Use of Ledipasvir/Sofosbuvir (LDV/SOF) in Patients with Advanced Chronic Kidney Disease (eGFR ≤30ml/min): A Case Series

( Meghan E. Sise ),( Naim Alkhouri ),( Brian Borg ),( Sooji Lee ),( Thomas Mcquaid ),( Joseph Llewellyn ),( Macky Natha ),( Shampa De-oertel ),( Diana M. Brainard ),( Marc Carp ),( Michael Fuchs ),( H 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: Little is known about the safety and efficacy of LDV/SOF in patients with advanced chronic kidney disease (CKD) with eGFR ≤ 30 ml/min or on hemodialysis. Yet, off-label use of LDV/SOF in this population occurs. Methods: Providers proactively reporting such off-label use to Gilead Sciences were asked to submit de-identified case reports. Demographics, clinical characteristics at baseline, during, and after LDV/SOF treatment, and adverse events were collected. Summary statistics and paired sample t-tests are presented. Results: Twenty-one case summaries were submitted. Median Age was 59 (range 26-71). Eleven patients (52%) were black, 20 had genotype 1 (13-1a, 4-1b) and one patient had genotype 3. Median pretreatment viral load was 1,680,000 IU (range 133,000-37,200,000 IU). Twelve patients (56%) were on hemodialysis and 9 had CKD Stage 4 (eGFR 15-29 ml/min), 13 (62%) had cirrhosis, 11 (50%) had diabetes, 5 had history of organ transplantation (4 kidney, 1 liver). All patients received full dose LDV/SOF for 12 weeks with one patient also receiving 200 mg Ribavirin every other day in combination. Eight adverse events were reported; 2 patients (10%) with anemia, 1 case of insomnia, nausea/vomiting, headache, and chest pain (5%) each. Of the 9 patients with CKD stage 4, 2 experienced an increase in eGFR and 5 a decrease in eGFR post treatment. All 21 patients achieved SVR 12 (100%). No patient discontinued treatment due to an adverse event. Conclusions: In this small case series describing the use of ledipasvir/sofosbuvir in Patients with Advanced Chronic Kidney Disease: 62% had cirrhosis, 52% had diabetes mellitus, and 57% were on hemodialysis. All 21 patients achieved SVR12 including 12 patients on hemodialysis. LDV/SOF was relatively well tolerated and there were no treatment discontinuations. Most patients had stable renal function before and after treatment with LDV/SOF.

A FEYNMAN FUNCTIONAL FOR THE GLOBAL POSITIONING SYSTEM

Facio, Brian-De Korean Mathematical Society 2001 대한수학회지 Vol.38 No.2

A Feynman functional formulation is given for the Global Positioning System, GPS. Both the sequential and analytic Feynman functionals are presented for the classical, exterior, gravity problems which included rigid body rotations, special relativity and some general relativity corrections. A mathematically rigorous approach is introduced whose solutions exist, are unique and which depend continuously on the intial data. This formulation is convergent and has the finite approximation property. It is emphasized that all of the problems studied are classical (not quantum) evolution systems.

Safety and efficacy of salvage conventional re-irradiation following stereotactic radiosurgery for spine metastases

Marcus A. Florez(Marcus A. Florez ),Brian De(Brian De ),Bhavana V. Chapman(Bhavana V. Chapman ),Anussara Prayongrat(Anussara Prayongrat ),Jonathan G. Thomas(Jonathan G. Thomas ),Thomas H. Beckham(Thom 대한방사선종양학회 2023 Radiation Oncology Journal Vol.41 No.1

Purpose: There has been limited work assessing the use of re-irradiation (re-RT) for local failure following stereotactic spinal radiosurgery (SSRS). We reviewed our institutional experience of conventionally-fractionated external beam radiation (cEBRT) for salvage therapy following SSRS local failure. Materials and Methods: We performed a retrospective review of 54 patients that underwent salvage conventional re-RT at previously SSRS-treated sites. Local control following re-RT was defined as the absence of progression at the treated site as determined by magnetic resonance imaging. Results: Competing risk analysis for local failure was performed using a Fine-Gray model. The median follow-up time was 25 months and median overall survival (OS) was 16 months (95% confidence interval [CI], 10.8–24.9 months) following cEBRT re-RT. Multivariable Cox proportional-hazards analysis revealed Karnofsky performance score prior to re-RT (hazard ratio [HR] = 0.95; 95% CI, 0.93– 0.98; p = 0.003) and time to local failure (HR = 0.97; 95% CI, 0.94–1.00; p = 0.04) were associated with longer OS, while male sex (HR = 3.92; 95% CI, 1.64–9.33; p = 0.002) was associated with shorter OS. Local control at 12 months was 81% (95% CI, 69.3–94.0). Competing risk multivariable regression revealed radioresistant tumors (subhazard ratio [subHR] = 0.36; 95% CI, 0.15–0.90; p = 0.028) and epidural disease (subHR = 0.31; 95% CI, 0.12–0.78; p =0.013) were associated with increased risk of local failure. At 12 months, 91% of patients maintained ambulatory function. Conclusion: Our data suggest that cEBRT following SSRS local failure can be used safely and effectively. Further investigation is needed into optimal patient selection for cEBRT in the retreatment setting.

Influence of Lumbar Lordosis on Posterior Rod Strain in Long-Segment Construct During Biomechanical Loading: A Cadaveric Study

Bernardo de Andrada Pereira,Anna G.U. Sawa,Jakub Godzik,Jennifer N. Lehrman,Juan S. Uribe,Jay D. Turner,Brian P. Kelly 대한척추신경외과학회 2021 Neurospine Vol.18 No.3

Objective: The lordotic shape of the lumbar spine differs substantially between individuals. Measuring and recording strain during spinal biomechanical tests is an effective method to infer stresses on spinal implants and predict failure mechanisms. The geometry of the spine may have a significant effect on the resultant force distribution, thereby directly affecting rod strain. Methods: Seven fresh-frozen cadaveric specimens (T12-sacrum) underwent standard (7.5 Nm) nondestructive sagittal plane tests: flexion and extension. The conditions tested were intact and pedicle screws and rods (PSR) at L1-sacrum. The posterior right rod was instrumented with strain gauges between L3–4 (index level) and the L5–S1 pedicle screw. All specimens underwent lateral radiographs before testing. Lordotic angles encompassing different levels (L5–S1, L4–S1, L3–S1, L2–S1, and L1–S1) were measured and compared with rod strain. Data were analyzed using Pearson correlation analyses. Results: Strong positive correlations were observed between lordosis and posterior rod strain across different conditions. The L3–S1 lordotic angle in the unloaded intact condition correlated with peak rod strain at L3–4 with PSR during flexion (R=0.76, p=0.04). The same angle in the unloaded PSR condition correlated with peak strain in the PSR condition during extension (R=-0.79, p=0.04). The unloaded intact L2–S1 lordotic angle was significantly correlated with rod strain at L3–4 in the PSR condition during flexion (R=0.85, p=0.02) and extension (R=-0.85, p=0.02) and with rod strain at L5–S1 in the PSR condition during flexion (R=0.84, p=0.04). Conclusion: Lordosis measured on intact and instrumented conditions has strong positive correlations with posterior rod strain in cadaveric testing.

Biomechanics of Circumferential Cervical Fixation Using Posterior Facet Cages: A Cadaveric Study

Bernardo de Andrada Pereira,Joshua E. Heller,Jennifer N. Lehrman,Anna G.U. Sawa,Brian P. Kelly 대한척추신경외과학회 2021 Neurospine Vol.18 No.1

Objective: Anterior cervical discectomy and fusion (ACDF) is a common procedure for the treatment of cervical disease. Circumferential procedures are options for multilevel pathology. Potential complications of multilevel anterior procedures are dysphagia and pseudarthrosis, whereas potential complications of posterior surgery include development of cervical kyphosis and postoperative chronic neck pain. The addition of posterior cervical cages (PCCs) to multilevel ACDF is a minimally invasive option to perform circumferential fusion. This study evaluated the biomechanical performance of 3-level circumferential fusion with PCCs as supplemental fixation to anteriorly placed allografts, with and without anterior plate fixation. Methods: Nondestructive flexibility tests (1.5 Nm) performed on 6 cervical C2–7 cadaveric specimens intact and after discectomy (C3–6) in 3 instrumented conditions: allograft with anterior plate (G+P), PCC with allograft and plate (PCC+G+P), and PCC with allograft alone (PCC+G). Range of motion (ROM) data were analyzed using 1-way repeated-measures analysis of variance. Results: All instrumented conditions resulted in significantly reduced ROM at the 3 instrumented levels (C3–6) compared to intact spinal segments in flexion, extension, lateral bending, and axial rotation (p<0.001). No significant difference in ROM was found between G+P and PCC+G+P conditions or between G+P and PCC+G conditions, indicating similar stability between these conditions in all directions of motion. Conclusion: All instrumented conditions resulted in considerable reduction in ROM. The added reduction in ROM through the addition of PCCs did not reach statistical significance. Circumferential fusion with anterior allograft, without plate and with PCCs, has comparable stability to ACDF with allograft and plate.

Biomechanical Effects of Proximal Polyetheretherketone Rod Extension on the Upper Instrumented and Adjacent Levels in a Human Long-Segment Construct: A Cadaveric Model

Bernardo de Andrada Pereira,Jennifer N. Lehrman,Anna G.U. Sawa,Piyanat Wangsawatwong,Jakub Godzik,David S. Xu,Jay D. Turner,Brian P. Kelly,Juan S. Uribe 대한척추신경외과학회 2022 Neurospine Vol.19 No.3

Objective: The high mechanical stress zone at the sudden transition from a rigid to flexible region is involved in proximal junctional kyphosis (PJK) physiopathology. We evaluated the biomechanical performance of polyetheretherketone (PEEK) rods used as a nontraditional long semirigid transition phase from a long-segment metallic rod construct to the nonfused thoracic spine. Methods: Pure moment range of motion (ROM) tests (7.5 Nm) were performed on 7 cadaveric spine segments followed by compression (200 N). Specimens were tested in the following conditions: (1) intact; (2) T10-pelvis pedicle screws and rods (PSRs); and (3) extending the proximal construct to T6 using PEEK rods (PSR+PEEK). T10–11 rod strain, T9 anterolateral bone strain, and T10 screw bending moments were analyzed. Results: At the upper instrumented vertebra (UIV)+1, PSR+PEEK versus PSR significantly decreased ROM in flexion (115%, p = 0.02), extension (104%, p = 0.003), left lateral bending (46%, p = 0.02), and right lateral bending (63%, p = 0.008). Also, at UIV+1, PSR+PEEK versus intact significantly decreased ROM in flexion (111%, p = 0.01) and extension (105%, p = 0.003). The UIV+1 anterior column bone strain was significantly reduced with PSR+ PEEK versus PSR during right lateral bending (p = 0.02). Rod strain polarities reversed with PEEK rods in all loading directions except compression. Conclusion: Extending a long-segment construct using PEEK rods caused a decrease in adjacent-level hypermobility as a consequence of long-segment immobilization and also redistributed the strain on the UIV and adjacent levels, which might contribute to PJK physiopathology. Further studies are necessary to observe the clinical outcomes of this technique.

West meets East: How do rainforest beetles become circum-Pacific? Evolutionary origin of <i>Callipogon relictus</i> and allied species (Cerambycidae: Prioninae) in the New and Old Worlds

Kim, Sangil,de Medeiros, Bruno A.S.,Byun, Bong-Kyu,Lee, Seunghwan,Kang, Jung-Hoon,Lee, Bongwoo,Farrell, Brian D. Elsevier 2018 Molecular phylogenetics and evolution Vol.125 No.-

<P><B>Abstract</B></P> <P>The longhorn beetle genus <I>Callipogon</I> Audinet-Serville represents a small group of large wood-boring beetles whose distribution pattern exhibits a unique trans-Pacific disjunction between the East Asian temperate rainforest and the tropical rainforest of the Neotropics. To understand the biogeographic history underlying this circum-Pacific disjunct distribution, we reconstructed a molecular phylogeny of the subfamily Prioninae with extensive sampling of <I>Callipogon</I> using multilocus sequence data of 99 prionine and four parandrine samples (ingroups), together with two distant outgroup species. Our sampling of <I>Callipogon</I> includes 18 of the 24 currently accepted species, with complete representation of all species in our focal subgenera. Our phylogenetic analyses confirmed the purported affinity between the Palearctic <I>Callipogon relictus</I> and its Neotropical congeners. Furthermore, based on molecular dating under the fossilized birth–death (FBD) model with comprehensive fossil records and probabilistic ancestral range reconstructions, we estimated the crown group <I>Callipogon</I> to have originated in the Paleocene circa 60 million years ago (Ma) across the Neotropics and Eastern Palearctics. The divergence between the Palearctic <I>C. relictus</I> and its Neotropical congeners is explained as the result of a vicariance event following the demise of boreotropical forest across Beringia at the Eocene-Oligocene boundary. As <I>C. relictus</I> represents the unique relictual species that evidentiates the lineage’s expansive ancient distribution, we evaluated its conservation importance through species distribution modelling. Though we estimated a range expansion for <I>C. relictus</I> by 2050, we emphasize a careful implementation of conservation programs towards the protection of primary forest across its current habitats, as the species remains highly vulnerable to habitat disturbance.</P> <P><B>Highlights</B></P> <P> <UL> <LI> The first molecular phylogeny of world prionine longhorn beetles is presented. </LI> <LI> Wide ancient distribution of stem lineage <I>Callipogon relictus</I> is revealed. </LI> <LI> Systematic affinity between <I>C. relictus</I> and Neotropical congeners is confirmed. </LI> <LI> Climate-mediated Beringian vicariance explains the current disjunct distribution. </LI> <LI> Conservation importance of <I>C. relictus</I> is evaluated through distribution modelling. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Target enrichment adds values to history: DNA mining from museum specimens

Sang Il Kim,Bruno A. S. de Medeiros,Brian D. Farrell,Seunggwan Shin 한국응용곤충학회 2021 한국응용곤충학회 학술대회논문집 Vol.2021 No.10

Discovery of dual leucine zipper kinase (DLK, MAP3K12) inhibitors with activity in neurodegeneration models.

Patel, Snahel,Cohen, Frederick,Dean, Brian J,De La Torre, Kelly,Deshmukh, Gauri,Estrada, Anthony A,Ghosh, Arundhati Sengupta,Gibbons, Paul,Gustafson, Amy,Huestis, Malcolm P,Le Pichon, Claire E,Lin, Ha American Chemical Society 2015 Journal of medicinal chemistry Vol.58 No.1

<P>Dual leucine zipper kinase (DLK, MAP3K12) was recently identified as an essential regulator of neuronal degeneration in multiple contexts. Here we describe the generation of potent and selective DLK inhibitors starting from a high-throughput screening hit. Using proposed hinge-binding interactions to infer a binding mode and specific design parameters to optimize for CNS druglike molecules, we came to focus on the di(pyridin-2-yl)amines because of their combination of desirable potency and good brain penetration following oral dosing. Our lead inhibitor GNE-3511 (26) displayed concentration-dependent protection of neurons from degeneration in vitro and demonstrated dose-dependent activity in two different animal models of disease. These results suggest that specific pharmacological inhibition of DLK may have therapeutic potential in multiple indications.</P>

Does Acupuncture Therapy Alter Activation of Neural Pathway for Pain Perception in Irritable Bowel Syndrome?: A Comparative Study of True and Sham Acupuncture Using Functional Magnetic Resonance Imaging

( Winnie Cw Chu ),( Justin Cy Wu ),( David Tw Yew ),( Liang Zhang ),( Lin Shi ),( David Kw Yeung ),( De Feng Wang ),( Raymond Ky Tong ),( Ya Wen Chan ),( Li Xing Lao ),( Ping C Leung ),( Brian M Berma 대한소화기기능성질환·운동학회 2012 Journal of Neurogastroenterology and Motility (JNM Vol.18 No.3

Background/Aims Patients with irritable bowel syndrome (IBS) are characterized by abnormal central processing with altered brain activation in response to visceral nociceptive signals. The effect of electroacupuncture (EA) on IBS patients is unclear. The study is set to study the effect of EA on brain activation during noxious rectal distension in IBS patients using a randomized sham-controlled model. Methods Thirty IBS-diarrhea patients were randomized to true electroacupuncture or sham acupuncture. Functional MRI was performed to evaluate cerebral activation at the following time points: (1) baseline when there was rectal distension only, (2) rectal distension during application of EA, (3) rectal distension after cessation of EA and (4) EA alone with no rectal distension. Group comparison was made under each condition using SPM5 program. Results Rectal distension induced significant activation of the anterior cingulated cortex, prefrontal cortex, thalamus, temporal regions and cerebellum at baseline. During and immediately after EA, increased cerebral activation from baseline was observed in the anterior cingulated cortex, bilateral prefrontal cortex, thalamus, temporal regions and right insula in both groups. However, true electroacupuncture led to significantly higher activation at right insula, as well as pulvinar and medial nucleus of the thalamus when compared to sham acupuncture. Conclusions We postulate that acupuncture might have the potential effect of pain modulation in IBS by 2 actions: (1) modulation of serotonin pathway at insula and (2) modulation of mood and affection in higher cortical center via ascending pathway at the pulvinar and medial nucleus of the thalamus. (J Neurogastroenterol Motil 2012;18:305-316)