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ObjectiveBiomechanics represents the common final output through which all biopsychosocial constructs of back pain must pass, making it a rich target for phenotyping. To exploit this feature, several sites within the NIH Back Pain Consortium (BACPAC) have developed biomechanics measurement and phenotyping tools. The overall aims of this article were to: 1) provide a narrative review of biomechanics as a phenotyping tool; 2) describe the diverse array of tools and outcome measures that exist within BACPAC; and 3) highlight how leveraging these technologies with the other data collected within BACPAC could elucidate the relationship between biomechanics and other metrics used to characterize low back pain (LBP).MethodsThe narrative review highlights how biomechanical outcomes can discriminate between those with and without LBP, as well as among levels of severity of LBP. It also addresses how biomechanical outcomes track with functional improvements in LBP. Additionally, we present the clinical use case for biomechanical outcome measures that can be met via emerging technologies.ResultsTo answer the need for measuring biomechanical performance, our "Results" section describes the spectrum of technologies that have been developed and are being used within BACPAC.Conclusion and future directionsThe outcome measures collected by these technologies will be an integral part of longitudinal and cross-sectional studies conducted in BACPAC. Linking these measures with other biopsychosocial data collected within BACPAC increases our potential to use biomechanics as a tool for understanding the mechanisms of LBP, phenotyping unique LBP subgroups, and matching these individuals with an appropriate treatment paradigm.

Stream restorations are increasingly critical for managing and recovering freshwater biodiversity in human-dominated landscapes. However, few studies have quantified how rehabilitative actions promulgate through aquatic communities over decades. Here, a long-term dataset is analyzed for fish assemblage change, incorporating data pre- and post-restoration periods, and testing the extent to which native assemblage stability has increased over time. In the late 1950s, a large capacity dam was installed on Putah Creek (Solano County, CA, USA), which altered the natural flow regime, channel structure, geomorphic processes, and overall ecological function. Notably, downstream flows were reduced (especially during summer months) resulting in an aquatic assemblage dominated by warm-water nonnative species, while endemic native species subsisted at low levels as subordinates. A court-mediated Accord was ratified in 2000, providing a more natural flow regime, specifically for native and anadromous fishes in the stream. The richness of nonnative species decreased at every site following the Accord, while the richness of native species increased or stayed constant. At the three most upstream sites, native species richness increased over time and ultimately exceeded nonnative richness. Native assemblage recovery was strongest upriver, closer to flow releases and habitat restoration activities, and decreased longitudinally downstream. Rank-abundance curves through time revealed that, while species evenness was low throughout the study, dominance shifted from nonnative to native species in the upstream sites coincident with rehabilitation efforts. Mean rank shifts decreased following flow rehabilitation; thus the assemblage became increasingly stable over time following flow rehabilitation. Putah Creek's rehabilitation may represent a model for others interested in improving endemic freshwater communities in degraded ecosystems.

BackgroundMild hypoxic-ischemic encephalopathy (HIE) is increasingly recognized as a risk factor for neonatal brain injury. We examined the timing and pattern of brain injury in mild HIE.MethodsThis retrospective cohort study includes infants with mild HIE treated at 9 hospitals. Neonatal brain MRIs were scored by 2 reviewers using a validated classification system, with discrepancies resolved by consensus. Severity and timing of MRI brain injury (i.e., acute, subacute, chronic) was scored on the subset of MRIs that were performed at or before 8 days of age.ResultsOf 142 infants with mild HIE, 87 (61%) had injury on MRI at median age 5 (IQR 4-6) days. Watershed (23%), deep gray (20%) and punctate white matter (18%) injury were most common. Among the 125 (88%) infants who received a brain MRI at ≤8 days, mild (44%) injury was more common than moderate (11%) or severe (4%) injury. Subacute (37%) lesions were more commonly observed than acute (32%) or chronic lesions (1%).ConclusionSubacute brain injury is common in newborn infants with mild HIE. Novel neuroprotective treatments for mild HIE will ideally target both subacute and acute injury mechanisms.ImpactAlmost two-thirds of infants with mild HIE have evidence of brain injury on MRI obtained in the early neonatal period. Subacute brain injury was seen in 37% of infants with mild HIE. Neuroprotective treatments for mild HIE will ideally target both acute and subacute injury mechanisms.

Migration through 3D constrictions can cause nuclear rupture and mislocalization of nuclear proteins, but damage to DNA remains uncertain, as does any effect on cell cycle. Here, myosin II inhibition rescues rupture and partially rescues the DNA damage marker γH2AX, but an apparent block in cell cycle appears unaffected. Co-overexpression of multiple DNA repair factors or antioxidant inhibition of break formation also exert partial effects, independently of rupture. Combined treatments completely rescue cell cycle suppression by DNA damage, revealing a sigmoidal dependence of cell cycle on excess DNA damage. Migration through custom-etched pores yields the same damage threshold, with ∼4-µm pores causing intermediate levels of both damage and cell cycle suppression. High curvature imposed rapidly by pores or probes or else by small micronuclei consistently associates nuclear rupture with dilution of stiff lamin-B filaments, loss of repair factors, and entry from cytoplasm of chromatin-binding cGAS (cyclic GMP-AMP synthase). The cell cycle block caused by constricted migration is nonetheless reversible, with a potential for DNA misrepair and genome variation.

Tissue regeneration at an injured site depends on proliferation, migration, and differentiation of resident stem or progenitor cells, but solid tissues are often sufficiently dense and constricting that nuclei are highly stressed by migration. In this study, constricted migration of myoblastic cell types and mesenchymal stem cells (MSCs) increases nuclear rupture, increases DNA damage, and modulates differentiation. Fewer myoblasts fuse into regenerating muscle in vivo after constricted migration in vitro, and myodifferentiation in vitro is likewise suppressed. Myosin II inhibition rescues rupture and DNA damage, implicating nuclear forces, while mitosis and the cell cycle are suppressed by constricted migration, consistent with a checkpoint. Although perturbed proliferation fails to explain defective differentiation, nuclear rupture mislocalizes differentiation-relevant MyoD and KU80 (a DNA repair factor), with nuclear entry of the DNA-binding factor cGAS. Human MSCs exhibit similar damage, but osteogenesis increases-which is relevant to bone and to calcified fibrotic tissues, including diseased muscle. Tissue repair can thus be modulated up or down by the curvature of pores through which stem cells squeeze.

To discover leads for next-generation chemoprotective antimalarial drugs, we tested more than 500,000 compounds for their ability to inhibit liver-stage development of luciferase-expressing Plasmodium spp. parasites (681 compounds showed a half-maximal inhibitory concentration of less than 1 micromolar). Cluster analysis identified potent and previously unreported scaffold families as well as other series previously associated with chemoprophylaxis. Further testing through multiple phenotypic assays that predict stage-specific and multispecies antimalarial activity distinguished compound classes that are likely to provide symptomatic relief by reducing asexual blood-stage parasitemia from those which are likely to only prevent malaria. Target identification by using functional assays, in vitro evolution, or metabolic profiling revealed 58 mitochondrial inhibitors but also many chemotypes possibly with previously unidentified mechanisms of action.

The nucleus is physically linked to the cytoskeleton, adhesions, and extracellular matrix-all of which sustain forces, but their relationships to DNA damage are obscure. We show that nuclear rupture with cytoplasmic mislocalization of multiple DNA repair factors correlates with high nuclear curvature imposed by an external probe or by cell attachment to either aligned collagen fibers or stiff matrix. Mislocalization is greatly enhanced by lamin A depletion, requires hours for nuclear reentry, and correlates with an increase in pan-nucleoplasmic foci of the DNA damage marker γH2AX. Excess DNA damage is rescued in ruptured nuclei by cooverexpression of multiple DNA repair factors as well as by soft matrix or inhibition of actomyosin tension. Increased contractility has the opposite effect, and stiff tumors with low lamin A indeed exhibit increased nuclear curvature, more frequent nuclear rupture, and excess DNA damage. Additional stresses likely play a role, but the data suggest high curvature promotes nuclear rupture, which compromises retention of DNA repair factors and favors sustained damage.

ObjectiveTo evaluate the relationship between maternal self-reported race/ethnicity and persistent wheezing illness in former high-risk, extremely low gestational age newborns, and to quantify the contribution of socioeconomic, environmental, and biological factors on this relationship.Study designWe assessed persistent wheezing illness determined at 18-24 months corrected (for prematurity) age in survivors of a randomized trial. Parents/caregivers were surveyed for wheeze and inhaled asthma medication use quarterly to 12 months, and at 18 and 24 months. We used multivariable analysis to evaluate the relationship of maternal race to persistent wheezing illness, and identified mediators for this relationship via formal mediation analysis.ResultsOf 420 infants (25.2 ± 1.2 weeks of gestation and 714 ± 166 g at birth, 57% male, 34% maternal black race), 189 (45%) had persistent wheezing illness. After adjustment for gestational age, birth weight, and sex, infants of black mothers had increased odds of persistent wheeze compared with infants of nonblack mothers (OR = 2.9, 95% CI 1.9, 4.5). Only bronchopulmonary dysplasia, breast milk diet, and public insurance status were identified as mediators. In this model, the direct effect of race accounted for 69% of the relationship between maternal race and persistent wheeze, whereas breast milk diet, public insurance status, and bronchopulmonary dysplasia accounted for 8%, 12%, and 10%, respectively.ConclusionsAmong former high-risk extremely low gestational age newborns, infants of black mothers have increased odds of developing persistent wheeze. A substantial proportion of this effect is directly accounted for by race, which may reflect unmeasured environmental influences, and acquired and innate biological differences.Trial registrationClinicalTrials.gov: NCT01022580.

BackgroundHypoxic-ischemic encephalopathy (HIE) remains an important cause of neonatal death and frequently leads to significant long-term disability in survivors. Therapeutic hypothermia, while beneficial, still leaves many treated infants with lifelong disabilities. Adjunctive therapies are needed, and erythropoietin (Epo) has the potential to provide additional neuroprotection.ObjectivesThe aim of this study was to review the current incidence, mechanism of injury, and sequelae of HIE, and to describe a new phase III randomized, placebo-controlled trial of Epo neuroprotection in term and near-term infants with moderate to severe HIE treated with therapeutic hypothermia.MethodsThis article presents an overview of HIE, neuroprotective functions of Epo, and the design of a double-blind, placebo-controlled, multicenter trial of high-dose Epo administration, enrolling 500 neonates ≥36 weeks of gestation with moderate or severe HIE diagnosed by clinical criteria.Results and conclusionsEpo has robust neuroprotective effects in preclinical studies, and phase I/II trials suggest that multiple high doses of Epo may provide neuroprotection against brain injury in term infants. The High Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial will evaluate whether high-dose Epo reduces the combined outcome of death or neurodevelopmental disability when given in conjunction with hypothermia to newborns with moderate/severe HIE.

Stem cells are particularly 'plastic' cell types that are induced by various cues to become specialized, tissue-functional lineages by switching on the expression of specific gene programs. Matrix stiffness is among the cues that multiple stem cell types can sense and respond to. This seminar-style review focuses on mechanosensing of matrix elasticity in the differentiation or early maturation of a few illustrative stem cell types, with an intended audience of biologists and physical scientists. Contractile forces applied by a cell's acto-myosin cytoskeleton are often resisted by the extracellular matrix and transduced through adhesions and the cytoskeleton ultimately into the nucleus to modulate gene expression. Complexity is added by matrix heterogeneity, and careful scrutiny of the evident stiffness heterogeneity in some model systems resolves some controversies concerning matrix mechanosensing. Importantly, local stiffness tends to dominate, and 'durotaxis' of stem cells toward stiff matrix reveals a dependence of persistent migration on myosin-II force generation and also rigid microtubules that confer directionality. Stem and progenitor cell migration in 3D can be further affected by matrix porosity as well as stiffness, with nuclear size and rigidity influencing niche retention and fate choices. Cell squeezing through rigid pores can even cause DNA damage and genomic changes that contribute to de-differentiation toward stem cell-like states. Contraction of acto-myosin is the essential function of striated muscle, which also exhibit mechanosensitive differentiation and maturation as illustrated in vivo by beating heart cells and by the regenerative mobilization of skeletal muscle stem cells.

Marrow-derived macrophages are highly phagocytic, but whether they can also traffic into solid tumors and engulf cancer cells is questionable, given the well-known limitations of tumor-associated macrophages (TAMs). Here, SIRPα on macrophages from mouse and human marrow was inhibited to block recognition of its ligand, the "marker of self" CD47 on all other cells. These macrophages were then systemically injected into mice with fluorescent human tumors that had been antibody targeted. Within days, the tumors regressed, and single-cell fluorescence analyses showed that the more the macrophages engulfed, the more they accumulated within regressing tumors. Human-marrow-derived macrophages engorged on the human tumors, while TAMs were minimally phagocytic, even toward CD47-knockdown tumors. Past studies had opsonized tumors in situ with antibody and/or relied on mouse TAMs but had not injected SIRPα-inhibited cells; also, unlike past injections of anti-CD47, blood parameters remained normal and safe. Consistent with tumor-selective engorge-and-accumulate processes in vivo, phagocytosis in vitro inhibited macrophage migration through micropores that mimic features of dense 3D tissue. Accumulation of SIRPα-inhibited macrophages in tumors favored tumor regression for 1-2 weeks, but donor macrophages quickly differentiated toward non-phagocytic, high-SIRPα TAMs. Analyses of macrophages on soft (like marrow) or stiff (like solid tumors) collagenous gels demonstrated a stiffness-driven, retinoic-acid-modulated upregulation of SIRPα and the mechanosensitive nuclear marker lamin-A. Mechanosensitive differentiation was similarly evident in vivo and likely limited the anti-tumor effects, as confirmed by re-initiation of tumor regression by fresh injections of SIRPα-inhibited macrophages. Macrophage motility, phagocytosis, and differentiation in vivo are thus coupled.

Many of the most important molecules of life are polymers. In animals, the most abundant of the proteinaceous polymers are the collagens, which constitute the fibrous matrix outside cells and which can also self-assemble into gels. The physically measurable stiffness of gels, as well as tissues, increases with the amount of collagen, and cells seem to sense this stiffness. An understanding of this mechanosensing process in complex tissues, including fibrotic disease states with high collagen, is now utilizing 'omics data sets and is revealing polymer physics-type, nonlinear scaling relationships between concentrations of seemingly unrelated biopolymers. The nuclear structure protein lamin A provides one example, with protein and transcript levels increasing with collagen 1 and tissue stiffness, and with mechanisms rooted in protein stabilization induced by cytoskeletal stress. Physics-based models of fibrous matrix, cytoskeletal force dipoles, and the lamin A gene circuit illustrate the wide range of testable predictions emerging for tissues, cell cultures, and even stem cell-based tissue regeneration. Beyond the epigenetics of mechanosensing, the scaling in cancer of chromosome copy number variations and other mutations with tissue stiffness suggests that genomic changes are occurring by mechanogenomic processes that now require elucidation.

ObjectiveTo determine the effects of late surfactant on respiratory outcomes determined at 1-year corrected age in the Trial of Late Surfactant (TOLSURF), which randomized newborns of extremely low gestational age (≤28 weeks' gestational age) ventilated at 7-14 days to late surfactant and inhaled nitric oxide vs inhaled nitric oxide-alone (control).Study designCaregivers were surveyed in a double-blinded manner at 3, 6, 9, and 12 months' corrected age to collect information on respiratory resource use (infant medication use, home support, and hospitalization). Infants were classified for composite outcomes of pulmonary morbidity (no PM, determined in infants with no reported respiratory resource use) and persistent PM (determined in infants with any resource use in ≥3 surveys).ResultsInfants (n = 450, late surfactant n = 217, control n = 233) were 25.3 ± 1.2 weeks' gestation and 713 ± 164 g at birth. In the late surfactant group, fewer infants received home respiratory support than in the control group (35.8% vs 52.9%, relative benefit [RB] 1.28 [95% CI 1.07-1.55]). There was no benefit of late surfactant for No PM vs PM (RB 1.27; 95% CI 0.89-1.81) or no persistent PM vs persistent PM (RB 1.01; 95% CI 0.87-1.17). After adjustment for imbalances in baseline characteristics, relative benefit of late surfactant treatment increased: RB 1.40 (95% CI 0.89-1.80) for no PM and RB 1.24 (95% CI 1.08-1.42) for no persistent PM.ConclusionTreatment of newborns of extremely low gestational age with late surfactant in combination with inhaled nitric oxide decreased use of home respiratory support and may decrease persistent pulmonary morbidity.Trial registrationClinicalTrials.gov: NCT01022580.

A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal chemistry programs. The data for all of these assays are presented and analyzed to show how outstanding leads for many indications can be selected. These results reveal the immense potential for translating the dispersed expertise in biological assays involving human pathogens into drug discovery starting points, by providing open access to new families of molecules, and emphasize how a small additional investment made to help acquire and distribute compounds, and sharing the data, can catalyze drug discovery for dozens of different indications. Another lesson is that when multiple screens from different groups are run on the same library, results can be integrated quickly to select the most valuable starting points for subsequent medicinal chemistry efforts.

ObjectiveTo determine if multiple doses of erythropoietin (Epo) administered with hypothermia improve neuroradiographic and short-term outcomes of newborns with hypoxic-ischemic encephalopathy.MethodsIn a phase II double-blinded, placebo-controlled trial, we randomized newborns to receive Epo (1000 U/kg intravenously; n = 24) or placebo (n = 26) at 1, 2, 3, 5, and 7 days of age. All infants had moderate/severe encephalopathy; perinatal depression (10 minute Apgar

Mandibulofacial dysostosis with microcephaly (MFDM) is a multiple malformation syndrome comprising microcephaly, craniofacial anomalies, hearing loss, dysmorphic features, and, in some cases, esophageal atresia. Haploinsufficiency of a spliceosomal GTPase, U5-116 kDa/EFTUD2, is responsible. Here, we review the molecular basis of MFDM in the 69 individuals described to date, and report mutations in 38 new individuals, bringing the total number of reported individuals to 107 individuals from 94 kindreds. Pathogenic EFTUD2 variants comprise 76 distinct mutations and seven microdeletions. Among point mutations, missense substitutions are infrequent (14 out of 76; 18%) relative to stop-gain (29 out of 76; 38%), and splicing (33 out of 76; 43%) mutations. Where known, mutation origin was de novo in 48 out of 64 individuals (75%), dominantly inherited in 12 out of 64 (19%), and due to proven germline mosaicism in four out of 64 (6%). Highly penetrant clinical features include, microcephaly, first and second arch craniofacial malformations, and hearing loss; esophageal atresia is present in an estimated ∼27%. Microcephaly is virtually universal in childhood, with some adults exhibiting late "catch-up" growth and normocephaly at maturity. Occasionally reported anomalies, include vestibular and ossicular malformations, reduced mouth opening, atrophy of cerebral white matter, structural brain malformations, and epibulbar dermoid. All reported EFTUD2 mutations can be found in the EFTUD2 mutation database (http://databases.lovd.nl/shared/genes/EFTUD2).

ObjectiveTo assess whether late surfactant treatment in extremely low gestational age (GA) newborn infants requiring ventilation at 7-14 days, who often have surfactant deficiency and dysfunction, safely improves survival without bronchopulmonary dysplasia (BPD).Study designExtremely low GA newborn infants (GA ≤28 0/7 weeks) who required mechanical ventilation at 7-14 days were enrolled in a randomized, masked controlled trial at 25 US centers. All infants received inhaled nitric oxide and either surfactant (calfactant/Infasurf) or sham instillation every 1-3 days to a maximum of 5 doses while intubated. The primary outcome was survival at 36 weeks postmenstrual age (PMA) without BPD, as evaluated by physiological oxygen/flow reduction.ResultsA total of 511 infants were enrolled between January 2010 and September 2013. There were no differences between the treated and control groups in mean birth weight (701 ± 164 g), GA (25.2 ± 1.2 weeks), percentage born at GA

BackgroundErythropoietin is neuroprotective in animal models of neonatal hypoxic-ischemic encephalopathy. We previously reported a phase I safety and pharmacokinetic study of erythropoietin in neonates. This article presents the neurodevelopmental follow-up of infants who were enrolled in the phase I clinical trial.MethodsWe enrolled 24 newborns with hypoxic-ischemic encephalopathy in a dose-escalation study. Patients received up to six doses of erythropoietin in addition to hypothermia. All infants underwent neonatal brain magnetic resonance imaging (MRI) reviewed by a single neuroradiologist. Moderate-to-severe neurodevelopmental disability was defined as cerebral palsy with Gross Motor Function Classification System levels III-V or cognitive impairment based on Bayley Scales of Infant Development II mental developmental index or Bayley III cognitive composite score.ResultsOutcomes were available for 22 of 24 infants, at mean age 22 months (range, 8-34 months). There were no deaths. Eight (36%) had moderate-to-severe brain injury on neonatal MRI. Moderate-to-severe disability occurred in one child (4.5%), in the setting of moderate-to-severe basal ganglia and/or thalamic injury. Seven infants with moderate-to-severe watershed injury exhibited the following outcomes: normal (three), mild language delay (two), mild hemiplegic cerebral palsy (one), and epilepsy (one). All 11 patients with a normal brain MRI had a normal outcome.ConclusionsThis study is the first to describe neurodevelopmental outcomes in infants who received high doses of erythropoietin and hypothermia during the neonatal period. The findings suggest that future studies are warranted to assess the efficacy of this new potential neuroprotective therapy.

BackgroundRetrospective studies have shown that statins decrease the rate and severity of exacerbations, the rate of hospitalization, and mortality in chronic obstructive pulmonary disease (COPD). We prospectively studied the efficacy of simvastatin in preventing exacerbations in a large, multicenter, randomized trial.MethodsWe designed the Prospective Randomized Placebo-Controlled Trial of Simvastatin in the Prevention of COPD Exacerbations (STATCOPE) as a randomized, controlled trial of simvastatin (at a daily dose of 40 mg) versus placebo, with annual exacerbation rates as the primary outcome. Patients were eligible if they were 40 to 80 years of age, had COPD (defined by a forced expiratory volume in 1 second [FEV1] of less than 80% and a ratio of FEV1 to forced vital capacity of less than 70%), and had a smoking history of 10 or more pack-years, were receiving supplemental oxygen or treatment with glucocorticoids or antibiotic agents, or had had an emergency department visit or hospitalization for COPD within the past year. Patients with diabetes or cardiovascular disease and those who were taking statins or who required statins on the basis of Adult Treatment Panel III criteria were excluded. Participants were treated from 12 to 36 months at 45 centers.ResultsA total of 885 participants with COPD were enrolled for approximately 641 days; 44% of the patients were women. The patients had a mean (±SD) age of 62.2±8.4 years, an FEV1 that was 41.6±17.7% of the predicted value, and a smoking history of 50.6±27.4 pack-years. At the time of study closeout, the low-density lipoprotein cholesterol levels were lower in the simvastatin-treated patients than in those who received placebo. The mean number of exacerbations per person-year was similar in the simvastatin and placebo groups: 1.36±1.61 exacerbations and 1.39±1.73 exacerbations, respectively (P=0.54). The median number of days to the first exacerbation was also similar: 223 days (95% confidence interval [CI], 195 to 275) and 231 days (95% CI, 193 to 303), respectively (P=0.34). The number of nonfatal serious adverse events per person-year was similar, as well: 0.63 events with simvastatin and 0.62 events with placebo. There were 30 deaths in the placebo group and 28 in the simvastatin group (P=0.89).ConclusionsSimvastatin at a daily dose of 40 mg did not affect exacerbation rates or the time to a first exacerbation in patients with COPD who were at high risk for exacerbations. (Funded by the National Heart, Lung, and Blood Institute and the Canadian Institutes of Health Research; STATCOPE ClinicalTrials.gov number, NCT01061671.).

A skin conductance monitoring system was developed and shown to reliably acquire and record hot flash events in both supervised laboratory and unsupervised ambulatory conditions. The 7.2 × 3.8 × 1.2 cm(3) monitor consists of a disposable adhesive patch supporting two hydrogel electrodes and a reusable, miniaturized, enclosed electronic circuit board that snaps onto the electrodes. The monitor measures and records the skin conductance for seven days without external wires or telemetry and has an event marker that the subject can press whenever a hot flash is experienced. The accuracy of the system was demonstrated by comparing the number of hot flashes detected by algorithms developed during this research with the number identified by experts in hot flash studies. Three methods of detecting hot flash events were evaluated, but only two were fully developed. The two that were developed were an artificial neural network and a matched filter technique with multiple kernels implemented as a sliding form of the Pearson product-moment correlation coefficient. Both algorithms were trained on a 'development' cohort of 17 women and then validated using a second similar 'validation' cohort of 20. All subjects were between the ages of 40 and 60 and self-reported ten or more hot flashes per day over a three day period. The matched filter was the most accurate with a mean sensitivity of 0.92 and a mean specificity of 0.90 using the data from the development cohort and a mean sensitivity of 0.92 and a mean specificity of 0.87 using the data from the validation cohort. The matched filter was the method implemented in our processing software.

A high-speed (100 kHz A-scans/s) complex conjugate resolved 1 μm swept source optical coherence tomography (SS-OCT) system using coherence revival of the light source is suitable for dense three-dimensional (3-D) imaging of the anterior segment. The short acquisition time helps to minimize the influence of motion artifacts. The extended depth range of the SS-OCT system allows topographic analysis of clinically relevant images of the entire depth of the anterior segment of the eye. Patients with the type 1 Boston Keratoprosthesis (KPro) require evaluation of the full anterior segment depth. Current commercially available OCT systems are not suitable for this application due to limited acquisition speed, resolution, and axial imaging range. Moreover, most commonly used research grade and some clinical OCT systems implement a commercially available SS (Axsun) that offers only 3.7 mm imaging range (in air) in its standard configuration. We describe implementation of a common swept laser with built-in k-clock to allow phase stable imaging in both low range and high range, 3.7 and 11.5 mm in air, respectively, without the need to build an external MZI k-clock. As a result, 3-D morphology of the KPro position with respect to the surrounding tissue could be investigated in vivo both at high resolution and with large depth range to achieve noninvasive and precise evaluation of success of the surgical procedure.

PurposeTo report the results of imaging using high-resolution, Fourier domain anterior segment optical coherence tomography (AS-OCT) to evaluate patients with a type 1 Boston Keratoprosthesis (KPro).MethodsWe performed a retrospective comparative study of patients in whom we implanted the Boston KPro. A total of 26 eyes of 23 patients from the Cornea Service at the University of California Davis Eye Center were included. Subjects were evaluated with the Spectralis AS-OCT (Heidelberg Engineering GmbH).ResultsPreoperative diagnoses for KPro surgery included failed corneal transplant (69%), chemical burn (23%), and aniridia (8%). The average age of patients was 63.2 years (range, 17-88 years). Fifty-four percent of the patients were female. The mean duration between the KPro surgery and the acquisition of high-resolution AS-OCT imaging was 35.8 months (range, 2-90 months). The most commonly observed finding was retroprosthetic membrane formation, which we found in 77% of KPro eyes. In 65% of KPro eyes, we identified epithelium behind the front plate, and in 54%, we identified an epithelial lip over the anterior surface of the KPro front plate. In 31% of KPro eyes, we identified periprosthetic cysts, gaps or spaces, and thinning in the corneal carrier graft.ConclusionsFourier domain AS-OCT is a useful noninvasive imaging technique in patients with a KPro and provides the ability to identify changes that are sometimes difficult to appreciate by clinical evaluation. The higher resolution Fourier domain systems may aid in the clinical diagnosis and management of pathology that might not be imaged with instruments of lower resolution. AS-OCT has the potential for monitoring the anatomic stability of an implanted KPro and may also help to monitor for complications. Moreover, high-resolution imaging may enhance our understanding of periprosthetic anatomy.

ObjectiveTo determine the safety and pharmacokinetics of erythropoietin (Epo) given in conjunction with hypothermia for hypoxic-ischemic encephalopathy (HIE). We hypothesized that high dose Epo would produce plasma concentrations that are neuroprotective in animal studies (ie, maximum concentration = 6000-10000 U/L; area under the curve = 117000-140000 U*h/L).MethodsIn this multicenter, open-label, dose-escalation, phase I study, we enrolled 24 newborns undergoing hypothermia for HIE. All patients had decreased consciousness and acidosis (pH < 7.00 or base deficit ≥ 12), 10-minute Apgar score ≤ 5, or ongoing resuscitation at 10 minutes. Patients received 1 of 4 Epo doses intravenously: 250 (N = 3), 500 (N = 6), 1000 (N = 7), or 2500 U/kg per dose (N = 8). We gave up to 6 doses every 48 hours starting at

BackgroundAlthough the 23-valent pneumococcal polysaccharide vaccine (PPSV23) protects against invasive disease in young healthy persons, randomized controlled trials in chronic obstructive pulmonary disease (COPD) have demonstrated no benefit in the intention-to-treat population. We previously reported that the 7-valent diphtheria-conjugated pneumococcal polysaccharide vaccine (PCV7) is safe and induced greater serotype-specific immunoglobulin G (IgG) and functional antibody than did PPSV23 1 month after vaccination. We hypothesized that these advantages would persist at 1 and 2 years.MethodsOne hundred eighty-one patients with moderate to severe COPD were randomized to receive PPSV23 (n = 90) or PCV7 (1.0 mL; n = 91). We measured IgG by enzyme-linked immunosorbent assay and assessed functional antibody activity by a standardized opsonophagocytosis assay, reported as a killing index (OPK). We determined differences in IgG and OPK between vaccine groups at 1 and 2 years.ResultsRelative to PPSV23, PCV7 induced greater OPK at both 1 and 2 years for 6 of 7 serotypes (not 19F). This response was statistically greater for 5 of 7 serotypes at 1 year and 4 of 7 at 2 years. Comparable differences in IgG were observed but were less often statistically significant. Despite meeting Centers for Disease Control and Prevention criteria for PPSV23 administration, almost 50% of individuals had never been vaccinated. No differences in the frequency of acute exacerbations, pneumonia, or hospitalization were observed.ConclusionsPCV7 induces a greater functional antibody response than PPSV23 in patients with COPD that persists for 2 years after vaccination. This superior functional response supports testing of conjugate vaccination in studies examining clinical end points.Clinical trials registrationNCT00457977.

Previously reported studies identified analogues of propafenone that had potent antimalarial activity, reduced cardiac ion channel activity, and properties that suggested the potential for clinical development for malaria. Careful examination of the bioavailability, pharmacokinetics, toxicology, and efficacy of this series of compounds using rodent models revealed orally bioavailable compounds that are nontoxic and suppress parasitemia in vivo. Although these compounds possess potential for further preclinical development, they also carry some significant challenges.

BackgroundA clinical trial of mometasone furoate/formoterol fumarate (MF/F) administered via a metered-dose inhaler in subjects with moderate to very severe chronic obstructive pulmonary disease (COPD) investigated the efficacy and safety of a fixed-dose combination of MF/F.MethodsThis multicenter, double-blind, placebo-controlled trial had a 26-week treatment period and a 26-week safety extension. Subjects (n = 1055; ≥40 years) were current or ex- smokers randomized to twice-daily treatment with inhaled MF/F 400/10 μg, MF/F 200/10 μg, MF 400 μg, F 10 μg, or placebo. The coprimary endpoints of the trial were mean changes from baseline in forced expiratory volume in 1 second (FEV(1)) over 0-12 hours (AUC(0-12) FEV(1)) with MF/F versus MF, and in morning predose FEV(1) with MF/F versus F. Key secondary endpoints were quality of life (Saint George's Respiratory Questionnaire [SGRQ]), symptom-free nights, and partly stable COPD at 26 weeks, as well as time to first COPD exacerbation.ResultsSignificant improvements in FEV(1) AUC(0-12) occurred at endpoint with MF/F 400/10 and MF/F 200/10 versus MF 400 (P ≤ 0.007). Significant bronchodilation occurred in 5 minutes with MF/F, and serial spirometry demonstrated sustained FEV(1) improvements with MF/F over the treatment period. Significant improvements in morning predose FEV(1) occurred with both MF/F doses, and these effects were further investigated by excluding results for subjects whose morning FEV(1) data were collected >2 days after the last dose of study treatment. Improvements in SGRQ total scores surpassed the minimum clinically important difference of at least 4 units with MF/F 400/10. MF/F 400/10 significantly reduced the time-to-first COPD exacerbation. Similar proportions of subjects in all five treatment groups reported treatment-emergent adverse events. Rates of pneumonia were low (≤1.0%) across treatment groups.ConclusionMF/F 400/10 μg twice daily was shown to be an effective therapy for patients with moderate to very severe COPD, and both MF/F 400/10 μg twice daily and MF/F 200/10 μg twice daily were well tolerated.

BackgroundThe clinical efficacy and safety of a mometasone furoate/formoterol fumarate (MF/F) fixed-dose combination formulation administered via a metered-dose inhaler was investigated in patients with moderate to very severe chronic obstructive pulmonary disease (COPD).MethodsTwo 52-week, multicenter, double-blind, placebo-controlled trials with identical study designs were conducted in current or ex-smokers (aged ≥40 years), and pooled study results are presented herein. Subjects (n = 2251) were randomized to 26 weeks of twice-daily treatment with MF/F 400/10 μg, MF/F 200/10 μg, MF 400 μg, F 10 μg, or placebo. After the 26-week treatment period, placebo subjects completed the trial and 75% of subjects on active treatment entered a 26-week safety extension. Coprimary efficacy variables were mean changes in forced expiratory volume in one second (FEV(1)), area under the curve from 0 to 12 hours postdose (AUC(0-12 h)), and morning predose/trough FEV(1) from baseline to the week 13 endpoint. Key secondary efficacy variables were St George's Respiratory Questionnaire scores, symptom-free nights, time-to-first exacerbation, and partly stable COPD at the week 26 endpoint.ResultsIn the 26-week treatment period, significantly greater increases in FEV(1) AUC(0-12 h) occurred with MF/F 400/10 versus MF 400 and placebo at the week 13 and week 26 endpoints (P ≤ 0.032). These increases were over three-fold greater with MF/F 400/10 than with MF 400. Also, significantly greater increases in morning predose/trough FEV(1) occurred with MF/F 400/10 versus F 10 and placebo at the week 13 endpoint (P < 0.05). The increase was four-fold greater with MF/F 400/10 than with F 10. All active treatment groups achieved minimum clinically important differences from baseline (>4 units) in St George's Respiratory Questionnaire scores at week 26. Symptom-free nights increased by ≥14% in the MF/F 400/10, MF 400, and F 10 groups (P ≤ 0.033 versus placebo). The incidence of exacerbations was lower in the MF/F groups (≤33.3%) than it was in the MF, formoterol, and placebo groups (≥33.8%) over the 26-week treatment period. The incidence of adverse events was similar in the active-treated and placebo-treated subjects across 26 weeks of treatment. Over the 1-year study period, there were no notable differences in the incidence or types of adverse events between the MF/F 400/10 and MF/F 200/10 groups compared with the MF or formoterol groups. Differences in rates of individual treatment-emergent adverse events were