HCV, Alcoholic : PE-136 ; Sustained virologic response (SVR) in prior peginterferon/ribavirin (PR) treatment failures after retreatment with boceprevir (BOC) + PR: The PROVIDE study interim results

( Jp Bronowicki ),( M Davis ),( S Flamm ),( S Gordon ),( E Lawitz ),( E Yoshida ),( J Galati ),( V Luketic ),( J Mccone ),( I Jacobson ),( P Marcellin ),( A Muir1 ),( F Poordad ),( Ld Pedicone ),( W D 대한간학회 2012 춘·추계 학술대회 (KASL) Vol.2012 No.-

Background: Patients in the PR control arms of BOC Phase 2/3 studies who did not achieve SVR could enroll in PROVIDE and receive BOC+PR. This interim analysis examines the preliminary efficacy and safety of BOC+PR in patients who failed prior treatment with PR. Methods: BOC (800 mg TID with food) was given with P 1.5 mcg/kg/week and weight-based R (600-1400 mg/day) BID for up to 44 weeks. If >2 weeks had elapsed since end of treatment in the previous study, PR was given for 4 weeks before adding BOC. Protocol specified analyses include patients who received at least one dose of BOC. Denominators for on-treatment response include patients who reached the specific time point or discontinued. The denominators for SVR include all patients who reached end of follow-up, discontinued, or were treatment failures. Results: Characteristics of 168 enrolled patients were: 67% male, 84% Caucasian, mean age 52 years, mean BMI 27.9 kg/m2, 77% high viral load (>800,000 IU/mL; mean log10 6.26); 10% cirrhotic; 61% subtype 1a. Table shows the proportion of BOC treated patients with undetectable HCV RNA at tested time points. SVR was achieved in 40% of prior null responders (<2 log10 decline in HCV RNA at TW12 in prior study) and 68% of prior partial responders/relapsers; 78% (38/49) of prior null responders and 24% (26/107) of prior partial responders/ relapsers had <1 log10 decline in HCV RNA after the PR lead in. Overall SVR was 47% in patients with <1 log10 decline with lower SVR rates in prior null responders (36%) vs. prior partial responders/relapsers (65%). 68% of patients with >1 log decline achieved SVR (55% prior null responders; 70% prior partial responders/relapsers). Seven percent of patients discontinued due to AEs, while 48% experienced anemia, 34% dysgeusia and 22% neutropenia. Conclusions: BOC+PR achieved high SVR rates regardless of prior response to PR. The degree of interferon responsiveness after PR lead in correlates with prior response and can help predict SVR for prior null responders. The safety profile is comparable to that previously reported for BOC+PR.

Impact of Radiation Therapy on Outcomes After Spinal Instrumentation for Craniocervical Junction Malignancies

Matthew Muir,Laurence Rhines,Franco DeMonte,Claudio Tatsui,Shaan M. Raza 대한척추신경외과학회 2022 Neurospine Vol.19 No.2

Objective: Spinal reconstruction after resection of invasive craniocervical junction malignancies is fraught with technical and management considerations as well as a paucity of data in the existing literature. In this study, we describe our experience with craniocervical junction malignancies, especially the influence of radiation on the need for revision spinal instrumentation. Methods: We performed a retrospective chart review of all patients who underwent occipitocervical fixation between 2011 and 2019 at The University of Texas MD Anderson Cancer Center. Results: Twenty-five patients had primary malignancies and 12 (30%) had metastatic tumors. Thirteen (33%) underwent a staged resection in multiple operations during their hospital stay. Tumor resection was performed in 19 patients (48%), while only stabilization was performed in 21 patients (52%). Nine patients (23%) underwent expanded endoscopic transclival approaches for tumor resection, 10 patients (25%) an extreme lateral approach, and 2 patients (5%) an anterior open approach. Eleven patients underwent early postoperative radiation therapy (within 3 months) and 8 underwent delayed radiation therapy (between 3 months and 1 year in 7 patients). The revision rate was 8%, with a median time to revision surgery of 42 months. The administration and timing of adjuvant radiation therapy relative to surgery had no significant effect on the need for instrumentation revision on log-rank and Cox regression analyses (p < 0.05). Conclusion: Revision surgery was needed infrequently in our patients. Postoperative radiation therapy was not associated with hardware failure, indicating that the timing of radiation therapy should be dictated by the diagnosis and can be initiated postoperatively without delay.

Antenatal Thyroid Function Does Not Increase Risk of Gestational Diabetes Mellitus in a Multi-Ethnic Pregnancy Cohort

Christopher Alan Muir,Ashish Munsif,Kenrick Blaker,Yvonne Feng,Mario D’Souza,Shailja Tewari 대한갑상선학회 2020 International Journal of Thyroidology Vol.13 No.1

Background and Objectives: Subclinical hypothyroidism in pregnancy has been inconsistently associated with an increased risk of developing gestational diabetes mellitus (GDM). Materials and Methods: We retrospectively examined whether an antenatal thyroid stimulating hormone (TSH) level ≥2.5 mIU/L was associated with increased risk of GDM in 1147 pregnant women residing in a multi-ethnic suburban area of Sydney, Australia. Results: Despite a high prevalence of GDM and hypothyroidism in our study, women with antenatal TSH concentrations ≥2.5 mIU/L were not at increased risk for development of gestational diabetes. Traditional risk factors for GDM, such as maternal body mass index, ethnicity, previous GDM pregnancy and family history of type 2 diabetes were significant predictors of incident GDM on multivariable analyses. Conclusion: Mild elevations in antenatal TSH concentration did not significantly increase risk of incident GDM compared to healthy euthyroid women.

Long-Term Course of Cirrhosis Regression: Lessons from Patients with HCV Cirrhosis Following Successful Sofosbuvir-Based Treatment

( Ira Jacobson ),( Andrew J. Muir ),( Eric Lawitz ),( Edward Gane ),( Brian Conway ),( Peter J. Ruane ),( Ziad Younes ),( Frances Chen ),( Marianne Camargo ),( Anand P. Chokkalingam ),( C. Stephen Dje 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Aims: In patients with HCV cirrhosis, a sustained virologic response (SVR) is associated with improved clinical outcomes; however, the temporal course of changes in fibrosis is poorly understood. Our aim was to evaluate changes in noninvasive tests of fibrosis (NITs) in this setting to gain insights into the natural history of cirrhosis regression following removal of the causative exposure. Methods: We studied patients with HCV cirrhosis who achieved SVR with sofosbuvir (SOF)-based regimens (in a trial or clinical practice) in an ongoing, prospective cirrhosis registry (NCT02292706). Patients underwent routine clinical and laboratory assessments, including semi-annual Child-Pugh-Turcotte (CPT) scoring and measurement of the Enhanced Liver Fibrosis (ELF) test, as well as annual liver stiffness measurement by transient elastography (LS by TE). Changes in fibrosis were estimated based on ELF response (defined as ≥0.5 unit reduction), and shifts in estimated fibrosis categories based on ELF (F3, ELF 9.8-11.3; F4, ELF >11.3) and LS by TE (F3, 9.6-12.5 kPa; F4, >12.5 kPa). Logistic regression was used to identify predictors of fibrosis improvement as defined by NITs. Results: 1,574 subjects with HCV cirrhosis (32% female, 39% BMI ≥30 kg/㎡, 7% CPT class B/C) were included in this study; median interval between SVR and registry enrollment was 38 weeks (IQR 27-60). At enrollment, median (IQR) ELF was 14.3 (9.5, 22.1); 586 (37%) and 247 (16%) patients had ELF scores consistent with F3 and F4 fibrosis, respectively. Median LS by TE was 9.9 kPa (9.2, 10.8); 761 (57%) and 227 (17%) patients had LS consistent with F3 and F4 fibrosis, respectively. As of May 2019, median duration of follow-up after registry enrollment was 123 weeks (IQR 96, 168). At week 144, 49% of those with baseline CPT class B/C had improved CPT class, while 98% of those with baseline CPT class A remained in CPT class A. During follow-up, changes in ELF and LS by TE suggested fibrosis improvement in an increasing proportion of patients with both F3 and F4 fibrosis at enrollment (Figure 1). ELF score improved by >0.5 units at week 144 in 27% and 47% of patients with baseline F3 and F4 fibrosis, respectively. Predictors of ELF improvement included higher ELF (P<0.001) and AST (P=0.049), and lower platelets (P=0.02) and BMI (P=0.10) at registry baseline. Conclusions: In patients with cirrhosis in whom HCV has been eradicated by SOF-based therapy, NITs suggest significant fibrosis improvement in 25-50% of patients within 3 years. Associations between reductions in these NITs and improvements in clinical outcomes require evaluation during longer-term follow-up.

Adipose Tissue Dendritic Cells Are Independent Contributors to Obesity-Induced Inflammation and Insulin Resistance

Cho, Kae Won,Zamarron, Brian F.,Muir, Lindsey A.,Singer, Kanakadurga,Porsche, Cara E.,DelProposto, Jennifer B.,Geletka, Lynn,Meyer, Kevin A.,O’Rourke, Robert W.,Lumeng, Carey N. American Association of Immunologists 2016 Journal of Immunology Vol. No.

<P>Dynamic changes of adipose tissue leukocytes, including adipose tissue macrophage (ATM) and adipose tissue dendritic cells (ATDCs), contribute to obesity-induced inflammation and metabolic disease. However, clear discrimination between ATDC and ATM in adipose tissue has limited progress in the field of immunometabolism. In this study, we use CD64 to distinguish ATM and ATDC, and investigated the temporal and functional changes in these myeloid populations during obesity. Flow cytometry and immunostaining demonstrated that the definition of ATM as F4/80(+)CD11b(+) cells overlaps with other leukocytes and that CD45(+)CD64(+) is specific for ATM. The expression of core dendritic cell genes was enriched in CD11c(+)CD64(-) cells (ATDC), whereas core macrophage genes were enriched in CD45(+)CD64(+) cells (ATM). CD11c(+)CD64(-) ATDCs expressed MHC class II and costimulatory receptors, and had similar capacity to stimulate CD4(+) T cell proliferation as ATMs. ATDCs were predominantly CD11b(+) conventional dendritic cells and made up the bulk of CD11c(+) cells in adipose tissue with moderate high-fat diet exposure. Mixed chimeric experiments with Ccr2(-/-) mice demonstrated that high-fat diet induced ATM accumulation from monocytes was dependent on CCR2, whereas ATDC accumulation was less CCR2 dependent. ATDC accumulation during obesity was attenuated in Ccr7(-/-) mice and was associated with decreased adipose tissue inflammation and insulin resistance. CD45(+)CD64(+) ATM and CD45(+)CD64(-)CD11c(+) ATDCs were identified in human obese adipose tissue and ATDCs were increased in s.c. adipose tissue compared with omental adipose tissue. These results support a revised strategy for unambiguous delineation of ATM and ATDC, and suggest that ATDCs are independent contributors to adipose tissue inflammation during obesity.</P>

Crosstalk among Set1 complex subunits involved in H2B ubiquitylation-dependent H3K4 methylation

Jeon, Jongcheol,McGinty, Robert K,Muir, Tom W,Kim, Jung-Ae,Kim, Jaehoon Oxford University Press 2018 Nucleic acids research Vol.46 No.21

<P><B>Abstract</B></P><P>H2B ubiquitylation (H2Bub)-dependent H3K4 methylation is mediated by the multisubunit Set1 complex (Set1C) in yeast, but precisely how Set1C subunits contribute to this histone modification remains unclear. Here, using reconstituted Set1Cs and recombinant H2Bub chromatin, we identified Set1C subunits and domains involved in the H2Bub-dependent H3K4 methylation process, showing that the Spp1 PHDL domain, in conjunction with the Set1 n-SET domain, interacts with Swd1/Swd3 and that this interaction is essential for H2Bub-dependent H3K4 methylation. Importantly, Set1C containing an Spp1-Swd1 fusion bypasses the requirement for H2Bub for H3K4 methylation, suggesting that the role of H2Bub is to induce allosteric rearrangements of the subunit-interaction network within the active site of Set1C that are necessary for methylation activity. Moreover, the interaction between the Set1 N-terminal region and Swd1 renders the Spp1-lacking Set1C competent for H2Bub-dependent H3K4 methylation. Collectively, our results suggest that H2Bub induces conformational changes in Set1C that support H3K4 methylation activity.</P>

Review : The Low FODMAP Diet and Its Application in East and Southeast Asia

( Marina Iacovou ),( Victoria Tan ),( Jane G Muir ),( Peter R Gibson ) 대한소화기기능성질환·운동학회(구 대한소화관운동학회) 2015 Journal of Neurogastroenterology and Motility (JNM Vol.21 No.4

There is growing interest in using food choice/dietary change to influence clinical outcomes in patients with irritable bowel syndrome(IBS). The low fermentable oligo-, di-, mono-saccharides, and polyols (FODMAPs) diet is an evidence-based approach that is gaining popularity in many Western countries. The low FODMAP diet is based on restricting dietary intake of short chain carbohydrates that are slowly absorbed or indigestible and not absorbed during passage through the small intestine. These are collectively described as “FODMAPs” and comprise oligosaccharides (mostly fructans, galacto-oligosaccharides), sugar polyols, fructose in excess of glucose, and lactose in lactose malabsorbers. The general strategy of the diet is to avoid foods high in FODMAPs and replace them with foods low in FODMAPs, with long-term restriction limited to what is required to control symptoms. The likely mechanism of action is minimisation of the stimulation of mechanoreceptors exerted by distension of the intestinal lumen with water from osmotic effects and gases from bacterial fermentation in those with visceral hypersensitivity. The success of this dietary approach greatly depends on detailed knowledge about the FODMAP composition of food com - monly consumed in that country. While the content of foods associated with East and Southeast Asian cuisines has not been fully explored, major high FODMAP sources are frequently used and include onion, garlic, shallots, legumes/pulses, and wheat-based products. Thus, this dietary approach holds great promise in treating IBS patients in East and Southeast Asia. The aim of this review is to highlight how the diet is implemented, its efficacy, and troublesome ingredients frequently used in Asian dishes. (J Neurogastroenterol Motil 2015;21:459-470)

Carbon Fiber-Reinforced Polyetheretherketone Spinal Implants for Treatment of Spinal Tumors: Perceived Advantages and Limitations

Christopher Alvarez-Breckenridge,Romulo de Almeida,Ali Haider,Matthew Muir,Justin Bird,Robert North,Laurence Rhines,Claudio Tatsui 대한척추신경외과학회 2023 Neurospine Vol.20 No.1

Purpose: Carbon-fiber reinforced polyetheretherketone (CFRP)-based spinal implants are an alternative to titanium, offering less image artifact as their metallic counterparts while maintaining similar biomechanical and biocompatibility properties. Its use in the management of spinal tumors has been reported, however the perceived advantages related to improved imaging quality, radiation treatment planning, and detection of tumor recurrence have not been fully assessed. Methods: We performed a retrospective review of medical records amongst oncologic patients treated at MD Anderson Cancer Center with CFRP implants. Histology, tumor location, construct features, time of follow-up, adjuvant radiation, recurrences, overall survival, and hardware-related complications were recorded. Results: Sixty-nine consecutive patients were assessed (22 primary tumors, 47 metastases) and the median time for follow-up was 5.4 months. Amongst the cohort, a total of 491 CFRP pedicle screws were implanted. Hardware complications were observed in 5 cases (7.04%). Adjuvant radiation was completed in 8 patients with primary tumors and 29 patients with spinal metastases. A total of 28 patients (40.5%) from the combined primary and metastatic cohorts experienced systemic disease progression, with 12 patients (17.3%) demonstrating local recurrences. Amongst primary and metastatic tumors, overall survival (p = 0.363) and rate of local recurrence (p = 0.112) were similar. Conclusion: This largest series of CFRP implants demonstrates safe and effective spinal stabilization for patients with both primary and metastatic tumors. Enhanced postoperative imaging led to minimal imaging artifacts which facilitated postoperative radiation planning and the ability to detect local recurrence.

The use of imageless navigation to quantify cutting error in total knee arthroplasty

( Ran Schwarzkopf ),( Morteza Meftah ),( Scott E. Marwin ),( Michelle A. Zabat ),( Jeffrey M. Muir ),( Iain R. Lamb ) 대한슬관절학회 2021 대한슬관절학회지 Vol.33 No.-

Purpose: Navigated total knee arthroplasty (TKA) improves implant alignment by providing feedback on resection parameters based on femoral and tibial cutting guide positions. However, saw blade thickness, deflection, and cutting guide motion may lead to final bone cuts differing from planned resections, potentially contributing to suboptimal component alignment. We used an imageless navigation device to intraoperatively quantify the magnitude of error between planned and actual resections, hypothesizing final bone cuts will differ from planned alignment. Materials and methods: A retrospective study including 60 consecutive patients undergoing primary TKA using a novel imageless navigation device was conducted. Device measurements of resection parameters were obtained via attachment of optical trackers to femoral and tibial cutting guides prior to resection. Following resection, optical trackers were placed directly on the bone cut surface and measurements were recorded. Cutting guide and bone resection measurements of both femoral and tibial varus/valgus, femoral flexion, tibial slope angles, and both femoral and tibial medial and lateral resection depths were compared using a Student’s t-test. Results: Femoral cutting guide position differed from the actual cut by an average 0.6 ± 0.5° (p = 0.85) in the varus/ valgus angle and 1.0 ± 1.0° (p = 0.003) in the flexion/extension angle. The difference between planned and actual cut measurements for medial and lateral femoral resection depth was 1.1 ± 1.1 mm (p = 0.32) and 1.2 ± 1.0 mm (p = 0.067), respectively. Planned cut measurements based on tibial guide position differed from the actual cut by an average of 0.9 ± 0.8° (p = 0.63) in the varus/valgus angle and 1.1 ± 1.0° (p = 0.95) in slope angle. Measurement of medial and lateral tibial resection depth differed by an average of 0.1 ± 1.8 mm (p = 0.78) and 0.2 ± 2.1 mm (p = 0.85), respectively. Conclusions: Significant discrepancies between planned and actual femoral bone resection were demonstrated for flexion/extension angle, likely the result of cutting error. Our data highlights the importance of cut verification postresection to confirm planned resections are achieved, and suggests imageless navigation may be a source of feedback that would allow surgeons to intraoperatively adjust resections to achieve optimal implant alignment.

Delayed differentiation of potent effector CD8⁺ T cells reducing viremia and reservoir seeding in acute HIV infection

Takata, Hiroshi,Buranapraditkun, Supranee,Kessing, Cari,Fletcher, James L. K.,Muir, Roshell,Tardif, Virginie,Cartwright, Pearline,Vandergeeten, Claire,Bakeman, Wendy,Nichols, Carmen N.,Pinyakorn, Sute American Association for the Advancement of Scienc 2017 Science Translational Medicine Vol.9 No.377

<P>CD8(+) T cells play a critical role in controlling HIV viremia and could be important in reducing HIV-infected cells in approaches to eradicate HIV. The simian immunodeficiency virus model provided the proof of concept for a CD8(+) T cell-mediated reservoir clearance but showed conflicting evidence on the role of these cells to eliminate HIV-infected cells. In humans, HIV-specific CD8(+) T cell responses have not been associated with a reduction of the HIV-infected cell pool in vivo. We studied HIV-specific CD8(+) T cells in the RV254 cohort of individuals initiating ART in the earliest stages of acute HIV infection (AHI). We showed that the HIV-specific CD8(+) T cells generated as early as AHI stages 1 and 2 before peak viremia are delayed in expanding and acquiring effector functions but are endowed with higher memory potential. In contrast, the fully differentiated HIV-specific CD8(+) T cells at peak viremia in AHI stage 3 were more prone to apoptosis but were associated with a steeper viral load decrease after ART initiation. Their capacity to persist in vivo after ART initiation correlated with a lower HIV DNA reservoir. These findings demonstrate that HIV-specific CD8(+) T cell magnitude and differentiation are delayed in the earliest stages of infection. These results also demonstrate that potent HIV-specific CD8(+) T cells contribute to the reduction of the pool of HIV-producing cells and the HIV reservoir seeding in vivo and provide the rationale to design interventions aiming at inducing these potent responses to cure HIV infection.</P>