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Subanesthetic ketamine infusion therapy can produce fast-acting antidepressant effects in patients with major depression. How single and repeated ketamine treatment modulates the whole-brain functional connectome to affect clinical outcomes remains uncharacterized.
Data-driven whole brain functional connectivity (FC) analysis was used to identify the functional connections modified by ketamine treatment in patients with major depressive disorder (MDD). MDD patients (N = 61, mean age = 38, 19 women) completed baseline resting-state (RS) functional magnetic resonance imaging and depression symptom scales. Of these patients, n = 48 and n = 51, completed the same assessments 24 h after receiving one and four 0.5 mg/kg intravenous ketamine infusions. Healthy controls (HC) (n = 40, 24 women) completed baseline assessments with no intervention. Analysis of RS FC addressed effects of diagnosis, time, and remitter status.
Significant differences (p < 0.05, corrected) in RS FC were observed between HC and MDD at baseline in the somatomotor network and between association and default mode networks. These disruptions in FC in MDD patients trended toward control patterns with ketamine treatment. Furthermore, following serial ketamine infusions, significant decreases in FC were observed between the cerebellum and salience network (SN) (p < 0.05, corrected). Patient remitters showed increased FC between the cerebellum and the striatum prior to treatment that decreased following treatment, whereas non-remitters showed the opposite pattern.
Results support that ketamine treatment leads to neurofunctional plasticity between distinct neural networks that are shown as disrupted in MDD patients. Cortico-striatal-cerebellar loops that encompass the SN could be a potential biomarker for ketamine treatment.
As the pathophysiology of Covid-19 emerges, this paper describes dysphagia as a sequela of the disease, including its diagnosis and management, hypothesised causes, symptomatology in relation to viral progression, and concurrent variables such as intubation, tracheostomy and delirium, at a tertiary UK hospital.
During the first wave of the Covid-19 pandemic, 208 out of 736 patients (28.9 per cent) admitted to our institution with SARS-CoV-2 were referred for swallow assessment. Of the 208 patients, 102 were admitted to the intensive treatment unit for mechanical ventilation support, of which 82 were tracheostomised. The majority of patients regained near normal swallow function prior to discharge, regardless of intubation duration or tracheostomy status.
Dysphagia is prevalent in patients admitted either to the intensive treatment unit or the ward with Covid-19 related respiratory issues. This paper describes the crucial role of intensive swallow rehabilitation to manage dysphagia associated with this disease, including therapeutic respiratory weaning for those with a tracheostomy.
To explore the phenomenology of auditory verbal hallucinations (AVHs) in a clinical sample of young people who have a ‘non-psychotic’ diagnosis.
Ten participants aged 17–31 years with presentation of emotionally unstable personality disorder or post-traumatic stress disorder and frequent AVHs were recruited and participated in a qualitative study exploring their subjective experience of hearing voices. Photo-elicitation and ethnographic diaries were used to stimulate discussion in an otherwise unstructured walking interview.
‘Non-psychotic’ voices comprised auditory qualities such as volume and clarity. Participants commonly personified their voices, viewing them as distinct characters with which they could interact and form relationships. There appeared to be an intimate and unstable relationship between participant and voice, whereby voices changed according to the participants’ mood, insecurities, distress and circumstance. Equally, participants reacted to provocation by the voice, leading to changes in mood and circumstance through emotional and physical disturbances. In contrast to our previous qualitative work in psychosis, voice hearing was not experienced with a sense of imposition or control.
This phenomenological research yielded in-depth and novel accounts of ‘non-psychotic’ voices which were intimately linked to emotional experience. In contrast to standard reports of voices in disorders such as schizophrenia, participants described a complex and bi-directional relationship with their voices. Many other features were in common with voice hearing in psychosis. Knowledge of the phenomenology of hallucinations in non-psychotic disorders has the potential to inform future more successful management strategies. This report gives preliminary evidence for future research.
Cocaine abuse continues to be epidemic, and yet there are no FDA approved medications for the treatment of cocaine use disorders. A previous pilot study conducted by this author suggested that quetiapine may help reduce the cravings for cocaine in 22 individuals with cocaine dependence.
This 12-week, prospective, intent-to-treat, double-blind, randomized, placebo-controlled study examined the effectiveness of quetiapine (Seroquel SR™) versus matched placebo for the treatment of cocaine dependence in non-psychotic individuals. Sixty individuals with a diagnosis of cocaine dependence were randomized in this study, 29 into the quetiapine arm, and 31 into the placebo arm. Those who were randomized to quetiapine were titrated up to a target dose of 400 mg/day of quetiapine, while those on the placebo arm were given a matched placebo. All subjects had weekly clinic visits for a cognitive-behavioral therapy group session. Outcome measures included questionnaires of cocaine use, cravings for cocaine, and urine drug screen.
Initial analyses indicate that the intensity, frequency, and length of cocaine cravings were reduced over 6 weeks in both the quetiapine and placebo groups. All hazard analyses indicated that the total money spent on cocaine also decreased in both groups, with a trend toward greater decrements in cocaine use the longer they remained in the study. Data analyses are ongoing to determine the potential effect of quetiapine on treatment of cocaine addiction.
Conclusions regarding the use of quetiapine as a treatment for cocaine dependence will be discussed.
Catechol-O-methyltransferase (COMT) has a central role in brain dopamine, noradrenalin and adrenalin signaling, and has been suggested to be involved in the pathogenesis and pharmacological treatment of affective disorders. The functional single nucleotide polymorphism (SNP) in exon 4 (Val158Met, rs4680) influences the COMT enzyme activity. The Val158Met polymorphism is a commonly studied variant in psychiatric genetics, and initial studies in schizophrenia and bipolar disorder presented evidence for association with the Met allele. In unipolar depression, while some of the investigations point at an association between the Met/Met genotype and others have found a link between the Val/Val genotype and depression, most of the studies cannot detect any difference in Val158Met allele frequency between depressed individuals and controls.
In the present study, we further elucidated the impact of COMT polymorphisms including the Val158Met in MDD. We investigated 1,250 subjects with DSM-IV and/or ICD-10 diagnosis of major depression (MDD), and 1,589 control subjects from UK. A total of 24 SNPs spanning the COMT gene were successfully genotyped using the Illumina HumaHap610-Quad Beadchip (22 SNPs), SNPlex™ genotyping system (1 SNP), and Sequenom MassARRAY® iPLEX Gold (1 SNP). Statistical analyses were implemented using PASW Statistics18, FINETTI (http://ihg.gsf.de/cgi-bin/hw/hwa1.pl), UNPHASED version 3.0.10 program and Haploview 4.0 program.
Neither single-marker nor haplotypic association was found with the functional Val158Met polymorphism or with any of the other SNPs genotyped. Our findings do not provide evidence that COMT plays a role in MDD or that this gene explains part of the genetic overlap with bipolar disorder.
According to Oedegaard et al. (2010) the co-morbidity of migraine and bipolar disorder (BPD) is well documented in numerous epidemiological and clinical studies, and there are clear pathophysiological similarities. Interestingly, in a genome-wide scan, Lea et al. (2005) identified a susceptibility locus for a severe heritable form of common migraine on chromosome 3q29. With respect to BPD, a susceptibility region on chromosome 3q29 was identified in a genome-wide linkage scan (Bailer et al. 2002) and follow-up linkage analysis (Schosser et al. 2004). These findings were also supported by further fine-mapping of this region (Schosser et al. 2007). Since 3q29 is among the chromosomal regions implicated in migraine and bipolar linkage studies, the aim of the current study is to test for 3q29 association of migraine in sample of patients with BPD. The sample consists of 463 patients with a diagnosis of BPD (34.63% men, 65.37% women; mean age ± SD: 48.01 ± 11.26), as defined by the Diagnostic and Statistical Manual 4th edition operational criteria (DSM-IV) and the International Classification of Diseases 10th edition operational criteria (ICD-10), derived from the Bipolar Affective Disorder Case Control Study (BACCS). A total of 51 SNPs in the region of the 3q29 were genotyped using Sequenom MassARRAY® iPLEX Gold and tested for association with migraine. The results of this association study investigating the 3q29 region in a sample of patients with BPD will be presented.
As awareness of ADHD has increased throughout the world, interest has grown beyond the constellation of ADHD symptoms, including long-term effects and impact on people's lives.
To examine the consequences of childhood ADHD and the relevance of these outcomes in different world regions.
This analysis examined the publication trends of studies of long-term outcomes of ADHD over time and among world regions.
Study identification followed Cochrane guidelines. Twelve databases were searched for reports published in English 1980–2010. Limiting criteria were designed to maximize study inclusion while maintaining a high level of study rigor: the studies were to
(1) be peer-reviewed,
(2) be primary study reports,
(3) include a comparator group or baseline, and
(4) report outcome results measured for a mean of 8 years (prospective studies, range of all studies was 6 months-40 years) after the start of the study, in late adolescence, or adulthood.
The fully-defined electronic search yielded 4615 citations, which were then reviewed manually based on the titles and abstracts, yielding a final of 371 studies.
Study publication trends analysed included: publication year, country and world region of origin, outcome types, and study types. In general, the numbers of studies published per year globally has increased substantially (from 2 in 1980 to more than 40/year in 2007 and 2008) with differences observed between Europe and North America.
Analysis of publication trends can provide insight into outcomes of ADHD and the focus of specific world regions.
As awareness of ADHD has increased worldwide, interest has grown beyond the constellation of ADHD symptoms, to include long-term impact on people's lives and society in general.
Examine the results of studies of long-term life consequences of ADHD.
To identify areas of life affected long-term by ADHD and differences in outcomes with and without ADHD treatment.
Following Cochrane guidelines, 12 databases were searched for studies published in English (1980–2010). Limiting criteria maximized study inclusion while maintaining high study rigor: (1) peer-reviewed, (2) primary study reports, (3) including a comparator condition, and (4) reporting long-term outcomes (mean 8 years, range 6 months-40 years from study start for prospective studies; subjects in adolescence or adulthood for retrospective or cross-sectional studies). The fully-defined electronic search yielded 4615 citations. Manual review based on titles and abstracts yielded 340 studies included in this analysis of outcomes.
The majority of studies (86%, 243 of 281; studies of untreated ADHD only) showed that untreated ADHD has substantial negative long-term outcomes, encompassing nine broad-ranging areas of life: non-medicinal drug use/addictive behaviour, antisocial behaviour, academic achievement, occupational achievement, public services use, self-esteem, social function, obesity, and driving outcomes. In contrast, most studies including ADHD pharmacotherapy and/or non-pharmacotherapy (94%, 46 of 49) showed that compared with baseline or untreated ADHD, long-term outcomes improved or stabilized with treatment of ADHD.
ADHD has notable negative long-term consequences, and this negative impact may be reduced with treatment of ADHD. Supported by Shire Development Inc.
Numerous studies have applied novel multivariate statistical approaches to the analysis of brain alterations in patients with schizophrenia. However the diagnostic accuracy of the reported predictive models differs largely, making it difficult to evaluate the overall potential of these studies to inform clinical diagnosis.
We conducted a comprehensive literature search to identify all studies reporting performance of neuroimaging-based multivariate predictive models for the differentiation of patients with schizophrenia from healthy control subjects. The robustness of the results as well as the effect of potentially confounding continous variables (e.g. age, gender ratio, year of publication) was investigated.
The final sample consisted of n=37 studies studies including n=1491 patients with schizophrenia and n=1488 healthy controls. Metaanalysis of the complete sample showed a sensitivity of 80.7% (95%-CI: 77.0 to 83.9%) and a specificity of 80.2% (95%-CI: 83.3 to 76.7%). Separate analysis for the different imaging modalities showed similar diagnostic accuracy for the structural MRI studies (sensitivity 77.3%, specificity 78.7%), the fMRI studies (sensitivity 81.4%, specificity 82.4%) and resting-state fMRI studies (sensitivity 86.9%, specificity 80.3%). Moderator analysis showed significant effects of age of patients on sensitivity (p=0.021) and of positive-tonegative symptom ratio on specificity (p=0.028) indicating better diagnostic accuracy in older patients and patients with positive symptoms.
Our analysis indicate an overall sensitivity and overall specificity of around 80 % of neuroimaging-based predictive models for differentiating schizophrenic patients from healthy controls. The results underline the potential applicability of neuroimaging-based predictive models for the diagnosis of schizophrenia.
Animal research suggests that weight gain may be caused by olanzapine-induced melatonin suppression. We conducted a pilot study of psychiatric patients treated with olanzapine to examine if melatonin was suppressed and if so the dose needed to replace this deficit. The relationship between melatonin and metabolic indices was also examined.
Ten patients with schizophrenia (N=3), schizoaffective disorder (N=3), or bipolar disorder (N=4) completed the study. All patients were male, average age 50.6 years. Patients were treated with olanzapine for 5 weeks, then randomized to either 0.3mg (N=4) or 3mg (N=6) of melatonin supplementation in addition to the olanzapine for another 6 weeks. We obtained baseline, week-6, and week-12 measures of the major metabolite of melatonin in the urine, 6-Sulfatoxymelatonin (aMT6s) adjusted for creatinine excretion. We measures weekly weight, glycemia, cholesterol, and triglycerides.
Olanzapine treatment was associated with a trend toward decreases in melatonin from baseline to week-6 (p=.14). Analysis of a subsample of patients diagnosed with schizoaffective or bipolar disorder showed significant decreases from baseline to week-6 (p=.02). Both supplementation with melatonin by 0.3mg and 3mg increased urinary melatonin levels from week-6 to week-12 (p=.12 and p=.02 respectively). Total cholesterol increased initially but demonstrated a trend for decrease when melatonin was supplemented (p=.10).
Olanzapine appears to be related to melatonin suppression. Melatonin supplementation reverses this suppression and may have the potential to reverse metabolic effects associated with olanzapine. Further studies are needed to examine the metabolic effects of olanzapine with melatonin.
Cocaine abuse continues to be epidemic, and yet there are no FDA approved medications for the treatment of cocaine use disorders within the United States.
This 12-week, prospective, double-blind, randomized, placebo-controlled study examined the effectiveness of quetiapine (Seroquel XRTM) versus matched placebo for the treatment of cocaine dependence in non-psychotic individuals. Sixty Individuals with a diagnosis of cocaine dependence were randomized in this study. Those who were randomized to quetiapine (N=29) were titrated up to a target dose of 400 mg/day of quetiapine, while those in the placebo arm (N=31) were given a matched placebo. All subjects had weekly clinic visits and a cognitive-behavioral therapy group session. Outcome measures included questionnaires of cocaine use, money spent on cocaine, and urine drug screens (UDS).
The drop-out rate was substantial at 68%, however there were no group differences between the two arms of the study. Using a repeat measures ANCOVA, as a whole, the subjects in this study improved by reducing their self-reported use of cocaine (p=.018) and self reported money spent on cocaine (p=.041) over the course of the study. However, the quetiapine group was not significantly different from the placebo group. in addition, cox regression analyses yielded non-significant differences (p = .65) between groups in predicting sobriety, as defined as three weeks negative UDS.
This study did not find group differences between the quetiapine and placebo arms, indicating that quetiapine does not appear to be beneficial in the treatment of cocaine dependence.
Neurobiological models of auditory verbal hallucination (AVH) have been advanced by symptom capture functional magnetic resonance imaging (fMRI), where participants self-report hallucinations during scanning. To date, regions implicated are those involved with language, memory and emotion. However, previous studies focus on chronic schizophrenia, thus are limited by factors, such as medication use and illness duration. Studies also lack detailed phenomenological descriptions of AVHs. This study investigated the neural correlates of AVHs in patients with first episode psychosis (FEP) using symptom capture fMRI with a rich description of AVHs. We hypothesised that intrusive AVHs would be associated with dysfunctional salience network activity.
Sixteen FEP patients with frequent AVH completed four psychometrically validated tools to provide an objective measure of the nature of their AVHs. They then underwent fMRI symptom capture, utilising general linear models analysis to compare activity during AVH to the resting brain.
Symptom capture of AVH was achieved in nine patients who reported intrusive, malevolent and uncontrollable AVHs. Significant activity in the right insula and superior temporal gyrus (cluster size 141 mm3), and the left parahippocampal and lingual gyri (cluster size 121 mm3), P < 0.05 FDR corrected, were recorded during the experience of AVHs.
These results suggest salience network dysfunction (in the right insula) together with memory and language processing area activation in intrusive, malevolent AVHs in FEP. This finding concurs with others from chronic schizophrenia, suggesting these processes are intrinsic to psychosis itself and not related to length of illness or prolonged exposure to antipsychotic medication.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
Environmental information from place-names has largely been overlooked by geoarchaeologists and fluvial geomorphologists in analyses of the depositional histories of rivers and floodplains. Here, new flood chronologies for the rivers Teme, Severn, and Wye are presented, modelled from stable river sections excavated at Broadwas, Buildwas, and Rotherwas. These are connected by the Old English term *wæsse, interpreted as ‘land by a meandering river which floods and drains quickly’. The results reveal that, in all three places, flooding during the early medieval period occurred more frequently between AD 350–700 than between AD 700–1100, but that over time each river's flooding regime became more complex including high magnitude single events. In the sampled locations, the fluvial dynamics of localized flood events had much in common, and almost certainly differed in nature from other sections of their rivers, refining our understanding of the precise nature of flooding which their names sought to communicate. This study shows how the toponymic record can be helpful in the long-term reconstruction of historic river activity and for our understanding of past human perceptions of riverine environments.
Q fever (caused by Coxiella burnetii) is thought to have an almost world-wide distribution, but few countries have conducted national serosurveys. We measured Q fever seroprevalence using residual sera from diagnostic laboratories across Australia. Individuals aged 1–79 years in 2012–2013 were sampled to be proportional to the population distribution by region, distance from metropolitan areas and gender. A 1/50 serum dilution was tested for the Phase II IgG antibody against C. burnetii by indirect immunofluorescence. We calculated crude seroprevalence estimates by age group and gender, as well as age standardised national and metropolitan/non-metropolitan seroprevalence estimates. Of 2785 sera, 99 tested positive. Age standardised seroprevalence was 5.6% (95% confidence interval (CI 4.5%–6.8%), and similar in metropolitan (5.5%; 95% CI 4.1%–6.9%) and non-metropolitan regions (6.0%; 95%CI 4.0%–8.0%). More males were seropositive (6.9%; 95% CI 5.2%–8.6%) than females (4.2%; 95% CI 2.9%–5.5%) with peak seroprevalence at 50–59 years (9.2%; 95% CI 5.2%–13.3%). Q fever seroprevalence for Australia was higher than expected (especially in metropolitan regions) and higher than estimates from the Netherlands (2.4%; pre-outbreak) and US (3.1%), but lower than for Northern Ireland (12.8%). Robust country-specific seroprevalence estimates, with detailed exposure data, are required to better understand who is at risk and the need for preventive measures.
This proposed contribution to the special issue of ILWCH offers a theoretical re-consideration of the Liberian project. If, as is commonly supposed in its historiography and across contemporary discourse regarding its fortunes into the twenty-first century, Liberia is a notable, albeit contested, instance of the modern era's correctable violence in that it stands as an imperfect realization of the emancipated slave, the liberated colony, and the freedom to labor unalienated, then such representation continues to hide more than it reveals. This essay, instead, reads Liberia as an instructive leitmotif for the conversion of racial slavery's synecdochical plantation system in the Americas into the plantation of the world writ large: the global scene of antiblackness and the immutable qualification for enslavement accorded black positionality alone. Transitions between political economic systems—from slave trade to “re-colonization,” from Firestone occupation to dictatorial-democratic regimes—reemerge from this re-examination as crucial but inessential to understanding Liberia's position, and thus that of black laboring subjects, in the modern world. I argue that slavery is the simultaneous primitive accumulation of black land and bodies, but that this reality largely escapes current conceptualization of not only the history of labor but also that of enslavement. In other words, the African slave trade (driven first by Arabs in the Indian Ocean region, then Europeans in the Mediterranean, and, subsequently, Euro-Americans in the Atlantic) did not simply leave as its corollary effect, or byproduct, the underdevelopment of African societies. The trade in African flesh was at once the co-production of a geography of desire in which blackness is perpetually fungible at every scale, from the body to the nation-state to its soil—all treasures not simply for violation and exploitation, but more importantly, for accumulation and all manner of usage. The Liberian project elucidates this ongoing reality in distinctive ways—especially when we regard it through the lens of the millennium-plus paradigm of African enslavement. Conceptualizing slavery's “afterlife” entails exploring the ways that emancipation extended, not ameliorated, the chattel condition, and as such, impugns the efficacy of key analytic categories like “settler,” “native,” “labor,” and “freedom” when applied to black existence. Marronage, rather than colonization or emancipation, situates Liberia within the intergenerational struggle of, and over, black work against social death. Read as enslavement's conversion, this essay neither impugns nor heralds black action and leadership on the Liberian project at a particular historical moment, but rather agitates for centering black thought on the ongoing issue of black fungibility and social captivity that Liberia exemplifies. I argue that such a reading of Liberia presents a critique of both settler colonialism and of a certain conceptualization of the black radical tradition and its futures in heavily optimist, positivist, and political economic terms that are enjoying considerable favor in leading discourse on black struggle today.
Objectives: Research has shown that analyzing intrusion errors generated on verbal learning and memory measures is helpful for distinguishing between the memory disorders associated with Alzheimer’s disease (AD) and other neurological disorders, including Huntington’s disease (HD). Moreover, preliminary evidence suggests that certain clinical populations may be prone to exhibit different types of intrusion errors. Methods: We examined the prevalence of two new California Verbal Learning Test-3 (CVLT-3) intrusion subtypes – across-trial novel intrusions and across/within trial repeated intrusions – in individuals with AD or HD. We hypothesized that the encoding/storage impairment associated with medial-temporal involvement in AD would result in a greater number of novel intrusions on the delayed recall trials of the CVLT-3, whereas the executive dysfunction associated with subcortical-frontal involvement in HD would result in a greater number of repeated intrusions across trials. Results: The AD group generated significantly more across-trial novel intrusions than across/within trial repeated intrusions on the delayed cued-recall trials, whereas the HD group showed the opposite pattern on the delayed free-recall trials. Conclusions: These new intrusion subtypes, combined with traditional memory analyses (e.g., recall versus recognition performance), promise to enhance our ability to distinguish between the memory disorders associated with primarily medial-temporal versus subcortical-frontal involvement.
Introduction: There is increasing evidence supporting ultrasonography for the determination of optimal chest compression location during cardiac arrest. Radiological studies have demonstrated that in up to 1/3 of patients the aortic root or outflow tract is being compressed during standard CPR. Out-of-hospital-cardiac-arrests (OHCA) could benefit from cardiac localization, undertaken with scaled-down ultrasound equipment by which the largest fluid filled structure in the chest (the heart) is identified to guide optimal compression location. We intend to evaluate 1) where the left ventricle is in supine patients, 2) the accuracy and precision as well as 3) the feasibility and reliability of cardiac localization with a scaled down ultrasound device (bladder scanners). Methods: We are recruiting men and women over the age of 40. The scanning protocol involves using a bladder scanner on a 15-point grid over the subject's left chest and parasternal, midclavicular, and anterior axillary intercostal spaces 3-7. Detected volumes will be recorded, with the presumption that the intercostal space with the largest measured volume is centered over the heart. Echocardiography will then be used to confirm the bladder scanner accuracy and to better describe the patient's internal chest anatomy. Having assessed procedural feasibility on 3 pilot subjects, we are now recruiting 100 participants, with planned interim analysis at 50 participants for sample size reassessment. Maximal volume location frequencies from the echocardiograms will be described and assessed for variation utilizing the goodness-of-fit test. The proportion of agreement across the two modalities regarding the maximal volume location will also be examined. Results: Among the 3 volunteers (pilot study), the scanner identified fluid in 4-8 of 15 intercostal spaces. In each of the three pilot study patients, the maximal volume identified by the bladder scanner was found to be at the parasternal location of the 6th intercostal space. This was also the location of the mid left ventricular diameter on echocardiography. Conclusion: Our literature review and pilot study data support the premise that lay persons and emergency medical personnel may improve compressions (and thus outcomes) during OHCA by using a scaled-down ultrasound to identify the location of optimal compression. We are currently enrolling patients in our study.