Adjuvant Therapy Use for Patients With Inadequately Resected T1b-T3 Gallbladder Cancer.

INTRODUCTION: Up to 90% of patients undergo inadequate resection for incidentally diagnosed T1b-T3 gallbladder cancer (GBC). We evaluated whether adjuvant therapies (ATs) are associated with prolonged overall survival (OS) for patients undergoing inadequate resection of T1b-T3 GBC. METHODS: Patients who underwent inadequate resection, defined as simple cholecystectomy, for T1b-T3, Nx-N2, and M0 GBC were identified from the National Cancer Database (2004-2016). Patient characteristics, variables associated with AT use, and OS were described using the chi-square test, multivariable logistical regression, Kaplan-Meier, and Cox proportional hazard models. RESULTS: Of 1386 patients who met inclusion criteria, most received no AT (64%), 20% received chemotherapy (CT), and 16% received chemoradiotherapy (CRT). Patients who received no AT were generally older (51% ≥ 75 y) and had no comorbidities (65% Charlson Comorbidity Index 0). Among those who received AT, CRT rather than CT, tended to be employed for patients who were older (≥75 y) or had more comorbidities (Charlson Comorbidity Index ≥1). Patients with advanced disease (T3, positive lymph nodes, or positive margins) were more likely to receive CRT. For T1b-T3 GBC, any AT was associated with prolonged median OS compared to no AT (22 months versus 15 mo, P < 0.01). Relative to no AT, CT (hazard ratio 0.76, 95% confidence interval 0.67-0.92) and CRT (0.59, 95% confidence interval 0.49-0.72) were associated with decreased risk of death. CONCLUSIONS: AT was associated with prolonged OS for patients with inadequately resected T1b-T3 GBC. CRT may have a role in treatment for patients with high-risk disease following inadequate resection of T1b-T3 GBC.

Chemotherapy refusal and subsequent survival in healthy older women with high genomic risk estrogen receptor-positive breast cancer.

BACKGROUND: Patients with estrogen receptor (ER)-positive, HER2-negative breast cancer (BC), and high-risk 21-gene recurrence score (RS) results benefit from chemotherapy. We evaluated chemotherapy refusal and survival in healthy older women with high-RS, ER-positive BC. METHODS: Retrospective review of the National Cancer Database (2010-2017) identified women ≥ 65 years of age, with ER-positive, HER2-negative, high-RS (≥ 26) BC. Patients with Charlson Comorbidity Index ≥ 1, stage III/IV disease, or incomplete data were excluded. Women were compared by chemotherapy receipt or refusal using the Cochrane-Armitage test, multivariable logistical regression modeling, the Kaplan-Meier method, and Cox's proportional hazards modeling. RESULTS: 6827 women met study criteria: 5449 (80%) received chemotherapy and 1378 (20%) refused. Compared to women who received chemotherapy, women who refused were older (71 vs 69 years), were diagnosed more recently (2014-2017, 67% vs 61%), and received radiation less frequently (67% vs 71%) (p ≤ 0.05). Refusal was associated with decreased 5-year OS for women 65-74 (92% vs 95%) and 75-79 (85% vs 92%) (p ≤ 0.05), but not for women ≥ 80 years old (84% vs 91%; p = 0.07). On multivariable analysis, hazard of death increased with refusal overall (HR 1.12, 95% CI 1.04-1.2); but, when stratified by age, was not increased for women ≥ 80 years (HR 1.10, 95% CI 0.80-1.51). CONCLUSIONS: Among healthy women with high-RS, ER-positive BC, chemotherapy refusal was associated with decreased OS for women ages 65-79, but did not impact the OS of women ≥ 80 years old. Genomic testing may have limited utility in this population, warranting prudent shared decision-making and further study.

Clinical translational neuroimaging of the antioxidant effect of N-acetylcysteine on neural microstructure.

PURPOSE: Oxidative stress and downstream effectors have emerged as important pathological processes that drive psychiatric illness, suggesting that antioxidants may have a therapeutic role in psychiatric disease. However, no imaging biomarkers are currently available to track therapeutic response. The purpose of this study was to examine whether advanced DWI techniques are able to sensitively detect the potential therapeutic effects of the antioxidant N-acetylcysteine (NAC) in a Disc1 svΔ2 preclinical rat model of psychiatric illness. METHODS: Male and female Disc1 svΔ2 rats and age-matched, sex-matched Sprague-Dawley wild-type controls were treated with a saline vehicle or NAC before ex vivo MRI acquisition at P50. Imaging data were fit to DTI and neurite orientation dispersion and density imaging models and analyzed for region-specific changes in quantitative diffusion metrics. Brains were further processed for cellular quantification of microglial density and morphology. All experiments were repeated for Disc1 svΔ2 rats exposed to chronic early-life stress to test how gene-environment interactions might alter effectiveness of NAC therapy. RESULTS: The DTI and neurite orientation dispersion and density imaging analyses demonstrated amelioration of early-life, sex-specific neural microstructural deficits with concomitant differences in microglial morphology across multiple brain regions relevant to neuropsychiatric illness with NAC treatment, but only in male Disc1 svΔ2 rats. Addition of chronic early-life stress reduced the ability of NAC to restore microstructural deficits. CONCLUSION: These findings provide evidence for a treatment pathway targeting endogenous antioxidant capacity, and the clinical translational utility of neurite orientation dispersion and density imaging microstructural imaging to sensitively detect microstructural alterations resulting from antioxidant treatment.

The Addition of Chemoradiation to Adjuvant Chemotherapy is Associated With Improved Survival Following Upfront Surgical Resection for Pancreatic Cancer With Nodal Metastases.

BACKGROUND: It is unclear whether the addition of chemoradiation (CRT) to adjuvant chemotherapy (CT) following upfront resection of pancreatic ductal adenocarcinoma (PDAC) provides any benefit. While some studies have suggested a benefit to combined modality therapy (CMT) (adjuvant CT plus CRT), it is not clear if this benefit was related to increased CT usage in patients who received CMT. We sought to clarify the use of CMT in patients who underwent upfront resection of PDAC. METHODS: Patients with non-metastatic PDAC were retrospectively identified from the linked SEER-Medicare database. Those who underwent upfront resection were identified and divided into two cohorts - patients who received adjuvant CT and patients who received adjuvant CMT. Cohorts were compared. Univariate analysis described patient characteristics. Kaplan-Meier and multivariable Cox proportional hazards modeling were used to estimate overall survival (OS). RESULTS: 3555 patients were identified; 856 (24%) received CT and 573 (16%) received CMT. The median number of CT doses was 11 for both groups. Patients who received CMT were younger, diagnosed in the earlier time frame, and had fewer comorbidities. The median OS was 21 months and 18 months for those treated with CMT and CT (P < .0001), respectively, but when stratified by nodal status, the association with improved OS in the CMT cohort was only observed in node-positive patients. On multivariable analysis, receipt of CMT and removal of >15 lymph nodes decreased the risk of death (P < .05). DISCUSSION: Receipt of CMT following upfront resection for PDAC was associated with improved survival, which was confined to node-positive patients. The role of adjuvant CMT in PDAC with nodal metastases warrants further study.

Staff and participant perceptions of optimal recruitment and retention strategies for biomedical cohort studies in the Caribbean.

PURPOSE: To identify staff and participants perspectives of best practices that facilitate achieving enrollment and retention targets in biomedical cohort studies in Caribbean populations. METHODS: Eight focus group discussions (FGDs) were held with research stakeholders including research (i) nurses/study supervisors, (ii) field staff/data collectors, and (iii) rural and urban participants of the Third Jamaica Health and Lifestyle Survey (a national NCD risk factor survey with biospecimen collection) to capture qualitative data on experiences with recruitment, training, retention challenges and potential solutions or strategies for strengthening future efforts. RESULTS: Our findings indicate that trained, experienced study staff with good interpersonal communication skills enhanced the proficiency of field operations and attracted study participants. Targeted community and stakeholder engagement alongside strong support from the coordinating center increased the reach and efficiency of the data collectors. Timely participant feedback, gender-appropriate approaches, and socioeconomic balance enhanced equitable enrollment and retention of participants of cohort studies particularly the hard to reach groups. CONCLUSION: Well-functioning research teams using traditional and social media promotion, applying gender-appropriate and personalized approaches together with strategies for reaching the less accessible socioeconomic groups, are effective for recruiting and retaining members of a Caribbean cohort. These strategies may also enhance the recruitment of other Black populations in the Diaspora including the US and Caribbean into biomedical studies including cancer research.

Systematic review and meta-analysis of the prevalence of neuropathic-like pain and/or pain sensitization in people with knee and hip osteoarthritis.

OBJECTIVE: To determine the prevalence of neuropathic-like pain (NP) and pain sensitization (PS) defined by self-report questionnaires in knee and hip osteoarthritis, and whether prevalence is potentially explained by disease-severity or affected joint. DESIGN: MEDLINE, EMBASE, CINAHL were systematically searched (1990-April 2020) for studies describing the prevalence of NP and PS in knee and hip osteoarthritis using self-report questionnaires. Random-effects meta-analysis was performed. Statistical heterogeneity between studies and sub-groups (affected joint and population source as a proxy for disease severity) was assessed (I2 statistic and the Chi-squared test). RESULTS: From 2,706 non-duplicated references, 39 studies were included (2011-2020). Thirty-six studies reported on knee pain and six on hip pain. For knee osteoarthritis, the pooled prevalence of NP was: using PainDETECT, possible NP(score ≥13) 40% (95%CI 32-48%); probable NP(score >18) 20% (95%CI 15-24%); using Self-Report Leeds Assessment of Neuropathic Symptoms and Signs, 32% (95%CI 26-38%); using Douleur Neuropathique (DN4) 41% (95% CI 24-59%). The prevalence of PS using Central Sensitization Inventory (CSI) was 36% (95% CI 12-59%). For hip osteoarthritis, the pooled prevalence of NP was: using PainDETECT, possible NP 29% (95%CI 22-37%%); probable NP 9% (95%CI 6-13%); using DN4 22% (95%CI 12-31%) in one study. The prevalence of possible NP pain was higher at the knee (40%) than the hip (29%) (difference 11% (95% CI 0-22%), P = 0.05). CONCLUSIONS: Using self-report questionnaire tools, NP was more prevalent in knee than hip osteoarthritis. The prevalence of NP in knee and hip osteoarthritis were similar for each joint regardless of study population source or tool used. Whether defining NP using self-report questionnaires enables more effective targeted therapy in osteoarthritis requires investigation.

Overnight variation in tidal expiratory flow limitation in COPD patients and its correction: an observational study.

BACKGROUND: Tidal expiratory flow limitation (EFLT) is common among COPD patients. Whether EFLT changes during sleep and can be abolished during home ventilation is not known. METHODS: COPD patients considered for noninvasive ventilation used a ventilator which measured within-breath reactance change at 5 Hz (∆Xrs) and adjusted EPAP settings to abolish EFLT. Participants flow limited (∆Xrs > 2.8) when supine underwent polysomnography (PSG) and were offered home ventilation for 2 weeks. The EPAP pressure that abolished EFLT was measured and compared to that during supine wakefulness. Ventilator adherence and subjective patient perceptions were obtained after home use. RESULTS: Of 26 patients with supine EFLT, 15 completed overnight PSG and 10 the home study. In single night and 2-week home studies, EFLT within and between participants was highly variable. This was unrelated to sleep stage or body position with only 14.6% of sleep time spent within 1 cmH2O of the awake screening pressure. Over 2 weeks, mean EPAP was almost half the mean maximum EPAP (11.7 vs 6.4 cmH2O respectively). Group mean ∆Xrs was ≤ 2.8 for 77.3% of their home use with a mean time to abolish new EFLT of 5.91 min. Adherence to the ventilator varied between 71 and 100% in prior NIV users and 36-100% for naïve users with most users rating therapy as comfortable. CONCLUSIONS: Tidal expiratory flow limitation varies significant during sleep in COPD patients. This can be controlled by auto-titrating the amount of EPAP delivered. This approach appears to be practical and well tolerated by patients. TRIAL REGISTRATION: The trial was retrospectively registered at CT.gov NCT04725500.

Convergence of marine megafauna movement patterns in coastal and open oceans.

The extent of increasing anthropogenic impacts on large marine vertebrates partly depends on the animals' movement patterns. Effective conservation requires identification of the key drivers of movement including intrinsic properties and extrinsic constraints associated with the dynamic nature of the environments the animals inhabit. However, the relative importance of intrinsic versus extrinsic factors remains elusive. We analyze a global dataset of ∼2.8 million locations from >2,600 tracked individuals across 50 marine vertebrates evolutionarily separated by millions of years and using different locomotion modes (fly, swim, walk/paddle). Strikingly, movement patterns show a remarkable convergence, being strongly conserved across species and independent of body length and mass, despite these traits ranging over 10 orders of magnitude among the species studied. This represents a fundamental difference between marine and terrestrial vertebrates not previously identified, likely linked to the reduced costs of locomotion in water. Movement patterns were primarily explained by the interaction between species-specific traits and the habitat(s) they move through, resulting in complex movement patterns when moving close to coasts compared with more predictable patterns when moving in open oceans. This distinct difference may be associated with greater complexity within coastal microhabitats, highlighting a critical role of preferred habitat in shaping marine vertebrate global movements. Efforts to develop understanding of the characteristics of vertebrate movement should consider the habitat(s) through which they move to identify how movement patterns will alter with forecasted severe ocean changes, such as reduced Arctic sea ice cover, sea level rise, and declining oxygen content.

Evaluation of post-exposure prophylaxis practices to improve the cost-effectiveness of rabies control in human cases potentially exposed to rabies in southern Bhutan.

BACKGROUND: Rabies is endemic in southern Bhutan, associated with 1-2 human deaths and high post exposure prophylaxis (PEP) costs annually. Evaluation of clinicians' management of human cases potentially exposed to rabies could contribute to improving PEP prescribing practices to both reduce unnecessary costs associated with PEP and reach the target of zero human deaths due to rabies by 2023. METHODS: A cross-sectional survey of 50 clinicians' management of human cases potentially exposed to rabies was conducted in 13 health centers in high-rabies-risk areas of Bhutan during February-March 2016. RESULTS: Data were collected on clinicians' management of 273 human cases potentially exposed to rabies. The 50 clinicians comprised health assistants or clinical officers (55%) and medical doctors (45%) with a respective median of 19, 21 and 2 years' experience. There was poor agreement between clinicians' rabies risk assessment compared with an independent assessment for each case based on criteria in the National Rabies Management Guidelines (NRMG). Of the 194 cases for which clinicians recorded a rabies risk category, only 53% were correctly classified when compared with the NRMG. Clinicians were more likely to underestimate the risk of exposure to rabies and appeared to prescribe PEP independently of their risk classification.. Male health assistants performed the most accurate risk assessments while female health assistants performed the least accurate. Clinicians in Basic Health Units performed less accurate risk assessments compared with those in hospitals. CONCLUSIONS: This study highlights important discrepancies between clinicians' management of human cases potentially exposed to rabies and recommendations in the NRMG. In particular, clinicians were not accurately assessing rabies risk in potentially exposed cases and were not basing their PEP treatment on the basis of their risk assessment. This has significant implications for achieving the national goal of eliminating dog-mediated human rabies by 2030 and may result in unnecessary costs associated with PEP. Recommendations to improve clinician's management of human cases potentially exposed to rabies include: reviewing and updating the NRMG, providing clinicians with regular and appropriately targeted training about rabies risk assessment and PEP prescription, and regularly reviewing clinicians' practices.

Neurogenesis during Abstinence Is Necessary for Context-Driven Methamphetamine-Related Memory.

Abstinence from methamphetamine addiction enhances proliferation and differentiation of neural progenitors and increases adult neurogenesis in the dentate gyrus (DG). We hypothesized that neurogenesis during abstinence contributes to context-driven drug-seeking behaviors. To test this hypothesis, the pharmacogenetic rat model (GFAP-TK rats) was used to conditionally and specifically ablate neurogenesis in the DG. Male GFAP-TK rats were trained to self-administer methamphetamine or sucrose and were administered the antiviral drug valganciclovir (Valcyte) to produce apoptosis of actively dividing GFAP type 1 stem-like cells to inhibit neurogenesis during abstinence. Hippocampus tissue was stained for Ki-67, NeuroD, and DCX to measure levels of neural progenitors and immature neurons, and was stained for synaptoporin to determine alterations in mossy fiber tracts. DG-enriched tissue punches were probed for CaMKII to measure alterations in plasticity-related proteins. Whole-cell patch-clamp recordings were performed in acute brain slices from methamphetamine naive (controls) and methamphetamine experienced animals (+/-Valcyte). Spontaneous EPSCs and intrinsic excitability were recorded from granule cell neurons (GCNs). Reinstatement of methamphetamine seeking enhanced autophosphorylation of CaMKII, reduced mossy fiber density, and induced hyperexcitability of GCNs. Inhibition of neurogenesis during abstinence prevented context-driven methamphetamine seeking, and these effects correlated with reduced autophosphorylation of CaMKII, increased mossy fiber density, and reduced the excitability of GCNs. Context-driven sucrose seeking was unaffected. Together, the loss-of-neurogenesis data demonstrate that neurogenesis during abstinence assists with methamphetamine context-driven memory in rats, and that neurogenesis during abstinence is essential for the expression of synaptic proteins and plasticity promoting context-driven drug memory.SIGNIFICANCE STATEMENT Our work uncovers a mechanistic relationship between neurogenesis in the dentate gyrus and drug seeking. We report that the suppression of excessive neurogenesis during abstinence from methamphetamine addiction by a confirmed phamacogenetic approach blocked context-driven methamphetamine reinstatement and prevented maladaptive changes in expression and activation of synaptic proteins and basal synaptic function associated with learning and memory in the dentate gyrus. Our study is the first to demonstrate an interesting and dysfunctional role of adult hippocampal neurogenesis during abstinence to drug-seeking behavior in animals self-administering escalating amounts of methamphetamine. Together, these results support a direct role for the importance of adult neurogenesis during abstinence in compulsive-like drug reinstatement.

Identification of Clinical Characteristics Associated With High-Level Care Among Patients With Skin and Soft Tissue Infections.

STUDY OBJECTIVE: Serious adverse outcomes associated with skin and soft tissue infections are uncommon, and current hospitalization rates appear excessive. It would be advantageous to be able to differentiate between patients who require high-level inpatient services and those who receive little benefit from hospitalization. We sought to identify characteristics associated with the need for high-level inpatient care among emergency department patients presenting with skin and soft tissue infections. METHODS: We conducted a nonconcurrent review of existing records to identify emergency department (ED) patients treated for skin and soft tissue infections. For each case, we recorded the presence or absence of select criteria and whether the patient needed high-level care, defined as ICU admission, operating room surgical intervention, or death as the primary outcome. We applied recursive partitioning to identify the principal criteria associated with high-level care. RESULTS: We identified 2,923 patients, including 84 experiencing high-level events. Recursive partitioning identified 6 variables associated with high-level outcomes: abnormal computed tomography, magnetic resonance imaging, or ultrasonographic imaging result; systemic inflammatory response syndrome; history of diabetes; previous infection at the same location; older than 65 years; and an infection involving the hand. One or more of these variables were present in all 84 patients requiring high-level care. CONCLUSION: A limited number of simple clinical characteristics appear to be able to identify skin and soft tissue infection patients who require high-level inpatient services. Further research is needed to determine whether patients who do not exhibit these criteria can be safely discharged from the ED.

Helium-Induced Changes in Circulating Caveolin in Mice Suggest a Novel Mechanism of Cardiac Protection.

The noble gas helium (He) induces cardioprotection in vivo through unknown molecular mechanisms. He can interact with and modify cellular membranes. Caveolae are cholesterol and sphingolipid-enriched invaginations of the plasma-membrane-containing caveolin (Cav) proteins that are critical in protection of the heart. Mice (C57BL/6J) inhaled either He gas or adjusted room air. Functional measurements were performed in the isolated Langendorff perfused heart at 24 h post He inhalation. Electron paramagnetic resonance spectrometry (EPR) of samples was carried out at 24 h post He inhalation. Immunoblotting was used to detect Cav-1/3 expression in whole-heart tissue, exosomes isolated from platelet free plasma (PFP) and membrane fractions. Additionally, transmission electron microscopy analysis of cardiac tissue and serum function and metabolomic analysis were performed. In contrast to cardioprotection observed in in vivo models, the isolated Langendorff perfused heart revealed no protection after He inhalation. However, levels of Cav-1/3 were reduced 24 h after He inhalation in whole-heart tissue, and Cav-3 was increased in exosomes from PFP. Addition of serum to muscle cells in culture or naïve ventricular tissue increased mitochondrial metabolism without increasing reactive oxygen species generation. Primary and lipid metabolites determined potential changes in ceramide by He exposure. In addition to direct effects on myocardium, He likely induces the release of secreted membrane factors enriched in caveolae. Our results suggest a critical role for such circulating factors in He-induced organ protection.

Neuron-specific caveolin-1 overexpression improves motor function and preserves memory in mice subjected to brain trauma.

Studies in vitro and in vivo demonstrate that membrane/lipid rafts and caveolin (Cav) organize progrowth receptors, and, when overexpressed specifically in neurons, Cav-1 augments neuronal signaling and growth and improves cognitive function in adult and aged mice; however, whether neuronal Cav-1 overexpression can preserve motor and cognitive function in the brain trauma setting is unknown. Here, we generated a neuron-targeted Cav-1-overexpressing transgenic (Tg) mouse [synapsin-driven Cav-1 (SynCav1 Tg)] and subjected it to a controlled cortical impact model of brain trauma and measured biochemical, anatomic, and behavioral changes. SynCav1 Tg mice exhibited increased hippocampal expression of Cav-1 and membrane/lipid raft localization of postsynaptic density protein 95, NMDA receptor, and tropomyosin receptor kinase B. When subjected to a controlled cortical impact, SynCav1 Tg mice demonstrated preserved hippocampus-dependent fear learning and memory, improved motor function recovery, and decreased brain lesion volume compared with wild-type controls. Neuron-targeted overexpression of Cav-1 in the adult brain prevents hippocampus-dependent learning and memory deficits, restores motor function after brain trauma, and decreases brain lesion size induced by trauma. Our findings demonstrate that neuron-targeted Cav-1 can be used as a novel therapeutic strategy to restore brain function and prevent trauma-associated maladaptive plasticity.-Egawa, J., Schilling, J. M., Cui, W., Posadas, E., Sawada, A., Alas, B., Zemljic-Harpf, A. E., Fannon-Pavlich, M. J., Mandyam, C. D., Roth, D. M., Patel, H. H., Patel, P. M., Head, B. P. Neuron-specific caveolin-1 overexpression improves motor function and preserves memory in mice subjected to brain trauma.

Intrinsic reproductive isolating mechanisms in the maintenance of a hybrid zone between ecologically divergent subspecies.

Understanding factors involved in maintaining stable hybrid zones is important for predicting the ultimate fate of the interacting taxa, but the relative importance of mechanisms such as ecological selection and intrinsic reproductive isolation remains unclear. Most studies of reproductive isolation in hybrid zones have focused either on zones with strongly bimodal patterns in genotype or phenotype frequencies, with relatively strong isolation, or unimodal zones with relatively weak isolation, whereas less is known about more intermediate classes of hybrid zone. Here, we utilize a hybrid zone of this intermediate type occurring between northern and southern subspecies of Atlantic killifish, Fundulus heteroclitus, to identify isolating mechanisms playing a role in maintaining this type of zone. The two subspecies differ in environmental tolerance, and we found some evidence of microhabitat preference between subspecies within a small tidal creek at the centre of the hybrid zone. There was also an association between sex, mitochondrial genotype and habitat within this creek. Fertilization success did not differ between consubspecific and heterosubspecific crosses, but hatching success was significantly lower for crosses involving southern males and northern females, and crosses between southern females and northern males had altered developmental rates. Southern females and northern males showed patterns consistent with positive assortative mating. Together, these results indicate a role for a combination of factors including assortative mating and/or early hybrid inviability in the maintenance of this hybrid zone and suggest that hybrid zones with intermediate levels of reproductive isolation are likely to be maintained by multiple interacting isolating mechanisms.

Predicting medical students who will have difficulty during their clinical training.

BACKGROUND: We aimed to classify the difficulties students had passing their clinical attachments, and explore factors which might predict these problems. METHODS: We analysed data from regular student progress meetings 2008-2012. Problem categories were: medical knowledge, professional behaviour and clinical skills. For each category we then undertook a predictive risk analysis. RESULTS: Out of 561 students, 203 were found to have one or more problem category and so were defined as having difficulties. Prevalences of the categories were: clinical skills (67%), knowledge (59%) and professional behaviour (29%). A higher risk for all categories was associated with: male gender, international entry and failure in the first half of the course, but not with any of the minority ethnic groups. Professional and clinical skills problems were associated with lower marks in the Undergraduate Medical Admissions Test paper 2. Clinical skills problems were less likely in graduate students. CONCLUSIONS: In our students, difficulty with clinical skills was just as prevalent as medical knowledge deficit. International entry students were at highest risk for clinical skills problems probably because they were not selected by our usual criteria and had shorter time to become acculturated.

Genetic identification of istiophorid larvae from the Gulf of Mexico based on the analysis of mitochondrial DNA control region sequences.

Assigning relative importance of spawning and nursery habitats for threatened and endangered teleosts, such as those seen in the Gulf of Mexico (GoM), relies on the proper identification of the early life-history stages of the species of concern. Here, sequencing a portion of the mitochondrial DNA (mtDNA) control region (CR) I as barcodes is recommended to identify istiophorid (billfish) larvae in the Atlantic Ocean because of its high resolution and the intrinsic value of the levels of genetic variation that can be extracted from these data. The universality of the primers employed here demonstrates their utility for not only the positive identification of istiophorids in the GoM, but for any larval teleost occurring in areas recognized as larval hotspots worldwide.

Wheel running reduces ethanol seeking by increasing neuronal activation and reducing oligodendroglial/neuroinflammatory factors in the medial prefrontal cortex.

The therapeutic effects of wheel running (WR) during abstinence on reinstatement of ethanol seeking behaviors in rats that self-administered ethanol only (ethanol drinking, ED) or ED with concurrent chronic intermittent ethanol vapor experience (CIE-ED) were investigated. Neuronal activation as well as oligodendroglial and neuroinflammatory factors were measured in the medial prefrontal cortex (mPFC) tissue to determine cellular correlates associated with enhanced ethanol seeking. CIE-ED rats demonstrated escalated and unregulated intake of ethanol and maintained higher drinking than ED rats during abstinence. CIE-ED rats were more resistant to extinction from ethanol self-administration, however, demonstrated similar ethanol seeking triggered by ethanol contextual cues compared to ED rats. Enhanced seeking was associated with reduced neuronal activation, and increased number of myelinating oligodendrocyte progenitors and PECAM-1 expression in the mPFC, indicating enhanced oligodendroglial and neuroinflammatory response during abstinence. WR during abstinence enhanced self-administration in ED rats, indicating a deprivation effect. WR reduced reinstatement of ethanol seeking in CIE-ED and ED rats, indicating protection against relapse. The reduced ethanol seeking was associated with enhanced neuronal activation, reduced number of myelinating oligodendrocyte progenitors, and reduced PECAM-1 expression. The current findings demonstrate a protective role of WR during abstinence in reducing ethanol seeking triggered by ethanol contextual cues and establish a role for oligodendroglia-neuroinflammatory response in ethanol seeking. Taken together, enhanced oligodendroglia-neuroinflammatory response during abstinence may contribute to brain trauma in chronic alcohol drinking subjects and be a risk factor for enhanced propensity for alcohol relapse.