Polypharmacy in Multiple Sclerosis: Prevalence, Risks, and Mitigation Strategies.

PURPOSE OF REVIEW: Polypharmacy, the use of ≥ 5 medications, is common in people with multiple sclerosis and is associated with negative outcomes. The use of multiple medications is common for symptom management in people with multiple sclerosis, but risks drug-drug interactions and additive side effects. Multiple sclerosis providers should therefore focus on the appropriateness and risks versus benefits of pharmacotherapy in each patient. This review describes the prevalence and risks associated with polypharmacy in people with multiple sclerosis and offers strategies to identify and mitigate inappropriate polypharmacy. RECENT FINDINGS: Research in people with multiple sclerosis has identified risk factors and negative outcomes associated with polypharmacy. Medication class-specific investigations highlight their contribution to potentially inappropriate polypharmacy in people with multiple sclerosis. People with multiple sclerosis are at risk for inappropriate polypharmacy. Multiple sclerosis providers should review medications and consider their appropriateness and potential for deprescribing within the context of each patient.

NMR spin-rotation relaxation and diffusion of methane.

The translational diffusion-coefficient and the spin-rotation contribution to the 1H NMR relaxation rate for methane (CH4) are investigated using MD (molecular dynamics) simulations, over a wide range of densities and temperatures, spanning the liquid, supercritical, and gas phases. The simulated diffusion-coefficients agree well with measurements, without any adjustable parameters in the interpretation of the simulations. A minimization technique is developed to compute the angular velocity for non-rigid spherical molecules, which is used to simulate the autocorrelation function for spin-rotation interactions. With increasing diffusivity, the autocorrelation function shows increasing deviations from the single-exponential decay predicted by the Langevin theory for rigid spheres, and the deviations are quantified using inverse Laplace transforms. The 1H spin-rotation relaxation rate derived from the autocorrelation function using the "kinetic model" agrees well with measurements in the supercritical/gas phase, while the relaxation rate derived using the "diffusion model" agrees well with measurements in the liquid phase. 1H spin-rotation relaxation is shown to dominate over the MD-simulated 1H-1H dipole-dipole relaxation at high diffusivity, while the opposite is found at low diffusivity. At high diffusivity, the simulated spin-rotation correlation time agrees with the kinetic collision time for gases, which is used to derive a new expression for 1H spin-rotation relaxation, without any adjustable parameters.

Role of internal motions and molecular geometry on the NMR relaxation of hydrocarbons.

The role of internal motions and molecular geometry on 1H NMR relaxation rates in liquid-state hydrocarbons is investigated using MD (molecular dynamics) simulations of the autocorrelation functions for intramolecular and intermolecular 1H-1H dipole-dipole interactions. The effects of molecular geometry and internal motions on the functional form of the autocorrelation functions are studied by comparing symmetric molecules such as neopentane and benzene to corresponding straight-chain alkanes n-pentane and n-hexane, respectively. Comparison of rigid versus flexible molecules shows that internal motions cause the intramolecular and intermolecular correlation-times to get significantly shorter, and the corresponding relaxation rates to get significantly smaller, especially for longer-chain n-alkanes. Site-by-site simulations of 1H's across the chains indicate significant variations in correlation times and relaxation rates across the molecule, and comparison with measurements reveals insights into cross-relaxation effects. Furthermore, the simulations reveal new insights into the relative strength of intramolecular versus intermolecular relaxation as a function of internal motions, as a function of molecular geometry, and on a site-by-site basis across the chain.

Assessment and optimization of liver volume before major hepatic resection: Current guidelines and a narrative review.

Post hepatectomy liver failure (PHLF) remains a significant cause of morbidity and mortality after major liver resection. Although the etiology of PHLF is multifactorial, an inadequate functional liver remnant (FLR) is felt to be the most important modifiable predictor of PHLF. Pre-operative evaluation of FLR function and volume is of paramount importance before proceeding with any major liver resection. Patients with inadequate or borderline FLR volume must be considered for volume optimization strategies such as portal vein embolization (PVE), two stage hepatectomy with portal vein ligation (PVL), Yttrium-90 radioembolization, and associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). This paper provides an overview of assessing FLR volume and function, and discusses indications and outcomes of commonly used volume optimization strategies.

Prevention of allograft HCV recurrence with peri-transplant human monoclonal antibody MBL-HCV1 combined with a single oral direct-acting antiviral: A proof-of-concept study.

Patients with active hepatitis C virus (HCV) infection at transplantation experience rapid allograft infection, increased risk of graft failure and accelerated fibrosis. MBL-HCV1, a neutralizing human monoclonal antibody (mAb) targeting the HCV envelope, was combined with a licensed oral direct-acting antiviral (DAA) to prevent HCV recurrence post-transplant in an open-label exploratory efficacy trial. Eight subjects received MBL-HCV1 beginning on the day of transplant with telaprevir initiated between days 3 and 7 post-transplantation. Following FDA approval of sofosbuvir, two subjects received MBL-HCV1 starting on the day of transplant with sofosbuvir initiated on day 3. Combination treatment was administered for 8-12 weeks or until the stopping rule for viral rebound was met. The primary endpoint was undetectable HCV RNA at day 56 with exploratory endpoints of sustained virologic response (SVR) at 12 and 24 weeks post-treatment. Both subjects receiving mAb and sofosbuvir achieved SVR24. Four of eight subjects in the mAb and telaprevir group met the primary endpoint; one subject achieved SVR24 and three subjects relapsed 2-12 weeks post-treatment. The other four subjects experienced viral breakthrough. There were no serious adverse events related to study treatment. This proof-of-concept study demonstrates that peri-transplant immunoprophylaxis combined with a single oral direct-acting antiviral in the immediate post-transplant period can prevent HCV recurrence.

Management of acute upper gastrointestinal bleeding: an update for the general physician.

Acute upper gastrointestinal bleed (AUGIB) is one of the most common medical emergencies in the UK, with roughly one presentation every 6 min. Despite advances in therapeutics and endoscopy provision, mortality following AUGIB over the last two decades has remained high, with over 9,000 deaths annually in the UK; consequently, several national bodies have published UK-relevant guidelines. Despite this, the 2015 UK National Confidential Enquiry into Patient Outcome and Death in AUGIB highlighted variations in practice, raised concerns regarding suboptimal patient care and released a series of recommendations. This review paper incorporates the latest available evidence and UK-relevant guidelines to summarise the optimal pre-endoscopic, endoscopic, and post-endoscopic approach to and management of non-variceal and variceal AUGIB that will be of practical value to both general physicians and gastroenterologists.

A genomic case study of mixed fibrolamellar hepatocellular carcinoma.

BACKGROUND: Mixed fibrolamellar hepatocellular carcinoma (mFL-HCC) is a rare liver tumor defined by the presence of both pure FL-HCC and conventional HCC components, represents up to 25% of cases of FL-HCC, and has been associated with worse prognosis. Recent genomic characterization of pure FL-HCC identified a highly recurrent transcript fusion (DNAJB1:PRKACA) not found in conventional HCC. PATIENTS AND METHODS: We performed exome and transcriptome sequencing of a case of mFL-HCC. A novel BAC-capture approach was developed to identify a 400 kb deletion as the underlying genomic mechanism for a DNAJB1:PRKACA fusion in this case. A sensitive Nanostring Elements assay was used to screen for this transcript fusion in a second case of mFL-HCC, 112 additional HCC samples and 44 adjacent non-tumor liver samples. RESULTS: We report the first comprehensive genomic analysis of a case of mFL-HCC. No common HCC-associated mutations were identified. The very low mutation rate of this case, large number of mostly single-copy, long-range copy number variants, and high expression of ERBB2 were more consistent with previous reports of pure FL-HCC than conventional HCC. In particular, the DNAJB1:PRKACA fusion transcript specifically associated with pure FL-HCC was detected at very high expression levels. Subsequent analysis revealed the presence of this fusion in all primary and metastatic samples, including those with mixed or conventional HCC pathology. A second case of mFL-HCC confirmed our finding that the fusion was detectable in conventional components. An expanded screen identified a third case of fusion-positive HCC, which upon review, also had both conventional and fibrolamellar features. This screen confirmed the absence of the fusion in all conventional HCC and adjacent non-tumor liver samples. CONCLUSION: These results indicate that mFL-HCC is similar to pure FL-HCC at the genomic level and the DNAJB1:PRKACA fusion can be used as a diagnostic tool for both pure and mFL-HCC.

Short-Term Radiographic Results and Technique of Tibiotalocalcaneal Arthrodesis With a Posterior Anatomic Locking Plate.

Tibiotalocalcaneal arthrodesis is a salvage procedure for severe hindfoot/ankle deformities, arthritis, avascular necrosis of the talus, failed total ankle replacement, and Charcot neuroarthropathy. The methods for fixation include anterior and lateral plates, screws, retrograde intramedullary nails, and external fixation. The purpose of the present report was to describe the short-term radiographic outcomes and technique using a posterior approach with an anatomic-specific locking plate for tibiotalocalcaneal arthrodesis. Nine patients underwent tibiotalocalcaneal arthrodesis using a posterior locking plate. The medical records and radiographs were retrospectively reviewed for patient demographics, fusion rate, complications, and patient satisfaction. The mean patient age was 57.89 ± 10.8 years, and the follow-up period was 11.11 ± 4.74 months for the patients undergoing posterior tibiotalocalcaneal arthrodesis. The mean time to weightbearing in a shoe with a brace was 16.68 weeks. The ankle and subtalar joints had healed within a mean duration of 13.61 ± 2.96 weeks. Two patients (22%) developed nonunion, 1 at both the ankle and subtalar joint and 1 at the ankle only. The present report demonstrates an alternative posterior approach to joint preparation and fixation. Direct visualization of both joints and soft tissue coverage provide a viable option for posterior fusion in patients with compromised anterior and/or lateral skin envelopes.

Should ALPPS be Used for Liver Resection in Intermediate-Stage HCC?

BACKGROUND: Extended liver resections in patients with hepatocellular carcinoma (HCC) are problematic due to hepatitis, fibrosis, and cirrhosis. Associating liver partition with portal vein ligation for staged hepatectomy (ALPPS) has been promoted as a novel method to induce hypertrophy for patients with extensive colorectal liver metastases, but outcomes in HCC have not been well investigated. METHODS: All patients registered in the international ALPPS Registry ( www.alpps.org ) from 2010 to 2015 were studied. Hypertrophy of the future liver remnant, perioperative morbidity and mortality, age, overall survival, and other parameters were compared between patients with HCC and patients with colorectal liver metastases (CRLM). RESULTS: The study compared 35 patients with HCC and 225 patients with CRLM. The majority of patients undergoing ALPPS for HCC fall into the intermediate-stage category of the Barcelona clinic algorithm. In this study, hypertrophy was rapid and extensive for the HCC patients, albeit lower than for the CRLM patients (47 vs. 76 %; p < 0.002). Hypertrophy showed a linear negative correlation with the degrees of fibrosis. The 90-day mortality for ALPPS used to treat HCC was almost fivefold higher than for CRLM (31 vs. 7 %; p < 0.001). Multivariate analysis showed that patients older than 61 years had a significantly reduced overall survival (p < 0.004). CONCLUSION: The ALPPS approach induces a considerable hypertrophic response in HCC patients and allows resection of intermediate-stage HCC, albeit at the cost of a 31 % perioperative mortality rate. The use of ALPPS for HCC remains prohibitive for most patients and should be performed only for a highly selected patient population younger than 60 years with low-grade fibrosis.

Maintenance of reduction with suture button fixation devices for ankle syndesmosis repair.

BACKGROUND: Malreduction of the syndesmosis can lead to increased peak pressures and subsequent arthritis. The purpose of this study was to evaluate the initial syndesmotic reduction and radiographic maintenance when using a knotless suture button fixation device for treatment of syndesmotic injury. METHODS: A retrospective chart and radiographic review was performed to identify patients who underwent open reduction internal fixation of ankle syndesmosis ruptures treated with a knotless, suture button fixation system. Radiographic measurements included medial clear space, tibiofibular overlap, tibiofibular clear space, and the distance between buttons. Fifty-six patients underwent repair of an ankle fracture with syndesmotic rupture over a 3-year period, with a mean follow-up of 160.9 days. RESULTS: The tibiofibular clear space and tibiofibular overlap significantly improved from pre- to first postoperative, but also demonstrated some loss of fixation at final follow-up (P < .001). The distance between the buttons increased on average 1.1 mm from immediate postoperative to final follow-up, demonstrating some postoperative creep and loss of fixation in the system. A low complication rate and need for a revision operation was found in our patient cohort. Some loss of reduction did occur postoperatively, although this did not correlate to adverse patient outcomes. CONCLUSION: Syndesmotic stabilization, using a knotless suture button fixation device demonstrated adequate initial syndesmotic reduction, but also exhibited an increase in the tibiofibular clear space and tibiofibular overlap, relative to initial postfixation position, at short-term follow-up. LEVEL OF EVIDENCE: Level IV, retrospective case series.

Atrial fibrillation in patients undergoing liver transplantation-a single-center experience.

BACKGROUND: As the prevalence of atrial fibrillation rises with age and older patients increasingly receive transplants, the perioperative management of this common arrhythmia and its impact on outcomes in liver transplantation is of relevance. METHODS: Retrospective review of 757 recipients of liver transplantation from January 2002 through December 2011. RESULTS: Nineteen recipients (2.5%) had documented pre-transplantation atrial fibrillation. Sixteen patients underwent liver and 3 a combined liver-kidney transplantation. Three patients died within 30 days (84.2% 1-month survival) and another 3 within 1 year of transplantation (68.4% 1-year survival). Compared with patients without atrial fibrillation, the relative risk of death in the atrial fibrillation group was 5.29 at 1 month (P = .0034; 95% confidence interval [CI], 1.73-16.18) and 3.28 at 1 year (P = .0008; 95% CI, 1.63-6.59). Time to extubation and intensive care unit (ICU) and hospital readmissions were not different from the control cohort. Rapid ventricular response requiring treatment occurred in 4 patients during surgery and 7 after surgery, resulting in 3 ICU and 3 hospital readmissions. CONCLUSIONS: The results suggest that patients with atrial fibrillation may be at increased risk of mortality after liver transplantation. Optimization of medical therapy may decrease ICU and hospital readmission due to rapid ventricular response.

Hepatic venous outflow obstruction in pediatric liver transplantation: technical considerations in prevention, diagnosis, and management.

HVOO creates significant diagnostic and management dilemmas in pediatric liver transplant recipients, particularly with TVGs (split or reduced-size grafts). Numerous technical variations for the hepatic vein to IVC anastomosis have been described to minimize the incidence of this complication, but no consensus for an optimal anastomotic technique exists. One hundred and thirty-four liver transplants (70 TVGs) were performed in 124 patients between 1994 and 2011. These were divided into two cohorts. Group 1 (95 transplants, 41 TVGs) utilized a continuous running anastomosis. Group 2 (39 transplants, 29 TVGs) implemented a triangulated (three-stitch) anastomosis. All were reviewed for demographics, diagnostics, interventions, and outcome. The overall HVOO incidence was seven of 134 transplants (5.2%) and six of 70 transplants utilizing TVGs (8.6%). Group 1 incidence was five of 41 (12.2%) compared with one of 29 (3.4%; p = 0.20, OR 3.89) in Group 2. Liver Doppler was employed in all patients, and only three suggested HVOO. All patients with HVOO underwent venogram, at a median of 81 days post-transplant. All underwent percutaneous venoplasty and required 1-6 treatments, all resulting in HVOO resolution. Incidence of HVOO has improved since adopting the triangulated anastomosis, although not to a level of statistical significance. US is not adequately sensitive to exclude HVOO. Venogram is recommended in patients with prolonged ascites, and venoplasty has been highly successful in HVOO treatment.

A novel organ donor facility: a decade of experience with liver donors.

Transplant surgeons have historically traveled to donor hospitals, performing complex, time-sensitive procedures with unfamiliar personnel. This often involves air travel, significant delays, and frequently occurs overnight.In 2001, we established the nation's first organ recovery center. The goal was to increase efficiency,reduce costs and reduce surgeon travel. Liver donors and recipients, donor costs, surgeon hours and travel time, from April 1,2001 through December 31,2011 were analyzed. Nine hundred and fifteen liver transplants performed at our center were analyzed based on procurement location (living donors and donation after cardiac death donors were excluded). In year 1, 36% (9/25) of donor procurements occurred at the organ procurement organization (OPO) facility, rising to 93%(56/60) in the last year of analysis. Travel time was reduced from 8 to 2.7 h (p<0.0001), with a reduction of surgeon fly outs by 93% (14/15) in 2011. Liver organ donor charges generated by the donor were reduced by37% overall for donors recovered at the OPO facility versus acute care hospital. Organs recovered in this novel facility resulted in significantly reduced surgeon hours, air travel and cost. This practice has major implications for cost containment and OPO national policy and could become the standard of care.

Effect of donor body mass index on the outcome of donation after cardiac death kidneys: how big is too big?

INTRODUCTION: Morbid obesity (MO) has become an epidemic in the United Sates and is associated with adverse effects on health. The purpose of this study was to examine the effects of MO on the short-term outcomes of kidneys transplanted from donation after cardiac death (DCD) donors. PATIENTS AND METHODS: Using a prospectively collected database, we reviewed 467 kidney transplantations performed at a single center between January 2008 and June 2011 to identify 67 recipients who received transplants from 40 DCD donors. The outcomes of 14 MO DCD donor kidneys were compared with 53 non-MO DCD grafts. MO was defined as a body mass index ≥ 35. Mean patient follow-up was 16 months. RESULTS: The MO and non-MO DCD donor groups were similar with respect to donor and recipient age, gender, race, cause of death and renal disease, time from withdrawal of life support to organ perfusion, mean human leukocyte antigen (HLA) mismatch, and overall recipient survival. Organs from MO DCD donors also had comparable rates of delayed graft function (21.4% vs 20.0%; P = not significant [NS]). At 1 year post-transplantation, a small but statistically insignificant difference was observed in the graft survival rates of MO and non-MO donors (87% vs. 96%; P = NS). One MO kidney had primary nonfunction. CONCLUSIONS: These data demonstrate that kidneys procured from MO DCD donors have equivalent short-term outcomes compared with non-MO grafts and should continue to be used. Further investigation is needed to examine the effect of MO on long-term renal allograft survival.

Immune responses to collagen-IV and fibronectin in renal transplant recipients with transplant glomerulopathy.

Antibodies (Abs) to donor HLA (donor-specific antibodies [DSA]) have been associated with transplant glomerulopathy (TG) following kidney transplantation (KTx). Immune responses to tissue-restricted self-antigens (self-Ags) have been proposed to play a role in chronic rejection. We determined whether KTx with TG have immune responses to self-Ags, Collagen-IV (Col-IV) and fibronectin (FN). DSA were determined by solid phase assay, Abs against Col-IV and FN by enzyme-linked immunosorbent assay and CD4+ T cells secreting interferon gamma (IFN-γ), IL-17 or IL-10 by ELISPOT. Development of Abs to self-Ags following KTx increased the risk for TG with an odds ratio of 22 (p-value = 0.001). Abs to self-Ags were IgG and IgM isotypes. Pretransplant Abs to self-Ags increased the risk of TG (22% vs. 10%, p < 0.05). Abs to self-Ags were identified frequently in KTx with DSA. TG patients demonstrated increased Col-IV and FN specific CD4+ T cells secreting IFN-γ and IL-17 with reduction in IL-10. We conclude that development of Abs to self-Ags is a risk factor and having both DSA and Abs to self-Ags increases the risk for TG. The increased frequency of self-Ag-specific IFN-γ and IL-17 cells with reduction in IL-10 demonstrate tolerance breakdown to self-Ags which we propose play a role in the pathogenesis of TG.

Second-order resummed thermodynamic perturbation theory for central-force associating potential: multi-patch colloidal models.

We propose a second-order version of the resummed thermodynamic perturbation theory for patchy colloidal models with arbitrary number of multiply bondable patches. The model is represented by the hard-sphere fluid system with several attractive patches on the surface and resummation is carried out to account for blocking effects, i.e., when the bonding of a particle restricts (blocks) its ability to bond with other particles. The theory represents an extension of the earlier proposed first order resummed thermodynamic perturbation theory for central force associating potential and takes into account formation of the rings of the particles. In the limiting case of singly bondable patches (total blockage), the theory reduces to Wertheim thermodynamic perturbation theory for associating fluids. Closed-form expressions for the Helmholtz free energy, pressure, internal energy, and chemical potential of the model with an arbitrary number of equivalent doubly bondable patches are derived. Predictions of the theory for the model with two patches appears to be in a very good agreement with predictions of new NVT and NPT Monte Carlo simulations, including the region of strong association.

Renal function at two years in liver transplant patients receiving everolimus: results of a randomized, multicenter study.

In a 24-month prospective, randomized, multicenter, open-label study, de novo liver transplant patients were randomized at 30 days to everolimus (EVR) + Reduced tacrolimus (TAC; n = 245), TAC Control (n = 243) or TAC Elimination (n = 231). Randomization to TAC Elimination was stopped prematurely due to a significantly higher rate of treated biopsy-proven acute rejection (tBPAR). The incidence of the primary efficacy endpoint, composite efficacy failure rate of tBPAR, graft loss or death postrandomization was similar with EVR + Reduced TAC (10.3%) or TAC Control (12.5%) at month 24 (difference -2.2%, 97.5% confidence interval [CI] -8.8%, 4.4%). BPAR was less frequent in the EVR + Reduced TAC group (6.1% vs. 13.3% in TAC Control, p = 0.010). Adjusted change in estimated glomerular filtration rate (eGFR) from randomization to month 24 was superior with EVR + Reduced TAC versus TAC Control: difference 6.7 mL/min/1.73 m(2) (97.5% CI 1.9, 11.4 mL/min/1.73 m(2), p = 0.002). Among patients who remained on treatment, mean (SD) eGFR at month 24 was 77.6 (26.5) mL/min/1.73 m(2) in the EVR + Reduced TAC group and 66.1 (19.3) mL/min/1.73 m(2) in the TAC Control group (p < 0.001). Study medication was discontinued due to adverse events in 28.6% of EVR + Reduced TAC and 18.2% of TAC Control patients. Early introduction of everolimus with reduced-exposure tacrolimus at 1 month after liver transplantation provided a significant and clinically relevant benefit for renal function at 2 years posttransplant.

Formative evaluation of ontology learning methods for entity discovery by using existing ontologies as reference standards.

OBJECTIVE: Developing a two-step method for formative evaluation of statistical Ontology Learning (OL) algorithms that leverages existing biomedical ontologies as reference standards. METHODS: In the first step optimum parameters are established. A 'gap list' of entities is generated by finding the set of entities present in a later version of the ontology that are not present in an earlier version of the ontology. A named entity recognition system is used to identify entities in a corpus of biomedical documents that are present in the 'gap list', generating a reference standard. The output of the algorithm (new entity candidates), produced by statistical methods, is subsequently compared against this reference standard. An OL method that performs perfectly will be able to learn all of the terms in this reference standard. Using evaluation metrics and precision-recall curves for different thresholds and parameters, we compute the optimum parameters for each method. In the second step, human judges with expertise in ontology development evaluate each candidate suggested by the algorithm configured with the optimum parameters previously established. These judgments are used to compute two performance metrics developed from our previous work: Entity Suggestion Rate (ESR) and Entity Acceptance Rate (EAR). RESULTS: Using this method, we evaluated two statistical OL methods for OL in two medical domains. For the pathology domain, we obtained 49% ESR, 28% EAR with the Lin method and 52% ESR, 39% EAR with the Church method. For the radiology domain, we obtain 87% ESA, 9% EAR using Lin method and 96% ESR, 16% EAR using Church method. CONCLUSION: This method is sufficiently general and flexible enough to permit comparison of any OL method for a specific corpus and ontology of interest.