Protracted Duration Research Articles

352: Laboring beyond the obstetric care consensus (OCC) labor dystocia guidelines: Proceed with caution

To evaluate whether or not allowing women to labor beyond the OCC labor dystocia guidelines is associated with increased maternal and neonatal complications. This is a retrospective chart review performed on 640 nulliparous, term, singleton, vertex (NTSV) patients delivering between January 2013 and May 2017 at an academic community hospital managed by the residents’ service. Forty-eight were identified with protracted active labor: ≥ 6cm and protracted at least 6 hours without change in dilation (beyond the OCC guidelines). We then compared the prospect of vaginal delivery and maternal and neonatal complications in this group with two others: those who had protracted labor within the OCC guidelines (4-6 hours in the active phase without cervical change) (N=47) as well as those that did not experience protracted labor (N=371). Women that labored beyond the OCC guidelines had a 42.5% vaginal delivery rate (mean duration of total protraction 9.1 +/- 2.1 hours). However, they also had a statistically significant higher rate of cesarean delivery (P<.001), quantified blood loss (QBL) (P=.01), and NICU admission rates (P<.001) compared to those laboring within the OCC guidelines. We also noted an increase in suspected intrauterine infection or inflammation (triple I) (P=.008), need for maternal blood transfusion (P=.01) and maternal length of stay (LOS) (P<.001) between those with protracted labor >6h and non-protracted labor. Rates of neonatal sepsis and 5-minute Apgar <7 were not statistically significant between the groups. There were no maternal ICU admissions, cesarean hysterectomies, or maternal/neonatal deaths. Women who labored beyond the OCC labor dystocia guidelines can still achieve vaginal delivery, but with increased select maternal and newborn risks. Still, there were no serious complications in either group. Proceeding with labor beyond the OCC guideline may be considered, but with caution.

Temporal genetic patterns of diversity and structure evidence chaotic genetic patchiness in a spiny lobster.

Population structure of many marine organisms is spatially patchy and varies within and between years, a phenomenon defined as chaotic genetic patchiness. This results from the combination of planktonic larval dispersal and environmental stochasticity. Additionally, in species with bi-partite life, postsettlement selection can magnify these genetic differences. The high fecundity (up to 500,000 eggs annually) and protracted larval duration (12-24months) and dispersal of the southern rock lobster, Jasus edwardsii, make it a good test species for chaotic genetic patchiness and selection during early benthic life. Here, we used double digest restriction site-associated DNA sequencing (ddRADseq) to investigate chaotic genetic patchiness and postsettlement selection in this species. We assessed differences in genetic structure and diversity of recently settled pueruli across four settlement years and between two sites in southeast Australia separated by approximately 1,000km. Postsettlement selection was investigated by identifying loci under putative positive selection between recently settled pueruli and postpueruli and quantifying differences in the magnitude and strength of the selection at each year and site. Genetic differences within and among sites through time in neutral SNP markers indicated chaotic genetic patchiness. Recently settled puerulus at the southernmost site exhibited lower genetic diversity during years of low puerulus catches, further supporting this hypothesis. Finally, analyses of outlier SNPs detected fluctuations in the magnitude and strength of the markers putatively under positive selection over space and time. One locus under putative positive selection was consistent at both locations during the same years, suggesting the existence of weak postsettlement selection.

Discovery of leucokinin-like neuropeptides that modulate a specific parameter of feeding motor programs in the molluscan model, Aplysia

A better understanding of neuromodulation in a behavioral system requires identification of active modulatory transmitters. Here, we used identifiable neurons in a neurobiological model system, the mollusc Aplysia, to study neuropeptides, a diverse class of neuromodulators. We took advantage of two types of feeding neurons, B48 and B1/B2, in the Aplysia buccal ganglion that might contain different neuropeptides. We performed a representational difference analysis (RDA) by subtraction of mRNAs in B48 versus mRNAs in B1/B2. The RDA identified an unusually long (2025 amino acids) peptide precursor encoding Aplysia leucokinin-like peptides (ALKs; e.g. ALK-1 and ALK-2). Northern blot analysis revealed that, compared with other ganglia (e.g. the pedal-pleural ganglion), ALK mRNA is predominantly present in the buccal ganglion, which controls feeding behavior. We then used in situ hybridization and immunohistochemistry to localize ALKs to specific neurons, including B48. MALDI-TOF MS on single buccal neurons revealed expression of 40 ALK precursor-derived peptides. Among these, ALK-1 and ALK-2 are active in the feeding network; they shortened the radula protraction phase of feeding motor programs triggered by a command-like neuron. We also found that this effect may be mediated by the ALK-stimulated enhancement of activity of an interneuron, which has previously been shown to terminate protraction. We conclude that our multipronged approach is effective for determining the structure and defining the diverse functions of leucokinin-like peptides. Notably, the ALK precursor is the first verified nonarthropod precursor for leucokinin-like peptides with a novel, marked modulatory effect on a specific parameter (protraction duration) of feeding motor programs.

Analysis of safety-related regulatory actions by Japan's pharmaceutical regulatory agency.

To evaluate the safety-related regulatory actions implemented by Japan's Pharmaceuticals and Medical Devices Agency (PMDA) in 2012. We analyzed serious safety issues appended to drug package inserts (PIs) in Japan in 2012. The issues were characterized according to drug class, adverse event, years since drug approval, initiator of regulatory actions, revised section of PI, and evidence source. We also quantified the durations from signal detection to tentative decision and from tentative decision to regulatory action. We identified 144 serious safety issues during the study period, and the majority of evidence originated from spontaneous reports (83.5%). The PMDA initiated regulatory actions for half of all safety issues, and the median duration from drug approval to regulatory action was 8years (interquartile range [IQR], 3-26.5years). The median duration was 49days (IQR, 0-362days) from signal detection to tentative decision and 84days (IQR, 63-136days) from tentative decision to regulatory action. Several safety issues involving older drugs and multiple products had protracted decision-making durations. Most safety issues led to prompt regulatory actions predominantly based on spontaneous reports. Some safety issues that were not easily detected by the spontaneous reporting system were identified years after approval. In addition, several safety issues required assessments of multiple drug products, which prolonged the decision-making process.

Abstract 1848: Autocrine IGF1 signaling mediates the survival of pancreatic cancer cells following the ablation of oncogenes

Abstract Pancreatic cancer is an extremely lethal disease, which is mostly associated with the gain-of-function mutation in KRAS gene. Due to a very high frequency of activating mutations within the KRAS gene, mutant KRAS is considered a rational therapeutic target in pancreatic cancer. In line with the existing idea that oncogenic KRAS is required for the maintenance of pancreatic cancer, we show a complete macroscopic regression of both primary and orthotopically transplanted tumors in our ligand-regulatable (Doxycycline) mouse model of KRASG12D-driven pancreatic cancer. This finding indicate that the expression, and provides a strong rationale for the development of KRAS targeted therapy for the treatment of pancreatic cancer. However, in our current study, despite the complete macroscopic regression of PDACs upon downregulation of oncogenic KRAS, few cancer cells always survived and remained dormant for a protracted duration. These residual cancer cells were responsible for the rapid recurrence upon KRAS reactivation. Using a genome-wide gene expression (RNA-Seq) analysis of in vivo-derived bulk and residual cancer cells followed by biochemical analysis, we identified a significant increase in autocrine IGF-1/AKT signaling in residual cancer cells. We also identified IGF1 signaling as a common survival mechanism of residual cancer cells in c-MYC-driven pancreatic tumor model. Pharmacological inhibition of IGF-1R signaling significantly delayed the tumor recurrence in both the tumor models, suggesting the crucial role of IGF-1R signaling in the survival of cancer cells in the absence of oncogenic drivers. Our findings from animal models were also validated in human pancreatic cancer cell lines harboring KRAS mutations, by demonstrating a compensatory increase in IGF1 signaling in response to a conditional knockdown of KRAS in vitro and in vivo. Collectively, all our findings from mouse model and human cancer cell studies strongly indicate that residual cancer cells can survive in the absence of tumor driving oncogenes by upregulation of autocrine IGF1 signaling loop. Thus, targeting oncogenic drivers along with IGF-1R signaling might be an effective strategy for prevention of tumor recurrence in pancreatic cancer. Citation Format: Nirakar Rajbhandari. Autocrine IGF1 signaling mediates the survival of pancreatic cancer cells following the ablation of oncogenes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1848. doi:10.1158/1538-7445.AM2017-1848

Nutritional Challenges in Patients After Intestinal Auto-Transplantation and Ex-Vivo Surgery

Introduction: Intestinal auto-transplantation (IATx) and ex-vivo surgery is a novel surgical strategy to treat patients with conventionally unresectable abdominal neoplasms involving the mesenteric root. Adequate nutrition after surgery is crucial, but major surgery and early motility problems can delay the initiation of oral diets and warrant supplemental parenteral (PN) and/or enteral nutrition (EN) for protracted durations. Nutritional challenges after IATx and ex-vivo surgery have not previously been well-described. Methods: Eleven patients aged 7 to 68 (median, 49) underwent IATx and ex-vivo surgery at our center from 2009 to 2016. A retrospective chart review was performed to evaluate nutritional status, tolerance of an oral diet and need of PN and EN support. These factors were assessed both pre and peri-operatively as well as at 3 months post-operatively. Results: Six patients underwent isolated IATx, and 5 underwent both liver and IATx. Seven patients are currently alive without evidence of disease with a median of 7 years follow-up. Prior to surgery, 10 out of 11 patients were tolerating oral diets without need for additional PN or EN. Pre-operative BMI ranged from 14.6-30.4 (median, 20.9). Post-operatively, PN was initiated in all patients from 1-15 days after surgery (median, 5) and continued from 12-122 days (median, 32.5) with the exception of one patient who underwent a total enterectomy and required subsequent allotransplantation with ongoing PN use. EN was initiated in nine patients from 4-117 days after surgery (median, 17). Enteral supplementation has been ongoing in 7 patients and weaned off completely in 2. One patient was started directly on an oral diet without EN and another required allotransplantation with ongoing PN use. Oral diets were initiated in all patients from 5 -115 days (median, 14) after surgery and at 3-month follow-up, all patients were tolerating oral diets, with BMI ranging from 15.2-27.7 (median 18.5). Conclusion: IATx and ex-vivo surgery presents a unique challenge with respect to nutritional management. Patients undergoing these complex surgeries may have difficulty maintaining adequate nutrition with an oral diet alone in the immediate post-operative period and beyond, and may require prolonged support with PN and EN. Nutritional status must be closely monitored and optimized accordingly in this population.

Mechanisms for the functional differentiation of the propulsive and braking roles of the forelimbs and hindlimbs during quadrupedal walking in primates and felines.

During quadrupedal walking in most animals, the forelimbs play a net braking role, whereas the hindlimbs are net propulsive. However, the mechanism by which this differentiation occurs remains unclear. Here, we test two models to explain this pattern using primates and felines: (1) the horizontal strut effect (in which limbs are modeled as independent struts), and (2) the linked strut model (in which limbs are modeled as linked struts with a center of mass in between). Video recordings were used to determine point of contact, timing of mid-stance, and limb protraction/retraction duration. Single-limb forces were used to calculate contact time, impulses and the proportion of the stride at which the braking-to-propulsive transition (BP) occurred for each limb. We found no association between the occurrence of the BP and mid-stance, little influence of protraction and retraction duration on the braking-propulsive function of a limb, and a causative relationship between vertical force distribution between limbs and the patterns of horizontal forces. These findings reject the horizontal strut effect, and provide some support for the linked strut model, although predictions were not perfectly matched. We suggest that the position of the center of mass relative to limb contact points is a very important, but not the only, factor driving functional differentiation of the braking and propulsive roles of the limbs in quadrupeds. It was also found that primates have greater differences in horizontal impulse between their limbs compared with felines, a pattern that may reflect a fundamental arboreal adaptation in primates.

Conditions for Endemicity: Qualitative Population Dynamics in a Long-running Outbreak of Ebola Virus Disease

Ebola virus disease (EVD) struck West Africa in 2013-2016 in an epidemic of unprecedented scope, with over 28000 cases and 11000 fatalities in the affected region. The protracted duration of the outbreak - more than two-and-one-half years of active transmission - raises questions about the persistence of EVD. In this brief paper, we qualitatively examine conditions supporting long-running EVD epidemics via a susceptible - exposed - infectious - recovered - deceased-infectious differential equations model that incorporates births and non disease-related deaths. We define an 'effective epidemiological population' to include contagious individuals recently deceased from the disease. Under a constant effective epidemiological population condition, we consider the basic reproductive number R0&nbsp;and use Lyapunov function arguments to establish conditions in the parameter space supporting an exchange of stability from the disease-free equilibrium to an endemic equilibrium.

Conditions for endemicity: qualitative population dynamics in a long-running outbreak of Ebola virus disease

AbstractEbola virus disease (EVD) struck West Africa in 2013–2016 in an epidemic of unprecedented scope, with over 28000 cases and 11000 fatalities in the affected region. The protracted duration of the outbreak – more than two-and-one-half years of active transmission – raises questions about the persistence of EVD. In this brief paper, we qualitatively examine conditions supporting long-running EVD epidemics via a susceptible – exposed – infectious – recovered – deceased-infectious differential equations model that incorporates births and non disease-related deaths. We define an ‘effective epidemiological population’ to include contagious individuals recently deceased from the disease. Under a constant effective epidemiological population condition, we consider the basic reproductive number and use Lyapunov function arguments to establish conditions in the parameter space supporting an exchange of stability from the disease-free equilibrium to an endemic equilibrium.

Post-breast surgery pain syndrome: establishing a consensus for the definition of post-mastectomy pain syndrome to provide a standardized clinical and research approach - a review of the literature and discussion.

Post-mastectomy pain syndrome (PMPS) is a frequent complication of breast surgery. There is currently no standard definition for this chronic pain syndrome. The purpose of this review was to establish a consensus for defining PMPS by identifying the various elements included in the definitions and how they vary across the literature, determining how these definitions affect the methodological components therein, and proposing a definition that appropriately encompasses all of the appropriate elements. We searched PubMed to retrieve all studies and case reports on PMPS, and we analyzed definitions of PMPS, inclusion/exclusion criteria, and methods of measuring PMPS. Twenty-three studies were included in this review. We identified 7 independent domains for defining PMPS: surgical breast procedure, neuropathic nature, pain of at least moderate intensity, protracted duration, frequent symptoms, appropriate location of the symptoms and exacerbation with movement. These domains were used with varying frequency. Inclusion/exclusion criteria and methods for assessing PMPS also varied markedly. To prevent future discrepancies in both the clinical and research settings, we propose a new and complete definition based on the results of our review: PMPS is pain that occurs after any breast surgery; is of at least moderate severity; possesses neuropathic qualities; is located in the ipsilateral breast/chest wall, axilla, and/or arm; lasts at least 6 months; occurs at least 50% of the time; and may be exacerbated by movements of the shoulder girdle.

Identification of adult knee primary bone tumour symptom presentation: A qualitative study

ObjectivesThe aim of this study was to identify the symptom presentation of adult knee primary bone tumours from onset to Consultant diagnosis, from combined patient and healthcare professional perspectives. Materials and methodsA qualitative study using in-depth semi-structured interviews recruited a purposive sample of adult patients with a knee primary bone tumour (n = 8) and healthcare professionals with expertise in orthopaedic oncology (n = 6). Following informed consent, recorded interviews explored participants' experiences of symptom presentation. A grounded theory approach was utilised to analyse transcribed data, producing themes. Methods to increase rigour and trustworthiness were employed. Recruitment continued until data saturation was achieved. ResultsFour key themes were established: 1] Symptoms started with intermittent pain which became more severe and more constant, 2] Pain was mechanical in nature but became more difficult to ease; 3] The pain story was unusual with a protracted symptom duration and failure to improve with conservative treatment; 4] Non-painful symptoms included swelling, and systemic signs were uncommon. More similarities between healthcare professionals' and patients' perceptions were found at Consultant diagnosis compared to onset. ConclusionNew insights of symptom presentation, particularly in the early stages have been provided which are not reflected in current guidelines. Although starting similarly to routine musculoskeletal presentations, a number of distinctive features may enable earlier diagnosis.

Assessment of Change in Palatal Sensation in Obstructive Sleep Apnea Patients by Using Two-Point Palatal Discrimination.

Objectives.Patients with obstructive sleep apnea syndrome (OSAS) have impaired responses to inspiratory resistive loading during sleep. This may be due, in part, to a change in the upper airway sensation. Therefore, we hypothesized that patients with OSAS have diminished upper airway sensation due to snoring.Methods.A total of 53 participants were selected based on clinical evaluation and polysomnography. Two-point discrimination was measured with modified calipers in the tongue and soft palate.Results.A total of 10 participants were included in the control group, 12 participants in the simple snoring group, and 27 participants in the OSAS group. There were 12 patients in the impaired sensation group of the OSAS group. On comparing polysomnography, patients with impairment of their palatal sensory input in two-point discrimination (TPD) had a more protracted duration of the longest snoring episode than those with simple snoring and normal sensation. Patients with decreased sensory input in TPD had longer average duration of snoring episodes and relative snoring time than those with simple snoring and normal sensory input in cold uvular TPD. Comparison of the cold uvular TPD for normal sensation and impaired sensation in patients with OSAS after treatment showed a different trend.Conclusion.Impaired sensation of the soft palate was correlated with the longest snoring episode duration, average snoring episode duration, and relative snoring time. It is helpful in detecting the early stage of neural degradation in OSAS patients by assessing snoring components of polysomnography and TPD in the soft palate.

Specific Factors Influence Postconcussion Symptom Duration among Youth Referred to a Sports Concussion Clinic

To identify the clinical factors that influence the duration of postconcussion symptoms among youth referred to a sports concussion clinic. A retrospective cohort study was conducted to evaluate several potential predictors of symptom duration via a Cox proportional hazards analyses. The individual postconcussion symptom scores were highly correlated, so these symptoms were analyzed in the statistical model as coefficients derived from principal component analyses. Among 1953 youth with concussion, 1755 (89.9%) had dates of reported symptom resolution. The remainder (10.1%) were lost to follow-up and censored. The median time to recovery was 18days (range 1-353days). By 30days, 72.6% had recovered; by 60days, 91.4% had recovered; and by 90days, 96.8% had recovered. Several variables in a multivariate Cox model predicted postconcussion symptom duration: female sex (P<.001, hazard ratio [HR]=1.28), continued activity participation (P=.02, HR=1.13), loss of consciousness (P=.03, HR=1.18), anterograde amnesia (P=.04, HR=1.15), premorbid headaches (P=.03, HR=1.15), symptom components from the day of concussion (emotion, P=.03, HR=1.08), and the day of clinic evaluation (cognitive-fatigue, P<.001, HR=1.22; cephalalgic, P<.001, HR=1.27; emotional, P=.05, HR=1.08; arousal-stimulation, P=.003, HR=1.1). In univariate analyses, greater symptom scores generally predicted longer symptom durations. Worsening of symptoms from the day of concussion to the day of clinic evaluation also predicted longer recovery (P<.001, HR=1.59). Several factors help to predict protracted postconcussion symptom durations among youth referred to a sports concussion clinic.

On the deep structure of social affect: Attitudes, emotions, sentiments, and the case of "contempt".

Contempt is typically studied as a uniquely human moral emotion. However, this approach has yielded inconclusive results. We argue this is because the folk affect concept "contempt" has been inaccurately mapped onto basic affect systems. "Contempt" has features that are inconsistent with a basic emotion, especially its protracted duration and frequently cold phenomenology. Yet other features are inconsistent with a basic attitude. Nonetheless, the features of "contempt" functionally cohere. To account for this, we revive and reconfigure the sentiment construct using the notion of evolved functional specialization. We develop the Attitude-Scenario-Emotion (ASE) model of sentiments, in which enduring attitudes represent others' social-relational value and moderate discrete emotions across scenarios. Sentiments are functional networks of attitudes and emotions. Distinct sentiments, including love, respect, like, hate, and fear, track distinct relational affordances, and each is emotionally pluripotent, thereby serving both bookkeeping and commitment functions within relationships. The sentiment contempt is an absence of respect; from cues to others' low efficacy, it represents them as worthless and small, muting compassion, guilt, and shame and potentiating anger, disgust, and mirth. This sentiment is ancient yet implicated in the ratcheting evolution of human ultrasocialty. The manifolds of the contempt network, differentially engaged across individuals and populations, explain the features of "contempt," its translatability, and its variable experience as "hot" or "cold," occurrent or enduring, and anger-like or disgust-like. This rapprochement between psychological anthropology and evolutionary psychology contributes both methodological and empirical insights, with broad implications for understanding the functional and cultural organization of social affect.

Mixed Amiodarone-Induced Thyrotoxicosis Refractory to Medical Therapy and Plasmapheresis

Amiodarone-induced thyrotoxicosis (AIT) is associated with increased mortality in older individuals with impaired ventricular function, underlying the importance of rapid restoration and maintenance of euthyroidism. Plasmapheresis for treating thyrotoxicosis has shown mixed results. A 61-year-old gentleman was hospitalized for progressively worsening dyspnea, palpitations, tremor and generalized weakness. He had a history of atrial fibrillation, coronary artery disease, heart failure and type 2 diabetes. He had been diagnosed with AIT 4 months prior to admission, after which amiodarone was discontinued, and he was started on prednisone and methimazole which was later changed to propylthiouracil. Physical examination revealed irregular tachycardia, lid lag, fine hand tremor, proximal muscle weakness, pedal edema and a small, smooth, non-tender thyroid gland without bruit. Hormonal investigations revealed low TSH of 0.02 mcr IU/mL (reference: 0.28 - 3.89), high free T4 of 4.88 ng/dL (reference: 0.58 - 1.64), high free T3 of 5.4 pg/mL (reference: 2.5 - 3.9) and normal total T3 of 114 ng/dL (reference: 87 - 178). Thyroglobulin antibody, thyroid peroxidase antibody and thyroid stimulating immunoglobulin were undetectable. Echocardiogram revealed reduced left ventricle ejection fraction of 25%. Ultrasound showed a bilaterally heterogeneous, hypovascular and hypoechoic thyroid. I-123 scan revealed very low uptake. These findings were suggestive of destructive type 2 AIT. However, the lack of a good response to steroids argued for type 1 AIT. Given his poor response to medical therapy and increased cardiovascular risk for an urgent thyroidectomy, plasmapheresis was instituted in an attempt to lower the thyroid hormone levels. Eight daily cycles provided only modest clinical and biochemical improvement. Subsequently, he underwent total thyroidectomy leading to improvement of thyrotoxicosis. Histopathology of the thyroid demonstrated intrafollicular histiocytes, patchy fibrosis and involuted follicles, suggestive of destructive thyroiditis. On follow-up 2 months later, he remained clinically euthyroid on levothyroxine replacement with stable cardiac status. This case represents mixed/indeterminate AIT of protracted duration refractory to thionamides and steroids. Plasmapheresis did not provide clinical improvement and only modestly lowered the free T4 level. Euthyroidism was finally achieved following total thyroidectomy. This finding suggests the limitations of utilizing plasmapheresis as a therapeutic modality prior to definitive treatment in AIT. J Endocrinol Metab. 2015;5(3):220-223 doi: http://dx.doi.org/10.14740/jem278w

The tuberculosis drug discovery and development pipeline and emerging drug targets.

The recent accelerated approval for use in extensively drug-resistant and multidrug-resistant-tuberculosis (MDR-TB) of two first-in-class TB drugs, bedaquiline and delamanid, has reinvigorated the TB drug discovery and development field. However, although several promising clinical development programs are ongoing to evaluate new TB drugs and regimens, the number of novel series represented is few. The global early-development pipeline is also woefully thin. To have a chance of achieving the goal of better, shorter, safer TB drug regimens with utility against drug-sensitive and drug-resistant disease, a robust and diverse global TB drug discovery pipeline is key, including innovative approaches that make use of recently acquired knowledge on the biology of TB. Fortunately, drug discovery for TB has resurged in recent years, generating compounds with varying potential for progression into developable leads. In parallel, advances have been made in understanding TB pathogenesis. It is now possible to apply the lessons learned from recent TB hit generation efforts and newly validated TB drug targets to generate the next wave of TB drug leads. Use of currently underexploited sources of chemical matter and lead-optimization strategies may also improve the efficiency of future TB drug discovery. Novel TB drug regimens with shorter treatment durations must target all subpopulations of Mycobacterium tuberculosis existing in an infection, including those responsible for the protracted TB treatment duration. This review summarizes the current TB drug development pipeline and proposes strategies for generating improved hits and leads in the discovery phase that could help achieve this goal.

All cravings are not created equal.

We argued that it is important to consider urge intensity when examining the neural correlates of craving [1]. While we believed there were important conceptual and empirical reasons for this position (illustrated empirically by differences between deprived and nondeprived samples), we noted that researchers often have ignored the potential significance of urge levels. We were gratified to see that the commentators generally seemed comfortable with what we had wondered might be viewed as a controversial critique [2–4]. We hope that moving forward researchers conducting “craving” studies with nondeprived smokers will address whether their findings may instead relate to less intense states of desire. Moeller et al. [2] suggest that the concept of craving requires refinement and propose additional factors besides deprivation that might distinguish between “low-level desire and clinically-relevant craving.” We agree that deprivation is just one factor addressing the broader issue that urge intensity warrants increased attention [5] and that the role of deprivation in craving varies across drugs of abuse. We also concur that improved assessment of craving is needed in neuroimaging research, although doing so in the context of a multi-trial design may prove problematic due to the likely protracted duration of robust craving responses and potential carryover effects [6, 7]. Potvin found “inspiring” our central point that urge intensity matters, but requested additional data to address potential overlapping activation between studies of deprived and nondeprived smokers, which we provide in supplemental tables. Deprived and nondeprived samples yielded largely divergent activation patterns, with only 3 of 22 foci identified across study types overlapping. Although we observed some overlap in the rACC, the overlapping portion was significantly smaller than the region exhibiting more reliable activation for deprived versus nondeprived studies (240 mm2 versus 960 mm2, respectively). We hope that these new data, coupled with the observation that cue exposure generates more reliable activation across a much larger portion of the rACC in deprived groups provides more persuasive evidence of our general premise that uncontrollable and moderate cravings may trigger different brain responses, especially in light of recent work linking the rACC to clinically-relevant reductions in craving [8–13]. We agree with Thayer and Weiland [4] that there still may be value to studying smokers experiencing mild desire. We believe, though, that study designs should be guided by theory and the specific goals of the study. Like Thayer and Weiland, we believe that our understanding of addiction will benefit not only from studying brain responses during states of intense desire (craving), but also by examining brain activity when this desire is satisfied [e.g., 14] or actively inhibited [e.g., 15]. As they note, addressing the potential influence of acute nicotine (and nicotine withdrawal for that matter) on hemodynamics and neurovascular coupling is also warranted, although effects may be complex [e.g., 16] In sum, we agree with all the commentators that there may well be a host of variables that influence the neural correlates of craving. We hope that this set of papers and commentaries reinforces the view that not all cravings are equivalent, that there is a need for increased focus on the manner in which craving is conceptualized, manipulated and measured, and that deprivation level is a particularly important variable to consider.

Shoulder arthroscopy and complications: Can we afford to relax?

Shoulder arthroscopy and complications: Can we afford to relax?

Multiple episodes of anatexis in a collisional orogen: Zircon evidence from migmatite in the Dabie orogen

A combined study of mineral inclusions, U–Pb ages and trace elements was carried out on zircon from migmatites in the Dabie orogen. The results provide insights into multistage anatexis of ultrahigh-pressure metamorphic rocks in the continental collision orogen. Zircon grains in thin sections and mounts record four episodes of magmatic, metamorphic and anatectic events: (1) middle Neoprotrozoic U–Pb ages for domains that contain Qz ± Ap ± Pl inclusions and exhibit high Th/U ratios (> 0.1), steep HREE patterns with marked negative Eu anomalies, dating protolith emplacement; (2) late Triassic U–Pb ages of 212 ± 5 to 219 ± 4 Ma for domains that contain Cpx ± Grt inclusions and show low Th/U ratios (< 0.1), flat HREE patterns without negative Eu anomalies, dating quartz eclogite-facies metamorphism during the early exhumation of deeply subducted continental crust; (3) U–Pb ages of 192 ± 4 to 200 ± 4 Ma for domains that contain multiphase solid inclusions of Qz + Pl + Hem + Cal, Qz + Kfs + Ep, Qz + Bt + Ap and Qz + Pl + Bt, and exhibit low Th/U ratios (< 0.1), steeper HREE patterns with negative Eu anomalies and high Nb and Ta contents, dating the first episode of anatexis in association with granulite-facies overprinting during the late exhumation; and (4) early Cretaceous U–Pb ages of 124 ± 1 to 140 ± 4 Ma for domains that contain Qz inclusion and show variable Th/U ratios, typical magmatic REE patterns, dating the second episode of anatexis which occurred during the Cretaceous in the postcollisional stage. The zircon domains in the two episodes of anatexis exhibit a large range of U–Pb ages, suggesting protracted durations of anatexis in both exhumational and postcollisional stages. There are considerable differences in the compositions of zircons between the two episodes of anatexis, suggesting differential behaviors of their anatexis. The first episode of anatexis is caused by dehydration melting in association with decompressional exhumation, resulting in coprecipitation of zircon and REE-rich minerals such as allanite/epidote and monazite from the anatectic melt. The second episode of anatexis is caused by both dehydration and hydration melting due to breakdown of monazite and hydrous minerals such as allanite/epidote and amphibole with local focus of aqueous solutions. This leads to variable Th/U ratios but relatively consistent magmatic zircon-like trace element compositions, with the widespread occurrence of poikilitic amphibole in the leucosome. In either case, the anatectic zircons record the partial melting of ultrahigh-pressure metamorphic rocks at different times and P–T conditions.

Endothelial cell regulation of cardiac metabolism following diabetes.

The earliest change that occurs in the diabetic heart is reduced glucose consumption, with a switch to utilization of fatty acids (FA) predominantly as an energy resource. Although this adaptation might be beneficial in the short-term, over a protracted duration, it is potentially catastrophic given the malicious effects produced by high FA in cardiomyocytes. In this review, we describe how the endothelial cell (EC), a "first-responder" to hyperglycemia, communicates with the underlying cardiomyocyte. As this cross-talk is expected to facilitate increased FA delivery to, and utilization by, the cardiomyocyte, understanding this conversationshould assist in devising new therapeutic strategies to prevent or delay diabetic heart disease.