Improving blood product management in placenta accreta patients with severe bleeding: institutional experience.

BACKGROUND: Placenta accrete spectrum (PAS) is a significant risk factor for postpartum hemorrhage and effective blood product management is critical in ensuring patient safety. In PAS patients undergoing cesarean section (CS) blood transfusion management guided by the combined clinical experience of the anesthesiologist and surgeon with point-of-care coagulation testing appears safe and effective. We describe and evaluate our experience and identify potential areas for improvement with blood product management in this patient population. METHODS: A retrospective chart review of peri-operative demographic, anesthetic, and obstetric data was conducted for all patients with PAS undergoing CS between 2012 and 2018 at our center. To facilitate a practical evaluation of blood product management, we divided patients into two groups based on the severity of bleeding. RESULTS: A total of 221 parturients with PAS underwent CS, with 133 in group 1 requiring excessive amounts of transfusion and 88 in group 2 requiring management similar to other uncomplicated CS cases. There were no deaths or instances of disseminated intravascular coagulation, and intensive care unit admission occurred in five cases (2.2%). Patients in group 1 had higher mean nadir values of intra-operative hemoglobin and platelet count. We observed a high rate of missing data for peri-operative measurement of lactate and fibrinogen, PAS grade documentation, and temperature monitoring. CONCLUSION: Given no significant morbidity or mortality, clinical judgment in experienced centers appears safe for the management of PAS patients undergoing CS. The adoption of an institutional protocol and point-of-care coagulation testing could decrease over-transfusion and associated complications.

On the intersystem crossing rate in a Platinum(II) donor-bridge-acceptor triad.

The rates of ultrafast intersystem crossing in acceptor-bridge-donor molecules centered on Pt(II) acetylides are investigated. Specifically, a Pt(II) trans-acetylide triad NAP--Pt--Ph-CH2-PTZ [1], with acceptor 4-ethynyl-N-octyl-1,8-naphthalimide (NAP) and donor phenothiazine (PTZ), is examined in detail. We have previously shown that optical excitation in [1] leads to a manifold of singlet charge-transfer states, S*, which evolve via a triplet charge-transfer manifold into a triplet state 3NAP centered on the acceptor ligand and partly to a charge-separated state 3CSS (NAP--Pt-PTZ+). A complex cascade of electron transfer processes was observed, but intersystem crossing (ISC) rates were not explicitly resolved due to lack of spin selectivity of most ultrafast spectroscopies. Here we revisit the question of ISC with a combination and complementary analysis of (i) transient absorption, (ii) ultrafast broadband fluorescence upconversion, FLUP, which is only sensitive to emissive states, and (iii) femtosecond stimulated Raman spectroscopy, FSR. Raman resonance conditions allow us to observe S* and 3NAP exclusively by FSR, through vibrations which are pertinent only to these two states. This combination of methods enabled us to extract the intersystem crossing rates that were not previously accessible. Multiple timescales (1.6 ps to ∼20 ps) are associated with the rise of triplet species, which can now be assigned conclusively to multiple ISC pathways from a manifold of hot charge-transfer singlet states. The analysis is consistent with previous transient infrared spectroscopy data. A similar rate of ISC, up to 20 ps, is observed in the trans-acetylide NAP--Pt--Ph [2] which maintains two acetylide groups across the platinum center but lacks a donor unit, whilst removal of one acetylide group in mono-acetylide NAP--Pt-Cl [3] leads to >10-fold deceleration of the intersystem crossing process. Our work provides insight on the intersystem crossing dynamics of the organo-metallic complexes, and identifies a general method based on complementary ultrafast spectroscopies to disentangle complex spin, electronic and vibrational processes following photoexcitation.

Experience from the selection and nutritional preparation for Expedition ICE MAIDEN: the first successful all-female unassisted Antarctic traverse.

INTRODUCTION: Expedition ICE MAIDEN (Ex IM) was the first all-female unsupported crossing of Antarctica. We describe the prerequisite selection and training, comparing those who formed the final team with other participants, and discuss how the expedition diet was established. METHODS: All women serving in the British Army were invited to participate. Following initial assessments, successful women completed three training/selection ski expeditions. Between expeditions 1 and 2, participants completed 6 months rigorous UK-based training. Weight was measured before and after the 6 months UK-based training, expeditions 2 and 3, and body composition by skinfold before and after expedition 2. Participant feedback, body composition and weight changes were applied to modify the expedition diet and provide weight gain targets prior to Ex IM. RESULTS: Following 250 applications, 50 women were assessed and 22, 12 and seven women attended training expeditions 1, 2 and 3, respectively. The final team of six women lost more weight than other participants during UK-based training (mean (SD) change -1.3 (1.5) kg vs -0.5 (1.6) kg, respectively, p=0.046) and during training expedition 2 (-2.8 (0.8) kg vs -1.7 (0.4) kg, respectively, p=0.048), when they also gained more lean mass (+2.1 (0.8) kg vs +0.4 (0.7) kg, respectively, p=0.004). The Ex IM diet provided 5000 kCal/day, comprising approximately 45% carbohydrate, 45% fat and 10% protein. Median (range) weight change between expedition 3 and Ex IM was +8.7 (-1.9 to +14.3) kg. CONCLUSIONS: The selected Ex IM team demonstrated favourable training-associated body composition changes. Training-associated weight loss informed the expeditionary diet design.

Is glutamate associated with fear extinction and cognitive behavior therapy outcome in OCD? A pilot study.

Cognitive behavioral therapy (CBT) including exposure and response prevention is a well-established treatment for obsessive-compulsive disorder (OCD) and is based on the principles of fear extinction. Fear extinction is linked to structural and functional variability in the ventromedial prefrontal cortex (vmPFC) and has been consistently associated with glutamate neurotransmission. The relationship between vmPFC glutamate and fear extinction and its effects on CBT outcome have not yet been explored in adults with OCD. We assessed glutamate levels in the vmPFC using 3T magnetic resonance spectroscopy, and fear extinction (learning and recall) using skin conductance responses during a 2-day experimental paradigm in OCD patients (n = 17) and in healthy controls (HC; n = 13). Obsessive-compulsive patients (n = 12) then received manualized CBT. Glutamate in the vmPFC was negatively associated with fear extinction recall and positively associated with CBT outcome (with higher glutamate levels predicting a better outcome) in OCD patients. Glutamate levels in the vmPFC in OCD patients were not significantly different from those in HC, and were not associated with OCD severity. Our results suggest that glutamate in the vmPFC is associated with fear extinction recall and CBT outcome in adult OCD patients.

Cochlear implant symmetry via template.

Current trends in bilateral cochlear implantation (CI) favor a minimally invasive subperiosteal pocket technique. Symmetric receiver-stimulator (R/S) placement is an important goal for bilateral CI, especially with regard to patient satisfaction. In this article, we describe a method easily adopted to achieve optimal symmetry. Upon reviewing the Senior Author's 11 bilateral CI cases using the direct subperiosteal pocket technique with the proposed "mirror template," we found improved symmetry, which translated into high patient and family satisfaction regarding the aesthetics of the symmetric R/S placement.

PET imaging of dopamine-D2 receptor internalization in schizophrenia.

Recent genetic, molecular and post-mortem studies suggest impaired dopamine (DA)-D2 receptor (D2R) trafficking in patients with schizophrenia (SZ). Imaging and preclinical studies have shown agonist-induced D2R internalization can be imaged with positron emission tomography (PET) using D2R radiotracers combined with psychostimulant challenge. This is feasible if radiotracer binding is measured when postchallenge DA levels have returned to baseline, following the initial competition phase between DA and radiotracer for binding to D2R. Here we used 'late-phase' imaging after challenge to test the hypothesis that impaired D2R internalization in SZ leads to blunted late-phase displacement, or a faster return to baseline, in patients compared with healthy controls (HCs). We imaged 10 patients with SZ and 9 HCs with PET and [11C]raclopride at baseline and two times (3-5 and 6-10 h) following 0.5 mg kg-1 dextroamphetamine. We measured binding potential relative to non-displaceable compartment (BPND) and derived percent reduction from baseline (ΔBPND) for each postamphetamine scan. To test the hypothesis that time course of return of striatal BPND to baseline differed between SZ and HCs, we implemented a linear model with ΔBPND as dependent variable, time after amphetamine as repeated measure and time after amphetamine and diagnostic group as fixed effects. Neither diagnostic group nor interaction of diagnostic group-by-time after amphetamine significantly affected striatal ΔBPND (F=1.38, P=0.26; F=0.51, P=0.61). These results show similar pattern of return of BPND to baseline as a function of time in patients with SZ and HC, suggesting that striatal D2R internalization as measured by our imaging paradigm is normal in patients with SZ.

Continuous flow hygroscopicity-resolved relaxed eddy accumulation (Hy-Res REA) method of measuring size-resolved sodium chloride particle fluxes.

The accurate representation of aerosols in climate models requires direct ambient measurement of the size- and composition-dependent particle production fluxes. Here, we present the design, testing, and analysis of data collected through the first instrument capable of measuring hygroscopicity-based, size-resolved particle fluxes using a continuous-flow Hygroscopicity-Resolved Relaxed Eddy Accumulation (Hy-Res REA) technique. The Hy-Res REA system used in this study includes a 3D sonic anemometer, two fast-response solenoid valves, two condensation particle counters, a scanning mobility particle sizer, and a hygroscopicity tandem differential mobility analyzer. The different components of the instrument were tested inside the US Environmental Protection Agency's Aerosol Test Facility for sodium chloride and ammonium sulfate particle fluxes. The new REA system design does not require particle accumulation, and therefore avoids the diffusional wall losses associated with long residence times of particles inside the air collectors of traditional REA devices. A linear relationship was found between the sodium chloride particle fluxes measured by eddy covariance and REA techniques. The particle detection limit of the Hy-Res REA flux system is estimated to be ~3 × 105 m-2 s-1. The estimated sodium chloride particle classification limit, for the mixture of sodium chloride and ammonium sulfate particles of comparable concentrations, is ~6 × 106 m-2 s-1.

PET imaging of dopamine-D2 receptor internalization in schizophrenia.

This corrects the article DOI: 10.1038/mp.2017.107.

Deficits in striatal dopamine release in cannabis dependence.

Most drugs of abuse lead to a general blunting of dopamine release in the chronic phase of dependence, which contributes to poor outcome. To test whether cannabis dependence is associated with a similar dopaminergic deficit, we examined striatal and extrastriatal dopamine release in severely cannabis-dependent participants (CD), free of any comorbid conditions, including nicotine use. Eleven CD and 12 healthy controls (HC) completed two positron emission tomography scans with [11C]-(+)-PHNO, before and after oral administration of d-amphetamine. CD stayed inpatient for 5-7 days prior to the scans to standardize abstinence. Magnetic resonance spectroscopy (MRS) measures of glutamate in the striatum and hippocampus were obtained in the same subjects. Percent change in [11C]-(+)-PHNO-binding potential (ΔBPND) was compared between groups and correlations with MRS glutamate, subclinical psychopathological and neurocognitive parameters were examined. CD had significantly lower ΔBPND in the striatum (P=0.002, effect size (ES)=1.48), including the associative striatum (P=0.003, ES=1.39), sensorimotor striatum (P=0.003, ES=1.41) and the pallidus (P=0.012, ES=1.16). Lower dopamine release in the associative striatum correlated with inattention and negative symptoms in CD, and with poorer working memory and probabilistic category learning performance in both CD and HC. No relationships to MRS glutamate and amphetamine-induced subclinical positive symptoms were detected. In conclusion, this study provides evidence that severe cannabis dependence-without the confounds of any comorbidity-is associated with a deficit in striatal dopamine release. This deficit extends to other extrastriatal areas and predicts subclinical psychopathology.

Whey protein gel composites in the diet of goats increased the omega-3 and omega-6 content of milk fat.

Previously, feeding whey protein gels containing polyunsaturated fatty acids (PUFA) reduced their rumen biohydrogenation and increased their concentration in milk fat of Holstein cows. Our objective was to test the efficacy of whey protein isolate (WPI) gels produced in a steam tunnel as a method to alter the fatty acid (FA) composition of the milk lipids. Four primiparous Lamancha goats in midlactation were fed three diets in a 3 × 4 Latin square design. The WPI gels were added to a basal concentrate mix that contained one of three lipid sources: (i) 100% soya bean oil (S) to create (WPI/S), (ii) a 1:1 (wt/wt) mixture of S and linseed (L) oil to create (WPI/SL), or (iii) 100% L to create (WPI/L). Periods were 22 days with the first 10 days used as an adjustment phase followed by a 12-day experimental phase. During the adjustment phase, all goats received a rumen available source of lipid, yellow grease, to provide a baseline for milk FA composition. During the experimental phase, each goat received its assigned WPI. Milk FA concentration of C18:2 n-6 and C18:3 n-3 reached 9.3 and 1.64 g/100 g FA, respectively, when goats were fed WPI/S. Feeding WPI/SL increased the C18:2 n-6 and C18:3 n-3 concentration to 6.22 and 4.36 g/100 g FA, and WPI/L increased C18:2 n-6 and C18:3 n-3 to 3.96 and 6.13 g/100 g FA respectively. The adjusted transfer efficiency (%) of C18:3 n-3 to milk FA decreased significantly as dietary C18:3 n-3 intake increased. Adjusted transfer efficiency for C18:2 n-6 did not change with increasing intake of C18:2 n-6. The WPI gels were effective at reducing rumen biohydrogenation of PUFA; however, we observed a change in the proportion increase of C18:3 n-3 in milk FA suggesting possible regulation of n-3 FA to the lactating caprine mammary gland.

AAV ancestral reconstruction library enables selection of broadly infectious viral variants.

Adeno-associated virus (AAV) vectors have achieved clinical efficacy in treating several diseases. However, enhanced vectors are required to extend these landmark successes to other indications and protein engineering approaches may provide the necessary vector improvements to address such unmet medical needs. To generate new capsid variants with potentially enhanced infectious properties and to gain insights into AAV's evolutionary history, we computationally designed and experimentally constructed a putative ancestral AAV library. Combinatorial variations at 32 amino acid sites were introduced to account for uncertainty in their identities. We then analyzed the evolutionary flexibility of these residues, the majority of which have not been previously studied, by subjecting the library to iterative selection on a representative cell line panel. The resulting variants exhibited transduction efficiencies comparable to the most efficient extant serotypes and, in general, ancestral libraries were broadly infectious across the cell line panel, indicating that they favored promiscuity over specificity. Interestingly, putative ancestral AAVs were more thermostable than modern serotypes and did not use sialic acids, galactose or heparan sulfate proteoglycans for cellular entry. Finally, variants mediated 19- to 31-fold higher gene expression in the muscle compared with AAV1, a clinically used serotype for muscle delivery, highlighting their promise for gene therapy.

Directed evolution of novel adeno-associated viruses for therapeutic gene delivery.

Gene therapy vectors based on adeno-associated virus (AAV) are currently in clinical trials for numerous disease targets, such as muscular dystrophy, hemophilia, Parkinson's disease, Leber's congenital amaurosis and macular degeneration. Despite its considerable promise and emerging clinical success, several challenges impede the broader implementation of AAV gene therapy, including the prevalence of neutralizing antibodies in the human population, low transduction of a number of therapeutically relevant cell and tissue types, an inability to overcome physical and cellular barriers in vivo and a relatively limited carrying capacity. These challenges arise as the demands we place on AAV vectors are often different from or even at odds with the properties nature bestowed on their parent viruses. Viral-directed evolution-the iterative generation of large, diverse libraries of viral mutants and selection for variants with specific properties of interest-offers an approach to address these problems. Here we outline progress in creating novel classes of AAV variant libraries and highlight the successful isolation of variants with novel and advantageous in vitro and in vivo gene delivery properties.

Multimodal imaging of reversible cerebral vasoconstriction syndrome: a series of 6 cases.

RCVS is a clinical condition of recurrent severe headaches that may be associated with ischemic or hemorrhagic stroke and that is defined by the presence of segmental vasoconstriction in multiple cerebral arteries. The angiographic appearance resembles vasculitis, except that the abnormalities resolve during the course of several months. Because the treatment of RCVS differs from that for vasculitis, radiologists must understand the clinical and radiologic features so as to better guide imaging algorithms and facilitate diagnosis. We present a series of 6 cases of RCVS that highlight the imaging features across multiple modalities.

Neurocognitive contributions to verbal fluency deficits in frontotemporal lobar degeneration.

OBJECTIVE: To test the hypothesis that different neurocognitive networks underlie verbal fluency deficits in frontotemporal lobar degeneration (FTLD). METHODS: Letter ("FAS") and semantic ("animal") fluency tests were administered to patients with a behavioral/dysexecutive disorder (bvFTLD; n = 71), semantic dementia (SemD; n = 21), and progressive nonfluent aphasia (PNFA; n = 26). Tests measuring working memory, naming/lexical retrieval, and semantic knowledge were also obtained. MRI voxel-based morphometry (VBM) studies were obtained on a subset of these patients (bvFTLD, n = 51; PNFA, n = 11; SemD, n = 10). RESULTS: Patients with SemD were disproportionately impaired on the semantic fluency measure. Reduced output on this test was correlated with impaired performance on naming/lexical retrieval tests. VBM analyses related reduced letter and semantic fluency to anterior and inferior left temporal lobe atrophy. Patients with bvFTLD were equally impaired on both fluency tests. Poor performance on both fluency tests was correlated with low scores on working memory and naming/lexical retrieval measures. In this group, MRI-VBM analyses related letter fluency to bilateral frontal atrophy and semantic fluency to left frontal/temporal atrophy. Patients with PNFA were also equally impaired on fluency tests. Reduced semantic fluency output was correlated with reduced performance on naming/lexical retrieval tests. MRI-VBM analyses related semantic fluency to the right frontal lobe and letter fluency to left temporal atrophy. CONCLUSIONS: Distinct neurocognitive networks underlie impaired performance on letter and semantic fluency tests in frontotemporal lobar degeneration subgroups.

Democracy, individual rights and the regulation of science.

Whether the US Constitution guarantees a right to conduct scientific research is a question that has never been squarely addressed by the United States Supreme Court. Similarly, the extent to which the First Amendment protects the right to communicate the results of scientific research is an issue about which there is scant judicial authority. This article suggests that a crucial guidepost for exploring both these uncharted areas of constitutional law should be whether restrictions on scientific research or communication truly implicate fundamental individual rights or instead primarily concern issues of general social welfare-issues that in a democracy are properly decided by the representative branches of government or their delegates, not by the judiciary.

Lumbar discectomy outcomes vary by herniation level in the Spine Patient Outcomes Research Trial.

BACKGROUND: The Spine Patient Outcomes Research Trial showed an overall advantage for operative compared with nonoperative treatment of lumbar disc herniations. Because a recent randomized trial showed no benefit for operative treatment of a disc at the lumbosacral junction (L5-S1), we reviewed subgroups within the Spine Patient Outcomes Research Trial to assess the effect of herniation level on outcomes of operative and nonoperative care. METHODS: The combined randomized and observation cohorts of the Spine Patient Outcomes Research Trial were analyzed by actual treatment received stratified by level of disc herniation. Overall, 646 L5-S1 herniations, 456 L4-L5 herniations, and eighty-eight upper lumbar (L2-L3 or L3-L4) herniations were evaluated. Primary outcome measures were the Short Form-36 bodily pain and physical functioning scales and the modified Oswestry Disability Index assessed at six weeks, three months, six months, one year, and two years. Treatment effects (the improvement in the operative group minus the improvement in the nonoperative group) were estimated with use of longitudinal regression models, adjusting for important covariates. RESULTS: At two years, patients with upper lumbar herniations (L2-L3 or L3-L4) showed a significantly greater treatment effect from surgery than did patients with L5-S1 herniations for all outcome measures: 24.6 and 7.1, respectively, for bodily pain (p = 0.002); 23.4 and 9.9 for Short Form-36 physical functioning (p = 0.014); and -19 and -10.3 for Oswestry Disability Index (p = 0.033). There was a trend toward greater treatment effect for surgery at L4-L5 compared with L5-S1, but this was significant only for the Short Form-36 physical functioning subscale (p = 0.006). Differences in treatment effects between the upper lumbar levels and L4-L5 were significant for Short Form-36 bodily pain only (p = 0.018). CONCLUSIONS: The advantage of operative compared with nonoperative treatment varied by herniation level, with the smallest treatment effects at L5-S1, intermediate effects at L4-L5, and the largest effects at L2-L3 and L3-L4. This difference in effect was mainly a result of less improvement in patients with upper lumbar herniations after nonoperative treatment.

Secular trends in kidney disease: is the decreased incidence of renal replacement therapy due to a decrease in chronic kidney disease incidence?

AIMS: Little is known about trends in renal replacement therapy among patients with chronic kidney disease (CKD) or about changes in the incidence of CKD. We studied the incidence of renal replacement therapy within the population of a health maintenance organization (HMO) both among the entire HMO population and among those with CKD. METHODS: We calculated yearly incidence rates of renal replacement therapy for each year from 1998 to 2005. We defined CKD using the National Kidney Foundation definition of 2 estimated glomerular filtration rates below 60 ml/min/1.73 m2 90 or more days apart. Poisson regression assessed year-to-year differences. RESULTS: The number of patients with CKD rose consistently from 3,861 in 1998 to 5,242 in 2005. The proportion of patients who had been diagnosed with hypertension rose from 86.7% (starting renal replacement therapy) or 34.5% (with CKD) to 99.1 and 46.9%. The proportion of patients with diabetes changed little throughout the years studied. The mean estimated glomerular filtration rate among CKD patients rose minimally from 38.4 ml/min/1.73 m2 in 1998 to 39.9 ml/min/1.73 m2 in 2005. Age- and sex-adjusted rates of RRT among patients with CKD varied (p=0.0034), but did not follow a consistent pattern over time. CONCLUSIONS: Incidence of renal replacement therapy among patients with CKD changed little between 1998 and 2005, despite an increase in the number of patients diagnosed with CKD. The discrepancy may be due to increased laboratory identification of CKD.

Signal pathway profiling of epithelial and stromal compartments of colonic carcinoma reveals epithelial-mesenchymal transition.

Molecular crosstalk, including reciprocal stimulation, is theorized to take place between epithelial cancer cells and surrounding non-neoplastic stromal cells. This is the rationale for stromal therapy, which could eliminate support of a cancer by its genetically stable stroma. Epithelial-stromal crosstalk is so far poorly documented in vivo, and cell cultures and animal experiments may not provide accurate models. The current study details stromal-epithelial signalling pathways in 35 human colon cancers, and compares them with matched normal tissues using quantitative proteomic microarrays. Lysates prepared from separately microdissected epithelium and stroma were analysed using antibodies against 61 cell signalling proteins, most of which recognize activated phospho-isoforms. Analyses using unsupervised and supervised statistical methods suggest that cell signalling pathway profiles in stroma and epithelium appear more similar to each other in tumours than in normal colon. This supports the concept that coordinated crosstalk occurs between epithelium and stroma in cancer and suggests epithelial-mesenchymal transition. Furthermore, the data herein suggest that it is driven by cell proliferation pathways and that, specifically, several key molecules within the mitogen-activated protein kinase pathway may play an important role. Given recent findings of epithelial-mesenchymal transition in therapy-resistant tumour epithelium, these findings could have therapeutic implications for colon cancer.