectomy.

Am J Pathol 2020 04 5;190(4):817-829. Epub 2020 Feb 5.

Department of Bioengineering and Therapeutic Sciences, Liver Center, University of California, San Francisco, California. Electronic address:

Liver regeneration is a fundamental biological process required for sustaining body homeostasis and restoring liver function after injury. Emerging evidence demonstrates that cytokines, growth factors, and multiple signaling pathways contribute to liver regeneration. Mammalian target of rapamycin complex 2 (mTORC2) regulates cell metabolism, proliferation and survival. The major substrates for mTORC2 are the AGC family members of kinases, including AKT, SGK, and PKC-α. We investigated the functional roles of mTORC2 during liver regeneration. Partial hepatectomy (PHx) was performed in liver-specific Rictor (the pivotal unit of mTORC2 complex) knockout (Rictor) and wild-type (Rictor) mice. Rictor-deficient mice were found to be more intolerant to PHx and displayed higher mortality after PHx. Mechanistically, loss of Rictor resulted in decreased Akt phosphorylation, leading to a delay in hepatocyte proliferation and lipid droplets formation along liver regeneration. Overall, these results indicate an essential role of the mTORC2 signaling pathway during liver regeneration.
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http://dx.doi.org/10.1016/j.ajpath.2019.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180798PMC
April 2020

Evaluating quality of life tools in North American patients with erythropoietic protoporphyria and X-linked protoporphyria.

JIMD Rep 2019 Nov 14;50(1):9-19. Epub 2019 Sep 14.

Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai New York New York.

Background: Erythropoietic protoporphyria (EPP) and X-linked Protoporphyria (XLP) are rare photodermatoses presenting with severe phototoxicity. Although anecdotally, providers who treat EPP patients acknowledge their life-altering effects, tools that fully capture their impact on quality of life (QoL) are lacking.

Methods: Adult patients with EPP/XLP were given four validated QoL tools: the Patient Reported Outcomes Measurement Information System 57 (PROMIS-57), the Hospital Anxiety and Depression Scale (HADS), the Illness Perception Questionnaire Revised (IPQR), and an EPP-Specific tool. All patients received the PROMIS-57 while the HADS, IPQR, and EPP-Specific tools were introduced at a later date. Associations between responses and clinical phenotypes were explored.

Results: Two hundred and two patients were included; 193 completed PROMIS-57, 104 completed IPQR, 103 completed HADS, and 107 completed the EPP-Specific tool. The IPQR showed that patients strongly believed EPP/XLP had a negative impact on their lives. Mean scores in anxiety and depression domains of both HADS and PROMIS-57 were normal; however, anxiety scores from HADS were borderline/abnormal in 20% of patients. The EPP-Specific tool revealed a decreased QoL in most patients. The PROMIS-57 showed that 21.8% of patients have clinically significant pain interference. Several tool domains correlated with measures of disease severity, most being from the PROMIS-57.

Conclusions: Impaired QoL is an important consequence of EPP/XLP. PROMIS-57 was most sensitive in evaluating impaired QoL in EPP/XLP. Further research is needed to compare the effectiveness of it for assessing response to treatment.
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http://dx.doi.org/10.1002/jmd2.12052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850979PMC
November 2019

Evaluating the Patient-Reported Outcomes Measurement Information System scales in acute intermittent porphyria.

Genet Med 2020 03 6;22(3):590-597. Epub 2019 Nov 6.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Purpose: Acute intermittent porphyria (AIP) is a rare inborn error of heme biosynthesis characterized by life-threatening acute attacks. Few studies have assessed quality of life (QoL) in AIP and those that have had small sample sizes and used tools that may not have captured important domains.

Methods: Baseline data from the Porphyrias Consortium's Longitudinal Study were obtained for 259 patients, including detailed disease and medical history data, and the following Patient-Reported Outcomes Measurement Information System (PROMIS) scales: anxiety, depression, pain interference, fatigue, sleep disturbance, physical function, and satisfaction with social roles. Relationships between PROMIS scores and clinical and biochemical AIP features were explored.

Results: PROMIS scores were significantly worse than the general population across all domains, except depression. Each domain discriminated well between asymptomatic and symptomatic patients with symptomatic patients having worse scores. Many important clinical variables like symptom frequency were significantly associated with domain scores in univariate analyses, showing responsiveness of the scales, specifically pain interference and fatigue. However, most regression models only explained ~20% of the variability observed in domain scores.

Conclusion: Pain interference and fatigue were the most responsive scales in measuring QoL in this AIP cohort. Future studies should assess whether these scales capture longitudinal disease progression and treatment response.
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http://dx.doi.org/10.1038/s41436-019-0683-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060090PMC
March 2020

Tumor treating fields and maintenance temozolomide for newly-diagnosed glioblastoma: a cost-effectiveness study.

J Med Econ 2019 Oct 20;22(10):1006-1013. Epub 2019 May 20.

Department of Pharmacy, The Comparative Health Outcomes, Policy, and Economics (CHOICE) Institute, University of Washington , Seattle , WA , USA.

The EF-14 trial demonstrated that adding tumor treating fields (TTFields) to maintenance temozolomide (TMZ) significantly extends progression-free survival (PFS) and overall survival (OS) for newly-diagnosed glioblastoma (GBM) patients. This study assessed the cost-effectiveness of TTFields and TMZ for newly-diagnosed GBM from the US healthcare system perspective. Outcomes for newly-diagnosed GBM patients were estimated over a lifetime horizon using an area under the curve model with three states: stable disease, progressive disease, or death. The survival model integrated the 5-year EF-14 trial results with long-term GBM epidemiology data and US background mortality rates. Adverse event rates were derived from the EF-14 trial data. Utility values to determine quality-adjusted life-years, adverse event costs, and supportive care costs were obtained from published literature. A 3% discount rate was applied to future costs and outcomes. One-way and probabilistic sensitivity analyses were performed to assess result uncertainty due to parameter variability. Treatment with TTFields and TMZ was estimated to result in a mean increase in survival of 1.25 life years (95% credible range [CR] = 0.89-1.67) and 0.96 quality-adjusted life years (QALYs) (95% CR = 0.67-1.30) compared to treatment with TMZ alone. The incremental total cost was $188,637 (95% CR = $145,324-$225,330). The incremental cost-effectiveness ratio (ICER) was $150,452 per life year gained and $197,336 per QALY gained. The model was most sensitive to changes in the cost of TTFields treatment. Adding TTFields to maintenance TMZ resulted in a substantial increase in the estimated mean lifetime survival and quality-adjusted survival for newly-diagnosed GBM patients. Treatment with TTFields can be considered cost-effective within the reported range of willingness-to-pay thresholds in the US.
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http://dx.doi.org/10.1080/13696998.2019.1614933DOI Listing
October 2019

The Cost of Hypoglycemia Associated With Type 2 Diabetes Mellitus in Taiwan.

Value Health Reg Issues 2019 May 16;18:84-90. Epub 2019 Feb 16.

Lilly Diabetes, Eli Lilly and Co, Taipei, Taiwan.

Objectives: To quantify the incremental burden of patients with type 2 diabetes mellitus (T2DM) and a hypoglycemic event in Taiwan using the National Health Insurance Research Database.

Methods: Data from 2000 through 2013 with an index period of 2001 through 2012 from the National Health Insurance Research Database's 2-million-patient sample were used. Using a nested case-control study design, patients were indexed if they reported a diagnosis of T2DM during the index period. Patients with T2DM with a hypoglycemic event (defined by International Classification of Diseases, Ninth Revision, Clinical Modification codes) during the index period were identified. Patients with T2DM without a hypoglycemic event were included to form a 4:1 (controls to cases) matched cohort on the basis of age, sex, the Charlson Comorbidity Index, and the T2DM diagnosis date. Both cohorts were followed up for 1 year after the hypoglycemic event and had their treatment utilization, resource utilization, and healthcare costs measured.

Results: A total of 144 213 patients with T2DM were identified, with 3 651 (2.5%) recording a hypoglycemic event. Before matching, patients with T2DM with a hypoglycemic event were, on average, older (64.2 vs 56.6) and had higher mean CCI scores (2.4 vs 1.9) than did patients with T2DM without a hypoglycemic event. After matching, patients with T2DM and a hypoglycemic event incurred an additional $1353 in average direct healthcare costs during the 1 year of follow-up compared with the matched cohort. Patients with T2DM with hypoglycemia also spent an additional 5.9 days in the hospital during the follow-up period compared with the matched cohort.

Conclusions: Patients with hypoglycemic events, on average, experienced a substantially higher economic burden than did their counterparts without a hypoglycemic event during the same period.
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http://dx.doi.org/10.1016/j.vhri.2019.01.002DOI Listing
May 2019

Acute Hepatic Porphyrias: Review and Recent Progress.

Hepatol Commun 2019 Feb 20;3(2):193-206. Epub 2018 Dec 20.

Section of Gastroenterology and Hepatology, Department of Internal Medicine Wake Forest University School of Medicine Winston-Salem NC.

The acute hepatic porphyrias (AHPs) are a group of four inherited diseases of heme biosynthesis that present with episodic, acute neurovisceral symptoms. The four types are 5-aminolevulinic acid (ALA) dehydratase deficiency porphyria, acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria. Their diagnoses are often missed or delayed because the clinical symptoms mimic other more common disorders. Recent results indicate that acute intermittent porphyria, the most severe of the more common types of AHP, is more prevalent than previously thought, occurring in about 1 in 1600 Caucasians, but with low clinical penetrance (approximately 2%-3%). Here we provide an updated review of relevant literature and discuss recent and emerging advances in treatment of these disorders. Symptomatic attacks occur primarily in females between 14 and 45 years of age. AHP is diagnosed by finding significantly elevated levels of porphyrin precursors ALA and porphobilinogen in urine. Acute attacks should be treated promptly with intravenous heme therapy to avoid the development of potentially irreversible neurologic sequelae. All patients should be counseled about avoiding potential triggers for acute attacks and monitored regularly for the development of long-term complications. Their first-degree relatives should undergo targeted gene testing. Patients who suffer recurrent acute attacks can be particularly challenging to manage. Approximately 20% of patients with recurrent symptoms develop chronic and ongoing pain and other symptoms. We discuss newer treatment options in development, including small interfering RNA, to down-regulate ALA synthase-1 and/or wild-type messenger RNA of defective genes delivered selectively to hepatocytes for these patients. We expect that the newer treatments will diminish and perhaps obviate the need for liver transplantation as treatment of these inborn metabolic disorders.
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http://dx.doi.org/10.1002/hep4.1297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357830PMC
February 2019

Tissue Repair in the Mouse Liver Following Acute Carbon Tetrachloride Depends on Injury-Induced Wnt/β-Catenin Signaling.

Hepatology 2019 06 9;69(6):2623-2635. Epub 2019 Apr 9.

Institute for Stem Cell Biology and Regenerative Medicine, Department of Developmental Biology, Howard Hughes Medical Institute, Stanford School of Medicine, Stanford, CA.

In the liver, Wnt/β-catenin signaling is involved in regulating zonation and hepatocyte proliferation during homeostasis. We examined Wnt gene expression and signaling after injury, and we show by in situ hybridization that Wnts are activated by acute carbon tetrachloride (CCl ) toxicity. Following injury, peri-injury hepatocytes become Wnt-responsive, expressing the Wnt target gene axis inhibition protein 2 (Axin2). Lineage tracing of peri-injury Axin2 hepatocytes shows that during recovery the injured parenchyma becomes repopulated and repaired by Axin2 descendants. Using single-cell RNA sequencing, we show that endothelial cells are the major source of Wnts following acute CCl toxicity. Induced loss of β-catenin in peri-injury hepatocytes results in delayed repair and ultimately injury-induced lethality, while loss of Wnt production from endothelial cells leads to a delay in the proliferative response after injury. Conclusion: Our findings highlight the importance of the Wnt/β-catenin signaling pathway in restoring tissue integrity following acute liver toxicity and establish a role of endothelial cells as an important Wnt-producing regulator of liver tissue repair following localized liver injury.
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http://dx.doi.org/10.1002/hep.30563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7043939PMC
June 2019

Axis inhibition protein 1 (Axin1) Deletion-Induced Hepatocarcinogenesis Requires Intact β-Catenin but Not Notch Cascade in Mice.

Hepatology 2019 12 11;70(6):2003-2017. Epub 2019 Apr 11.

Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA.

Inactivating mutations of axis inhibition protein 1 (AXIN1), a negative regulator of the Wnt/β-Catenin cascade, are among the common genetic events in human hepatocellular carcinoma (HCC), affecting approximately 10% of cases. In the present manuscript, we sought to define the genetic crosstalk between Axin1 mutants and Wnt/β-catenin as well as Notch signaling cascades along hepatocarcinogenesis. We discovered that c-MET activation and AXIN1 mutations occur concomitantly in ~3%-5% of human HCC samples. Subsequently, we generated a murine HCC model by means of CRISPR/Cas9-based gene deletion of Axin1 (sgAxin1) in combination with transposon-based expression of c-Met in the mouse liver (c-Met/sgAxin1). Global gene expression analysis of mouse normal liver, HCCs induced by c-Met/sgAxin1, and HCCs induced by c-Met/∆N90-β-Catenin revealed activation of the Wnt/β-Catenin and Notch signaling in c-Met/sgAxin1 HCCs. However, only a few of the canonical Wnt/β-Catenin target genes were induced in c-Met/sgAxin1 HCC when compared with corresponding lesions from c-Met/∆N90-β-Catenin mice. To study whether endogenous β-Catenin is required for c-Met/sgAxin1-driven HCC development, we expressed c-Met/sgAxin1 in liver-specific Ctnnb1 null mice, which completely prevented HCC development. Consistently, in AXIN1 mutant or null human HCC cell lines, silencing of β-Catenin strongly inhibited cell proliferation. In striking contrast, blocking the Notch cascade through expression of either the dominant negative form of the recombinant signal-binding protein for immunoglobulin kappa J region (RBP-J) or the ablation of Notch2 did not significantly affect c-Met/sgAxin1-driven hepatocarcinogenesis. Conclusion: We demonstrated here that loss of Axin1 cooperates with c-Met to induce HCC in mice, in a β-Catenin signaling-dependent but Notch cascade-independent way.
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http://dx.doi.org/10.1002/hep.30556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206928PMC
December 2019

Evaluation of an electronic health record structured discharge summary to provide real time adverse event reporting in thoracic surgery.

BMJ Qual Saf 2019 04 18;28(4):310-316. Epub 2019 Jan 18.

Departments of Surgery and Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

Background: The reporting of adverse events (AE) remains an important part of quality improvement in thoracic surgery. The best methodology for AE reporting in surgery is unclear. An AE reporting system using an electronic discharge summary with embedded data collection fields, specifying surgical procedure and complications, was developed. The data are automatically transferred daily to a web-based reporting system.

Methods: We determined the accuracy and sustainability of this electronic real time data collection system (ERD) by comparing the completeness of record capture on procedures and complications with coded discharge data (administrative data), and with the standard of chart audit at two intervals. All surgical procedures performed for 2 consecutive months at initiation (Ti) and 1 year later (T1yr) were audited by an objective trained abstractor. A second abstractor audited 10% of the charts.

Results: The ERD captured 71/72 (99%) of charts at Ti and 56/65 (86%) at T1yr. Comparing the presence/absence of complications between ERD and chart audit demonstrated at Ti a high sensitivity and specificity, positive predictive value (PPV) of 95.5%, negative predictive value (NPV) of 93.9% with a kappa of 0.872 (95% CI 0.750 to 0.994), and at T1yr a sensitivity, specificity, PPV and NPV of 100% with a kappa of 1.0 (95% CI 1.0). Comparing the presence/absence of complications between administrative data and chart audit at Ti demonstrated a low sensitivity, high specificity and a kappa of 0.471 (95% CI 0.256 to 0.686), and at T1yr a low sensitivity, high specificity of 85% and a kappa of 0.479 (95% CI 0.245 to 0.714).

Conclusions: We found that the ERD can provide accurate real time AE reporting in thoracic surgery, has advantages over previous reporting methodologies and is an alternative system for surgical clinical teams developing AE reporting systems.
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http://dx.doi.org/10.1136/bmjqs-2018-008090DOI Listing
April 2019

Inflammatory Cytokine TNFα Promotes the Long-Term Expansion of Primary Hepatocytes in 3D Culture.

Cell 2018 11;175(6):1607-1619.e15

Howard Hughes Medical Institute, Department of Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address:

In the healthy adult liver, most hepatocytes proliferate minimally. However, upon physical or chemical injury to the liver, hepatocytes proliferate extensively in vivo under the direction of multiple extracellular cues, including Wnt and pro-inflammatory signals. Currently, liver organoids can be generated readily in vitro from bile-duct epithelial cells, but not hepatocytes. Here, we show that TNFα, an injury-induced inflammatory cytokine, promotes the expansion of hepatocytes in 3D culture and enables serial passaging and long-term culture for more than 6 months. Single-cell RNA sequencing reveals broad expression of hepatocyte markers. Strikingly, in vitro-expanded hepatocytes engrafted, and significantly repopulated, the injured livers of Fah mice. We anticipate that tissue repair signals can be harnessed to promote the expansion of otherwise hard-to-culture cell-types, with broad implications.
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http://dx.doi.org/10.1016/j.cell.2018.11.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497386PMC
November 2018

Nanoscale Bupivacaine Formulations To Enhance the Duration and Safety of Intravenous Regional Anesthesia.

ACS Nano 2019 01 19;13(1):18-25. Epub 2018 Nov 19.

Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology , Boston Children's Hospital, Harvard Medical School , Boston , Massachusetts 02115 , United States.

Intravenous regional anesthesia (IVRA; Bier block) is commonly used to anesthetize an extremity for surgery. Limitations of the procedure include pain from the required tourniquet, the toxicity that can occur from systemic release of local anesthetics, and the lack of postoperative pain relief. We hypothesized that the nanoencapsulation of the local anesthetic would prolong local anesthesia and enhance safety. Here, we developed an ∼15 nm micellar bupivacaine formulation (M-Bup) and tested it in a rat tail vein IVRA model, in which active agents were restricted in the tail by a tourniquet for 15 min. After tourniquet removal, M-Bup provided local anesthesia for 4.5 h, which was two times longer than that from a larger dose of free bupivacaine. Approximately 100 nm liposomal bupivacaine (L-Bup) with the same drug dose as M-Bup did not cause anesthesia. Blood levels of bupivacaine after tourniquet removal were lower in animals receiving M-Bup than L-Bup or free bupivacaine, demonstrating enhanced safety. Tissue reaction to M-Bup was benign.
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http://dx.doi.org/10.1021/acsnano.8b05408DOI Listing
January 2019

Estimated lifetime survival benefit of tumor treating fields and temozolomide for newly diagnosed glioblastoma patients.

CNS Oncol 2018 07 20;7(3):CNS23. Epub 2018 Aug 20.

Department of Pharmacy, University of Washington, Seattle, WA 98195, USA.

Aim: To estimate the mean lifetime survival benefit, an essential component of health economic evaluations in oncology, of adding tumor treating fields (TTFields) to maintenance temozolomide (TMZ) for newly diagnosed glioblastoma patients.

Methods: We integrated EF-14 trial data with glioblastoma epidemiology data. The model provided for an evidence-based approach to estimate lifetime survival for the material number of EF-14 trial patients still alive at 5 years.

Results & Conclusion: Patients treated with TTFields and TMZ had an incremental mean lifetime survival of 1.8 years (TTFields/TMZ: 4.2 vs TMZ alone: 2.4). Patients alive at year 2 after starting TTFields had a 20.7% probability of surviving to year 10. The results presented here provide the required incremental survival benefit necessary for a future assessment of the incremental cost-effectiveness of TTFields.
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http://dx.doi.org/10.2217/cns-2018-0010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200060PMC
July 2018

Estimating the cost-effectiveness of an infant 13-valent pneumococcal conjugate vaccine national immunization program in China.

PLoS One 2018 25;13(7):e0201245. Epub 2018 Jul 25.

Pfizer Inc. Collegeville, PA, United States of America.

Background: The burden of pneumococcal disease in China is high, and a 13-valent pneumococcal conjugate vaccine (PCV13) recently received regulatory approval and is available to Chinese infants. PCV13 protects against the most prevalent serotypes causing invasive pneumococcal disease (IPD) in China, but will not provide full societal benefits until made broadly available through a national immunization program (NIP).

Objective: To estimate clinical and economic benefits of introducing PCV13 into a NIP in China using local cost estimates and accounting for variability in vaccine uptake and indirect (herd protection) effects.

Methods: We developed a population model to estimate the effect of PCV13 introduction in China. Modeled health states included meningitis, bacteremia, pneumonia (PNE), acute otitis media, death and sequelae, and no disease. Direct healthcare costs and disease incidence data for IPD and PNE were derived from the China Health Insurance and Research Association database; all other parameters were derived from published literature. We estimated total disease cases and associated costs, quality-adjusted life years (QALYs), and deaths for three scenarios from a Chinese Payer Perspective: (1) direct effects only, (2) direct+indirect effects for IPD only, and (3) direct+indirect effects for IPD and inpatient PNE.

Results: Scenario (1) resulted in 370.3 thousand QALYs gained and 12.8 thousand deaths avoided versus no vaccination. In scenarios (2) and (3), the PCV13 NIP gained 383.2 thousand and 3,580 thousand QALYs, and avoided 13.1 thousand and 147.5 thousand deaths versus no vaccination, respectively. In all three scenarios, the vaccination cost was offset by cost reductions from prevented disease yielding net costs of ¥29,362.32 million, ¥29,334.29 million, and ¥13,524.72 million, respectively. All resulting incremental cost-effectiveness ratios fell below a 2x China GDP cost-effectiveness threshold across a range of potential vaccine prices.

Discussion: Initiation of a PCV13 NIP in China incurs large upfront costs but is good value for money, and is likely to prevent substantial cases of disease among children and non-vaccinated individuals.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201245PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6059448PMC
January 2019

Predicting the tissue depth for remote triggering of drug delivery systems.

J Control Release 2018 09 18;286:55-63. Epub 2018 Jul 18.

Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Externally triggerable drug delivery systems have promising potential in providing flexible control of the timing, duration, and intensity of treatment according to patient's needs, while reducing side effects and increasing therapeutic efficacy. However, a limitation to translating such systems into clinical practice is the difficulty to predict the tissue depth at which such systems could be safely used in vivo (e.g. activatable at the target site with a clinically-safe energy dosage). An effective method is needed to evaluate the clinical potential of externally triggerable drug delivery systems. Here we have a method and approach to predicting the tissue depth at which a drug delivery system can be safely triggered in vivo by an external energy source. We used in vitro and ex vivo experiments combined with a mathematical model to develop a method to predict activated drug release at different tissue depths, which was then validated in vivo. We constructed these models for liposomal drug delivery systems triggered by two of the most commonly studied external stimuli: ultrasound and near infrared light. We developed the approach in two prevalent tissue types: muscle and fat. Our method identified two important parameters in the activation of drug delivery systems in tissue: 1) the ability of the activating energy to penetrate tissue, 2) the sensitivity of the system to the activation source. The method was validated by correlation with triggered sciatic nerve block in the rat in vivo, demonstrating that this approach provided an accurate estimate of activated release at different tissue depths.
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http://dx.doi.org/10.1016/j.jconrel.2018.07.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6179450PMC
September 2018

Estimating the response and economic burden of rheumatoid arthritis patients treated with biologic disease-modifying antirheumatic drugs in Taiwan using the National Health Insurance Research Database (NHIRD).

PLoS One 2018 6;13(4):e0193489. Epub 2018 Apr 6.

Taipei Medical University, Taipei, Taiwan.

Background: Previous studies in Taiwan utilizing the Taiwan's National Health Insurance Database (NHIRD) have estimated the direct healthcare costs of RA patients, but they have not focused on patients on bDMARDs, or considered patients' response to therapy.

Objectives: The objective of this study was to estimate the rate of inadequate response for patients newly treated with biologic disease-modifying antirheumatic drugs (bDMARDs) as well as their costs and resource use.

Methods: Data were from the catastrophic illness file within the NHIRD from 1/1/2009 to 12/31/2013. Patients with RA, which was categorized by the presence of a catastrophic illness card, that were previously bDMARD-naïve, were included in this study if they initiated their first bDMARD during the index period. The index period included all of 2010, a pre-index period consisting of the index date- 365 days, and a follow-up period including the index date to 365 days post-index, were also included. Previously biologically-naïve patients were indexed into the study on the date of their first claim for a bDMARD. A validated algorithm was used to examine the rate of inadequate response (IR) in the biologically-naïve cohort of patients. Inadequate responders met one or more of the following criteria during their year of follow-up: low adherence (proportion of days covered <0.80); switched to or added a second bDMARD; added a new conventional synthetic DMARD (csDMARD); received ≥1 glucocorticoid injection; or increased oral glucocorticoid dosing. All-cause mean annual direct costs and resource use were measured in the year of follow-up. Costs were converted from NT$ to USD using 1 NT$ = 0.033 USD.

Results: A total of 818 patients with RA initiated their first bDMARD (54% etanercept and 46% adalimumab) in 2010. After one year of follow-up, 32% (n = 258) were classified as stable, 66% (n = 540) had an IR, and 2% (n = 20) were lost to follow-up. During the follow-up period mean annual total direct costs were $16,136 for stable patients compared to $14,154 for patients with IR. Mean annual non-medication direct costs were $937 for stable patients and $1,574 for patients with IR. Mean annual hospitalizations were higher for patients with IR (0.46) compared to stable patients (0.10) during the one year follow-up period.

Conclusions: The majority of patients that were previously naïve to bDMARDs had an IR to their first bDMARD during the year of follow-up. Patients with an IR had numerically increased all-cause resource utilization and non-medication costs during the follow-up period compared to patients with stable disease. This level of IR suggests an unmet need in the RA treatment paradigm.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193489PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889158PMC
July 2018

Prolonged Duration Local Anesthesia Using Liposomal Bupivacaine Combined With Liposomal Dexamethasone and Dexmedetomidine.

Anesth Analg 2018 04;126(4):1170-1175

From the Department of Anesthesiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.

Background: The relatively short duration of effect of local anesthetics has been addressed by encapsulation in drug delivery systems. Codelivery with a single compound that produces an adjuvant effect on nerve block but without intrinsic local anesthetic properties can further prolong the nerve block effect. Here, we investigated whether codelivery of more than 1 encapsulated adjuvant compound can further enhance nerve blockade.

Methods: Liposomes loaded with bupivacaine (Bup), dexamethasone phosphate (DexP), or dexmedetomidine (DMED) were synthesized and its in vitro drug release profiles were determined. Animals (Sprague-Dawley rats) were injected with liposomal Bup (Lipo-Bup) and adjuvants at the sciatic nerve and underwent a modified hot plate test to assess the degree of nerve block. The duration of block was monitored and the tissue reaction was assessed.

Results: Coinjection of Lipo-Bup with liposomal DexP (Lipo-DexP) and liposomal DMED (Lipo-DMED) prolonged the duration of sciatic nerve block 2.9-fold compared to Lipo-Bup alone (95% confidence interval, 1.9- to 3.9-fold). The duration of the block using this combination was significantly increased to 16.2 ± 3.5 hours compared to Lipo-Bup with a single liposomal adjuvant (8.7 ± 2.4 hours with Lipo-DMED, P = .006 and 9.9 ± 5.9 hours with Lipo-DexP, P = .008). The coinjection of Lipo-Bup with liposomal adjuvants decreased tissue inflammation (P = .014) but did not have a significant effect on myotoxicity when compared to Lipo-Bup alone. Coinjection of Lipo-Bup with unencapsulated adjuvants prolonged the duration of nerve block as well (25.0 ± 6.3 hours; P < .001) however was accompanied by systemic side effects.

Conclusions: Codelivery of Lipo-DexP and Lipo-DMED enhanced the efficacy of Lipo-Bup. This benefit was also seen with codelivery of both adjuvant molecules in the unencapsulated state, but with marked systemic toxicity.
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http://dx.doi.org/10.1213/ANE.0000000000002719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856594PMC
April 2018

Hollow Silica Nanoparticles Penetrate the Peripheral Nerve and Enhance the Nerve Blockade from Tetrodotoxin.

Nano Lett 2018 01 11;18(1):32-37. Epub 2017 Dec 11.

Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology, Boston Children's Hospital, Harvard Medical School , Boston, Massachusetts 02115, United States.

The efficacy of tetrodotoxin (TTX), a very potent local anesthetic, is limited by its poor penetration through barriers to axonal surfaces. To address this issue, we encapsulated TTX in hollow silica nanoparticles (TTX-HSN) and injected them at the sciatic nerve in rats. TTX-HSN achieved an increased frequency of successful blocks, prolonged the duration of the block, and decreased the toxicity compared to free TTX. In animals injected with fluorescently labeled HSN, the imaging of frozen sections of nerve demonstrated that HSN could penetrate into nerve and that the penetrating ability of silica nanoparticles was highly size-dependent. These results demonstrated that HSN could deliver TTX into the nerve, enhancing efficacy while improving safety.
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http://dx.doi.org/10.1021/acs.nanolett.7b02461DOI Listing
January 2018