Publications by authors named "Steven Martin"

214 Publications

Ensure Palestinians have access to COVID-19 vaccines.

Lancet 2021 02 9;397(10276):791-792. Epub 2021 Feb 9.

Salim El Hoss Bioethics and Professionalism Programme, American University of Beirut, Beirut 1107 2020, Lebanon. Electronic address:

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http://dx.doi.org/10.1016/S0140-6736(21)00190-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906633PMC
February 2021

Population Pharmacokinetics of Tofacitinib in Patients With Moderate to Severe Ulcerative Colitis.

Clin Pharmacol Drug Dev 2021 Mar 29;10(3):229-240. Epub 2021 Jan 29.

Pfizer Inc, Groton, Connecticut, USA.

Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We characterized tofacitinib pharmacokinetics in patients with moderate to severe UC, and the effects of covariates on variability in pharmacokinetic parameter estimates. Data were pooled from 1 8-week phase 2 and 2 8-week phase 3 induction studies, and a 52-week phase 3 maintenance study (N = 1096). Population pharmacokinetic analysis was conducted using nonlinear mixed-effects modeling. Potential predictors of apparent oral clearance (CL/F) and volume of distribution (V/F) were evaluated. The PK was described by a 1-compartment model parameterized in terms of CL/F (26.3 L/hour [h]) and V/F (115.8 L), with first-order absorption (K ; 9.85 h ) and lag time (0.236 h). The derived elimination half-life was approximately 3.05 h. In the final model, baseline creatinine clearance, sex, and race (Asian vs non-Asian) were significant covariates for CL/F; significant covariates for V/F were age, sex, and body weight; baseline albumin and baseline Mayo score were not significant covariates. CL/F between-patient variability was estimated at 22%. Tofacitinib exposure did not change significantly over the duration of induction/maintenance treatment in patients with UC. Although statistically significant covariate effects on CL/F and V/F were observed, the magnitude of the effects are not clinically significant. Therefore, dose adjustment/restrictions for age, body weight, sex, race, or baseline disease severity are not required during tofacitinib treatment. ClinicalTrials.gov numbers: NCT00787202, NCT01465763, NCT01458951, NCT01458574.
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http://dx.doi.org/10.1002/cpdd.899DOI Listing
March 2021

Joint Spreading Factor and Channel Assignment in Multi-Operator LoRaWAN Deployments.

Sensors (Basel) 2020 Dec 29;21(1). Epub 2020 Dec 29.

Université Paris-Saclay, LRI, 91190 Gif-sur-Yvette, France.

LoRaWAN is a popular internet of things (IoT) solution over the unlicensed radio band. It sustains low-cost, durable, and long range IoT wireless communications. Nonetheless, with over 24 billion connected IoT devices being expected by the end of the year, and over 50 billion by 2025, the concurrent and legacy approaches to spreading factor and channel assignment in LoRaWAN networks can no longer keep up. This is exacerbated with the growing densification of IoT device deployments and, with the increasing requirements for better throughput and packet delivery ratios. In this paper, we propose a proportional fair-based joint optimal formulation for spreading factor and channel assignment in multi-operator LoRaWAN deployments. The objective of this problem is to maximize the total sum of the logarithmic normalized throughput. We split the problem into two subproblems, and propose a game theoretic approach to solving them. We prove that our games converge towards a pure Nash equilibrium and, afterwards, solve the optimization problems using both semi-distributed and completely distributed algorithms. Via simulations, we show that our algorithms greatly improve the total normalized throughput for LoRaWAN as well as the packet success rate, in comparison to the legacy approaches.
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http://dx.doi.org/10.3390/s21010162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794734PMC
December 2020

Safety and immunogenicity of an adjuvanted adhesin vaccine in healthy women with and without histories of recurrent urinary tract infections: results from a first-in-human phase 1 study.

Hum Vaccin Immunother 2020 Dec 16:1-9. Epub 2020 Dec 16.

Sequoia Sciences, Inc ., St. Louis, MO, USA.

Antibiotic resistance among gram-negative bacteria continues to rise globally at an alarming rate. New vaccines that prevent bacterial infections and reduce antibiotic use could provide a potential solution to these problems. This study focused on development of an investigational vaccine to prevent recurrent urinary traction infections (UTI) caused by gram-negative bacteria that use type 1 pili to adhere to, invade, and colonize human bladders. The vaccine antigen is FimH, an adhesin protein on the tip of type 1 pili with a lectin binding domain that enables attachment to glycoproteins on mammalian bladders. This was a phase 1, open-label, dose escalation study evaluating the vaccine in 67 healthy women with and without histories of recurrent UTI. The objectives of the study were to evaluate the safety, tolerability, and immunogenicity of different dosages of the antigen and adjuvant of the vaccine. All dosages were well-tolerated and a low incidence of systemic reactions occurred. No serious adverse events related to the vaccine were reported. The vaccine induced both binding and functional antibodies. The women with histories of recurrent UTI demonstrated greater than 150-fold increases in antibodies against the N-terminal region of FimH. Based on the results of this phase 1 study, this vaccine is proceeding to a double-blind, randomized, placebo-controlled phase 2 study. If this vaccine is successful in future studies, it could potentially prevent millions of recurrent UTI globally and reduce the development of antibiotic resistance.
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http://dx.doi.org/10.1080/21645515.2020.1834807DOI Listing
December 2020

Utility of Suprasternal Transinnominate Artery for Alternate Access in Transcatheter Aortic Valve Replacement.

Innovations (Phila) 2021 Jan-Feb;16(1):58-62. Epub 2020 Oct 30.

159566 CHI Nebraska Heart Hospital, Lincoln, NE, USA.

Objective: Despite advancements in transcatheter aortic valve replacement (TAVR) technology, alternate access strategies are still required when transfemoral access is unsuitable. In these often anatomically complex group of patients, we sought to evaluate the safety and feasibility of suprasternal transinnominate (TI) artery access for TAVR.

Methods: At our institution, 652 patients underwent TAVR from November 2011 through February 2020. Of these, 23 patients underwent TI TAVR via a 5-cm suprasternal incision without special instrumentation. Outcomes of interest were technical considerations, postoperative complications, and perioperative recovery in relation to established access strategies.

Results: The mean Society of Thoracic Surgeons risk score was 8.6 ± 4.2 and the average age was 75 ± 8. All patients underwent TI TAVR using a self-expanding (12), or balloon-expandable (11) transcatheter heart valve. Average postoperative stay was 2 ± 0.7 days (range 2 to 4) with most 20/23 (87%) being discharged to home. There was no 30-day mortality or readmission. There was 1 access-site complication and 1 cerebrovascular accident within 30 days, both intraoperative, with excellent recovery. All patients had either trivial (19) or mild (4) aortic regurgitation on 30-day echocardiography.

Conclusions: TAVR via suprasternal TI access is feasible, safe, provides satisfactory perioperative recovery and adds to the options when patients require alternate access. Further data would be optimal to validate this single-center experience.
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http://dx.doi.org/10.1177/1556984520967653DOI Listing
October 2020

Real-world clinical and virological outcomes in a retrospective multiethnic cohort study of 341 untreated and tenofovir disoproxil fumarate-treated chronic hepatitis B pregnant patients in North America.

Aliment Pharmacol Ther 2020 12 27;52(11-12):1707-1716. Epub 2020 Oct 27.

Division of Gastroenterology and Hepatology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.

Background: There are limited long-term data on outcomes of chronic hepatitis B (CHB) in untreated and tenofovir disoproxil fumarate (TDF)-treated women during pregnancy.

Aims: To assess clinical outcomes in a multiethnic cohort of patients during pregnancy and post-partum in a low HBV endemic region.

Methods: Retrospective real-world study of women with CHB (treated or untreated with TDF) from 2011 to 2019; data including ALT, HBV DNA, HBeAg and liver stiffness measurement were collected during pregnancy and post-partum.

Results: In 341 women (446 pregnancies) followed for a median of 33 months (IQR: 26.7-39.5) post-partum, 19% (65/341) received TDF (11 initiated pre-pregnancy, 53 for mother-to-child transmission (MTCT) prevention). During follow-up, 72/341 had subsequent pregnancy, including 18/53 on TDF for MTCT risk, of whom 7/18 were re-treated. In all TDF-treated women, HBV DNA declined but rebounded after TDF withdrawal (median baseline, near birth and early follow-up levels were 7.2, 3.0 and 5.5 log IU/mL respectively [P < 0.01]). In HBeAg+ patients (65/341) ALT flares were more common (P = 0.03), especially for those who stopped TDF post-partum, requiring re-treatment in 21% (11/53). In comparison, 54% (116/215) of untreated women had a post-partum ALT flare; one with fulminant hepatitis underwent transplant 13 months post-partum. HBsAg clearance occurred in 2.6% (9/341, 3/9 HBeAg+, 2/9 TDF treated) at median 30 months (IQR: 23-40) and 37% (24/65) of HBeAg+ patients had HBeAg loss at median 17 months (IQR: 12-26) post-partum.

Conclusions: Post-partum ALT flares were common, especially after TDF withdrawal. Overall, 37% achieved HBeAg clearance and 2.9% had HBsAg loss during long-term follow-up.
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http://dx.doi.org/10.1111/apt.16123DOI Listing
December 2020

Comparability Considerations and Challenges for Expedited Development Programs for Biological Products.

Drugs R D 2020 Dec;20(4):301-306

Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.

Expedited development programs for biological products to be used in the treatment of serious conditions bring about challenges because of the compressed clinical development timeframes. As expedited development does not lessen the quality expectations, one challenge is providing adequate chemistry, manufacturing, and control (CMC) information required to support approval of a biological product. In particular, the analytical comparability and, in some cases, pharmacokinetic comparability studies needed to bridge the clinical material to the commercial material could delay submission of applications for life-saving medicines. While there is the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Topic Q5E guidance on assessing comparability of biological products before and after manufacturing changes, specific guidance on the emerging issue of conducting comparability exercises in the face of expedited drug development is lacking. In July 2019, clinical pharmacologists and product quality chemists from the US FDA and industry representatives convened an FDA workshop for a scientific exchange about considerations and challenges around conducting comparability exercises for expedited programs for biological products. This article highlights discussions from the workshop.
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http://dx.doi.org/10.1007/s40268-020-00321-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691403PMC
December 2020

Increasing ventilator surge capacity in COVID 19 pandemic: design, manufacture and in vitro-in vivo testing in anaesthetized healthy pigs of a rapid prototyped mechanical ventilator.

BMC Res Notes 2020 Sep 7;13(1):421. Epub 2020 Sep 7.

Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.

Objective: The advent of new technologies has made it possible to explore alternative ventilator manufacturing to meet the worldwide shortfall for mechanical ventilators especially in pandemics. We describe a method using rapid prototyping technologies to create an electro-mechanical ventilator in a cost effective, timely manner and provide results of testing using an in vitro-in vivo testing model.

Results: Rapid prototyping technologies (3D printing and 2D cutting) were used to create a modular ventilator. The artificial manual breathing unit (AMBU) bag connected to wall oxygen source using a flow meter was used as air reservoir. Controlled variables include respiratory rate, tidal volume and inspiratory: expiratory (I:E) ratio. In vitro testing and In vivo testing in the pig model demonstrated comparable mechanical efficiency of the test ventilator to that of standard ventilator but showed the material limits of 3D printed gears. Improved gear design resulted in better ventilator durability whilst reducing manufacturing time (< 2-h). The entire cost of manufacture of ventilator was estimated at 300 Australian dollars. A cost-effective novel rapid prototyped ventilator for use in patients with respiratory failure was developed in < 2-h and was effective in anesthetized, healthy pig model.
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http://dx.doi.org/10.1186/s13104-020-05259-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475714PMC
September 2020

A Dynamic Quantitative Systems Pharmacology Model of Inflammatory Bowel Disease: Part 2 - Application to Current Therapies in Crohn's Disease.

Clin Transl Sci 2021 01 21;14(1):249-259. Epub 2020 Aug 21.

Pharmacometrics, Global Clinical Pharmacology, Pfizer Inc., Cambridge, Massachusetts, USA.

Inflammatory bowel disease (IBD) is a heterogeneic disease with a variety of treatments targeting different mechanisms. A multistate, mechanistic, mathematical model of IBD was developed in part 1 of this two-part article series. In this paper, application of the model to predict response of key clinical biomarkers following different treatment options for Crohn's disease was explored. Five therapies, representing four different mechanisms of action, were simulated in the model and longitudinal profiles of key clinical markers, C-reactive protein and fecal calprotectin were compared with clinical observations. Model simulations provided an accurate match with both central tendency and variability observed in biomarker profiles. We also applied the model to predict biomarker and clinical response in an experimental, combination therapy of existing therapeutic options and provide possible mechanistic basis for the increased response. Overall, we present a validated, modular, mechanistic model construct, which can be applied to explore key biomarkers and clinical outcomes in IBD.
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http://dx.doi.org/10.1111/cts.12850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877864PMC
January 2021

A Dynamic Quantitative Systems Pharmacology Model of Inflammatory Bowel Disease: Part 1 - Model Framework.

Clin Transl Sci 2021 01 21;14(1):239-248. Epub 2020 Aug 21.

Pharmacometrics, Global Clinical Pharmacology, Pfizer Inc., Cambridge, Massachusetts, USA.

A mechanistic, multistate, mathematical model of inflammatory bowel disease (IBD) was developed by including key biological mechanisms in blood and gut, including cell differentiation, cytokine production, and clinical biomarkers. The model structure is consistent between healthy volunteers and IBD disease phenotype, with 24 parameters changed between diseases. Modular nature of the model allows for easy incorporation of new mechanisms or modification of existing interactions. Model simulations for steady-state levels of proteins and cells in the blood and gut using a population approach are consistent with published data. By simulating the response of two clinical biomarkers, C-reactive protein and fecal calprotectin, to parameter perturbations, the model explores hypotheses for possible treatment mechanisms. With additional experimental validation and addition of drug treatments, the model provides a platform to test hypothesis on treatment effects in IBD.
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http://dx.doi.org/10.1111/cts.12849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877855PMC
January 2021

Rethinking the need for a platelet transfusion threshold of 50 × 10 /L for lumbar puncture in cancer patients.

Transfusion 2020 Oct 18;60(10):2243-2249. Epub 2020 Aug 18.

Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Background: Lumbar puncture (LP) is a frequently performed diagnostic and therapeutic procedure in oncology patients. Transfusing to a minimum preprocedural platelet threshold of 50 × 10 /L is widely upheld without good quality evidence. The objective was to compare the outcomes of LPs performed with platelets above and below this threshold. An increased risk of adverse events in patients with lower platelet counts was not expected. As a corollary, transfusion reaction rates incurred by transfusing to this recommended threshold are also reported.

Methods: A total of 2259 LPs performed on 1137 oncology patients (adult, n = 871, and pediatric, n = 266) were retrospectively analyzed between February 2011 and December 2017. The incidence of LP-related complications for groups above and below the minimum platelet threshold was compared. Traumatic tap was defined as 500 or more red blood cells per high-power field in the cerebral spinal fluid. Groups were compared using the 2-Proportion Z-test and Fisher exact test.

Results: At time of LP, the total number of events with platelets less than 50 × 10 /L and 50 × 10 /L or greater were 110 and 2149, respectively. There were no significant differences in LP-associated complications between patients with platelet counts above or below 50 × 10 /L (P = .29). Patients with a pre-LP platelet count of less than 50 × 10 /L had a higher proportion of traumatic taps (P < .001). Three patients developed transfusion-related adverse events.

Conclusion: Patients with platelet counts less than 50 × 10 /L did not have a higher incidence of clinically significant post-lumbar puncture complications (P = .29).
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http://dx.doi.org/10.1111/trf.15988DOI Listing
October 2020

Optimization and qualification of an assay that demonstrates that a FimH vaccine induces functional antibody responses in women with histories of urinary tract infections.

Hum Vaccin Immunother 2021 Jan 23;17(1):283-292. Epub 2020 Jul 23.

Sequoia Sciences, Inc., 1912 Innerbelt Business Center Drive , St. Louis, MO, USA.

Recurrent urinary tract infections (rUTI) are a serious disease associated with morbidities and mortality. Resistance to the standard of care antibiotics is now widespread because of the continued use of antibiotics among people who suffer from rUTI. We are therefore developing a vaccine to prevent recurrences among patients with rUTI. The antigen of the vaccine is FimH, a bacterial adhesin protein, and the vaccine is adjuvanted with a TLR-4 agonist. In a Phase 1 clinical study evaluating the vaccine, immunized individuals produced FimH-binding antibodies. Here we describe the optimization, qualification, and use of an assay to assess the functionality of these anti-FimH antibodies. The suitability of the assay for its intended purpose was demonstrated by selectivity, specificity, sensitivity, and intra-assay and inter-assay precision. The acceptance criteria were achieved for all parameters including intra-assay precision with ≤10% relative standard deviations and inter-assay precision with ≤25% relative standard deviations. The results presented herein suggest this functional assay will be important for supporting the vaccine's efficacy in future human studies. Furthermore and of great significance, these results prove that vaccine-induced functional antibodies can be elicited in rUTI patients against an essential virulence factor, FimH.
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http://dx.doi.org/10.1080/21645515.2020.1770034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872045PMC
January 2021

Early Return to Play After Intramedullary Screw Fixation of Acute Jones Fractures in Collegiate Athletes: 22-Year Experience.

Orthop J Sports Med 2020 Apr 24;8(4):2325967120912423. Epub 2020 Apr 24.

Blue Ridge Orthopedics, Department of Orthopedic Surgery, Prisma Health-Upstate, Seneca, South Carolina, USA.

Background: There is disagreement among team physicians, without conclusive evidence, as to when high-level athletes with a Jones fracture should be allowed to return to play after being treated operatively with an intramedullary screw.

Purpose: To report our experience of early return to sport in collegiate athletes after intramedullary screw fixation of Jones fractures.

Study Design: Case series; Level of evidence, 4.

Methods: We identified all collegiate athletes with an acute fracture at the base of the fifth metatarsal treated by 1 of 2 orthopaedic surgeons with intramedullary screw fixation over a 22-year period (1994-2015), and we performed a retrospective review of their records. Fixation consisted of a single intramedullary screw. Athletes were allowed to bear weight as tolerated in a walking boot immediately postoperatively and return to play as soon as they could tolerate activity. Patients were contacted to complete patient-reported outcome scores that included the Foot and Ankle Ability Measure (FAAM) score, a brief survey specific to our study, and follow-up radiographs.

Results: A total of 26 acute Jones fractures were treated in 25 collegiate athletes (mean age, 20 years; range, 18-23 years). Overall, the athletes returned to play at an average of 3.6 weeks (range, 1.5-6 weeks). Three screws were removed for symptomatic skin irritation. There was 1 refracture after screw removal that was done after radiographic and clinical documentation of fracture union, which was treated with repeat cannulated percutaneous screw fixation. One screw was observed on radiographs to be broken at 1 year postoperatively, but the fracture was healed and the athlete was playing National Collegiate Athletic Association Division I sports without symptoms and continued to play professionally without symptoms. Of 25 athletes, 19 completed the FAAM at an average follow-up of 8.6 years (range, 1.5-20.0 years). They reported scores of 94.9% (range, 70.2%-100%) for the activities of daily living subscale and 89.1% (range, 42.9%-100%) for the sports subscale. Follow-up radiographs were obtained, and no nonunion, malunion, or additional hardware complications were identified.

Conclusion: Athletes with acute Jones fractures can safely be allowed to return to play after intramedullary screw fixation as soon as their symptoms allow, without significant complications. In our experience, this is usually within 4 weeks from injury.
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http://dx.doi.org/10.1177/2325967120912423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219008PMC
April 2020

Effects of an Acute Strength and Conditioning Training Session on Dual-Energy X-Ray Absorptiometry Results.

J Strength Cond Res 2020 Apr;34(4):901-904

Department of Health and Kinesiology, Texas A&M University, College Station, Texas.

Lytle, JR, Stanelle, ST, Kravits, DM, Ellsworth, RL, Martin, SE, Green, JS, and Crouse, SF. Effects of an acute strength and conditioning training session on dual-energy x-ray absorptiometry results. J Strength Cond Res 34(4): 901-904, 2020-The purpose of this study was to determine whether an athletic strength and conditioning (S&C) session will alter body composition estimates of a dual-energy x-ray absorptiometry (DXA) scan. Twenty-two strength-trained individuals (15 men, 7 women, 24 ± 2 years, 174.2 ± 8.5 cm, 83.5 ± 15.0 kg) volunteered to participate in the study. Each subject underwent 2 DXA scans, before and after completion of the S&C session, which consisted of upper- and lower-body resistance exercises and interval running. Subjects consumed a free-living meal before the first scan, after which only ad libitum water intake was consumed until completing the second scan. Results were analyzed through sex by time repeated-measures analysis of variance. If no interaction effect was observed, results were next analyzed through correlated t-test (α = 0.05). Significant sex by time interactions were observed for arm total and lean mass, as well as a significant main effect of time showing a decrease in arm lean mass after the S&C session. Values before and after the S&C session that resulted in significant differences via correlated t-test are displayed in Table 1. Results revealed a significant decrease in total mass, arm and leg percent fat, and trunk lean mass, and an increase in leg lean mass.
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http://dx.doi.org/10.1519/JSC.0000000000003504DOI Listing
April 2020

Transiently elevated plasma methionine, -adenosylmethionine and -adenosylhomocysteine: Unreported laboratory findings in a patient with NGLY1 deficiency, a congenital disorder of deglycosylation.

JIMD Rep 2019 Sep 22;49(1):21-29. Epub 2019 Jul 22.

Department of Medical Genetics Cumming School of Medicine, University of Calgary Calgary Alberta Canada.

We report on a 5-year-old female born to consanguineous parents, ascertained at the age of 23 months for an elevated plasma methionine level, a mildly abnormal total plasma homocysteine (tHcy), and elevated aminotransferases. She had global developmental delay, microcephaly, dysmorphic facial features, hypotonia, nystagmus and tremor in her upper extremities. Metabolic investigations demonstrated elevations in plasma methionine, plasma -adenosylmethionine (SAM) and plasma -adenosylhomocysteine (SAH), with normal urine adenosine levels. Some of the elevations persisted for over 1 year. Sequencing of the and genes was negative for causative variants. Plasma methionine normalized 1 year after ascertainment, but SAM and SAH continued to be elevated for six more months before normalization, and aminotransferases remained mildly elevated. Whole exome sequencing demonstrated a homozygous pathogenic variant; NM_018297.3(NGLY1):c.1405C>T (p.Arg469*) in exon 9 of the gene, for which both parents were heterozygous. To our knowledge, this is the first report of NGLY1 deficiency with elevations in plasma methionine, SAM and SAH and a slight elevation of tHcy. Less than 20 patients have been reported with NGLY1 deficiency worldwide and this case expands on the biochemical phenotype of this newly discovered inborn error of metabolism.
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http://dx.doi.org/10.1002/jmd2.12064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718116PMC
September 2019

Predicting V[Combining Dot Above]O2max From Treadmill Performance in American-Style Football Athletes.

J Strength Cond Res 2019 Feb 18. Epub 2019 Feb 18.

Department of Athletics, Texas A&M University, College Station, Texas.

Crouse, SF, Tolson, H, Lytle, J, Johnson, KA, Martin, SE, Green, JS, Oliver, J, Carbuhn, A, Lambert, B, and Bramhall, JP. Predicting V[Combining Dot Above]O2max from treadmill performance in American-style football athletes. J Strength Cond Res XX(X): 000-000, 2019-Prediction equations are often used to estimate V[Combining Dot Above]O2max in the general population but are lacking for American-style football (ASF) athletes. We sought to develop a regression model to estimate V[Combining Dot Above]O2max from treadmill exercise time in ASF athletes and compare our football V[Combining Dot Above]O2max model with 2 published prediction equations (Foster et al., 1984, and Bruce, 1973). American-style football athletes (N = 472, age = 18 ± 1 year, height = 186.1 ± 8.2 cm, and body mass = 101.8 ± 20.4 kg) underwent treadmill exercise to voluntary exhaustion (Bruce protocol). Maximal exercise time was recorded in minutes (Tmin), and V[Combining Dot Above]O2max was simultaneously measured (M-V[Combining Dot Above]O2max, mlO2·kg·min) by an automated gas-analysis system. Athletes were then randomly divided into validation and cross-validation groups (n = 236). Linear regression yielded estimates of V[Combining Dot Above]O2max from Tmin as follows: validation V[Combining Dot Above]O2max = 4.012 × Tmin - 4.628 (r = 0.678, p < 0.001, and SEE = 4.07); cross-validation V[Combining Dot Above]O2max = 4.025 × Tmin - 4.693 (r = 0.661, p < 0.001, and SEE = -4.16). These equations had a cross-validation coefficient of 0.813 and a double cross-validation coefficient of 0.823. Differences between the slopes of the 2 equations were not significant (t-test, p = 0.9603). Because validation and cross-validation groups were not statistically different on any variables measured (multivariate analysis of variance, p > 0.05), all athletes were combined to yield our final prediction equation: football V[Combining Dot Above]O2max = 4.017 × Tmin - 4.644 (r = 0.670, p < 0.001, and SEE = 4.11). Repeated-measures analysis of variance demonstrated significant differences (p < 0.001) in estimates of V[Combining Dot Above]O2max among Foster (44.1 ± 6.1), Bruce (47.1 ± 5.5), and our football (45.1 ± 5.8) equations. Foster and Bruce V[Combining Dot Above]O2max estimates were also significantly different from M-V[Combining Dot Above]O2max (x[Combining Overline] diff = -0.975 and 1.995, respectively, p < 0.001). V[Combining Dot Above]O2max of ASF athletes can be reasonably estimated by our football prediction equation using maximal treadmill time as the predictor.
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http://dx.doi.org/10.1519/JSC.0000000000003071DOI Listing
February 2019

Predicting V[Combining Dot Above]O2max From Treadmill Performance in American-Style Football Athletes.

J Strength Cond Res 2019 Apr;33(4):1028-1034

Department of Athletics, Texas A&M University, College Station, Texas.

Crouse, SF, Tolson, H, Lytle, J, Johnson, KA, Martin, SE, Green, JS, Oliver, J, Carbuhn, A, Lambert, B, and Bramhall, JP. Predicting V[Combining Dot Above]O2max from treadmill performance in American-style football athletes. J Strength Cond Res 33(4): 1028-1034, 2019-Prediction equations are often used to estimate V[Combining Dot Above]O2max in the general population but are lacking for American-style football (ASF) athletes. We sought to develop a regression model to estimate V[Combining Dot Above]O2max from treadmill exercise time in ASF athletes and compare our football V[Combining Dot Above]O2max model with 2 published prediction equations (Foster et al., 1984, and Bruce, 1973). American-style football athletes (N = 472, age = 18 ± 1 year, height = 186.1 ± 8.2 cm, and body mass = 101.8 ± 20.4 kg) underwent treadmill exercise to voluntary exhaustion (Bruce protocol). Maximal exercise time was recorded in minutes (Tmin), and V[Combining Dot Above]O2max was simultaneously measured (M-V[Combining Dot Above]O2max, mlO2·kg·min) by an automated gas-analysis system. Athletes were then randomly divided into validation and cross-validation groups (n = 236). Linear regression yielded estimates of V[Combining Dot Above]O2max from Tmin as follows: validation V[Combining Dot Above]O2max = 4.012 × Tmin - 4.628 (r = 0.678, p < 0.001, and SEE = 4.07); cross-validation V[Combining Dot Above]O2max = 4.025 × Tmin - 4.693 (r = 0.661, p < 0.001, and SEE = -4.16). These equations had a cross-validation coefficient of 0.813 and a double cross-validation coefficient of 0.823. Differences between the slopes of the 2 equations were not significant (t-test, p = 0.9603). Because validation and cross-validation groups were not statistically different on any variables measured (multivariate analysis of variance, p > 0.05), all athletes were combined to yield our final prediction equation: football V[Combining Dot Above]O2max = 4.017 × Tmin - 4.644 (r = 0.670, p < 0.001, and SEE = 4.11). Repeated-measures analysis of variance demonstrated significant differences (p < 0.001) in estimates of V[Combining Dot Above]O2max among Foster (44.1 ± 6.1), Bruce (47.1 ± 5.5), and our football (45.1 ± 5.8) equations. Foster and Bruce V[Combining Dot Above]O2max estimates were also significantly different from M-V[Combining Dot Above]O2max ((Equation is included in full-text article.)diff = -0.975 and 1.995, respectively, p < 0.001). V[Combining Dot Above]O2max of ASF athletes can be reasonably estimated by our football prediction equation using maximal treadmill time as the predictor.
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http://dx.doi.org/10.1519/JSC.0000000000003071DOI Listing
April 2019

Perceived stressors and coping mechanisms of female migrant domestic workers in Singapore.

PLoS One 2019 20;14(3):e0210717. Epub 2019 Mar 20.

Institute for Infection and Immunity, St George's, University of London, London, United Kingdom.

Introduction: Worldwide, there are between 50-67 million migrant domestic workers, the majority of whom are women. In many countries, provisions are not in place to protect female migrant domestic workers. These women may be at risk of occupational and social stressors, including exploitation and abuse, which may negatively impact on their quality of life, including psychological health. Research examining the occupational, social, and psychological needs of FMDWs from a public health perspective is critical to guide the development of policies which ensure wellbeing, prevent abuse, and align with international priorities to improve population health. Though there have been a number of high-profile incidents of exploitation and abuse, there has been limited research on the stressors experienced by these communities, their perceived impact, or coping mechanisms.

Materials And Methods: Thematic analysis was used to analyse qualitative free-text written responses collected as part of a cross-sectional survey on the relationship between social and occupational stressors and the health and quality of life of FMDWs in Singapore. Responses correspond to open-ended questions in the qualitative component of the survey examining three domains: causes of stress, coping strategies, and what people can do to help with stress.

Results: Responses from 182 FMDWs were analysed. Key themes were identified around causes of stress (including 'work and agency', 'the pervasiveness of financial need', and 'family and obligation'), coping strategies, and social support. Each theme describes key factors which contribute to the occupational and social stressors experienced and reported by FMDWs.

Discussion: This research highlights the stressors FMDWs in Singapore experience, as well as key coping mechanisms. There is a clear need for policies which facilitate FMDWs' ability to utilise these coping resources, and which protect against coercive or exploitative employment conditions. Strategies are also needed to monitor and evaluate policies intended to protect FMDWs, and to strengthen the implementation of global frameworks targeted at improving workplace conditions and workers' rights.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0210717PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426224PMC
November 2019

Horizontal Transmission of Hepatitis B Virus From Mother to Child Due to Immune Escape Despite Immunoprophylaxis.

J Pediatr Gastroenterol Nutr 2019 05;68(5):e81-e84

National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba.

Hepatitis B virus (HBV) vaccination starting at birth is approximately 95% effective in preventing mother-to-child transmission to infants born to HBV-infected mothers. A higher risk of transmission is associated with birth to a highly viremic mother, often due to transplacental exposure, while later horizontal transmission is much less common, particularly following complete vaccination. This study reports a case of infection in an older child despite appropriate immunoprophylaxis starting at birth and an apparent protective immune response post-vaccination. Two immune escape mutations within the antigenic determinant of the surface antigen-coding region were observed in the child's dominant HBV sequence, whereas the maternal HBV variant lacked mutations at both sites. Ultra-deep sequencing confirmed the presence of 1 mutation at low levels within the maternal HBV quasispecies population, suggesting early exposure to the child followed by viral evolution resulting in immunoprophylaxis escape and chronic infection.
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http://dx.doi.org/10.1097/MPG.0000000000002318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510327PMC
May 2019

Health assets in a global context: a systematic review of the literature.

BMJ Open 2019 02 3;9(2):e023810. Epub 2019 Feb 3.

Institute for Health and Human Development, University of East London, London, UK.

Objective: To provide an up-to-date overview of health assets in a global context both from a theoretical perspective and its practical applications to address health inequalities and achieve sustainable health.

Design: A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.

Data Sources: A comprehensive search, including 10 electronic bibliographic databases and hand searches, was undertaken to capture the wide range of terms associated with 'health assets' and 'asset-based approaches to health'.

Eligibility Criteria: Any peer-reviewed published and grey literature in English related to 'health assets' or 'assets' in a 'health' context was included without any date, country or study design restrictions and the quality of evidence was appraised according to the Oxford Level of Evidence.

Outcomes: A broad consideration of all outcome measures including clinical outcomes, patient-level, community-level and population-level impacts and costs, was adopted.

Results: 478 publications were included. Health assets were researched in 40 countries, predominantly in the West such as the USA and the UK. A number of broad health assets were identified including community and individual assets. Even though research was conducted in a number of different settings, most occurred in the community, clinical, care or educational settings. A wide variety of interventions and approaches were implemented, most commonly related to education and/or training, asset mapping or asset approaches.

Conclusions: Globally, authors most often referred to general 'health assets', 'assets' or some form of 'community asset' in relation to health. Overall, the idea of health assets is framed within a positive paradigm focusing on health creation rather than curative approaches. The sustained credibility of the global 'health assets' literature depends on future research on definitional, theoretical and evaluative issues in order to convince policy-makers and service commissioners of its necessity and added value to the traditional deficit approach.
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http://dx.doi.org/10.1136/bmjopen-2018-023810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367963PMC
February 2019

Predicting Energy Expenditure of an Acute Resistance Exercise Bout in Men and Women.

Med Sci Sports Exerc 2019 07;51(7):1532-1537

Department of Orthopedics and Sports Medicine, Houston Methodist Hospital, Houston, TX.

The energy expenditure of resistance exercise (RE) is an important consideration for exercise prescription and weight management, yet prediction models are lacking.

Purpose: This study aimed to develop regression equations to predict energy expenditure (kcal) for RE involving each major muscle group using commonly measured demographic and exercise variables as predictors.

Methods: Fifty-two healthy, active subjects (27 men, 25 women, age 20-58 yr, height 174.1 ± 10.5 cm, weight 188.7 ± 42.6 kg, V˙O2max 36.8 ± 9.2 mL·kg⋅min) were strength tested to estimate their one-repetition maximum 1 wk before their experimental RE bout. The experimental RE bout consisted of a warm-up set followed by 2-3 sets (2-min turnover) of 8-12 reps at 60%-70% of predicted one-repetition maximum for leg press, chest press, leg curl, lat pull, leg extension, triceps push down, and biceps curl. Kilocalories were estimated from V˙O2 measured continuously throughout the RE bout via an automated metabolic cart. Total exercise volume (TV) was calculated as sets × reps × weight lifted. Multiple linear regression (stepwise removal) was used to determine the best model (highest adjusted R) to predict the kilocalorie consumption of the total workout and of the individual RE lifts.

Results: The derived regression equation for the net kilocalorie consumption of an RE bout was as follows: total net kilocalorie = 0.874 (height, cm) - 0.596 (age, yr) - 1.016 (fat mass, kg) + 1.638 (lean mass, kg) + 2.461 (TV × 10) - 110.742 (R = 0.773, SEE = 28.5 kcal). Significant equations were also derived for individual lifts (R = 0.62 to 0.83).

Conclusions: Net energy expenditure for a total RE bout and for individual RE can be reasonably estimated in adult men and women using commonly measured demographic and RE variables.
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http://dx.doi.org/10.1249/MSS.0000000000001925DOI Listing
July 2019

Elimination of 72-Hour Quantitative Fecal Fat Testing by Restriction, Laboratory Consultation, and Evaluation of Specimen Weight and Fat Globules.

J Appl Lab Med 2018 Nov;3(3):357-365

Calgary Laboratory Services, Section of Clinical Biochemistry, Calgary, Alberta, Canada.

Background: The 72-h quantitative fecal fat test has been mostly obsolete for many years. Our objective was to reduce and eliminate the use of this test, while providing suitable alternatives.

Methods: We assessed (2010-2016) utilization of the fecal fat test in Calgary, Central Alberta, and Southern Alberta, Canada. Alternatives were identified through literature review and consultation with gastroenterologist stakeholders. Logistic regression and ROC curves were used to characterize discrimination power of 72-h specimen weight on abnormal fat excretion. This was also examined in 91 subspecimens that were additionally tested for the presence of fat globules.

Results: As 69% of fecal fat tests (total, 106/year) were on adults (age ≥ 18), stakeholders agreed that adult specimens should not be tested until ordering physicians consulted with a clinical biochemist. This change reduced fecal fat testing by 81% to 20/year in 2015. The 72-h specimen weight was a significant predictor of abnormal fat excretion [P < 0.001; area under curve (AUC) = 0.75-0.79, n = 115-417] in historic fecal fat data. A similar result was observed among subspecimens (AUC = 0.70), which improved when additionally considering the presence of fat globules (AUC = 0.74). Stakeholders consented to replacing fecal fat with a comparison of specimen weight to cutpoints with 80% specificity for abnormal fat excretion, and the test for fat globules.

Conclusion: Through stakeholder engagement, we implemented changes that eliminated 72-h quantitative fecal fat testing in a large geographic region in Alberta, Canada. Future fecal fat orders would be reflexed to an assessment of 72-h specimen weight and a qualitative test for fat globules in stool.
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http://dx.doi.org/10.1373/jalm.2018.026229DOI Listing
November 2018

Understanding Geographic and Neighborhood Variations in Overdose Death Rates.

J Community Health 2019 04;44(2):272-283

University of Delaware, Newark, DE, USA.

The current opioid epidemic continues to challenge us in new and potentially troubling ways. For example, research today finds more overdose deaths occurring in rural, rather than urban, geographic areas. Yet, studies have often ignored heterogeneities within these spaces and the neighborhood variations therein. Using geodemographic classification, we investigate neighborhood differences in overdose death rates by geographical areas to further understand where and among what groups the problem might be most concentrated. For deaths between 2013 and 2016, we find significant variation in rates among neighborhoods, defined by their socio-economic and demographic characteristics. For example, overdose death rates vary up to 13-fold among neighborhoods within geographic areas. Our results overall show that while the rural or urban classification of a geographic area is important in understanding the current overdose problem, a more segmented analysis by neighborhood's socio-economic and demographic makeup is also necessary.
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http://dx.doi.org/10.1007/s10900-018-0583-0DOI Listing
April 2019

Review of referral criteria to lipid clinics and outcomes of treatment in four UK centres.

Int J Clin Pract 2018 Sep;72(9):e13242

Department of Metabolic Medicine/Chemical Pathology, Queen's Hospital, Burton-on-Trent, UK.

Background: Little data exist on the referral patterns and effectiveness of lipid clinics.

Methods: An audit was conducted in four clinics of 100 consecutive referrals each. Data were recorded on referral criteria, cardiovascular disease (CVD) risk factors, drug history, investigations, diagnoses, therapies, results and referrals.

Results: Patients were aged 56 ± 14 years, 47% were male and 87% were primary prevention. Risk factors included smoking (16%), type 2 diabetes (13%) and hypertension (13%). Referrals were made for hypercholesterolaemia (68%), diagnosis of FH (31%), statin intolerance (23%) and hypertriglyceridaemia (23%). Initial total cholesterol (TC) was 7.65 ± 2.64 mmol/L, triglycerides (TG) 2.17 (0.41-76.9 mmol/L) mmol/L, HDL-C 1.53 ± 0.71 mmol/L, LDL-C 4.57 ± 1.66 mmol/L with non-HDL-C 5.90 ± 2.09 mmol/L. Criteria for FH were met in 21% with genetic testing in 13% and lipid cascade testing in 30% of index cases. Triglycerides >20 mmol/L were present in 4%. The diagnosis was changed in 21%: hypercholesterolaemia (7%), mixed hyperlipidaemia (7%) and hypertriglyceridaemia (7%). Hepatic steatosis was identified in 14.5%. Lipoprotein(a) levels >125 nmol/L occurred in 41% in one clinic. Therapy changes included altered statins (40%), addition of a fibrate (11%) or ezetimibe (8%). These reduced TC by 1.92 mmol/L (19%; P = 0.0001), LDL-C 1.07 mmol/L (15%; P = 0.02), non-HDL-C 1.50 mmol/L (16%; P < 0.001), and TG 2.3 (-4 to 38) mmol/L (16%; P < 0.001) with 11% extra achieving TG <5 mmol/L while HDL-C increased by 7% (P = 0.37).

Conclusions: Lipid clinics have diverse functions including diagnosis of FH, managing severe hypercholesterolaemia, mixed hyperlipidaemia and statin intolerance. Effectiveness criteria of average reductions of 1.5 mmol/L in TC or non-HDL-C, 1 mmol/L in LDL-C and 2 mmol/L in TG would be reasonable for newly referred patients.
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http://dx.doi.org/10.1111/ijcp.13242DOI Listing
September 2018

Translation, psychometric validation, and baseline results of the Patient-Reported Outcomes Measurement Information System (PROMIS) pediatric measures to assess health-related quality of life of patients with pediatric lymphoma in Malawi.

Pediatr Blood Cancer 2018 11 17;65(11):e27353. Epub 2018 Jul 17.

Cancer Program, UNC Project-Malawi, Lilongwe, Malawi.

Introduction: Internationally validated tools to measure patient-reported health-related quality of life (HRQoL) are available, but efforts to translate and culturally validate such tools in sub-Saharan Africa (SSA) are scarce, particularly among children.

Methods: The Patient-Reported Outcomes Measurement Information System 25-item pediatric short form (PROMIS-25) assesses six HRQoL domains-mobility, anxiety, depression, fatigue, peer relationships, and pain interference-by asking four questions per domain. There is a single-item pain intensity item. The PROMIS-25 was translated into Chichewa and validated for use in Malawi using mixed qualitative and quantitative methods. The validity and reliability of the PROMIS-25 was assessed.

Results: Fifty-four pediatric patients with lymphoma completed the PROMIS-25. Structural validity was supported by interitem correlations and principal component analysis. Reliability of each scale was satisfactory (range alpha = 0.71-0.93). Known group validity testing showed that anemic children had worse fatigue (P = 0.016) and children with poor performance status had worse mobility (P < 0.001) and pain interference (P = 0.005). Compared to children with cancer in the United States, children from Malawi reported lower levels of mobility, higher anxiety, higher depressive symptoms, higher fatigue, better satisfaction with peer relationships, and higher pain interference.

Conclusion: Translation and cultural validation of the PROMIS-25 into Chichewa for Malawi was successful. Baseline HRQoL for patients with pediatric lymphoma in Malawi is poor for all domains except peer relationships. This emphasizes an urgent need to address HRQoL among children undergoing cancer treatment in SSA using self-reported instruments validated within the local context.
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http://dx.doi.org/10.1002/pbc.27353DOI Listing
November 2018

Bifidenone: Structure-Activity Relationship and Advanced Preclinical Candidate.

J Med Chem 2018 08 25;61(15):6736-6747. Epub 2018 Jul 25.

Sequoia Sciences, Inc. , 1912 Innerbelt Business Center Drive , St. Louis , Missouri 63114 , United States.

Bifidenone is a novel natural tubulin polymerization inhibitor that exhibits antiproliferative activity against a range of human cancer cell lines, making it an attractive candidate for development. A synthetic route was previously developed to alleviate supply constraints arising from its isolation in microgram quantities from a Gabonese tree. Using that previously published route, we present here 42 analogues that were synthesized to examine the structure-activity relationship of bifidenone derivatives. In addition to in vitro cytotoxicity data, data from murine xenograft and pharmacokinetic studies were used to evaluate the analogues. Compounds 45b and 46b were found to demonstrate promising efficacy in murine xenograft experiments, and 46b had significantly more potent in vitro antiproliferative activity against taxane-resistant cell lines compared to that of paclitaxel.
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http://dx.doi.org/10.1021/acs.jmedchem.7b01644DOI Listing
August 2018

Conversion of calibration curves for accurate estimation of molecular weight averages and distributions of polyether polyols by conventional size exclusion chromatography.

J Chromatogr A 2018 Aug 24;1563:28-36. Epub 2018 Apr 24.

The Dow Chemical Company, Core R&D Analytical Sciences, Midland, MI, 48674, USA. Electronic address:

Accurate measurement of molecular weight averages (M¯M¯M¯) and molecular weight distributions (MWD) of polyether polyols by conventional SEC (size exclusion chromatography) is not as straightforward as it would appear. Conventional calibration with polystyrene (PS) standards can only provide PS apparent molecular weights which do not provide accurate estimates of polyol molecular weights. Using polyethylene oxide/polyethylene glycol (PEO/PEG) for molecular weight calibration could improve the accuracy, but the retention behavior of PEO/PEG is not stable in THF-based (tetrahydrofuran) SEC systems. In this work, two approaches for calibration curve conversion with narrow PS and polyol molecular weight standards were developed. Equations to convert PS-apparent molecular weight to polyol-apparent molecular weight were developed using both a rigorous mathematical analysis and graphical plot regression method. The conversion equations obtained by the two approaches were in good agreement. Factors influencing the conversion equation were investigated. It was concluded that the separation conditions such as column batch and operating temperature did not have significant impact on the conversion coefficients and a universal conversion equation could be obtained. With this conversion equation, more accurate estimates of molecular weight averages and MWDs for polyether polyols can be achieved from conventional PS-THF SEC calibration. Moreover, no additional experimentation is required to convert historical PS equivalent data to reasonably accurate molecular weight results.
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http://dx.doi.org/10.1016/j.chroma.2018.04.050DOI Listing
August 2018

Prospective utility study of patients with multiple cardiovascular events.

J Med Econ 2018 Jun 3;21(6):616-621. Epub 2018 Apr 3.

g Royal Free London NHS Foundation Trust , Barnet , UK.

Objectives: The effects of acute coronary syndrome (ACS) events on health-related quality-of-life (HRQoL) and the time dependency of these effects are unknown. This study aimed to characterize health utilities in ACS patients to aid development of future economic models estimating the cost per quality-adjusted life-year impact of ACS events and potential treatments.

Methods: Multi-center, non-interventional, longitudinal evaluation of health utility in patients experiencing ACS or stroke events. EuroQol-5 dimension 3 level (EQ-5D-3L) surveys were sent to patients (≥18 years) from three UK centers, 1 month after hospital discharge for myocardial infarction (MI), unstable angina (UA), or stroke. Patient demographics, lifestyle, and baseline utility score were collected in the first survey. Follow-up surveys were sent at 6, 12, 18, and 24 months to prospectively capture utility and subsequent health events. Two methods of patient identification were adopted-prospective, where the patient's qualifying events occurred after the study index date, and retrospective, where the patient's qualifying event occurred prior to the study index date. General healthy population utility values were assumed for pre-event HRQoL.

Results: Between January 2011 and March 2014, 2,103 prospectively (n = 1,350)/retrospectively (n = 753) identified patients (mean age = 68.3 years; 67.9% male) responded: MI = 55.9% (n = 1,176), UA = 42.7% (n = 898), stroke = 1.4% (n = 29); 24% had type 2 diabetes. Post-event utility values were lower than general healthy population values, although significant differences in utility between subsequent 6 (n = 1,031, change = -0.002), 12 (n = 1,096, change = -0.008), 18 (n = 1,246, change = -0.007), and 24 (n = 1,277, change = -0.004) month timepoints were not detected. Through multivariate regression analyses, wheelchair use, current smoking, and secondary mental and joint health events were associated with the greatest statistically significant utility decrements.

Conclusions: This study indicates that health utility decreases following a cardiovascular event and, although some improvement occurs over the subsequent 24 months, general healthy population utility is not necessarily attained.
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http://dx.doi.org/10.1080/13696998.2018.1454453DOI Listing
June 2018

Exposure-response characterization of tofacitinib efficacy in moderate to severe ulcerative colitis: Results from a dose-ranging phase 2 trial.

Br J Clin Pharmacol 2018 06 23;84(6):1136-1145. Epub 2018 Mar 23.

Pfizer Inc, Collegeville, PA, USA.

Aims: Tofacitinib is an oral, small molecule JAK inhibitor being investigated for ulcerative colitis (UC). In a phase 2 dose-ranging study, tofacitinib demonstrated efficacy vs. placebo as UC induction therapy. In this posthoc analysis, we aimed to compare tofacitinib dose and plasma concentration as predictors of efficacy and identify covariates that determined efficacy in patients with UC.

Methods: One- and two-compartment pharmacokinetic models, with first-order absorption and elimination, were evaluated to describe plasma tofacitinib concentration-time data at baseline and week 8. Relationships between tofacitinib exposure (dose, average plasma drug concentration during a dosing interval at steady state [C ] and trough plasma concentration at steady state [C ]) and week 8 efficacy endpoints were characterized using logistic regression analysis. Baseline disease, demographics, prior and concurrent UC treatment were evaluated as covariates.

Results: Plasma tofacitinib concentrations increased proportionately with dose and estimated oral clearance, and C values were not significantly different between baseline and week 8. Dose, C and C performed similarly as predictors of efficacy based on statistical criteria for model fit and comparison of model predictions for each endpoint. Individual C values were similar between clinical remitters and nonremitters at predicted efficacious doses (10 and 15 mg twice daily). Baseline Mayo score was a significant determinant of efficacy. Predicted differences from placebo in clinical remission at 10 mg twice daily for patients with baseline Mayo score >8 and ≤8 were 39% (95% CI: 7-70) and 21% (-2-50), respectively.

Conclusions: Exposure-response characterization demonstrated the potential of tofacitinib 10 and 15 mg twice daily as induction therapy for UC without monitoring of plasma drug concentrations for dose optimization.
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http://dx.doi.org/10.1111/bcp.13523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980553PMC
June 2018