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1.  Web-based data management for a phase II clinical trial in ALS 
The objective was to report on the creation, features and performance of a web-based data management system for a two-stage phase II randomized clinical trial of Co-Enzyme Q10 in ALS. We created a relatively comprehensive web-based data system that provided electronic data entry; patient management utilities; adverse event reporting, safety monitoring, and invoice generation; and standardized coding for medications and adverse events. In stage 1, clinical sites submitted 7207 forms reporting on 105 patients followed for 10 months. Less than 0.7% of submitted forms contained errors. At the time of the delivery of the analysis data set, only four errors remained unresolved. Data were available quickly, with a median time from event to data posting of two days. The data set was locked and the analysis data set produced nine days after the final patient visit. A survey of trial personnel yielded generally positive feedback, with 75% of respondents wishing to use a similar system in the future. Given sufficient resources, a comprehensive web-based data management system can meet the need for clean, available data in clinical trials in ALS and similar diseases, and can contribute significantly to their efficient execution.
doi:10.3109/17482960802378998
PMCID: PMC5810546  PMID: 19922127
2.  Immunocytochemical Organization and Sour Taste Activation in the Rostral Nuc. Solitary Tract of Mice 
Sensory inputs from the oropharynx terminate in both the trigeminal brainstem complex and the rostral part of the nucleus of the solitary tract (nTS). Taste information is conveyed via the facial and glossopharyngeal nerves while general mucosal innervation is carried by the trigeminal and glossopharyngeal nerves. In contrast, the caudal nTS receives general visceral information largely from the vagus nerve. Although the caudal nTS shows clear morphological and molecularly delimited subdivisions, the rostral part does not. Thus, linking taste-induced patterns of activity to morphological subdivisions in the nTS is challenging. To test whether molecularly-defined features of the rostral nTS correlate with patterns of taste-induced activity, we combined immunohistochemistry for markers of various visceral afferent and efferent systems with c-Fos-based activity maps generated by stimulation with a sour tastant, 30mM citric acid. We further dissociated taste-related activity from activity arising from acid-sensitive general mucosal innervation by comparing acid-evoked c-Fos in wildtype and “taste blind”, P2X2/P2X3 double knockout (P2X-dblKO) mice. In wildtype mice, citric acid stimulation evoked significant c-Fos activation in the central part of the rostral nTS – activity that was largely absent in the P2X-dblKO mice. P2X-dblKO mice, like wildtype mice, did exhibit acid-induced c-Fos activity in the dorsomedial trigeminal brainstem nucleus situated laterally adjacent to the rostral nTS. This dorsomedial nucleus also showed substantial innervation by trigeminal nerve fibers immunoreactive for CGRP, a marker for polymodal nociceptors suggesting that trigeminal general mucosal innervation carries information about acids in the oral cavity.
Graphical Abstract
Responses to sour (acid) stimuli occur not only within taste-responsive regions of the nucleus of the solitary tract (nTS), highlighted by P2X2-immunoreactive fibers (green) but also within the dorsomedial nucleus of the brainstem trigeminal complex (DMSp5), which receives input from polymodal nociceptors of the oral cavity, marked by CGRP-immunoreactivity (red).
doi:10.1002/cne.24059
PMCID: PMC5138149  PMID: 27292295
CGRP; acid; c-Fos; trigeminal; esophagus; oropharynx; RRID: AB_2040054; RRID: AB_572253; RRID: AB_518351; RRID: AB_518147; RRID: AB_2314042
3.  NaV channel variants in patients with painful and nonpainful peripheral neuropathy 
Neurology: Genetics  2017;3(6):e207.
Objective:
To examine the incidence of nonsynonymous missense variants in SCN9A (NaV1.7), SCN10A (NaV1.8), and SCN11A (NaV1.9) in patients with painful and nonpainful peripheral neuropathy.
Methods:
Next-generation sequencing was performed on 457 patient DNA samples provided by the Peripheral Neuropathy Research Registry (PNRR). The patient diagnosis was as follows: 278 idiopathic peripheral neuropathy (67% painful and 33% nonpainful) and 179 diabetic distal polyneuropathy (77% painful and 23% nonpainful).
Results:
We identified 36 (SCN9A), 31 (SCN10A), and 15 (SCN11A) nonsynonymous missense variants, with 47.7% of patients carrying a low-frequency (minor allele frequency <5%) missense variant in at least 1 gene. The incidence of previously reported gain-of-function missense variants was low (≤3%), and these were detected in patients with and without pain. There were no significant differences in missense variant allele frequencies of any gene, or SCN9A haplotype frequencies, between PNRR patients with painful or nonpainful peripheral neuropathy. PNRR patient SCN9A and SCN11A missense variant allele frequencies were not significantly different from the Exome Variant Server, European American (EVS-EA) reference population. For SCN10A, there was a significant increase in the alternate allele frequency of the common variant p.V1073A and low-frequency variant pS509P in PNRR patients compared with EVS-EA and the 1000 Genomes European reference populations.
Conclusions:
These results suggest that identification of a genetically defined subpopulation for testing of NaV1.7 inhibitors in patients with peripheral neuropathy is unlikely and that additional factors, beyond expression of previously reported disease “mutations,” are more important for the development of painful neuropathy than previously discussed.
doi:10.1212/NXG.0000000000000207
PMCID: PMC5732007
5.  Unravelling Darwin's entangled bank: architecture and robustness of mutualistic networks with multiple interaction types 
Trying to unravel Darwin's entangled bank further, we describe the architecture of a network involving multiple forms of mutualism (pollination by animals, seed dispersal by birds and plant protection by ants) and evaluate whether this multi-network shows evidence of a structure that promotes robustness. We found that species differed strongly in their contributions to the organization of the multi-interaction network, and that only a few species contributed to the structuring of these patterns. Moreover, we observed that the multi-interaction networks did not enhance community robustness compared with each of the three independent mutualistic networks when analysed across a range of simulated scenarios of species extinction. By simulating the removal of highly interacting species, we observed that, overall, these species enhance network nestedness and robustness, but decrease modularity. We discuss how the organization of interlinked mutualistic networks may be essential for the maintenance of ecological communities, and therefore the long-term ecological and evolutionary dynamics of interactive, species-rich communities. We suggest that conserving these keystone mutualists and their interactions is crucial to the persistence of species-rich mutualistic assemblages, mainly because they support other species and shape the network organization.
doi:10.1098/rspb.2016.1564
PMCID: PMC5136579  PMID: 27881755
coupled networks; keystone mutualists; modularity; nestedness; structure–stability relationships
6.  A Phase 2 Randomized Study of Ramucirumab (IMC-1121B) with or without Dacarbazine in Patients with Metastatic Melanoma 
SUMMARY
Background
To evaluate the efficacy and safety of ramucirumab (IMC-1121B; LY3009806), a fully human monoclonal antibody targeting the vascular endothelial growth factor receptor-2, alone and in combination with dacarbazine in chemotherapy-naïve patients with metastatic melanoma (MM).
Methods
Eligible patients received ramucirumab (10 mg/kg) + dacarbazine (1000 mg/m2) (Arm A) or ramucirumab only (10 mg/kg) (Arm B) every 3 weeks. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), overall response, and safety.
Findings
Of 106 randomized patients, 102 received study treatment (Arm A, N = 52; Arm B, N = 50). Baseline characteristics were similar in both arms. Median PFS was 2·6 months (Arm A) and 1·7 months (Arm B); median 6-month PFS rates were 30·7% and 17·9% and 12-month PFS rates were 23·7% and 15·6%, respectively. In Arm A, 9 (17·3%) patients had partial response (PR) and 19 (36·5%), stable disease (SD); PR and SD in Arm B were 2 (4·0%) and 21 (42·0%), respectively. Median OS was 8·7 months in Arm A and 11·1 months in Arm B. Patients in both arms tolerated the treatment with limited grade 3/4 toxicities.
Interpretation
Ramucirumab alone or in combination with dacarbazine was associated with an acceptable safety profile in patients with MM. Although the study was not powered for comparison between treatment arms, PFS appeared greater with combination therapy. Sustained disease control was observed on both study arm
Funding
Funded by ImClone Systems LLC, a wholly-owned subsidiary of Eli Lilly and Company, Bridgewater, NJ
doi:10.1016/j.ejca.2014.03.289
PMCID: PMC5702465  PMID: 24930625
7.  Live Monitoring of Blastemal Cell Contributions During Appendage Regeneration 
Current biology : CB  2016;26(22):2981-2991.
SUMMARY
The blastema is a mass of progenitor cells that enables regeneration of amputated salamander limbs or fish fins. Methodology to label and track blastemal cell progeny has been deficient, restricting our understanding of appendage regeneration. Here, we created a system for clonal analysis and quantitative imaging of hundreds of blastemal cells and their respective progeny in living adult zebrafish undergoing fin regeneration. Amputation stimulates resident cells within a limited recruitment zone to reset proximodistal (PD) positional information and assemble the blastema. Within the newly formed blastema, the spatial coordinates of connective tissue progenitors are predictive of their ultimate contributions to regenerated skeletal structures, indicating early development of an approximate PD pre-pattern. Calcineurin regulates size recovery by controlling the average number of progeny divisions without disrupting this pre-pattern. Our longitudinal clonal analyses of regenerating zebrafish fins provide evidence that connective tissue progenitors are rapidly organized into a scalable blueprint of lost structures.
Graphical abstract
doi:10.1016/j.cub.2016.08.072
PMCID: PMC5121098  PMID: 27839971
8.  Conditional survival estimates for cancer patients 
Oncotarget  2017;8(49):84639-84640.
doi:10.18632/oncotarget.21497
PMCID: PMC5689561
conditional survival; cancer; prognosis; staging
9.  Uncertainty in the Bayesian meta-analysis of normally distributed surrogate endpoints 
We investigate the effect of the choice of parameterisation of meta-analytic models and related uncertainty on the validation of surrogate endpoints. Different meta-analytical approaches take into account different levels of uncertainty which may impact on the accuracy of the predictions of treatment effect on the target outcome from the treatment effect on a surrogate endpoint obtained from these models. A range of Bayesian as well as frequentist meta-analytical methods are implemented using illustrative examples in relapsing–remitting multiple sclerosis, where the treatment effect on disability worsening is the primary outcome of interest in healthcare evaluation, while the effect on relapse rate is considered as a potential surrogate to the effect on disability progression, and in gastric cancer, where the disease-free survival has been shown to be a good surrogate endpoint to the overall survival. Sensitivity analysis was carried out to assess the impact of distributional assumptions on the predictions. Also, sensitivity to modelling assumptions and performance of the models were investigated by simulation. Although different methods can predict mean true outcome almost equally well, inclusion of uncertainty around all relevant parameters of the model may lead to less certain and hence more conservative predictions. When investigating endpoints as candidate surrogate outcomes, a careful choice of the meta-analytical approach has to be made. Models underestimating the uncertainty of available evidence may lead to overoptimistic predictions which can then have an effect on decisions made based on such predictions.
doi:10.1177/0962280215597260
PMCID: PMC5642004  PMID: 26271918
Meta-analysis; surrogate endpoints; Bayesian statistics; bivariate meta-analysis; meta-regression
10.  Enterococcus faecalis Uses a Phosphotransferase System Permease and a Host Colonization-Related ABC Transporter for Maltodextrin Uptake 
Journal of Bacteriology  2017;199(9):e00878-16.
ABSTRACT
Maltodextrin is a mixture of maltooligosaccharides, which are produced by the degradation of starch or glycogen. They are mostly composed of α-1,4- and some α-1,6-linked glucose residues. Genes presumed to code for the Enterococcus faecalis maltodextrin transporter were induced during enterococcal infection. We therefore carried out a detailed study of maltodextrin transport in this organism. Depending on their length (3 to 7 glucose residues), E. faecalis takes up maltodextrins either via MalT, a maltose-specific permease of the phosphoenolpyruvate (PEP):carbohydrate phosphotransferase system (PTS), or the ATP binding cassette (ABC) transporter MdxEFG-MsmX. Maltotriose, the smallest maltodextrin, is primarily transported by the PTS permease. A malT mutant therefore exhibits significantly reduced growth on maltose and maltotriose. The residual uptake of the trisaccharide is catalyzed by the ABC transporter, because a malT mdxF double mutant no longer grows on maltotriose. The trisaccharide arrives as maltotriose-6″-P in the cell. MapP, which dephosphorylates maltose-6′-P, also releases Pi from maltotriose-6″-P. Maltotetraose and longer maltodextrins are mainly (or exclusively) taken up via the ABC transporter, because inactivation of the membrane protein MdxF prevents growth on maltotetraose and longer maltodextrins up to at least maltoheptaose. E. faecalis also utilizes panose and isopanose, and we show for the first time, to our knowledge, that in contrast to maltotriose, its two isomers are primarily transported via the ABC transporter. We confirm that maltodextrin utilization via MdxEFG-MsmX affects the colonization capacity of E. faecalis, because inactivation of mdxF significantly reduced enterococcal colonization and/or survival in kidneys and liver of mice after intraperitoneal infection.
IMPORTANCE Infections by enterococci, which are major health care-associated pathogens, are difficult to treat due to their increasing resistance to clinically relevant antibiotics, and new strategies are urgently needed. A largely unexplored aspect is how these pathogens proliferate and which substrates they use in order to grow inside infected hosts. The use of maltodextrins as a source of carbon and energy was studied in Enterococcus faecalis and linked to its virulence. Our results demonstrate that E. faecalis can efficiently use glycogen degradation products. We show here that depending on the length of the maltodextrins, one of two different transporters is used: the maltose-PTS transporter MalT, or the MdxEFG-MsmX ABC transporter. MdxEFG-MsmX takes up longer maltodextrins as well as complex molecules, such as panose and isopanose.
doi:10.1128/JB.00878-16
PMCID: PMC5388810  PMID: 28242718
enterococci; maltodextrin; phosphotransferase system; ABC transporter; host colonization
11.  CHA2DS2-VASc Score and Adverse Outcomes in Patients with Heart Failure with Reduced Ejection Fraction and Sinus Rhythm 
European journal of heart failure  2016;18(10):1261-1266.
Aims
To determine whether the CHA2DS2-VASc score can predict adverse outcomes such as death, ischemic stroke, and major hemorrhage, in patients with systolic heart failure in sinus rhythm.
Methods and Results
CHA2DS2-VASc scores were calculated for 1,101 patients randomized to warfarin and 1,123 patients randomized to aspirin. Adverse outcomes were defined as death or ischemic stroke, death alone, ischemic stroke alone, and major hemorrhage. Using proportional hazards models, we found that each 1-point increase in the CHA2DS2-VASc score was associated with increased hazard of death or ischemic stroke events (hazard ratio [HR] for the warfarin arm = 1.21 [1.13–1.30], p<0.001; for aspirin, HR = 1.20 [1.11–1.29], p<0.001). Similar increased hazards for higher CHA2DS2-VASc scores were observed for death alone, ischemic stroke alone, and major hemorrhage. Overall performance of the CHA2DS2-VASc score was assessed using c-statistics for full models containing the risk score, treatment assignment, and score-treatment interaction, with the c-statistics for the full models ranging from 0.57 for death to 0.68 for major hemorrhage.
Conclusions
The CHA2DS2-VASc score predicted adverse outcomes in patients with systolic HF in sinus rhythm, with modest prediction accuracy.
doi:10.1002/ejhf.613
PMCID: PMC5053869  PMID: 27444219
heart failure; warfarin; sinus rhythm; stroke; bleeding
12.  Global and Targeted Pathway Impact of Gliomas on White Matter Integrity Based on Lobar Localization 
Cureus  null;9(9):e1660.
Primary brain tumors comprise 28% of all tumors and 80% of malignant tumors. Pathophysiology of high-grade gliomas includes significant distortion of white matter architecture, necrosis, the breakdown of the blood brain barrier, and increased intracranial pressure. Diffusion tensor imaging (DTI), a diffusion weighted imaging technique, can be used to assess white matter architecture. Use of DTI as a non-invasive pathophysiological tool to analyze glioma impact on white matter microstructure has yet to be fully explored.
Preliminary assessment of DTI tractography was done as a measure of intracranial tumor impact on white matter architecture. Specifically, we addressed three questions: 1) whether glioma differentially affects local white matter structure compared to metastasis, 2) whether glioma affects tract integrity of major white matter bundles, 3) whether glioma lobe localization affects tract integrity of different white matter bundles.
In this study, we retrospectively investigated preoperative DTI scans from 24 patients undergoing tumor resection. Fiber tractography was estimated using a deterministic fiber tracking algorithm in DSI (diffusion spectrum imaging) Studio. The automatic anatomical labeling (AAL) atlas was used to define the left and right (L/R) hemisphere regions of interest (ROI). In addition, the John Hopkins University (JHU) White Matter Atlas was used to auto-segment major white matter bundle ROIs. For all tracts derived from ROI seed targets, we computed the following parameters: tract number, tract length, fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD).
The DTI tractography analysis revealed that white matter integrity in the hemisphere ipsilateral to intracranial tumor was significantly compromised compared to the control contralateral hemisphere. No differences were observed between high vs low-grade gliomas, however, gliomas induced significantly greater white matter degradation than metastases. In addition, targeted analysis of major white matter bundles important for sensory/motor function (i.e., corticospinal tract and superior longitudinal fasciculus) revealed tract-parameter specific susceptibility due to the presence of the tumor. Finally, major tract bundles were differentially affected based on lobar localization of the glioma.
These DTI-based tractographic analyses complement findings from gross histopathological examination of glioma impact on neural tissue. Global and focal white matter architecture, ipsilateral to glioma, shows higher rates of degradation or edema – based on DTI tractographic metrics – in comparison to normal brain or metastases. Gliomas, which arise in the parietal lobe, also have a higher negative impact (potentially due to increased edema) on white matter integrity of the superior longitudinal fasciculus(SLF) than those which arise in the frontal lobe. Future studies will focus on using preoperative and postoperative tractography to predict functional deficits following resective surgery.
doi:10.7759/cureus.1660
PMCID: PMC5675599
tractography; primary brain glioma; diffusion tensor imaging; intracranial tumor; white matter tracts
13.  Mitochondrial Disease Patients’ Perception of Dietary Supplements’ Use 
Molecular genetics and metabolism  2016;119(1-2):100-108.
Surveys of mitochondrial disease physicians conducted through the Mitochondrial Medicine Society have shown that virtually all providers recommend a variety of dietary supplements as treatments to their patients in an effort to enhance energy production and reduce oxidative stress. In this survey, we asked patients and their parents about their experiences taking these dietary supplements for mitochondrial disease. The survey was disseminated through the North American Mitochondrial Disease Consortium (NAMDC) and the Rare Disease Clinical Research Network (RDCRN) registries and gathered 162 responses. The study ascertaine each patient’s mitochondrial disease diagnosis, dietary supplements used, adjunct therapy, and effects of the supplements on symptoms and health.
Regardless of the specific underlying mitochondrial disease, the majority of the survey respondents stated they are or have been on dietary supplements. Most patients take more than four supplements primarily coenzyme Q10, L-carnitine, and riboflavin. The majority of patients taking supplements reported health benefits from the supplements. The onset of perceived benefits was between 2 weeks to 3 months of initiating intake. Supplements seem to be safe, with only 28% of patients experiencing mild side-effects and only 5.6% discontinuing their intake due to intolerance. Only 9% of patients had insurance coverage for their supplements and when paying out of pocket, 95% of them spend up to $500/month. Despite the use of concomitant therapies (prescribed medications, physical therapy, diet changes and other), 45.5% of patients think that dietary supplements are the only intervention improving their symptoms. Some limitations of this study include the retrospective collection of data probably associated with substantial recall bias, lack of longitudinal follow up to document pre- and post-supplement clinical status and second hand reports by parents for children which may reflect parents’ subjective interpretation of symptoms severity and supplements effect rather than real patients’ experience. More extensive prospective studies will help further elucidate this topic.
doi:10.1016/j.ymgme.2016.07.005
PMCID: PMC5031526  PMID: 27444792
Mitochondrial disease; Dietary supplements; survey
14.  Use of intraoperative local field potential spectral analysis to differentiate basal ganglia structures in Parkinson's disease patients 
Physiological Reports  2017;5(12):e13322.
Abstract
Identification of brain structures traversed during implantation of deep brain‐stimulating (DBS) electrodes into the subthalamic nucleus (STN‐DBS) for the treatment of Parkinson's disease (PD) frequently relies on subjective correspondence between kinesthetic response and multiunit activity. However, recent work suggests that local field potentials (LFP) could be used as a more robust signal to objectively differentiate subcortical structures. The goal of this study was to analyze the spectral properties of LFP collected during STN‐DBS in order to objectively identify commonly traversed brain regions and improve our understanding of aberrant oscillations in the PD‐related pathophysiological cortico‐basal ganglia network. In 21 PD patients, LFP were collected and analyzed during STN‐DBS implantation surgery. Spectral power for delta‐, theta‐, alpha‐, low‐beta‐, and high‐beta‐frequency bands was assessed at multiple depths throughout the subcortical structures traversed on the trajectory to the ventral border of STN. Similar to previous findings, beta‐band oscillations had an increased magnitude within the borders of the motor‐related area of STN, however, across several subjects, we also observed increased high‐beta magnitude within the borders of thalamus. Comparing across all patients using relative power, we observed a gradual increase in the magnitude of both low‐ and high‐beta‐frequency bands as the electrode descended from striatum to STN. These results were also compared with frequency bands below beta, and similar trends were observed. Our results suggest that LFP signals recorded during the implantation of a DBS electrode evince distinct oscillatory signatures that distinguish subcortical structures.
doi:10.14814/phy2.13322
PMCID: PMC5492209  PMID: 28642341
Basal ganglia; deep brain stimulation; local field potential; Parkinson's disease
15.  Survey of maternal sleep practices in late pregnancy in a multi-ethnic sample in South Auckland, New Zealand 
Background
The Auckland Stillbirth study demonstrated a two-fold increased risk of late stillbirth for women who did not go to sleep on their left side. Two further studies have confirmed an increased risk of late stillbirth with supine sleep position. As sleep position is modifiable, we surveyed self-reported late pregnancy sleep position, knowledge about sleep position, and views about changing going-to-sleep position.
Methods
Participants in this 2014 survey were pregnant women (n = 377) in their third trimester from South Auckland, New Zealand, a multi-ethnic and predominantly low socio-economic population. An ethnically-representative sample was obtained using random sampling. Multivariable logistic regression was performed to identify factors independently associated with non-left sided going-to-sleep position in late pregnancy.
Results
Respondents were 28 to 42 weeks’ gestation. Reported going-to-sleep position in the last week was left side (30%), right side (22%), supine (3%), either side (39%) and other (6%). Two thirds (68%) reported they had received advice about sleep position. Non-left sleepers were asked if they would be able to change to their left side if it was better for their baby; 87% reported they would have little or no difficulty changing. Women who reported a non-left going-to-sleep position were more likely to be of Maori (aOR 2.64 95% CI 1.23–5.66) or Pacific (aOR 2.91 95% CI 1.46–5.78) ethnicity; had a lower body mass index (BMI) (aOR 0.93 95% CI 0.89–0.96); and were less likely to sleep on the left-hand side of the bed (aOR 3.29 95% CI 2.03–5.32).
Conclusions
Maternal going-to-sleep position in the last week was side-lying in 91% of participants. The majority had received advice to sleep on their side or avoid supine sleep position. Sleeping on the left-hand side of the bed was associated with going-to-sleep on the left side. Most non-left sleepers reported their sleeping position could be modified to the left side suggesting a public health intervention about sleep position is likely to be feasible in other multi-ethnic communities.
Electronic supplementary material
The online version of this article (doi:10.1186/s12884-017-1378-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12884-017-1378-5
PMCID: PMC5474014  PMID: 28623890
Stillbirth; Pregnancy; Sleep position
16.  Age at menarche and lung function: a Mendelian randomization study 
European Journal of Epidemiology  2017;32(8):701-710.
A trend towards earlier menarche in women has been associated with childhood factors (e.g. obesity) and hypothesised environmental exposures (e.g. endocrine disruptors present in household products). Observational evidence has shown detrimental effects of early menarche on various health outcomes including adult lung function, but these might represent spurious associations due to confounding. To address this we used Mendelian randomization where genetic variants are used as proxies for age at menarche, since genetic associations are not affected by classical confounding. We estimated the effects of age at menarche on forced vital capacity (FVC), a proxy for restrictive lung impairment, and ratio of forced expiratory volume in one second to FVC (FEV1/FVC), a measure of airway obstruction, in both adulthood and adolescence. We derived SNP-age at menarche association estimates for 122 variants from a published genome-wide meta-analysis (N = 182,416), with SNP-lung function estimates obtained by meta-analysing three studies of adult women (N = 46,944) and two of adolescent girls (N = 3025). We investigated the impact of departures from the assumption of no pleiotropy through sensitivity analyses. In adult women, in line with previous evidence, we found an effect on restrictive lung impairment with a 24.8 mL increase in FVC per year increase in age at menarche (95% CI 1.8–47.9; p = 0.035); evidence was stronger after excluding potential pleiotropic variants (43.6 mL; 17.2–69.9; p = 0.001). In adolescent girls we found an opposite effect (−56.5 mL; −108.3 to −4.7; p = 0.033), suggesting that the detrimental effect in adulthood may be preceded by a short-term post-pubertal benefit. Our secondary analyses showing results in the same direction in men and boys, in whom age at menarche SNPs have also shown association with sexual development, suggest a role for pubertal timing in general rather than menarche specifically. We found no effect on airway obstruction (FEV1/FVC).
Electronic supplementary material
The online version of this article (doi:10.1007/s10654-017-0272-9) contains supplementary material, which is available to authorized users.
doi:10.1007/s10654-017-0272-9
PMCID: PMC5591357  PMID: 28624884
Mendelian randomization; Menarche; Puberty; Lung function; FVC; FEV1/FVC
17.  Phase I Study of Veliparib (ABT-888) Combined with Cisplatin and Vinorelbine in Advanced Triple-Negative Breast Cancer and/or BRCA Mutation-Associated Breast Cancer 
PURPOSE
Cisplatin is synergistic with vinorelbine and the poly(ADP-ribose) polymerase (PARP) inhibitor veliparib, and has anti-neoplastic activity in TNBC and BRCA mutation-associated breast cancer. This phase I study assessed veliparib with cisplatin and vinorelbine.
PATIENTS AND METHODS
A 3+3 dose escalation design evaluated veliparib administered BID for 14 days with cisplatin (75 mg/m2 day 1) and vinorelbine (25 mg/m2 days 1,8) every 21 days, for six to ten cycles, followed by veliparib monotherapy. Pharmacokinetics, measurement of poly(ADP-ribose) in peripheral blood mononuclear cells, and preliminary efficacy were assessed. Immunohistochemistry and gene expression profiling were evaluated as potential predictors of response.
RESULTS
Forty-five patients enrolled in nine dose cohorts plus five in an expansion cohort at the highest dose level and recommended phase II dose, 300 mg BID. Maximum tolerated dose of veliparib was not reached. Neutropenia (36%), anemia (30%), and thrombocytopenia (12%) were the most common grade 3/4 adverse events. Best overall response for 48 patients was radiologic response with 9-week confirmation for 17 (35%; 2 complete, 15 partial), and stable disease for 21 (44%). Germline BRCA mutation presence versus absence was associated with 6-month progression-free survival (10 of 14 (71%) vs 8 of 27 (30%), mid-p=0.01). Median progression-free survival for all 50 patients was 5.5 months (95% confidence interval 4.1–6.7).
CONCLUSION
Veliparib at 300 mg BID combined with cisplatin and vinorelbine is well tolerated with encouraging response rates. A phase II randomized trial is planned to assess veliparib’s contribution to cisplatin chemotherapy in metastatic TNBC and BRCA mutation-associated breast cancer.
Translational Relevance
We hypothesize that TNBC tumors have defects in homologous recombination DNA repair similar to BRCA mutation associated tumors, which will render them sensitive to platinum therapy and PARP inhibition. This report describes a phase I study that explored the safety and efficacy of cisplatin, vinorelbine and veliparib. This combination was tolerable and reached the highest dose of veliparib in combination with chemotherapy used in breast cancer to date. Antineoplastic activity was observed both in BRCA mutation associated breast cancer and in BRCA wild-type TNBC. We measured changes in PARP activity and performed gene expression profiling and immunohistochemistry studies. Based on promising results from this study, a randomized phase II study has been developed to evaluate the addition of veliparib to cisplatin chemotherapy for patients with advanced TNBC. This study will incorporate a multi-pronged biomarker approach to identify a homologous recombination repair deficiency (HRD) phenotype that derives benefit from PARP inhibition.
doi:10.1158/1078-0432.CCR-15-2137
PMCID: PMC4911292  PMID: 26801247
triple-negative; BRCA mutation; veliparib; ABT-888
18.  Going to sleep in the supine position is a modifiable risk factor for late pregnancy stillbirth; Findings from the New Zealand multicentre stillbirth case-control study 
PLoS ONE  2017;12(6):e0179396.
Objective
Our objective was to test the primary hypothesis that maternal non-left, in particular supine going-to-sleep position, would be a risk factor for late stillbirth (≥28 weeks of gestation).
Methods
A multicentre case-control study was conducted in seven New Zealand health regions, between February 2012 and December 2015.
Cases (n = 164) were women with singleton pregnancies and late stillbirth, without congenital abnormality. Controls (n = 569) were women with on-going singleton pregnancies, randomly selected and frequency matched for health region and gestation.
The primary outcome was adjusted odds of late stillbirth associated with self-reported going-to-sleep position, on the last night. The last night was the night before the late stillbirth was thought to have occurred or the night before interview for controls. Going-to-sleep position on the last night was categorised as: supine, left-side, right-side, propped or restless. Multivariable logistic regression adjusted for known confounders.
Results
Supine going-to-sleep position on the last night was associated with increased late stillbirth risk (adjusted odds ratios (aOR) 3.67, 95% confidence interval (CI) 1.74 to 7.78) with a population attributable risk of 9.4%. Other independent risk factors for late stillbirth (aOR, 95% CI) were: BMI (1.04, 1.01 to 1.08) per unit, maternal age ≥40 (2.88, 1.31 to 6.32), birthweight <10th customised centile (2.76, 1.59 to 4.80), and <6 hours sleep on the last night (1.81, 1.14 to 2.88). The risk associated with supine-going-to-sleep position was greater for term (aOR 10.26, 3.00 to 35.04) than preterm stillbirths (aOR 3.12, 0.97 to 10.05).
Conclusions
Supine going-to-sleep position is associated with a 3.7 fold increase in overall late stillbirth risk, independent of other common risk factors. A public health campaign encouraging women not to go-to-sleep supine in the third trimester has potential to reduce late stillbirth by approximately 9%.
doi:10.1371/journal.pone.0179396
PMCID: PMC5469491  PMID: 28609468
19.  Assessing the suitability of summary data for two-sample Mendelian randomization analyses using MR-Egger regression: the role of the I2 statistic 
Background
MR-Egger regression has recently been proposed as a method for Mendelian randomization (MR) analyses incorporating summary data estimates of causal effect from multiple individual variants, which is robust to invalid instruments. It can be used to test for directional pleiotropy and provides an estimate of the causal effect adjusted for its presence. MR-Egger regression provides a useful additional sensitivity analysis to the standard inverse variance weighted (IVW) approach that assumes all variants are valid instruments. Both methods use weights that consider the single nucleotide polymorphism (SNP)-exposure associations to be known, rather than estimated. We call this the `NO Measurement Error’ (NOME) assumption. Causal effect estimates from the IVW approach exhibit weak instrument bias whenever the genetic variants utilized violate the NOME assumption, which can be reliably measured using the F-statistic. The effect of NOME violation on MR-Egger regression has yet to be studied.
Methods
An adaptation of the I2 statistic from the field of meta-analysis is proposed to quantify the strength of NOME violation for MR-Egger. It lies between 0 and 1, and indicates the expected relative bias (or dilution) of the MR-Egger causal estimate in the two-sample MR context. We call it IGX2. The method of simulation extrapolation is also explored to counteract the dilution. Their joint utility is evaluated using simulated data and applied to a real MR example.
Results
In simulated two-sample MR analyses we show that, when a causal effect exists, the MR-Egger estimate of causal effect is biased towards the null when NOME is violated, and the stronger the violation (as indicated by lower values of IGX2), the stronger the dilution. When additionally all genetic variants are valid instruments, the type I error rate of the MR-Egger test for pleiotropy is inflated and the causal effect underestimated. Simulation extrapolation is shown to substantially mitigate these adverse effects. We demonstrate our proposed approach for a two-sample summary data MR analysis to estimate the causal effect of low-density lipoprotein on heart disease risk. A high value of IGX2 close to 1 indicates that dilution does not materially affect the standard MR-Egger analyses for these data.
Conclusions
Care must be taken to assess the NOME assumption via the IGX2 statistic before implementing standard MR-Egger regression in the two-sample summary data context. If IGX2 is sufficiently low (less than 90%), inferences from the method should be interpreted with caution and adjustment methods considered.
doi:10.1093/ije/dyw220
PMCID: PMC5446088  PMID: 27616674
Mendelian randomization; MR-Egger regression; measurement error; I2 statistic; simulation extrapolation
20.  A framework for the investigation of pleiotropy in two‐sample summary data Mendelian randomization 
Statistics in Medicine  2017;36(11):1783-1802.
Mendelian randomization (MR) uses genetic data to probe questions of causality in epidemiological research, by invoking the Instrumental Variable (IV) assumptions. In recent years, it has become commonplace to attempt MR analyses by synthesising summary data estimates of genetic association gleaned from large and independent study populations. This is referred to as two‐sample summary data MR. Unfortunately, due to the sheer number of variants that can be easily included into summary data MR analyses, it is increasingly likely that some do not meet the IV assumptions due to pleiotropy. There is a pressing need to develop methods that can both detect and correct for pleiotropy, in order to preserve the validity of the MR approach in this context. In this paper, we aim to clarify how established methods of meta‐regression and random effects modelling from mainstream meta‐analysis are being adapted to perform this task. Specifically, we focus on two contrastin g approaches: the Inverse Variance Weighted (IVW) method which assumes in its simplest form that all genetic variants are valid IVs, and the method of MR‐Egger regression that allows all variants to violate the IV assumptions, albeit in a specific way. We investigate the ability of two popular random effects models to provide robustness to pleiotropy under the IVW approach, and propose statistics to quantify the relative goodness‐of‐fit of the IVW approach over MR‐Egger regression. © 2017 The Authors. Statistics in Medicine Published by JohnWiley & Sons Ltd
doi:10.1002/sim.7221
PMCID: PMC5434863  PMID: 28114746
instrumental variables; Mendelian randomization; meta‐analysis; MR‐Egger regression; pleiotropy
21.  Selective suppression of the human aryl hydrocarbon receptor function can be mediated through binding interference at the C-terminal half of the receptor 
Biochemical pharmacology  2016;107:91-100.
The human aryl hydrocarbon receptor is a cytosolic signaling molecule which affects immune response and aberrant cell growth. Canonical signaling of the receptor requires the recruitment of coactivators to the promoter region to remodel local chromatin structure. We predicted that interference of this recruitment would block the aryl hydrocarbon receptor function. To prove that, we employed phage display to identify nine peptides of twelve-amino-acid in length which target the C-terminal half of the human aryl hydrocarbon receptor, including the region where coactivators bind. Eight 12mer peptides, in the form of GFP fusion, suppressed the ligand-dependent transcription of six AHR target genes (cyp1a1, cyp1a2, cyp1b1, ugt1a1, nqo1, and ahrr) in different patterns in Hep3B cells, whereas the AHR antagonist CH-223191 suppressed all these target genes similarly. Three of the 12mer peptides (namely 11-3, 1–7, and 7-3) suppressed the 3MC-induced, CYP1A1-dependent EROD activity and the ROS production caused by benzo[a]pyrene. These 12mer peptides suppressed the AHR function synergistically with CH-223191. In conclusion, we provide evidence that targeting the C-terminal half of the human aryl hydrocarbon receptor is a viable, new approach to selectively block the receptor function.
doi:10.1016/j.bcp.2016.03.004
PMCID: PMC4821718  PMID: 26970402
22.  Attitudes toward prevention of mtDNA-related diseases through oocyte mitochondrial replacement therapy 
Human Reproduction (Oxford, England)  2016;31(5):1058-1065.
STUDY QUESTION
Among women who carry pathogenic mitochondrial DNA (mtDNA) point mutations and healthy oocyte donors, what are the levels of support for developing oocyte mitochondrial replacement therapy (OMRT) to prevent transmission of mtDNA mutations?
SUMMARY ANSWER
The majority of mtDNA carriers and oocyte donors support the development of OMRT techniques to prevent transmission of mtDNA diseases.
WHAT IS KNOWN ALREADY
Point mutations of mtDNA cause a variety of maternally inherited human diseases that are frequently disabling and often fatal. Recent developments in (OMRT) as well as pronuclear transfer between embryos offer new potential options to prevent transmission of mtDNA disease. However, it is unclear whether the non-scientific community will approve of embryos that contain DNA from three people.
STUDY DESIGN, SIZE, DURATION
Between 1 June 2012 through 12 February 2015, we administered surveys in cross-sectional studies of 92 female carriers of mtDNA point mutations and 112 healthy oocyte donors.
PARTICIPANTS/MATERIALS, SETTING, METHODS
The OMRT carrier survey was completed by 92 female carriers of an mtDNA point mutation. Carriers were recruited through the North American Mitochondrial Disease Consortium (NAMDC), the United Mitochondrial Disease Foundation (UMDF), patient support groups, research and private patients followed at the Columbia University Medical Center (CUMC) and patients' referrals of maternal relatives. The OMRT donor survey was completed by 112 women who had donated oocytes through a major in vitro fertilization clinic.
MAIN RESULTS AND THE ROLE OF CHANCE
All carriers surveyed were aware that they could transmit the mutation to their offspring, with 78% (35/45) of women, who were of childbearing age, indicating that the risk was sufficient to consider not having children, and 95% (87/92) of all carriers designating that the development of this technique was important and worthwhile. Of the 21 surveyed female carriers considering childbearing, 20 (95%) considered having their own biological offspring somewhat or very important and 16 of the 21 respondents (76%) were willing to donate oocytes for research and development. Of 112 healthy oocyte donors who completed the OMRT donor survey, 97 (87%) indicated that they would donate oocytes for generating a viable embryo through OMRT.
LIMITATIONS, REASONS FOR CAUTION
Many of the participants were either patients or relatives of patients who were already enrolled in a research-oriented database, or who sought care in a tertiary research university setting, indicating a potential sampling bias. The survey was administered to a select group of individuals, who carry, or are at risk for carrying, mtDNA point mutations. These individuals are more likely to have been affected by the mutation or have witnessed first-hand the devastating effects of these mutations. It has not been established whether the general public would be supportive of this work. This survey did not explicitly address alternatives to OMRT.
WIDER IMPLICATIONS OF THE FINDINGS
This is the first study indicating a high level of interest in the development of these methods among women affected by the diseases or who are at risk of carrying mtDNA mutations as well as willingness of most donors to provide oocytes for the development of OMRT.
STUDY FUNDING/COMPETING INTEREST(S)
This work was conducted under the auspices of the NAMDC (Study Protocol 7404). NAMDC (U54NS078059) is part of the NCATS Rare Diseases Clinical Research Network (RDCRN). RDCRN is an initiative of the Office of Rare Diseases Research (ORDR) and NCATS. NAMDC is funded through a collaboration between NCATS, NINDS, NICHD and NIH Office of Dietary Supplements. The work was also supported by the Bernard and Anne Spitzer Fund and the New York Stem Cell Foundation (NYSCF). Dr Hirano has received research support from Santhera Pharmaceuticals and Edison Pharmaceuticals for studies unrelated to this work. None of the other authors have conflicts of interest.
TRIAL REGISTRATION NUMBER
Not applicable.
doi:10.1093/humrep/dew033
PMCID: PMC4840023  PMID: 26936885
mitochondria; nuclear transfer; genetic disorders; mitochondrial DNA; mitochondrial disease; in vitro fertilization; oocyte; mitochondrial replacement therapy; mtDNA
23.  Cost-Effectiveness/Cost-Benefit Analysis of Newborn Screening for Severe Combined Immune Deficiency in Washington State 
The Journal of pediatrics  2016;172:127-135.
Objective
To evaluate the expected cost-effectiveness and net benefit of the recent implementation of newborn screening (NBS) for severe combined immunodeficiency (SCID) in Washington State.
Study design
We constructed a decision analysis model to estimate the costs and benefits of NBS in an annual birth cohort of 86 600 infants based on projections of avoided infant deaths. Point estimates and ranges for input variables, including the birth prevalence of SCID, proportion detected asymptomatically without screening through family history, screening test characteristics, survival rates, and costs of screening, diagnosis, and treatment were derived from published estimates, expert opinion, and the Washington NBS program. We estimated treatment costs stratified by age of identification and SCID type (with or without adenosine deaminase deficiency). Economic benefit was estimated using values of $4.2 and $9.0 million per death averted. We performed sensitivity analyses to evaluate the influence of key variables on the incremental cost-effectiveness ratio (ICER) of net direct cost per life-year saved.
Results
Our model predicts an additional 1.19 newborn infants with SCID detected preclinically through screening, in addition to those who would have been detected early through family history, and 0.40 deaths averted annually. Our base-case model suggests an ICER of $35 311 per life-year saved, and a benefit-cost ratio of either 5.31 or 2.71. Sensitivity analyses found ICER values <$100 000 and positive net benefit for plausible assumptions on all variables.
Conclusions
Our model suggests that NBS for SCID in Washington is likely to be cost-effective and to show positive net economic benefit.
doi:10.1016/j.jpeds.2016.01.029
PMCID: PMC4846488  PMID: 26876279
24.  T-Cell Therapy Using Interleukin-21–Primed Cytotoxic T-Cell Lymphocytes Combined With Cytotoxic T-Cell Lymphocyte Antigen-4 Blockade Results in Long-Term Cell Persistence and Durable Tumor Regression 
Journal of Clinical Oncology  2016;34(31):3787-3795.
Purpose
Peripheral blood–derived antigen-specific cytotoxic T cells (CTLs) provide a readily available source of effector cells that can be administered with minimal toxicity in an outpatient setting. In metastatic melanoma, this approach results in measurable albeit modest clinical responses in patients resistant to conventional therapy. We reasoned that concurrent cytotoxic T-cell lymphocyte antigen-4 (CTLA-4) checkpoint blockade might enhance the antitumor activity of adoptively transferred CTLs.
Patients and Methods
Autologous MART1-specific CTLs were generated by priming with peptide-pulsed dendritic cells in the presence of interleukin-21 and enriched by peptide-major histocompatibility complex multimer-guided cell sorting. This expeditiously yielded polyclonal CTL lines uniformly expressing markers associated with an enhanced survival potential. In this first-in-human strategy, 10 patients with stage IV melanoma received the MART1-specific CTLs followed by a standard course of anti–CTLA-4 (ipilimumab).
Results
The toxicity profile of the combined treatment was comparable to that of ipilimumab monotherapy. Evaluation of best responses at 12 weeks yielded two continuous complete remissions, one partial response (PR) using RECIST criteria (two PRs using immune-related response criteria), and three instances of stable disease. Infused CTLs persisted with frequencies up to 2.9% of CD8+ T cells for as long as the patients were monitored (up to 40 weeks). In patients who experienced complete remissions, PRs, or stable disease, the persisting CTLs acquired phenotypic and functional characteristics of long-lived memory cells. Moreover, these patients also developed responses to nontargeted tumor antigens (epitope spreading).
Conclusion
We demonstrate that combining antigen-specific CTLs with CTLA-4 blockade is safe and produces durable clinical responses, likely reflecting both enhanced activity of transferred cells and improved recruitment of new responses, highlighting the promise of this strategy.
doi:10.1200/JCO.2015.65.5142
PMCID: PMC5477923  PMID: 27269940
25.  Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci 
Jones, Gregory T. | Tromp, Gerard | Kuivaniemi, Helena | Gretarsdottir, Solveig | Baas, Annette F. | Giusti, Betti | Strauss, Ewa | van 't Hof, Femke N.G. | Webb, Thomas R. | Erdman, Robert | Ritchie, Marylyn D. | Elmore, James R. | Verma, Anurag | Pendergrass, Sarah | Kullo, Iftikhar J. | Ye, Zi | Peissig, Peggy L. | Gottesman, Omri | Verma, Shefali S. | Malinowski, Jennifer | Rasmussen-Torvik, Laura J. | Borthwick, Kenneth M. | Smelser, Diane T. | Crosslin, David R. | de Andrade, Mariza | Ryer, Evan J. | McCarty, Catherine A. | Böttinger, Erwin P. | Pacheco, Jennifer A. | Crawford, Dana C. | Carrell, David S. | Gerhard, Glenn S. | Franklin, David P. | Carey, David J. | Phillips, Victoria L. | Williams, Michael J. A. | Wei, Wenhua | Blair, Ross | Hill, Andrew A. | Vasudevan, Thodor M. | Lewis, David R. | Thomson, Ian | Krysa, Jo | Hill, Geraldine B. | Roake, Justin | Merriman, Tony R. | Oszkinis, Grzegorz | Galora, Silvia | Saracini, Claudia | Abbate, Rosanna | Pulli, Raffaele | Pratesi, Carlo | Saratzis, Athanasios | Verissimo, Ana R. | Bumpstead, Suzannah | Badger, Stephen A. | Clough, Rachel E. | Cockerill, Gillian | Hafez, Hany | Scott, D. Julian A. | Futers, T. Simon | Romaine, Simon P. R. | Bridge, Katherine | Griffin, Kathryn J. | Bailey, Marc A | Smith, Alberto | Thompson, Matthew M. | van Bockxmeer, Frank M. | Matthiasson, Stefan E. | Thorleifsson, Gudmar | Thorsteinsdottir, Unnur | Blankensteijn, Jan D. | Teijink, Joep A. W. | Wijmenga, Cisca | de Graaf, Jacqueline | Kiemeney, Lambertus A. | Lindholt, Jes S. | Hughes, Anne | Bradley, Declan T. | Stirrups, Kathleen | Golledge, Jonathan | Norman, Paul E. | Powell, Janet T. | Humphries, Steve E. | Hamby, Stephen E. | Goodall, Alison H. | Nelson, Christopher P. | Sakalihasan, Natzi | Courtois, Audrey | Ferrell, Robert E. | Eriksson, Per | Folkersen, Lasse | Franco-Cereceda, Anders | Eicher, John D. | Johnson, Andrew D. | Betsholtz, Christer | Ruusalepp, Arno | Franzén, Oscar | Schadt, Eric E. | Björkegren, Johan L. M. | Lipovich, Leonard | Drolet, Anne M. | Verhoeven, E. L. | Zeebregts, C. J. | Geelkerken, R. H. | van Sambeek, Marc R. | van Sterkenburg, S. M. | de Vries, J. P. | Stefansson, Kari | Thompson, John R. | de Bakker, Paul I. W. | Deloukas, Panos | Sayers, Robert D. | Harrison, Seamus C. | van Rij, Andre | Samani, Nilesh J. | Bown, Matthew J.
Circulation research  2016;120(2):341-353.
Rationale
Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA.
Objective
To identify additional AAA risk loci using data from all available genome-wide association studies (GWAS).
Methods and Results
Through a meta-analysis of 6 GWAS datasets and a validation study totalling 10,204 cases and 107,766 controls we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches we observed no new associations between the lead AAA SNPs and coronary artery disease, blood pressure, lipids or diabetes. Network analyses identified ERG, IL6R and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9.
Conclusions
The 4 new risk loci for AAA appear to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease.
doi:10.1161/CIRCRESAHA.116.308765
PMCID: PMC5253231  PMID: 27899403
Aneurysm; Basic Science Research; Genetic, Association Studies; Genetics; Vascular Disease; Abdominal aortic aneurysm; genetics; meta-analysis; matrix metalloproteinases; genome-wide association studies; bioinformatics

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