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Gale crater, the field site for NASA's Mars Science Laboratory Curiosity rover, contains a diverse and extensive record of aeolian deposition and erosion. This study focuses on a series of regularly spaced, curvilinear, and sometimes branching bedrock ridges that occur within the Glen Torridon region on the lower northwest flank of Aeolis Mons, the central mound within Gale crater. During Curiosity's exploration of Glen Torridon between sols ∼2300-3080, the rover drove through this field of ridges, providing the opportunity for in situ observation of these features. This study uses orbiter and rover data to characterize ridge morphology, spatial distribution, compositional and material properties, and association with other aeolian features in the area. Based on these observations, we find that the Glen Torridon ridges are consistent with an origin as wind-eroded bedrock ridges, carved during the exhumation of Mount Sharp. Erosional features like the Glen Torridon ridges observed elsewhere on Mars, termed periodic bedrock ridges (PBRs), have been interpreted to form transverse to the dominant wind direction. The size and morphology of the Glen Torridon PBRs are consistent with transverse formative winds, but the orientation of nearby aeolian bedforms and bedrock erosional features raise the possibility of PBR formation by a net northeasterly wind regime. Although several formation models for the Glen Torridon PBRs are still under consideration, and questions persist about the nature of PBR-forming paleowinds, the presence of PBRs at this site provides important constraints on the depositional and erosional history of Gale crater., (© 2022 Jet Propulsion Laboratory. California Institute of Technology. Government sponsorship acknowledged.)

The type 5 metabotropic glutamate receptor, mGlu 5 , has been proposed as a potential therapeutic target for the treatment of several neurodegenerative diseases. In preclinical neurodegenerative disease models, novel allosteric modulators have been shown to improve cognitive performance and reduce disease-related pathology. A common pathological hallmark of neurodegenerative diseases is a chronic neuroinflammatory response, involving glial cells such as astrocytes and microglia. Since mGlu 5 is expressed in astrocytes, targeting this receptor could provide a potential mechanism by which neuroinflammatory processes in neurodegenerative disease may be modulated. This review will discuss current evidence that highlights the potential of mGlu 5 allosteric modulators to treat neurodegenerative diseases, including Alzheimer's disease, Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Furthermore, this review will explore the role of mGlu 5 in neuroinflammatory responses, and the potential for this G protein-coupled receptor to modulate neuroinflammation., Competing Interests: GB, ES, KB, and SB are all employees of Sosei Heptares. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Budgett, Bakker, Sergeev, Bennett and Bradley.)

Introduction: Uterine incision based on the placental location in open maternal-fetal surgery (OMFS) has never been evaluated in regard to maternal or fetal outcomes., Objective: The aim of this study was to investigate whether an anterior placenta was associated with increased rates of intraoperative, perioperative, antepartum, obstetric, or neonatal complications in mothers and babies who underwent OMFS for fetal myelomeningocele (fMMC) closure., Methods: Data from the international multicenter prospective registry of patients who underwent OMFS for fMMC closure (fMMC Consortium Registry, December 15, 2010-June 31, 2019) was used to compare fetal and maternal outcomes between anterior and posterior placental locations., Results: The placental location for 623 patients was evenly distributed between anterior (51%) and posterior (49%) locations. Intraoperative fetal bradycardia (8.3% vs. 3.0%, p = 0.005) and performance of fetal resuscitation (3.6% vs. 1.0%, p = 0.034) occurred more frequently in cases with an anterior placenta when compared to those with a posterior placenta. Obstetric outcomes including membrane separation, placental abruption, and spontaneous rupture of membranes were not different among the 2 groups. However, thinning of the hysterotomy site (27.7% vs. 17.7%, p = 0.008) occurred more frequently in cases of an anterior placenta. Gestational age (GA) at delivery (p = 0.583) and length of stay in the neonatal intensive care unit (p = 0.655) were similar between the 2 groups. Fetal incision dehiscence and wound revision were not significantly different between groups. Critical clinical outcomes including fetal demise, perinatal death, and neonatal death were all infrequent occurrences and not associated with the placental location., Conclusions: An anterior placental location is associated with increased risk of intraoperative fetal resuscitation and increased thinning at the hysterotomy closure site. Individual institutional experiences may have varied, but the aggregate data from the fMMC Consortium did not show a significant impact on the GA at delivery or maternal or fetal clinical outcomes., (© 2021 S. Karger AG, Basel.)

Introduction: Programs and services available through the aging services network can help community-dwelling older adults to age in place but are often not discussed in routine primary care. The primary care liaison was developed as a novel integration intervention to address this disconnect., Methods: Employed by an Area Agency on Aging, primary care liaisons performed outreach to primary care with the goal of raising awareness of community-based programs, resources, and services available to older adults and their caregivers and facilitating referrals. The evaluation of the primary care liaison model, conducted from December 2015 to February 2019, used the Reach, Effectiveness, Adoption, Implementation, Maintenance framework and assessed reach (number of clinics contacted), adoption (number of referrals to the Area Agency on Aging), implementation (number of follow-up contacts with a practice), and effectiveness (proportion of referrals reached and provided relevant resources)., Results: The primary care liaisons contacted a median of 18.5 clinics per month (IQR=15-31). Primary care referrals averaged >100 per month, and referrals increased over time. Successful follow-up outreach visits had a median of 3 (IQR=2-10), and follow-up contacts had a median of 3 (IQR=1-7) per practice. Three quarters of caregivers for people with dementia reached by Area Agency on Aging staff were provided with information about relevant resources., Conclusions: The primary care liaison model is feasible, fosters ongoing interactions between primary care and Area Agencies on Aging, and connects older adults and their caregivers to relevant programs and services. Adoption of the primary care liaison model by other Area Agencies on Aging across the U.S. may help further the vision of optimized health and well-being of older adults., (Copyright © 2021 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: The Caribbean is an important global biodiversity hotspot. Adaptive radiations there lead to many speciation events within a limited period and hence are particularly prominent biodiversity generators. A prime example are freshwater fish of the genus Limia, endemic to the Greater Antilles. Within Hispaniola, nine species have been described from a single isolated site, Lake Miragoâne, pointing towards extraordinary sympatric speciation. This study examines the evolutionary history of the Limia species in Lake Miragoâne, relative to their congeners throughout the Caribbean., Results: For 12 Limia species, we obtained almost complete sequences of the mitochondrial cytochrome b gene, a well-established marker for lower-level taxonomic relationships. We included sequences of six further Limia species from GenBank (total N  = 18 species). Our phylogenies are in concordance with other published phylogenies of Limia. There is strong support that the species found in Lake Miragoâne in Haiti are monophyletic, confirming a recent local radiation. Within Lake Miragoâne, speciation is likely extremely recent, leading to incomplete lineage sorting in the mtDNA. Future studies using multiple unlinked genetic markers are needed to disentangle the relationships within the Lake Miragoâne clade., (© 2021. The Author(s).)

Current therapies for Alzheimer's disease seek to correct for defective cholinergic transmission by preventing the breakdown of acetylcholine through inhibition of acetylcholinesterase, these however have limited clinical efficacy. An alternative approach is to directly activate cholinergic receptors responsible for learning and memory. The M1-muscarinic acetylcholine (M1) receptor is the target of choice but has been hampered by adverse effects. Here we aimed to design the drug properties needed for a well-tolerated M1-agonist with the potential to alleviate cognitive loss by taking a stepwise translational approach from atomic structure, cell/tissue-based assays, evaluation in preclinical species, clinical safety testing, and finally establishing activity in memory centers in humans. Through this approach, we rationally designed the optimal properties, including selectivity and partial agonism, into HTL9936-a potential candidate for the treatment of memory loss in Alzheimer's disease. More broadly, this demonstrates a strategy for targeting difficult GPCR targets from structure to clinic., Competing Interests: Declaration of interests T.T. and M.W. are shareholders and board members of Sosei Heptares. The authors A.J.H.B., G.A.B., K.A.B., J.B., J.E.C., M.S.C., R.M.C., J.C.E., E.H., A.J., C.J.L., J.L., F.H.M., P.J.N., K.O., G.O., J.C.P., M.P., N.R., P.R., B.G.T., R.T.S., C.d.G., G.M., and B.T. are or have been employees of Heptares Therapeutics and are shareholders of Sosei Heptares., (Copyright © 2021. Published by Elsevier Inc.)

GPR84 is a poorly characterized, nominally orphan, proinflammatory G protein-coupled receptor that can be activated by medium chain length fatty acids. It is attracting considerable interest as a potential therapeutic target for antagonist ligands in both inflammatory bowel diseases and idiopathic pulmonary fibrosis. Successful screening of more than 300 000 compounds from a small molecule library followed by detailed analysis of some 50 drug-like hits identified 3-((5,6-bis(4-methoxyphenyl)-1,2,4-triazin-3-yl)methyl)-1 H -indole as a high affinity and highly selective competitive antagonist of human GPR84. Tritiation of a di-iodinated form of the core structure produced [ 3 H]3-((5,6-diphenyl-1,2,4-triazin-3-yl)methyl)-1 H -indole, which allowed effective measurement of receptor levels in both transfected cell lines and lipopolysaccharide-treated THP-1 monocyte/macrophage cells. Although this compound series lacks significant affinity at mouse GPR84, homology modeling and molecular dynamics simulations provided a potential rationale for this difference, and alteration of two residues in mouse GPR84 to the equivalent amino acids in the human orthologue, predicted to open the antagonist binding pocket, validated this model. Sequence alignment of other species orthologues further predicted binding of the compounds as high affinity antagonists at macaque, pig, and dog GPR84 but not at the rat orthologue, and pharmacological experiments confirmed these predictions. These studies provide a new class of GPR84 antagonists that display species selectivity defined via receptor modeling and mutagenesis., Competing Interests: The authors declare the following competing financial interest(s): S.P.M. and A.M. are employees of BioAscent Discovery Ltd, and M.B. and K.A.B. are employees of Sosei Heptares. The other authors declare no conflicts of interest., (© 2021 The Authors. Published by American Chemical Society.)

Excessive adiposity is associated with altered oxygen tension and comorbidities in humans. In contrast, marine mammals have high adiposity with no apparent detrimental effects. However, partial pressure of oxygen (Po 2 ) in their subcutaneous adipose tissue (blubber) and its relationship with fatness have not been reported. We measured Po 2 and temperature at different blubber depths in 12 healthy juvenile grey seals. Fatness was estimated from blubber thickness and morphometric parameters. Simultaneously, we monitored breathing pattern; heart rate and arterial blood saturation with a pulse oximeter; and relative changes in total hemoglobin, deoxyhemoglobin, and oxyhemoglobin in blubber capillaries using near-infrared spectroscopy (NIRS) as proxies for local oxygenation changes. Blubber Po 2 ranged from 14.5 to 71.4 mmHg (39.2 ± 14.1 mmHg), which is similar to values reported in other species. Blubber Po 2 was strongly and negatively associated with fatness (LME: p < 0.0001, R 2 marginal = 0.53, R 2 conditional = 0.64, n = 10), but not with blubber depth. No other parameters explained variability in Po 2 , suggesting arterial blood and local oxygen delivery did not vary within and between measurements. The fall in blubber Po 2 with increased fatness in seals is consistent with other animal models of rapid fat deposition. However, the Po 2  levels at which blubber becomes hypoxic and consequences of low blubber Po 2 for its health and function, particularly in very fat individuals, remain unknown. How seals avoid detrimental effects of low oxygen tension in adipose tissue, despite their high and fluctuating adiposity, is a fruitful avenue to explore., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Mars' sedimentary rock record preserves information on geological (and potential astrobiological) processes that occurred on the planet billions of years ago. The Curiosity rover is exploring the lower reaches of Mount Sharp, in Gale crater on Mars. A traverse from Vera Rubin ridge to Glen Torridon has allowed Curiosity to examine a lateral transect of rock strata laid down in a martian lake ~3.5 billion years ago. We report spatial differences in the mineralogy of time-equivalent sedimentary rocks <400 meters apart. These differences indicate localized infiltration of silica-poor brines, generated during deposition of overlying magnesium sulfate-bearing strata. We propose that destabilization of silicate minerals driven by silica-poor brines (rarely observed on Earth) was widespread on ancient Mars, because sulfate deposits are globally distributed., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Persistent organic pollutants (POPs) are endocrine disruptors that alter adipose tissue development, regulation and function. Top marine predators are particularly vulnerable because they possess large fat stores that accumulate POPs. However, links between endocrine or adipose tissue function disruption and whole animal energetics have rarely been investigated. We predicted the impact of alterations to blubber metabolic characteristics and circulating thyroid hormone (TH) levels associated with polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), and organochlorine pesticides (OCPs) on suckling mass gain and weaning mass in wild grey seal pups. Glucose uptake by inner blubber was a strong predictor of whole animal mass gain rate, which in turn, resulted in heavier weaning mass. Weaning mass was predicted to increase by 3.7 ± 1.59 (sem) %, through increased mass gain rate, in the absence of the previously reported suppressive effect of dioxin-like PCB (DL-PCBs) on blubber glucose uptake. PBDEs were, conversely, associated with faster mass gain. Alleviation of this effect was predicted to reduce weaning mass by 6.02 ± 1.86% (sem). To better predict POPs effects on energy balance, it is crucial to determine if and how PBDEs promote mass gain in grey seal pups. Weaning mass was negatively related to total T3 (TT3) levels. A 20% (range = 9.3-31.7%) reduction in TT3 by DL-PCBs partially overcame the effect of DL-PCB -mediated reduction in blubber glucose uptake. Overall, DL-PCBs were thus predicted to reduce weaning mass by 1.86 ± 1.60%. Organohalogen impacts on whole-animal energy balance in grey seal pups appear to partially offset each other through opposing effects on different mechanisms. POP effects were generally minor, but the largest POP-induced reductions in weaning mass were predicted to occur in pups that were already small. Since weaning mass is positively related to first-year survival, POPs may disproportionately affect smaller individuals, and could continue to have population-level impacts even when levels are relatively low compared to historical values. Our findings show how in vitro experiments combined with measurements in vivo can help elucidate mechanisms that underpin energy balance regulation and help to quantify the magnitude of disruptive effects by contaminants and other stressors in wildlife., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The identification of cannabinoid ligands Cannabidiol and O-1918 as inverse agonists of the orphan receptor GPR52 is reported. Detailed characterisation of GPR52 pharmacology and modelling of the proposed receptor interaction is described. The identification of a novel and further CNS pharmacology for the polypharmacological agent and marketed drug Cannabidiol is noteworthy., Competing Interests: The authors declare no conflict of interest., (Crown Copyright © 2021 Published by Elsevier Ltd.)

The metabotropic glutamate receptor 5 (mGlu 5 ) is a recognized central nervous system therapeutic target for which several negative allosteric modulator (NAM) drug candidates have or are continuing to be investigated for various disease indications in clinical development. Direct measurement of target receptor occupancy (RO) is extremely useful to help design and interpret efficacy and safety in nonclinical and clinical studies. In the mGlu 5 field, this has been successfully achieved by monitoring displacement of radiolabeled ligands, specifically binding to the mGlu 5 receptor, in the presence of an mGlu 5 NAM using in vivo and ex vivo binding in rodents and positron emission tomography imaging in cynomolgus monkeys and humans. The aim of this study was to measure the RO of the mGlu 5 NAM HTL0014242 in rodents and cynomolgus monkeys and to compare its plasma and brain exposure-RO relationships with those of clinically tested mGlu 5 NAMs dipraglurant, mavoglurant, and basimglurant. Potential sources of variability that may contribute to these relationships were explored. Distinct plasma exposure-response relationships were found for each mGlu 5 NAM, with >100-fold difference in plasma exposure for a given level of RO. However, a unified exposure-response relationship was observed when both unbound brain concentration and mGlu 5 affinity were considered. This relationship showed <10-fold overall difference, was fitted with a Hill slope that was not significantly different from 1, and appeared consistent with a simple E max model. This is the first time this type of comparison has been conducted, demonstrating a unified brain exposure-RO relationship across several species and mGlu 5 NAMs with diverse properties. SIGNIFICANCE STATEMENT: Despite the long history of mGlu 5 as a therapeutic target and progression of multiple compounds to the clinic, no formal comparison of exposure-receptor occupancy relationships has been conducted. The data from this study indicate for the first time that a consistent, unified relationship can be observed between exposure and mGlu 5 receptor occupancy when unbound brain concentration and receptor affinity are taken into account across a range of species for a diverse set of mGlu 5 negative allosteric modulators, including a new drug candidate, HTL0014242., (Copyright © 2021 by The Author(s).)

Extraformational sediment recycling (old sedimentary rock to new sedimentary rock) is a fundamental aspect of Earth's geological record; tectonism exposes sedimentary rock, whereupon it is weathered and eroded to form new sediment that later becomes lithified. On Mars, tectonism has been minor, but two decades of orbiter instrument-based studies show that some sedimentary rocks previously buried to depths of kilometers have been exposed, by erosion, at the surface. Four locations in Gale crater, explored using the National Aeronautics and Space Administration's Curiosity rover, exhibit sedimentary lithoclasts in sedimentary rock: At Marias Pass, they are mudstone fragments in sandstone derived from strata below an erosional unconformity; at Bimbe, they are pebble-sized sandstone and, possibly, laminated, intraclast-bearing, chemical (calcium sulfate) sediment fragments in conglomerates; at Cooperstown, they are pebble-sized fragments of sandstone within coarse sandstone; at Dingo Gap, they are cobble-sized, stratified sandstone fragments in conglomerate derived from an immediately underlying sandstone. Mars orbiter images show lithified sediment fans at the termini of canyons that incise sedimentary rock in Gale crater; these, too, consist of recycled, extraformational sediment. The recycled sediments in Gale crater are compositionally immature, indicating the dominance of physical weathering processes during the second known cycle. The observations at Marias Pass indicate that sediment eroded and removed from craters such as Gale crater during the Martian Hesperian Period could have been recycled to form new rock elsewhere. Our results permit prediction that lithified deltaic sediments at the Perseverance (landing in 2021) and Rosalind Franklin (landing in 2023) rover field sites could contain extraformational recycled sediment.

This paper provides an overview of the Curiosity rover's exploration at Vera Rubin ridge (VRR) and summarizes the science results. VRR is a distinct geomorphic feature on lower Aeolis Mons (informally known as Mount Sharp) that was identified in orbital data based on its distinct texture, topographic expression, and association with a hematite spectral signature. Curiosity conducted extensive remote sensing observations, acquired data on dozens of contact science targets, and drilled three outcrop samples from the ridge, as well as one outcrop sample immediately below the ridge. Our observations indicate that strata composing VRR were deposited in a predominantly lacustrine setting and are part of the Murray formation. The rocks within the ridge are chemically in family with underlying Murray formation strata. Red hematite is dispersed throughout much of the VRR bedrock, and this is the source of the orbital spectral detection. Gray hematite is also present in isolated, gray-colored patches concentrated toward the upper elevations of VRR, and these gray patches also contain small, dark Fe-rich nodules. We propose that VRR formed when diagenetic event(s) preferentially hardened rocks, which were subsequently eroded into a ridge by wind. Diagenesis also led to enhanced crystallization and/or cementation that deepened the ferric-related spectral absorptions on the ridge, which helped make them readily distinguishable from orbit. Results add to existing evidence of protracted aqueous environments at Gale crater and give new insight into how diagenesis shaped Mars' rock record., (©2020. The Authors.)

Images from the Mars Science Laboratory (MSL) mission of lacustrine sedimentary rocks of Vera Rubin ridge on "Mt. Sharp" in Gale crater, Mars, have shown stark color variations from red to purple to gray. These color differences crosscut stratigraphy and are likely due to diagenetic alteration of the sediments after deposition. However, the chemistry and timing of these fluid interactions is unclear. Determining how diagenetic processes may have modified chemical and mineralogical signatures of ancient Martian environments is critical for understanding the past habitability of Mars and achieving the goals of the MSL mission. Here we use visible/near-infrared spectra from Mastcam and ChemCam to determine the mineralogical origins of color variations in the ridge. Color variations are consistent with changes in spectral properties related to the crystallinity, grain size, and texture of hematite. Coarse-grained gray hematite spectrally dominates in the gray patches and is present in the purple areas, while nanophase and fine-grained red crystalline hematite are present and spectrally dominate in the red and purple areas. We hypothesize that these differences were caused by grain-size coarsening of hematite by diagenetic fluids, as observed in terrestrial analogs. In this model, early primary reddening by oxidizing fluids near the surface was followed during or after burial by bleaching to form the gray patches, possibly with limited secondary reddening after exhumation. Diagenetic alteration may have diminished the preservation of biosignatures and changed the composition of the sediments, making it more difficult to interpret how conditions evolved in the paleolake over time., (©2020. The Authors.)

Metal contamination of food and water resources is a known public health issue in Arctic and sub-Arctic communities due to the proximity of many communities to mining and drilling sites. In addition, permafrost thaw may release heavy metals sequestered in previously frozen soils, potentially contaminating food and water resources by increasing the concentration of metals in freshwater, plants, and wildlife. Here we assess the enrichment of selected heavy metals in Alaskan soils by synthesizing publicly available data of soil metal concentrations. We analyzed data of soil concentrations of arsenic, chromium, mercury, nickel, and lead from over 1,000 samples available through the USGS Alaskan Geochemical Database to evaluate 1) the spatial distribution of sampling locations for soil metal analysis, 2) metal concentrations in soils from different land cover types and depths, and 3) the occurrence of soils in Alaska with elevated metal concentrations relative to other soils. We found substantial clustering of sample sites in the southwestern portion of Alaska in discontinuous and sporadic permafrost, while the continuous permafrost zone in Northern Alaska and the more populous Interior are severely understudied. Metal concentration varied by land cover type but lacked consistent patterns. Concentrations of chromium, mercury, and lead were higher in soils below 10 cm depth, however these deeper soils are under-sampled. Arsenic, chromium, mercury, nickel and lead concentrations exceeded average values for US soils by one standard deviation or more in 3.7% to 18.7% of the samples in this dataset. Our analysis highlights critical gaps that impede understanding of how heavy metals in thawing permafrost soils may become mobilized and increase exposure risk for Arctic communities., Competing Interests: The authors have declared that no competing interests exist.

The orexin system, which consists of the two G protein-coupled receptors OX 1 and OX 2 , activated by the neuropeptides OX-A and OX-B, is firmly established as a key regulator of behavioral arousal, sleep, and wakefulness and has been an area of intense research effort over the past two decades. X-ray structures of the receptors in complex with 10 new antagonist ligands from diverse chemotypes are presented, which complement the existing structural information for the system and highlight the critical importance of lipophilic hotspots and water molecules for these peptidergic GPCR targets. Learnings from the structural information regarding the utility of pharmacophore models and how selectivity between OX 1 and OX 2 can be achieved are discussed.

Background: The incidence of placenta accreta spectrum is rising. Management is most commonly with cesarean hysterectomy. These deliveries often are complicated by massive hemorrhage, urinary tract injury, and admission to the intensive care unit. Up to 60% of patients require transfusion of ≥4 units of packed red blood cells. There is also a significant risk of death of up to 7%., Objective: The purpose of this study was to assess the outcomes of patients with antenatal diagnosis of placenta percreta that was managed with delayed hysterectomy as compared with those patients who underwent immediate cesarean hysterectomy., Study Design: We performed a retrospective study of all patients with an antepartum diagnosis of placenta percreta at our large academic institution from January 1, 2012, to May 30, 2018. Patients were treated according to standard clinical practice that included scheduled cesarean delivery at 34-35 weeks gestation and intraoperative multidisciplinary decision-making regarding immediate vs delayed hysterectomy. In cases of delayed hysterectomy, the hysterotomy for cesarean birth used a fetal surgery technique to minimize blood loss, with a plan for hysterectomy 4-6 weeks after delivery. We collected data regarding demographics, maternal comorbidities, time to interval hysterectomy, blood loss, need for transfusion, occurrence of urinary tract injury and other maternal complications, and maternal and fetal mortality rates. Descriptive statistics were performed, and Wilcoxon rank-sum and chi-square tests were used as appropriate., Results: We identified 49 patients with an antepartum diagnosis of placenta percreta who were treated at Vanderbilt University Medical Center during the specified period. Of these patients, 34 were confirmed to have severe placenta accreta spectrum, defined as increta or percreta at the time of delivery. Delayed hysterectomy was performed in 14 patients: 9 as scheduled and 5 before the scheduled date. Immediate cesarean hysterectomy was completed in 20 patients: 16 because of intraoperative assessment of resectability and 4 because of preoperative or intraoperative bleeding. The median (interquartile range) estimated blood loss at delayed hysterectomy of 750 mL (650-1450 mL) and the sum total for delivery and delayed hysterectomy of 1300 mL (70 -2150 mL) were significantly lower than the estimated blood loss at immediate hysterectomy of 3000 mL (2375-4250 mL; P<.01 and P=.037, respectively). The median (interquartile range) units of packed red blood cells that were transfused at delayed hysterectomy was 0 (0-2 units), which was significantly lower than units transfused at immediate cesarean hysterectomy (4 units [2-8.25 units]; P<.01). Nine of 20 patients (45%) required transfusion of ≥4 units of red blood cells at immediate cesarean hysterectomy, whereas only 2 of 14 patients (14.2%) required transfusion of ≥4 units of red blood cells at the time of delayed hysterectomy (P=.016). There was 1 maternal death in each group, which were incidences of 7% and 5% in the delayed and immediate hysterectomy patients, respectively., Conclusion: Delayed hysterectomy may represent a strategy for minimizing the degree of hemorrhage and need for massive blood transfusion in patients with an antenatal diagnosis of placenta percreta by allowing time for uterine blood flow to decrease and for the placenta to regress from surrounding structures., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The metabotropic glutamate (mGlu) receptors are a family of eight class C G protein-coupled receptors (GPCRs) which modulate cell signaling and synaptic transmission to the major excitatory neurotransmitter l-glutamate (l-glutamic acid). Due to their role in modulating glutamate response, their widespread distribution in the central nervous system (CNS) and some evidence of dysregulation in disease, the mGlu receptors have become attractive pharmacological targets. As the orthosteric (glutamate) binding site is highly conserved across the eight mGlu receptors, it is difficult not only to generate ligands with subtype selectivity but, due to the nature of the binding site, with suitable drug-like properties to allow oral bioavailability and CNS penetration. Selective pharmacological targeting of a single receptor subtype can be achieved by targeting alternative (allosteric) binding sites. The nature of the allosteric binding pockets allows ligands to be developed that have good physical chemical properties as evidenced by several allosteric modulators of mGlu receptors entering clinical trials. The first negative allosteric modulators of the metabotropic glutamate 5 (mGlu 5 ) receptor were discovered from high throughput screening activities. An alternative approach to drug discovery is to use structural knowledge to enable structure-based drug design (SBDD), which allows the design of molecules in a more rational, rather than empirical, fashion. Here we will describe the process of SBDD in the discovery of the mGlu 5 negative allosteric modulator HTL0014242 and describe how knowledge of receptor structure can also be used to gain insights into the receptor activation mechanisms., Competing Interests: Conflict of interest K.A.B., J.A.C. are current, and B.G.T. former, employees of Sosei Heptares, a biopharmaceutical company that specializes in GPCR SBDD and have a mGlu(5) NAM in clinical trials., (© 2020 Elsevier Inc. All rights reserved.)

Children with bronchiectasis in a stable state have poor HRQoL and their parents report higher levels of anxiety and depression. Parental perception of HRQoL is associated with poorer parental psychological wellbeing. http://bit.ly/2lcf3uB., Competing Interests: Conflict of interest: N.S. Cox has nothing to disclose. Conflict of interest: C.J. Wilson has nothing to disclose. Conflict of interest: K.A. Bennett has nothing to disclose. Conflict of interest: K. Johnston has nothing to disclose. Conflict of interest: A. Potter has nothing to disclose. Conflict of interest: A.B. Chang has nothing to disclose. Conflict of interest: A.L. Lee has nothing to disclose.

Investigation of marine mammal dive-by-dive blood distribution and oxygenation has been limited by a lack of noninvasive technology for use in freely diving animals. Here, we developed a noninvasive near-infrared spectroscopy (NIRS) device to measure relative changes in blood volume and haemoglobin oxygenation continuously in the blubber and brain of voluntarily diving harbour seals. Our results show that seals routinely exhibit preparatory peripheral vasoconstriction accompanied by increased cerebral blood volume approximately 15 s before submersion. These anticipatory adjustments confirm that blood redistribution in seals is under some degree of cognitive control that precedes the mammalian dive response. Seals also routinely increase cerebral oxygenation at a consistent time during each dive, despite a lack of access to ambient air. We suggest that this frequent and reproducible reoxygenation pattern, without access to ambient air, is underpinned by previously unrecognised changes in cerebral drainage. The ability to track blood volume and oxygenation in different tissues using NIRS will facilitate a more accurate understanding of physiological plasticity in diving animals in an increasingly disturbed and exploited environment., Competing Interests: The authors have declared that no competing interests exist.

Objective: The Management of Myelomeningocele Study (MOMS) established several important benefits of myelomeningocele fetal closure, including decreased need for shunting at 30 months. However, the effects of fetal closure on long-term quality of life (QOL) have not been studied. In this study, the authors aimed to analyze the differences in long-term QOL between children treated with intrauterine repair and those treated with postnatal repair., Methods: Caregivers of children treated with either intrauterine or postnatal closure at a tertiary acute care hospital between 1997 and 2003 were contacted to participate. The Pediatric Quality of Life Inventory (PedsQL 4.0) and a surgical history questionnaire were administered over the phone. Responses to the QOL survey were reverse scored and linearly transformed to a 0-100 scale, with a higher score indicating better QOL. The Mann-Whitney U-test was used to analyze differences in means., Results: Seventy-four children had MMC repair between 1997 and 2003. Twenty-three (31%) of the patients' families responded to the PedsQL 4.0 questionnaire. Of these 23 children, 11 had intrauterine closure and 12 had postnatal closure. The intrauterine group did not differ in age (median [IQR] 17 years [14-17 years] vs 15 years [14-19 years], p = 0.926), sex (27.3% vs 41.7% male, p = 0.469), or lesion level (p = 0.199) from the postnatal group. Fewer patients in the intrauterine group underwent neurosurgical procedures than those in the postnatal group (55.6% vs 100%, p = 0.018). However, of the children receiving neurosurgical procedures, there was no difference in the number of procedures between the intrauterine and postnatal groups (median [IQR] 4 [2-10.5] vs 2.5 [1.75-6.25], p = 0.458). There was no difference in the percentage of children receiving nonneurosurgical procedures between the two groups (100% vs 100%, p > 0.99). Children who underwent intrauterine closure had significantly higher psychosocial health (median [IQR] 70.0 [56.7-83.3] vs 55.0 [42.1-60.0], p = 0.015) as well as total QOL (median [IQR] 56.5 [55.4-81.5] vs 49.5 [32.9-59.0], p = 0.019) than children with postnatal closure. Physical health was not significantly different between the two groups (median [IQR] 62.5 [37.5-78.1] vs 39.1 [18.8-59.4], p = 0.108)., Conclusions: Relative to postnatal closure, children who underwent intrauterine closure of MMC demonstrated better long-term QOL as measured by psychosocial and overall QOL metrics. Given that not all medical and socioeconomic confounders were adjusted for due to the low sample size, validation of these results in a larger population and across multiple centers is needed.

Background: Open maternal-fetal surgery for fetal myelomeningocele results in reduction in neonatal morbidity related to spina bifida but may be associated with fetal, neonatal, and maternal complications in subsequent pregnancies., Objective: The objective of this study was to ascertain obstetric risk in subsequent pregnancies after open maternal-fetal surgery for fetal myelomeningocele closure., Study Design: An international multicenter prospective observational registry created to track and report maternal, obstetric, fetal/neonatal, and subsequent pregnancy outcomes following open maternal-fetal surgery for fetal myelomeningocele was evaluated for subsequent pregnancy outcome variables. Institutional Review Board approval was obtained for the registry., Results: From 693 cases of open maternal-fetal surgery for fetal myelomeningocele closure entered into the registry, 77 subsequent pregnancies in 60 women were identified. The overall live birth rate was 96.2%, with 52 pregnancies delivering beyond 20 weeks gestational age and median gestational age at delivery of 37 (36.3-37.1) weeks. The uterine rupture rate was 9.6% (n = 5), resulting in 2 fetal deaths. Maternal transfusion was required in 4 patients (7.7%)., Conclusion: The risk of uterine rupture or dehiscence in subsequent pregnancies with associated fetal morbidity after open maternal-fetal surgery is significant, but is similar to that reported for subsequent pregnancies after classical cesarean deliveries. Future pregnancy considerations should be included in initial counseling for women contemplating open maternal-fetal surgery., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Preterm birth (PTB) is the leading cause of neonatal death, however, accurate prediction methods do not exist. Detection of early changes in the cervix, an organ that biochemically remodels to deliver the fetus, has potential to predict PTB risk. Researchers have employed light-based methods to monitor biochemical changes in the cervix during pregnancy, however, these approaches required patients to undergo a speculum examination which many patients find uncomfortable and is not standard practice during prenatal care. Herein, a visually guided optical probe is presented that measures the cervix via introduction by bimanual examination, a procedure that is commonly performed during prenatal visits and labor for tactile monitoring of the cervix. The device incorporates a Raman spectroscopy probe for biochemical monitoring and a camera for visualizing measurement location to ensure it is void of cervical mucus and blood. This probe was tested in 15 patients receiving obstetric and gynecological care, and results acquired with and without a speculum revealed similar spectra, demonstrating that the visually guided probe conserved data quality. Additionally, the majority of patients reported reduced discomfort from the device. In summary, the visual guidance probe successfully measured the cervix while integrating with standard prenatal care, reducing a barrier in clinical translation., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: The timing of hospital admission for women with spontaneous labor onset and the criteria used to assess active labor progress and diagnose labor dystocia may significantly influence women's risk for primary cesarean birth. Our aims were to assess associations of labor status at admission (i.e., preactive or active) and active labor progress (i.e., dystocic or physiologic) with oxytocin augmentation, cesarean birth, and adverse neonatal outcome rates., Methods: A sample of low-risk, nulliparous women admitted to hospitals for spontaneous labor onset was extracted from the Consortium on Safe Labor (n = 27 077). Binomial logistic regression was used to assess associations between labor classifications and outcomes., Results: At admission, 68.0% of women were in preactive labor and 32.0% were in active labor. Cesarean rates for these groups were 18.0% and 7.2%, respectively (adjusted odds ratio [AOR] 2.69; 95% CI 2.45-2.96). Oxytocin augmentation and adverse neonatal outcomes were more likely for women admitted in preactive labor. Among women admitted in active labor, 9.3% experienced labor dystocia and 90.7% progressed physiologically. Cesarean rates for these groups were 20.4% and 5.9%, respectively (AOR 3.02; 95% CI 2.45-3.73). Nearly half of the cesareans performed for dystocia among women admitted in active labor occurred when cervical dilation was physiologic. Oxytocin augmentation and adverse neonatal outcomes were more likely when active labor was dystocic., Conclusions: Adoption of evidence-based, standardized approaches for diagnosing active labor onset, assessing labor progress, and diagnosing dystocia may safely decrease oxytocin augmentation and cesarean birth rates in the United States., (© 2018 Wiley Periodicals, Inc.)

Persistent organic pollutants (POPs) are toxic, ubiquitous, resist breakdown, bioaccumulate in living tissue, and biomagnify in food webs. POPs can also alter energy balance in humans and wildlife. Marine mammals experience high POP concentrations, but consequences for their tissue metabolic characteristics are unknown. We used blubber explants from wild, gray seal ( Halichoerus grypus) pups to examine impacts of intrinsic tissue POP burden and acute experimental POP exposure on adipose metabolic characteristics. Glucose use, lactate production, and lipolytic rate differed between matched inner and outer blubber explants from the same individuals and between feeding and natural fasting. Glucose use decreased with blubber dioxin-like PCBs (DL-PCB) and increased with acute experimental POP exposure. Lactate production increased with DL-PCBs during feeding, but decreased with DL-PCBs during fasting. Lipolytic rate increased with blubber dichlorodiphenyltrichloroethane and its metabolites (DDX) in fasting animals, but declined with DDX when animals were feeding. Our data show that POP burdens are high enough in seal pups to alter adipose function early in life, when fat deposition and mobilization are vital. Such POP-induced alterations to adipose metabolic properties may significantly alter energy balance regulation in marine top predators, with the potential for long-term impacts on fitness and survival.

Objectives: To build effective applications, technology designers must understand consumer health needs. Pregnancy is a common health condition, and expectant families have unanswered questions. This study examined consumer health-related needs in pregnant women and caregivers and determined the types of needs that were not met., Materials and Methods: We enrolled pregnant women <36 weeks' gestational age and caregivers from advanced maternal-fetal and group prenatal care settings. Participant characteristics were collected through surveys, and health-related needs were elicited in semi-structured interviews. Researchers categorized needs by semantic type and whether they were met (ie, met, partially met, or unmet). Inter-rater reliability was measured by Cohen's kappa., Results: Seventy-one pregnant women and 29 caregivers participated and reported 1054 needs, 28% unmet, and 49% partially met. Need types were 66.2% informational, 15.9% logistical, 8.9% social, 8.6% medical, and 0.3% other. Inter-rater reliability was near perfect ( κ =0.95, P  < 0.001)., Discussion: Common topics of unmet needs were prognosis, life management, and need for emotional support. For pregnant women, these unmet needs focused around being healthy, childbirth, infant care, and being a good mother; caregivers' needs involved caring for the mother, the natural course of pregnancy, and life after pregnancy., Conclusion: Pregnant women and caregivers have a rich set of health-related needs with many not fully met. Caregivers' needs differed from those of pregnant women and may not be adequately addressed by resources designed for mothers. Many unmet needs involved stress and life management. Knowledge about consumer health needs can inform the design of better technologies for pregnancy.

Background: Geriatrics training is essential for future primary care providers. The Extension for Community Healthcare Outcomes (ECHO) model improves access to specialty care via case-based videoconferencing, but Project ECHO has not previously been designed to target residents., Objective: We designed Project ECHO-Geriatrics to deliver geriatrics education to primary care trainees using the ECHO model and evaluated self-rated geriatrics competency of trainees from the University of Washington Family Medicine Residency Network programs who participated between January 2016 and March 2017., Methods: We assessed outcomes of Project ECHO-Geriatrics through anonymous surveys. Participants rated didactics, case discussions, and geriatrics-specific knowledge before and after sessions on a 5-point scale (1, low, to 5, high). Participants were asked whether they planned to do anything differently in their practice and, if yes, to describe this change., Results: Fifteen sessions were held with 204 unique participants from 12 sites, with an average of 28 (range, 13-41) participants per session. From the 9 of 29 (31%) Family Medicine Residency Network programs that enrolled, 63% percent (116 of 184) of eligible residents attended. Sessions were highly rated (89% of responses were 4 or 5). Self-reported geriatrics-specific knowledge increased significantly (before 3.3 [SD = 0.89] versus after 4.0 [SD = 0.60], P < .001). Sixty-five percent (118 of 181) of participants reported plans to change their practice., Conclusions: Project ECHO-Geriatrics is an innovative, feasible way to train the future primary care workforce in geriatrics and grow the capacity to provide high-quality care to older adults., Competing Interests: Conflict of interest: The authors declare they have no competing interests. This work was presented as a poster at the American Geriatrics Society Annual Meeting, San Antonio, Texas, May 18–20, 2017. The content of this article is solely the responsibility of the investigators and does not necessarily represent the official views of the Health Resources and Services Administration or the US Department of Health and Human Services.

Background: The cervix must undergo significant biochemical remodeling to allow for successful parturition. This process is not fully understood, especially in instances of spontaneous preterm birth. In vivo Raman spectroscopy is an optical technique that can be used to investigate the biochemical composition of tissue longitudinally and noninvasively in human beings, and has been utilized to measure physiology and disease states in a variety of medical applications., Objective: The purpose of this study is to measure in vivo Raman spectra of the cervix throughout pregnancy in women, and to identify biochemical markers that change with the preparation for delivery and postpartum repair., Study Design: In all, 68 healthy pregnant women were recruited. Raman spectra were measured from the cervix of each patient monthly in the first and second trimesters, weekly in the third trimester, and at the 6-week postpartum visit. Raman spectra were measured using an in vivo Raman system with an optical fiber probe to excite the tissue with 785 nm light. A spectral model was developed to highlight spectral regions that undergo the most changes throughout pregnancy, which were subsequently used for identifying Raman peaks for further analysis. These peaks were analyzed longitudinally to determine if they underwent significant changes over the course of pregnancy (P < .05). Finally, 6 individual components that comprise key biochemical constituents of the human cervix were measured to extract their contributions in spectral changes throughout pregnancy using a linear combination method. Patient factors including body mass index and parity were included as variables in these analyses., Results: Raman peaks indicative of extracellular matrix proteins (1248 and 1254 cm -1 ) significantly decreased (P < .05), while peaks corresponding to blood (1233 and 1563 cm -1 ) significantly increased (P < .0005) in a linear manner throughout pregnancy. In the postpartum cervix, significant increases in peaks corresponding to actin (1003, 1339, and 1657 cm -1 ) and cholesterol (1447 cm -1 ) were observed when compared to late gestation, while signatures from blood significantly decreased. Postpartum actin signals were significantly higher than early pregnancy, whereas extracellular matrix proteins and water signals were significantly lower than early weeks of gestation. Parity had a significant effect on blood and extracellular matrix protein signals, with nulliparous patients having significant increases in blood signals throughout pregnancy, and higher extracellular matrix protein signals in early pregnancy compared to patients with prior pregnancies. Body mass index significantly affected actin signal contribution, with low body mass index patients showing decreasing actin contribution throughout pregnancy and high body mass index patients demonstrating increasing actin signals., Conclusion: Raman spectroscopy was successfully used to biochemically monitor cervical remodeling in pregnant women during prenatal visits. This foundational study has demonstrated sensitivity to known biochemical dynamics that occur during cervical remodeling, and identified patient variables that have significant effects on Raman spectra throughout pregnancy. Raman spectroscopy has the potential to improve our understanding of cervical maturation, and be used as a noninvasive preterm birth risk assessment tool to reduce the incidence, morbidity, and mortality caused by preterm birth., (Copyright © 2018. Published by Elsevier Inc.)

Understanding antibiotic biodegradation is important to the appreciation of their fate and removal from the environment. In this research an Isotope Ratio Mass Spectrometry (IRMS) method was developed to evaluate the extent of biodegradation of the antibiotic, sulphanilamide, in contaminated groundwater. Results indicted an enrichment in δ 13 C of 8.44‰ from -26.56 (at the contaminant source) to -18.12‰ (300m downfield of the source). These results confirm reductions in sulphanilamide concentrations (from 650 to 10mg/L) across the contaminant plume to be attributable to biodegradation (56%) vs. other natural attenuation processes, such as dilution or dispersion (42%). To understand the controls on sulphanilamide degradation ex-situ microcosms assessed the influence of sulphanilamide concentration, redox conditions and an alternative carbon source. Results indicated, high levels of anaerobic capacity (~50% mineralisation) to degrade sulphanilamide under high (263mg/L), moderate (10mg/L) and low (0.02mg/L) substrate concentrations. The addition of electron acceptors; nitrate and sulphate, did not significantly enhance the capacity of the groundwater to anaerobically biodegrade sulphanilamide. Interestingly, where alternative carbon sources were present, the addition of nitrate and sulphate inhibited sulphanilamide biodegradation. These results suggest, under in-situ conditions, when a preferential carbon source was available for biodegradation, sulphanilamide could be acting as a nitrogen and/or sulphur source. These findings are important as they highlight sulphanilamide being used as a carbon and a putative nitrogen and sulphur source, under prevailing iron reducing conditions., (Copyright © 2017. Published by Elsevier B.V.)

Young animals must learn to forage effectively to survive the transition from parental provisioning to independent feeding. Rapid development of successful foraging strategies is particularly important for capital breeders that do not receive parental guidance after weaning. The intrinsic and extrinsic drivers of variation in ontogeny of foraging are poorly understood for many species. Grey seals (Halichoerus grypus) are typical capital breeders; pups are abandoned on the natal site after a brief suckling phase, and must develop foraging skills without external input. We collected location and dive data from recently-weaned grey seal pups from two regions of the United Kingdom (the North Sea and the Celtic and Irish Seas) using animal-borne telemetry devices during their first months of independence at sea. Dive duration, depth, bottom time, and benthic diving increased over the first 40 days. The shape and magnitude of changes differed between regions. Females consistently had longer bottom times, and in the Celtic and Irish Seas they used shallower water than males. Regional sex differences suggest that extrinsic factors, such as water depth, contribute to behavioural sexual segregation. We recommend that conservation strategies consider movements of young naïve animals in addition to those of adults to account for developmental behavioural changes.

Background: Older adults are more susceptible to adverse events when administered certain medications at doses appropriate for younger adults., Objective: The aim of this study was to investigate the effect of default geriatric dosing on computerized physician order entry (CPOE) templates on the subsequent administration of recommended starting doses of opioids, benzodiazepines (BZDs) and non-steroidal anti-inflammatory drugs (NSAIDs) to older adults in the emergency department (ED)., Methods: This was a before-after comparison of the frequency of the recommended starting doses of high-risk medications to adults aged 65 years and older. Computerized records were queried for the administration of the above medication classes in two academic EDs over two similar 4-month periods in 2015 and 2016. Between study periods, the doses of high-risk medications on ED CPOE templates were adjusted for older adults based on established pharmacy guidelines and expert consensus., Results: There was a significant improvement in the rate of recommended dose administration of all medications of interest (27.3 vs. 32.5%, p < 0.001). Not surprisingly, the medications that were maximally impacted were also those most frequently prescribed, with a significant increase in the recommended dosing of opioids (29.0 vs. 35.2%, p < 0.001) accounting for the majority of the change. Although there were no differences in BZDs as a group, there were significant differences in selected BZDs such as midazolam and diazepam. Changes in the recommended dosing of NSAIDs could not be determined due to low numbers of administered doses in both phases of the study., Conclusion: Simple changes in the CPOE template resulted in increased administration of the recommended starting doses of high-risk medications to older adults in the ED.

Adipose tissue is fundamental to energy balance, which underpins fitness and survival. Knowledge of adipose regulation in animals that undergo rapid fat deposition and mobilisation aids understanding of their energetic responses to rapid environmental change. Tissue explants can be used to investigate adipose regulation in wildlife species with large fat reserves, when opportunities for organismal experimental work are limited. We investigated glucose removal, lactate, glycerol and NEFA accumulation in media, and metabolic gene expression in blubber explants from wild grey seals. Glycolysis was higher in explants incubated in 25 mM glucose (HG) for 24 h compared to controls (C: 5.5 mM glucose). Adipose-derived lactate likely contributes to high endogenous glucose production in seals. Lipolysis was not stimulated by HG or high hydrocortisone (HC: 500 nM hydrocortisone) and was lower in heavier animals. HC caused NEFA accumulation in media to decrease by ~30% relative to C in females, indicative of increased lipogenesis. Lipolysis was higher in males than females in C and HG conditions. Lower relative abundance of 11-β-hydroxysteroid dehydrogenase 1 mRNA in HG explants suggests glucose involvement in blubber cortisol sensitivity. Our findings can help predict energy balance responses to stress and nutritional state in seals, and highlight the use of explants to study fat tissue function in wildlife.

Significant benefits have been demonstrated with the use of peri-operative checklists. We assessed whether a read-aloud didactic action card would improve performance of cannula cricothyroidotomy in a simulated 'can't intubate, can't oxygenate' scenario. A 17-step action card was devised by an expert panel. Participants in their first 4 years of anaesthetic training were randomly assigned into 'no-card' or 'card' groups. Scenarios were video-recorded for analysis. Fifty-three participants (27 no-card and 26 card) completed the scenario. The number of steps omitted was mean (SD) 6.7 (2.0) in the no-card group vs. 0.3 (0.5); p < 0.001 in the card group, but the no-card group was faster to oxygenation by mean (95% CI) 35.4 (6.6-64.2) s. The Kappa statistic was 0.84 (0.73-0.95). Our study demonstrated that action cards are beneficial in achieving successful front-of-neck access using a cannula cricothyroidotomy technique. Further investigation is required to determine this tool's effectiveness in other front-of-neck access situations, and its role in teaching or clinical management., (© 2016 The Association of Anaesthetists of Great Britain and Ireland.)

Glucose is an important metabolic fuel and circulating levels are tightly regulated in most mammals, but can drop when body fuel reserves become critically low. Glucose is mobilized rapidly from liver and muscle during stress in response to increased circulating cortisol. Blood glucose levels can thus be of value in conservation as an indicator of nutritional status and may be a useful, rapid assessment marker for acute or chronic stress. However, seals show unusual glucose regulation: circulating levels are high and insulin sensitivity is limited. Accurate blood glucose measurement is therefore vital to enable meaningful health and physiological assessments in captive, wild or rehabilitated seals and to explore its utility as a marker of conservation relevance in these animals. Point-of-care devices are simple, portable, relatively cheap and use less blood compared with traditional sampling approaches, making them useful in conservation-related monitoring. We investigated the accuracy of a hand-held glucometer for 'instant' field measurement of blood glucose, compared with blood drawing followed by laboratory testing, in wild grey seals ( Halichoerus grypus ), a species used as an indicator for Good Environmental Status in European waters. The glucometer showed high precision, but low accuracy, relative to laboratory measurements, and was least accurate at extreme values. It did not provide a reliable alternative to plasma analysis. Poor correlation between methods may be due to suboptimal field conditions, greater and more variable haematocrit, faster erythrocyte settling rate and/or lipaemia in seals. Glucometers must therefore be rigorously tested before use in new species and demographic groups. Sampling, processing and glucose determination methods have major implications for conclusions regarding glucose regulation, and health assessment in seals generally, which is important in species of conservation concern and in development of circulating glucose as a marker of stress or nutritional state for use in management and monitoring.

Shipping noise is a threat to marine wildlife. Grey seals are benthic foragers, and thus experience acoustic noise throughout the water column, which makes them a good model species for a case study of the potential impacts of shipping noise. We used ship track data from the Celtic Sea, seal track data and a coupled ocean-acoustic modelling system to assess the noise exposure of grey seals along their tracks. It was found that the animals experience step changes in sound levels up to ~20dB at a frequency of 125Hz, and ~10dB on average over 10-1000Hz when they dive through the thermocline, particularly during summer. Our results showed large seasonal differences in the noise level experienced by the seals. These results reveal the actual noise exposure by the animals and could help in marine spatial planning., (Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.)

Background: The Management of Myelomeningocele Study was a multicenter randomized trial to compare prenatal and standard postnatal closure of myelomeningocele. The trial was stopped early at recommendation of the data and safety monitoring committee and outcome data for 158 of the 183 randomized women published., Objective: In this report, pregnancy outcomes for the complete trial cohort are presented. We also sought to analyze risk factors for adverse pregnancy outcome among those women who underwent prenatal myelomeningocele repair., Study Design: Pregnancy outcomes were compared between the 2 surgery groups. For women who underwent prenatal surgery, antecedent demographic, surgical, and pregnancy complication risk factors were evaluated for the following outcomes: premature spontaneous membrane rupture ≤34 weeks 0 days (preterm premature rupture of membranes), spontaneous membrane rupture at any gestational age, preterm delivery at ≤34 weeks 0 days, nonintact hysterotomy (minimal uterine wall tissue between fetal membranes and uterine serosa, or partial or complete dehiscence at delivery), and chorioamniotic membrane separation. Risk factors were evaluated using χ 2 and Wilcoxon tests and multivariable logistic regression., Results: A total of 183 women were randomized: 91 to prenatal and 92 to postnatal surgery groups. Analysis of the complete cohort confirmed initial findings: that prenatal surgery was associated with an increased risk for membrane separation, oligohydramnios, spontaneous membrane rupture, spontaneous onset of labor, and earlier gestational age at birth. In multivariable logistic regression of the prenatal surgery group adjusting for clinical center, earlier gestational age at surgery and chorioamniotic membrane separation were associated with increased risk of spontaneous membrane rupture (odds ratio, 1.49; 95% confidence interval, 1.01-2.22; and odds ratio, 2.96, 95% confidence interval, 1.05-8.35, respectively). Oligohydramnios was associated with an increased risk of subsequent preterm delivery (odds ratio, 9.21; 95% confidence interval, 2.19-38.78). Nulliparity was a risk factor for nonintact hysterotomy (odds ratio, 3.68; 95% confidence interval, 1.35-10.05)., Conclusion: Despite the confirmed benefits of prenatal surgery, considerable maternal and fetal risk exists compared with postnatal repair. Early gestational age at surgery and development of chorioamniotic membrane separation are risk factors for ruptured membranes. Oligohydramnios is a risk factor for preterm delivery and nulliparity is a risk factor for nonintact hysterotomy at delivery., (Copyright © 2016 Elsevier Inc. All rights reserved.)

In the last thirty years, the emergence and progression of biologging technology has led to great advances in marine predator ecology. Large databases of location and dive observations from biologging devices have been compiled for an increasing number of diving predator species (such as pinnipeds, sea turtles, seabirds and cetaceans), enabling complex questions about animal activity budgets and habitat use to be addressed. Central to answering these questions is our ability to correctly identify and quantify the frequency of essential behaviours, such as foraging. Despite technological advances that have increased the quality and resolution of location and dive data, accurately interpreting behaviour from such data remains a challenge, and analytical methods are only beginning to unlock the full potential of existing datasets. This review evaluates both traditional and emerging methods and presents a starting platform of options for future studies of marine predator foraging ecology, particularly from location and two-dimensional (time-depth) dive data. We outline the different devices and data types available, discuss the limitations and advantages of commonly-used analytical techniques, and highlight key areas for future research. We focus our review on pinnipeds - one of the most studied taxa of marine predators - but offer insights that will be applicable to other air-breathing marine predator tracking studies. We highlight that traditionally-used methods for inferring foraging from location and dive data, such as first-passage time and dive shape analysis, have important caveats and limitations depending on the nature of the data and the research question. We suggest that more holistic statistical techniques, such as state-space models, which can synthesise multiple track, dive and environmental metrics whilst simultaneously accounting for measurement error, offer more robust alternatives. Finally, we identify a need for more research to elucidate the role of physical oceanography, device effects, study animal selection, and developmental stages in predator behaviour and data interpretation.

Pain is recognized as a clinical complication in cystic fibrosis (CF), but the prevalence, characteristics and clinical associations of this co-morbidity have not been systematically reviewed. Electronic searches of six databases were performed. For inclusion in phase 1, studies reported a pain prevalence rate in CF and/or its clinical associations. For phase 2, included studies reported the measurement properties of validity, reliability and responsiveness of an instrument assessing pain in CF. Two independent reviewers rated the quality of evidence (phase 1) and the measurement properties using the 4-point COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist (phase 2). Of the 400 studies identified in the literature, 16 met the inclusion criteria for phase 1 and 5 for phase 2. The mean (SD) quality score (of 16) was 11.8 (2.3). The pooled prevalence of pain in adults with CF was 77% (95% confidence interval (CI): 57%-92%) and in children was 42% (95% CI: 0%-91%). Common regions of pain included back, abdomen, chest and limbs. In children and adults, pain was associated with a poorer quality of life (QOL) and significant interference with treatments. Measurement properties of three instruments (Brief Pain Inventory, Multidimensional Pain Inventory, Daily Pain Assessment-CF) were construct validity and criterion-predictive validity, with variable findings based on 'fair' to 'good' quality studies. Pain is a common problem in both children and adults with CF. It has negative clinical associations with QOL and the ability to successfully undertake treatment. Further research exploring the measurement properties of instruments assessing pain is required., (© The Author(s) 2016.)

Objective: To determine the current maternal and fetal selection criteria and operative approaches used at centers performing fetal myelomeningocele surgery., Methods: The 17 principal investigators participating in the Fetal Myelomeningocele Consortium were asked to participate in an anonymous online survey regarding the current practice of maternal-fetal surgery for neural tube defect repair and results were tabulated. The 35-question survey related to diagnostic testing, inclusion and exclusion criteria, and clinical management., Results: Sixty-five percent (11/17) of principal investigators responded to the survey and not all centers responded to all 35 questions. All centers continue to use magnetic resonance imaging in their preoperative evaluation. Diagnostic testing from amniocentesis is varied: 5 of 11 (45%) require amniotic fluid α-fetoprotein, 4 of 10 (40%) amniotic fluid acetylcholinesterase, and 8 of 11 (73%) DNA microarray. There is also variation from the Management of Myelomeningocele Study with regard to body mass index (BMI) (1/11; 9% would offer surgery with BMIs higher than 35), maternal medical risk factors (surgery would be offered for controlled pregestational diabetes [3/10 (30%)]), hepatitis C with negative viral load (4/11 [36%]), and human immunodeficiency virus with an undetectable viral load (1/10 [10%] or an obstetric history [3/11 (27%)] would offer surgery with a history of preterm delivery on progesterone). Ten of 11 (91%) centers did not consider ventriculomegaly of 18 mm and 9 of 11 (82%) centers did not consider lack of leg movement as an exclusion criteria. Nuances in the perioperative and intraoperative management were also reported, including 5 of 11 (45%) use intraoperative echocardiography and alterations in postoperative tocolytics., Conclusion: Variation in practice patterns for offering and performing maternal-fetal surgery for myelomeningocele repair exists among centers. Ongoing evaluation of inclusion and exclusion criteria as well as operative techniques is warranted to ensure continued safety, effectiveness, and beneficence.

Fragment screening of a thermostabilized mGlu5 receptor using a high-concentration radioligand binding assay enabled the identification of moderate affinity, high ligand efficiency (LE) pyrimidine hit 5. Subsequent optimization using structure-based drug discovery methods led to the selection of 25, HTL14242, as an advanced lead compound for further development. Structures of the stabilized mGlu5 receptor complexed with 25 and another molecule in the series, 14, were determined at resolutions of 2.6 and 3.1 Å, respectively.

Background: In recent years, a relationship between Helicobacter pylori and many disease conditions has been reported, however, studies in its relationship with multiple sclerosis (MS) have had contradictory results., Objective: To determine the association between the H. pylori infection and MS., Methods: 550 patients with MS were included in the study and were matched by gender and year of birth to 299 controls. Patients were assessed for clinical and demographic parameters. An enzyme immunoassay was used to detect the presence of specific IgG antibodies against H. pylori in the serum sample of both groups., Results: H. pylori seropositivity was found to be lower in the patients with MS than in controls (16% vs 21%) with the decrease pertaining to females (14% vs 22%, p=0.027) but not males (19% vs 20%, p=1.0). When adjusted for age at onset, year of birth and disease duration, H. pylori seropositive females presented with a lower disability score than seronegative females (p=0.049), while among males the reverse was true (p=0.025). There was no significant association between H. pylori seropositivity and relapse rate., Conclusions: Our results could reflect a protective role of H. pylori in the disease development. However, it may be that H. pylori infection is a surrogate marker for the 'hygiene hypothesis', a theory which postulates that early life infections are essential to prime the immune system and thus prevent allergic and autoimmune conditions later in life. The fact that the association between H. pylori seropositivity and MS risk was seen almost exclusively in females requires further investigation., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Animals that fast during breeding and/or development, such as phocids, must regulate energy balance carefully to maximize reproductive fitness and survival probability. Adiponectin, produced by adipose tissue, contributes to metabolic regulation by modulating sensitivity to insulin, increasing fatty acid oxidation by liver and muscle, and promoting adipogenesis and lipid storage in fat tissue. We tested the hypotheses that (1) circulating adiponectin, insulin, or relative adiponectin gene expression is related to nutritional state, body mass, and mass gain in wild gray seal pups; (2) plasma adiponectin or insulin is related to maternal lactation duration, body mass, percentage milk fat, or free fatty acid (FFA) concentration; and (3) plasma adiponectin and insulin are correlated with circulating FFA in females and pups. In pups, plasma adiponectin decreased during suckling (linear mixed-effects model [LME]: T = 4.49; P < 0.001) and the early postweaning fast (LME: T = 3.39; P = 0.004). In contrast, their blubber adiponectin gene expression was higher during the early postweaning fast than early in suckling (LME: T = 2.11; P = 0.046). Insulin levels were significantly higher in early (LME: T = 3.52; P = 0.004) and late (LME: T = 6.99; P < 0.001) suckling than in fasting and, given the effect of nutritional state, were also positively related to body mass (LME: T = 3.58; P = 0.004). Adiponectin and insulin levels did not change during lactation and were unrelated to milk FFA or percentage milk fat in adult females. Our data suggest that adiponectin, in conjunction with insulin, may facilitate fat storage in seals and is likely to be particularly important in the development of blubber reserves in pups.

The metabotropic glutamate receptor family includes many potential therapeutic targets for a wide range of neurological disorders however to date no approved drugs have progressed to market. For some receptor subtypes it has been difficult to separate therapeutic benefit from undesirable side effects. For others finding suitable drug like molecules has been challenging. Chemotypes identified from screening have been limited and difficult to optimise away from undesirable groups. Frequently within related series, compounds have switched from agonist to antagonists. Recently the structures of the transmembrane domain of mGlu1 and mGlu5 have been solved revealing the binding site of allosteric modulators which provides an understanding of the difficulties to date and an opportunity for future structure based approaches to drug design., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Heat shock proteins (HSPs) and antioxidants are key cellular defenses against stress. Seals routinely undergo protracted fasting, which is normally associated with physiological stress in other animals. We tested the hypotheses that (1) relative HSP70 protein abundance is higher in liver and blubber of fasting relative to suckling wild gray seal pups; (2) differences in HSP70 are mirrored in tissue superoxide dismutase (SOD) and catalase activity, as well as glutathione levels; (3) extracellular HSP70 correlates with hepatic and blubber HSP70 abundance; and (4) protein carbonylation, an index of oxidative damage, is lower in tissues with higher levels of these cellular stress markers. In contrast to our expectation, suckling pups had higher relative HSP70 abundance and glutathione levels in liver and blubber and higher hepatic catalase activity. Plasma HSP70 did not correlate with liver or blubber abundance of the protein. Suckling pups did not experience greater protein carbonylation, suggesting that cellular protective mechanisms prevent protein damage despite an apparent increase in cellular stress. SOD activity was not affected by nutritional state, but in blubber tissue, it was positively correlated with blubber thickness. Greater requirements for antioxidants and HSPs in suckling pups or in animals with thicker blubber could arise from rapid protein synthesis, high metabolic fuel availability, and/or exposure to lipophilic toxins. Developmental and nutritional changes in cellular defenses have important implications for gray seals' susceptibility to additional stress exposure.

Unlabelled: The molecular changes that occur with cervical remodelling during pregnancy are not completely understood. This study reviews Raman spectroscopy, an optical technique for detecting changes in the pregnant cervix, and reports preliminary studies on cervical remodelling in mice that suggest that the technique provides advantages over other methods., Conclusion: Raman spectroscopy is sensitive to biochemical changes in the pregnant cervix and has high potential as a tool for detecting premature cervical remodelling in pregnant women., (©2014 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Unlabelled: OBJECT.: As more pediatric neurosurgeons become involved with fetal myelomeningocele closure efforts, examining refined techniques in the overall surgical approach that could maximize beneficial outcomes becomes critical. The authors compared outcomes for patients who had undergone a modified technique with those for patients who had undergone fetal repair as part of the earlier Management of Myelomeningocele Study (MOMS)., Methods: Demographic and outcomes data were collected for a series of 43 delivered patients who had undergone in utero myelomeningocele closure at the Fetal Center at Vanderbilt from March 2011 through January 2013 (the study cohort) and were compared with data for 78 patients who had undergone fetal repair as part of MOMS (the MOMS cohort). For the study cohort, no uterine trocar was used, and uterine entry, manipulation, and closure were modified to minimize separation of the amniotic membrane. Weekly ultrasound reports were obtained from primary maternal-fetal medicine providers and reviewed. A test for normality revealed that distribution for the study cohort was normal; therefore, parametric statistics were used for comparisons., Results: The incidence of premature rupture of membranes (22% vs 46%, p = 0.011) and chorioamnion separation (0% vs 26%, p < 0.001) were lower for the study cohort than for the MOMS cohort. Incidence of oligohydramnios did not differ between the cohorts. The mean (± SD) gestational age of 34.4 (± 6.6) weeks for the study cohort was similar to that for the MOMS cohort (34.1 ± 3.1 weeks). However, the proportion of infants born at term (37 weeks or greater) was significantly higher for the study cohort (16 of 41; 39%) than for the MOMS cohort (16 of 78; 21%) (p = 0.030). Compared with 10 (13%) of 78 patients in the MOMS cohort, only 2 (4%) of 41 infants in the study cohort were delivered earlier than 30 weeks of gestation (p = 0.084, approaching significance). For the study cohort, 2 fetal deaths were attributed to the intervention, and both were believed to be associated with placental disruption; one of these mothers had previously unidentified thrombophilia. Mortality rates did not statistically differ between the cohorts., Conclusions: These early results suggest that careful attention to uterine entry, manipulation, and closure by the surgical team can result in a decreased rate of premature rupture of membranes and chorioamnion separation and can reduce early preterm delivery. Although these results are promising, their confirmation will require further study of a larger series of patients.

Phocid seals have been proposed as models for diabetes because they exhibit limited insulin response to glucose, high blood glucose and increasing insulin resistance when fasting. Liver glucose-6-phosphatase (G6Pase) catalyses the final step in glucose production and is central to glucose regulation in other animals. G6Pase comprises a translocase (SLC37A4) and a catalytic subunit (G6PC). G6PC and SLC37A4 expression and activity are normally regulated by nutritional state and glucostatic hormones, particularly insulin, and are elevated in diabetes. We tested the hypotheses that (1) grey seal G6PC and SLC37A4 cDNA and predicted protein sequences differ from other species' at functional sites, (2) relative G6Pase protein abundances are lower during feeding than fasting and (3) relative G6Pase protein abundances are related to insulin, insulin receptor phosphorylation and key metabolite levels. We show that G6PC and partial SLC37A4 cDNA sequences encode proteins sharing 82-95 % identity with other mammals. Seal G6PC contained no differences in sites responsible for activity, stability or subcellular location. Several substitutions in seal SLC37A4 were predicted to be tolerated with low probability, which could affect glucose production. Suckling pups had higher relative abundance of both subunits than healthy, postweaned fasting pups. Furthermore, relative G6PC abundance was negatively related to glucose levels. These findings contrast markedly with the response of relative hepatic G6Pase abundance to feeding, fasting, insulin, insulin sensitivity and key metabolites in other animals, and highlight the need to understand the regulation of enzymes involved in glucose control in phocids if these animals are to be informative models of diabetes.

Using isolated receptor conformations crystal structures of the adenosine A₂A receptor have been solved in active and inactive states. Studying the change in affinity of ligands at these conformations allowed qualitative prediction of compound efficacy in vitro in a system-independent manner. Agonist 5'-N-ethylcarboxamidoadenosine displayed a clear preference to bind to the active state receptor; inverse agonists (xanthine amine congener, ZM241385, SCH58261, and preladenant) bound preferentially to the inactive state, whereas neutral antagonists (theophylline, caffeine, and istradefylline) demonstrated equal affinity for active and inactive states. Ligand docking into the known crystal structures of the A₂A receptor rationalized the pharmacology observed; inverse agonists, unlike neutral antagonists, cannot be accommodated within the agonist-binding site of the receptor. The availability of isolated receptor conformations opens the door to the concept of "reverse pharmacology" whereby the functional pharmacology of ligands can be characterized in a system-independent manner by their affinity for a pair (or set) of G protein-coupled receptor conformations.