Two-Dimensional Fourier Transform Ion Cyclotron Resonance Mass Spectrometry by Matrix-Assisted Laser Desorption Ionization.

Two-dimensional Fourier transform ion cyclotron resonance (2D FTICR) mass spectrometry is a developing form of data-independent acquisition that allows for the simultaneous fragmentation and correlation of fragment ions to their precursors across a range of m/z values. The modern usage of 2D FTICR is performed using electrospray ionization (ESI) as the dried droplet preparation for matrix-assisted laser desorption ionization (MALDI) does not produce a consistent packet of ions over a number of scans. This work uses pneumatic spray techniques from mass spectrometry imaging to create a homogeneous surface for use with MALDI as an ionization source for 2D FTICR. A mixture of peptides and matrix was deposited onto a glass slide using an HTX pneumatic sprayer. MALDI was then used to ionize the peptide mixture for use with a standard 2D FTICR pulse sequence. The generated 2D spectrum reveals comparable structural information to spectra collected in a 1D experiment. Artifacts observed in the collected 2D MALDI spectra do not significantly differ from those expected from 2D ESI spectra.

Liver transplantation as an alternative for the treatment of non-resectable liver colorectal cancer: Advancing the therapeutic algorithm.

Colorectal cancer is a leading cause of cancer-related mortality, with nearly half of the affected patients developing liver metastases. For three decades, liver resection (LR) has been the primary curative strategy, yet its applicability is limited to about 20% of cases. Liver transplantation (LT) for unresectable metastases was attempted unsuccessfully in the 1990s, with high rates of perioperative death and recurrence. There is now more interest in this strategy due to improvements in systemic therapies and surgical techniques. A significant study conducted by the Oslo group showed that patients receiving liver transplants had a 60% chance of survival after five years. Significantly better results have been achieved by using advanced imaging for risk stratification and further refining selection criteria, especially in the Norvegian SECA trials. This review carefully charts the development and history of LT as a treatment option for colorectal cancer liver metastases. The revolutionary path from the early days of exploratory surgery to the current situation of cautious optimism is traced, highlighting the critical clinical developments and improved patient selection standards that have made LT a potentially curative treatment for such challenging very well selected cases.

Predictors of Intraoperative Difficulty and Postoperative Examination Abnormalities in 164 Orbital Operations.

BACKGROUND: Although orbital fractures are common, prediction of outcomes in orbital surgery can be quite challenging. PURPOSE: We aim to identify predictors of intraoperative difficulty, operating time, and postoperative examination abnormalities in subjects undergoing post-traumatic orbital reconstructions. STUDY DESIGN, SETTING, AND SAMPLE: This is a retrospective cohort study of all consecutive orbital operations performed at a private, Level 1 trauma center in Portland, Oregon, USA over an 82-month period. All subjects that underwent exploration of the internal orbit for traumatic indications during the study period were included in the cohort. PREDICTOR VARIABLES: Four plating styles, surgical approach (transorbital vs transantral), days from injury to first surgery, fracture size (approximated as a rectangle using linear measurements from computed tomography scans), anteroposterior fracture position, and medial wall involvement were examined. OUTCOME VARIABLES: The primary outcome variable was intraoperative difficulty (defined as requiring revision after intraoperative imaging or return to the operating room). Secondary outcome variables included operating time and postoperative examination abnormalities. COVARIATES: Age and sex were included. ANALYSES: χ2 and Regression analyses were performed using a significance level of P < .05. RESULTS: One hundred and sixty four orbital operations were performed (90 isolated injuries and 74 combined orbital/midface injuries) on 155 subjects (73% male, mean age 39.8 years, standard deviation 16.7). In subjects with isolated orbital fractures, medial wall involvement was associated with intraoperative difficulty (P = .01). When using a transantral approach, intraoperative difficulty was more likely in more anterior fractures (P = .02). Plating style was associated with operating time (P = .03), with median times from 81 to 105 minutes (range 21 to 248 minutes). Postoperative examination abnormalities were more likely in the transorbital approach group (P = .01). Neither days to first surgery nor intraoperative difficulty were associated with postoperative examination abnormalities. Postoperative eyelid changes were seen in 13.6% of transorbital approaches and 0% of transantral approaches. Correction of gaze restriction and enophthalmos were more likely than correction of diplopia (P < .01). CONCLUSIONS AND RELEVANCE: Medial wall involvement is associated with intraoperative difficulty in orbital surgery. Anteriorly positioned fractures are better treated transorbitally, while posterior fractures may be amenable to transantral repair, thus avoiding risk of lower eyelid changes.

Surgical Trainee Performance and Alignment With Surgical Program Director Expectations.

OBJECTIVE: To examine the alignment between graduating surgical trainee operative performance and a prior survey of surgical program director expectations. BACKGROUND: Surgical trainee operative training is expected to prepare residents to independently perform clinically important surgical procedures. METHODS: We conducted a cross-sectional observational study of US general surgery residents' rated operative performance for Core general surgery procedures. Residents' expected performance on those procedures at the time of graduation was compared to the current list of Core general surgery procedures ranked by their importance for clinical practice, as assessed via a previous national survey of general surgery program directors. We also examined the frequency of individual procedures logged by residents over the course of their training. RESULTS: Operative performance ratings for 29,885 procedures performed by 1861 surgical residents in 54 general surgery programs were analyzed. For each Core general surgery procedure, adjusted mean probability of a graduating resident being deemed practice-ready ranged from 0.59 to 0.99 (mean 0.90, standard deviation 0.08). There was weak correlation between the readiness of trainees to independently perform a procedure at the time of graduation and that procedure's historical importance to clinical practice ( p = 0.22, 95% confidence interval 0.01-0.41, P = 0.06). Residents also continue to have limited opportunities to learn many procedures that are important for clinical practice. CONCLUSION: The operative performance of graduating general surgery residents may not be well aligned with surgical program director expectations.

Effects of a Novel Beta Lactam Compound, MC-100093, on the Expression of Glutamate Transporters/Receptors and Ethanol Drinking Behavior of Alcohol-Preferring Rats.

Chronic ethanol exposure affects the glutamatergic system in several brain reward regions including the nucleus accumbens (NAc). Our laboratory has shown that chronic exposure to ethanol reduced the expression of glutamate transporter 1 (GLT-1) and cystine/glutamate exchanger (xCT) and, as a result, increased extracellular glutamate concentrations in the NAc of alcohol-preferring (P) rats. Moreover, previous studies from our laboratory reported that chronic ethanol intake altered the expression of certain metabotropic glutamate receptors in the brain. In addition to central effects, chronic ethanol consumption induced liver injury, which is associated with steatohepatitis. In the present study, we investigated the effects of chronic ethanol consumption in the brain and liver. Male P rats had access to a free choice of ethanol and water bottles for five weeks. Chronic ethanol consumption reduced GLT-1 and xCT expression in the NAc shell but not in the NAc core. Furthermore, chronic ethanol consumption increased fat droplet content as well as peroxisome proliferator-activated receptor alpha (PPAR-α) and GLT-1 expression in the liver. Importantly, treatment with the novel beta-lactam compound, MC-100093, reduced ethanol drinking behavior and normalized the levels of GLT-1 and xCT expression in the NAc shell as well as normalized GLT-1 and PPAR-α expression in the liver. In addition, MC-100093 attenuated ethanol-induced increases in fat droplet content in the liver. These findings suggest that MC-100093 may be a potential lead compound to attenuate ethanol-induced dysfunction in the glutamatergic system and liver injury. SIGNIFICANCE STATEMENT: This study identified a novel beta-lactam, MC-100093, that has demonstrated upregulatory effects on GLT-1. MC-100093 reduced ethanol drinking behavior and normalized levels of GLT-1 and xCT expression in the NAc shell as well as normalized GLT-1 and PPAR-α expression in the liver. In addition, MC-100093 attenuated ethanol-induced increases in fat droplet content in the liver.

Availability and utilisation pattern of agricultural waste at household level in selected areas of Bangladesh.

The use of organic fertilisers and soil amendments are almost universally recommended for improving the organic matter levels and maintaining soil health, but few studies documenting the actual availability and quality of such materials on smallholder farms are available. We selected a case study of 300 households from northern and southern Bangladesh to assess the types of waste materials available for recycling and their usage patterns at household level and we applied a novel approach to empirically identify household waste as input inefficiency in a production context. Northern districts have highly intensive farming systems whereas southern districts have low intensity farming. The total amount of agricultural waste produced at household level was estimated at 822 kg per month. Cow dung contributed about 65% of the total waste followed by animal feed refusal waste (11%), garbage (7%) and kitchen waste (6%). Most of the farmers utilised cow dung and wastes as organic fertiliser and lesser amounts as cooking fuel. Econometric analysis shows that the number of cattle and small ruminant per holding, total area of cultivated land and family size were significant factors that influence the amount of waste production at household level. Each household can reduce the chemical fertiliser cost by Tk. 1463 (US$ 17.84) per month by using compost prepared from household waste. There were ample opportunities for compost/vermicomposting and potential markets. The Department of Agricultural Extension from the public sector and private sector agents might motivate farmers to harvest the potential benefits of agricultural waste through effective management and utilisation.

Farmers' fertilizer use gaps relative to government recommendations in the saline coastal zone of the Ganges Delta.

Overuse or underuse of nutrients relative to recommendations is a likely cause of crop yield gaps and an impediment to the achievement of food security. Government-endorsed recommendations are developed to deliver the best evidence-based advice on balanced fertilizer; however, deviations of farmers' nutrient use from the recommendations are rarely examined. This study chose the salt-affected coastal zone of the Ganges Delta, where low crop productivity and cropping intensity by smallholders limit their income, to determine current nutrient use gaps for the first time of three cropping patterns in two representative districts of Bangladesh. A total of 246 farms were surveyed from three farm sizes. Farmers' nutrient use gaps were compared with Fertilizer Recommendation Guides published in 2012 (FRG-2012) and 2018 (FRG-2018). Relative to FRG-2012 recommendations, farmers used 12%, 70%, and 11% overdoses of N, P, and K, respectively, under two fully rice-based cropping patterns, but the level of overdoses increased with farm size. Rates of K (14%), S (28%), and Zn use were below the FRG-2012 recommendations, especially for the smallest category of farms. However, the FRG-2018, increased recommended N (5%), K (62%), S (12%), and Zn rates but reduced P (25%) rates for fully rice-based cropping patterns. In contrast with rice, regardless of farm size, farmers applied overdose nutrients to watermelon but compensated with underdoses in the subsequent monsoon rice implying that farmers prioritized fertilizer expenditure on the most profitable crop. For the cropping pattern with watermelon, farmers could reduce the use of N (69%) and P (46%) and increase the use of K (48%), S (5%), and B. Reducing NPK use gaps can save treasury for both the farmers and the governments by 39.1 and 73.8 USD ha-1, respectively, under fully rice-based cropping patterns. Finally, our findings suggest there is scope to promote crop yields and sustainable intensification through balanced fertilizer use in a vulnerable saline region. Supplementary Information: The online version contains supplementary material available at 10.1007/s13593-022-00797-1.

Are we ready to track climate-driven shifts in marine species across international boundaries? - A global survey of scientific bottom trawl data.

Marine biota are redistributing at a rapid pace in response to climate change and shifting seascapes. While changes in fish populations and community structure threaten the sustainability of fisheries, our capacity to adapt by tracking and projecting marine species remains a challenge due to data discontinuities in biological observations, lack of data availability, and mismatch between data and real species distributions. To assess the extent of this challenge, we review the global status and accessibility of ongoing scientific bottom trawl surveys. In total, we gathered metadata for 283,925 samples from 95 surveys conducted regularly from 2001 to 2019. We identified that 59% of the metadata collected are not publicly available, highlighting that the availability of data is the most important challenge to assess species redistributions under global climate change. Given that the primary purpose of surveys is to provide independent data to inform stock assessment of commercially important populations, we further highlight that single surveys do not cover the full range of the main commercial demersal fish species. An average of 18 surveys is needed to cover at least 50% of species ranges, demonstrating the importance of combining multiple surveys to evaluate species range shifts. We assess the potential for combining surveys to track transboundary species redistributions and show that differences in sampling schemes and inconsistency in sampling can be overcome with spatio-temporal modeling to follow species density redistributions. In light of our global assessment, we establish a framework for improving the management and conservation of transboundary and migrating marine demersal species. We provide directions to improve data availability and encourage countries to share survey data, to assess species vulnerabilities, and to support management adaptation in a time of climate-driven ocean changes.

TNF-Induced Interstitial Lung Disease in a Murine Arthritis Model: Accumulation of Activated Monocytes, Conventional Dendritic Cells, and CD21+/CD23- B Cell Follicles Is Prevented with Anti-TNF Therapy.

Interstitial lung disease (ILD) is a well-known extra-articular manifestation of rheumatoid arthritis (RA). RA-associated ILD (RA-ILD) exists on a wide spectrum, with variable levels of inflammatory and fibrotic activity, although all subtypes are regarded as irreversible pathologic conditions. In both articular and pulmonary manifestations, TNF is a significant pathogenic factor. Whereas anti-TNF therapy alleviates joint pathologic conditions, it exacerbates fibrotic RA-ILD. The TNF-transgenic (TNF-Tg) murine model of RA develops both inflammatory arthritis and an ILD that mimics a cellular nonspecific interstitial pneumonia pattern dominated by an interstitial accumulation of inflammatory cells with minimal-to-absent fibrosis. Given the model's potential to elucidate the genesis of inflammatory RA-ILD, we aim to achieve the following: 1) characterize the cellular accumulations in TNF-Tg lungs, and 2) assess the reversibility of inflammatory ILD following anti-TNF therapy known to resolve TNF-Tg inflammatory arthritis. TNF-Tg mice with established disease were randomized to anti-TNF or placebo therapy and evaluated with imaging, histology, and flow cytometric analyses, together with wild-type controls. Flow cytometry of TNF-Tg versus wild-type lungs revealed significant increases in activated monocytes, conventional dendritic cells, and CD21+/CD23- B cells that are phenotypically distinct from the B cells in inflamed nodes, which are known to accumulate in joint-draining lymph nodes. In contrast to human RA-ILD, anti-TNF treatment significantly alleviated both joint and lung inflammation. These results identify a potential role for activated monocytes, conventional dendritic cells, and CD21+/CD23- B cells in the genesis of RA-ILD, which exist in a previously unknown, reversible, prefibrotic stage of the disease.

Additional cardiovascular fitness when progressing from moderate- to high-intensity exercise training in previously trained breast cancer survivors.

PURPOSE: Cardiovascular disease, often secondary to chemotherapy, is the leading cause of death in BC survivors. Increased aerobic capacity improves post-rehabilitation survival; however, many cancer rehabilitation programs are limited to lower intensity training. High-intensity interval training (HIIT) is associated with the largest improvements in aerobic capacity; therefore, this study aimed to determine whether HIIT would cause a greater increase in VO2peak than continuous moderate-intensity (MICT) exercise in previously trained BC survivors. METHODS: Twenty BC survivors who had completed a low/moderate-intensity exercise rehabilitation program performed a VO2peak test and received a dual-energy X-ray absorptiometry (DXA) scan at baseline and after randomization into a 12-week HIIT or MICT program. ANOVA with repeated measures determined the effects of the different training programs on aerobic capacity and body composition. RESULTS: Both groups began the training program near or above age- and sex-matched VO2peak norms. Pre- to post-intervention improvements in VO2peak (P = 0.006) and waist circumference (P = 0.007) were found in both groups; however, there were no between-group differences. Minute ventilation and peak workload increased in the HIIT group (P < 0.05) but not the MICT group. Body composition was not different after either training program. CONCLUSIONS: These data suggest that transitioning from low/moderate-intensity exercise to moderate/high-intensity exercise causes further clinically relevant increases in VO2peak in previously trained BC survivors. HIIT did not cause a significantly greater improvement in VO2peak than MICT; however, future studies with greater intensity and frequency of training are encouraged.

Adolescent Intermittent Ethanol (AIE) Enhances the Dopaminergic Response to Ethanol within the Mesolimbic Pathway during Adulthood: Alterations in Cholinergic/Dopaminergic Genes Expression in the Nucleus Accumbens Shell.

A consistent preclinical finding is that exposure to alcohol during adolescence produces a persistent hyperdopaminergic state during adulthood. The current experiments determine that effects of Adolescent Intermittent Ethanol (AIE) on the adult neurochemical response to EtOH administered directly into the mesolimbic dopamine system, alterations in dendritic spine and gene expression within the nucleus accumbens shell (AcbSh), and if treatment with the HDACII inhibitor TSA could normalize the consequences of AIE. Rats were exposed to the AIE (4 g/kg ig; 3 days a week) or water (CON) during adolescence, and all testing occurred during adulthood. CON and AIE rats were microinjected with EtOH directly into the posterior VTA and dopamine and glutamate levels were recorded in the AcbSh. Separate groups of AIE and CON rats were sacrificed during adulthood and Taqman arrays and dendritic spine morphology assessments were performed. The data indicated that exposure to AIE resulted in a significant leftward and upward shift in the dose-response curve for an increase in dopamine in the AcbSh following EtOH microinjection into the posterior VTA. Taqman array indicated that AIE exposure affected the expression of target genes (Chrna7, Impact, Chrna5). The data indicated no alterations in dendritic spine morphology in the AcbSh or any alteration in AIE effects by TSA administration. Binge-like EtOH exposure during adolescence enhances the response to acute ethanol challenge in adulthood, demonstrating that AIE produces a hyperdopaminergic mesolimbic system in both male and female Wistar rats. The neuroadaptations induced by AIE in the AcbSh could be part of the biological basis of the observed negative consequences of adolescent binge-like alcohol exposure on adult drug self-administration behaviors.

Cyanogenic Glycoside Analysis in American Elderberry.

Cyanogenic glycosides (CNGs) are naturally occurring plant molecules (nitrogenous plant secondary metabolites) which consist of an aglycone and a sugar moiety. Hydrogen cyanide (HCN) is released from these compounds following enzymatic hydrolysis causing potential toxicity issues. The presence of CNGs in American elderberry (AE) fruit, Sambucus nigra (subsp. canadensis), is uncertain. A sensitive, reproducible and robust LC-MS/MS method was developed and optimized for accurate identification and quantification of the intact glycoside. A complimentary picrate paper test method was modified to determine the total cyanogenic potential (TCP). TCP analysis was performed using a camera-phone and UV-Vis spectrophotometry. A method validation was conducted and the developed methods were successfully applied to the assessment of TCP and quantification of intact CNGs in different tissues of AE samples. Results showed no quantifiable trace of CNGs in commercial AE juice. Levels of CNGs found in various fruit tissues of AE cultivars studied ranged from between 0.12 and 6.38 µg/g. In pressed juice samples, the concentration range measured was 0.29-2.36 µg/mL and in seeds the levels were 0.12-2.38 µg/g. TCP was highest in the stems and green berries. Concentration levels in all tissues were generally low and at a level that poses no threat to consumers of fresh and processed AE products.

The Rewarding and Anxiolytic Properties of Ethanol within the Central Nucleus of the Amygdala: Mediated by Genetic Background and Nociceptin.

In humans, alcohol is consumed for its rewarding and anxiolytic effects. The central nucleus of the amygdala (CeA) is considered a neuronal nexus that regulates fear, anxiety, and drug self-administration. Manipulations of the CeA alter ethanol (EtOH) consumption under numerous EtOH self-administration models. The experiments determined whether EtOH is reinforcing/anxiolytic within the CeA, whether selective breeding for high alcohol consumption alters the rewarding properties of EtOH in the CeA, and whether the reinforcing/anxiolytic effects of EtOH in the CeA are mediated by the neuropeptides corticotropin-releasing factor (CRF) and nociceptin. The reinforcing properties of EtOH were determined by having male Wistar and Taconic alcohol-preferring (tP) rats self-administer EtOH directly into the CeA. The expression of anxiety-like behaviors was assessed through multiple behavioral models (social interaction, acoustic startle, and open field). Coadministration of EtOH and a CRF1 antagonist (NBI35965) or nociceptin on self-administration into the CeA and anxiety-like behaviors was determined. EtOH was self-administered directly into the lateral CeA, and tP rats self-administered a lower concentration of EtOH than Wistar rats. EtOH microinjected into the lateral CeA reduced the expression of anxiety-like behaviors, indicating an anxiolytic effect. Coadministration of NBI35965 failed to alter the rewarding/anxiolytic properties of EtOH in the CeA. In contrast, coadministration of the nociceptin enhanced both EtOH reward and anxiolysis in the CeA. Overall, the data indicate that the lateral CeA is a key anatomic location that mediates the rewarding and anxiolytic effects of EtOH, and local nociceptin receptors, but not local CRF1 receptors, are involved in these behaviors. SIGNIFICANCE STATEMENT: Alcohol is consumed for the stimulatory, rewarding, and anxiolytic properties of the drug of abuse. The current data are the first to establish that alcohol is reinforcing and anxiolytic within the lateral central nucleus of the amygdala (CeA) and that the nociceptin system regulates these effects of alcohol within the CeA.

Dissecting Genetic Resistance to Fire Blight in Three Pear Populations.

Fire blight, caused by the bacterial pathogen Erwinia amylovora, is a persistent problem for pear (Pyrus spp.) growers in the United States. Growing resistant cultivars is one of the best options for managing fire blight. The cultivars Potomac and Old Home and the selection NJA2R59T69 display resistance to fire blight. As such, three mapping populations (El Dorado × Potomac, Old Home × Bartlett, and NJA2R59T69 × Bartlett) were developed to identify genomic regions associated with resistance to fire blight. Progeny were phenotyped during 2017 and 2018 by inoculating multiple actively growing shoots of field-grown seedling trees with E. amylovora isolate E153n via the cut-leaf method. Genotyping was conducted using the recently developed Axiom Pear 70 K Genotyping Array and chromosomal linkage groups were created for each population. An integrated two-way pseudo-testcross approach was used to map quantitative trait loci (QTLs). Resistance QTLs were identified on chromosome 2 for each population. The QTLs identified in the El Dorado × Potomac and Old Home × Bartlett populations are in the same region as QTLs that were previously identified in Harrow Sweet and Moonglow. The QTL in NJA2R59T69 mapped proximally to the previously identified QTLs and originated from an unknown Asian or occidental source. Future research will focus on further characterizing the resistance regions and developing tools for DNA-informed breeding.

Spontaneous Early Withdrawal Behaviors after Chronic 24-hour Free-Choice Access to Ethanol.

AIMS: Abstinence after chronic alcohol consumption leads to withdrawal symptoms, which are exacerbated after repeated cycles of relapse. This study examined withdrawal-like behaviors after chronic ethanol drinking, with or without repeated cycles of deprivation. METHODS: Male alcohol-preferring (P) rats had access to continuous ethanol (CE), chronic ethanol with repeated deprivation (RD), or remained ethanol naïve (EN). The RD group experienced seven cycles of 2 weeks of deprivation and 2 weeks of re-exposure to ethanol after an initial 6 weeks of ethanol access. Withdrawal was measured after an initial 24 h of ethanol re-exposure in the RD group, which coincided with the same day of ethanol access in the CE group. Withdrawal-like behavior was measured by (a) ethanol intake during the initial 24 h of re-exposure, (b) locomotor activity (LMA) in a novel field 9-13 h after removal of ethanol at the beginning of the fifth re-exposure cycle and (c) acoustic startle responding (ASR) 8-15 h after removal of ethanol at the beginning of the sixth re-exposure cycle. RESULTS: The RD rats displayed a 1-h alcohol deprivation effect (ADE) (temporary ethanol increase), relative to CE rats, during the first to fourth and seventh re-exposure cycles. RD and CE rats displayed significant increases in LMA than EN rats. Regarding ASR, RD rats displayed significantly greater ASR relative to EN rats. CONCLUSION: This study confirms that P rats meet the animal model criterion for ethanol-associated dependence, without a reliance on either behavioral (limited fluid access) or pharmacological (seizure threshold manipulation) challenges.

Polysubstance addiction vulnerability in mental illness: Concurrent alcohol and nicotine self-administration in the neurodevelopmental hippocampal lesion rat model of schizophrenia.

Multiple addictions frequently occur in patients with mental illness. However, basic research on the brain-based linkages between these comorbidities is extremely limited. Toward characterizing the first animal modeling of polysubstance use and addiction vulnerability in schizophrenia, adolescent rats with neonatal ventral hippocampal lesions (NVHLs) and controls had 19 weekdays of 1 hour/day free access to alcohol/sucrose solutions (fading from 10% sucrose to 10% alcohol/2% sucrose on day 10) during postnatal days (PD 35-60). Starting in adulthood (PD 63), rats acquired lever pressing for concurrent oral alcohol (10% with 2% sucrose) and iv nicotine (0.015 mg/kg/injection) across 15 sessions. Subsequently, 10 operant extinction sessions and 3 reinstatement sessions examined drug seeking upon withholding of nicotine, then both nicotine and alcohol, then reintroduction. Adolescent alcohol consumption did not differ between NVHLs and controls. However, in adulthood, NVHLs showed increased lever pressing at alcohol and nicotine levers that progressed more strongly at the nicotine lever, even as most pressing by both groups was at the alcohol lever. In extinction, both groups showed expected declines in effort as drugs were withheld, but NVHLs persisted with greater pressing at both alcohol and nicotine levers. In reinstatement, alcohol reaccess increased pressing, with NVHLs showing greater nicotine lever activity overall. Developmental temporal-limbic abnormalities that produce mental illness can thus generate adult polydrug addiction vulnerability as a mechanism independent from putative cross-sensitization effects between addictive drugs. Further preclinical modeling of third-order (and higher) addiction-mental illness comorbidities may advance our understanding and treatment of these complex, yet common brain illnesses.

A Randomized Controlled Trial Comparing Epidural Analgesia Versus Continuous Local Anesthetic Infiltration Via Abdominal Wound Catheter in Open Liver Resection.

AIM: To compare outcomes following open liver resection (OLR) between patients receiving thoracic epidural (EP) versus abdominal wound catheters plus patient-controlled analgesia (AWC-PCA). METHOD: Patients were randomized 1:1 to either EP or AWC-PCA within an enhanced recovery protocol. Primary outcome was length of stay (LOS), other variables included functional recovery, pain scores, peak flow, vasopressor and fluid requirements, and postoperative complications. RESULTS: Between April 2015 and November 2017, 83 patients were randomized to EP (n = 41) or AWC-PCA (n = 42). Baseline demographics were comparable. No difference was noted in LOS (EP 6 d (3-27) vs AWC-PCA 6 d (3-66), P = 0.886). Treatment failure was 20% in the EP group versus 7% in the AWC-PCA (P = 0.09). Preoperative anesthetic time was shorter in the AWC-PCA group, 49 minutes versus 62 minutes (P = 0.003). EP patients required more vasopressor support immediately postoperatively on day 0 (14% vs 54%, P = <0.001) and day 1 (5% vs 23%, P = 0.021). Pain scores were greater on day 0, afternoon of day 1 and morning of day 2 in the AWC-PCA group however were regarded as low at all time points. No other significant differences were noted in IV fluid requirements, nausea/sedation scores, days to open bowels, length of HDU, and postoperative complications. CONCLUSION: AWC-PCA was associated with reduced treatment failure and a reduced vasopressor requirement than EP up to 2 days postoperatively. While the use of AWC-PCA did not translate into a shorter LOS in this study, it simplified patient management after OLR. EP cannot be routinely recommended following open liver resections.

Prostatic capsular incision during radical prostatectomy has important oncological implications: a systematic review and meta-analysis.

INTRODUCTION: Prostatic capsular incision (CapI) is an iatrogenic breach of the prostatic capsule during radical prostatectomy (RP) that can cause positive surgical margins (PSMs) in organ-confined (pT2) prostate cancer, or the retention of benign prostatic tissue. We systematically interrogated the literature in order to clarify the definition of CapI, and the implications of this event for rates of PSM and biochemical recurrence (BCR). METHODS: A literature search was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria using the search terms 'capsular incision' AND 'prostatectomy', and variations of each. In all, 18 studies were eligible for inclusion. RESULTS: A total of 51 057 RP specimens were included. The incidence of CapI ranged from 1.3% to 54.3%. CapI definitions varied and included a breach of the prostatic capsule 'exposing both benign or malignant prostate cancer cells', 'malignant tissue only', or 'benign tissue only'. The incidence of PSMs due to CapI ranged from 2.8% to 71.7%. Our meta-analysis results found that when CapI was defined as 'exposing malignant tissue only in organ-confined prostate cancer' there was an increased risk of BCR compared to patients with pT2 disease and no CapI (relative risk 3.53, 95% confidence interval 2.82-4.41; P < 0.001). CONCLUSIONS: The absolute impact of CapI on oncological outcomes is currently unclear due to inconsistent definitions. However, the data imply an association between CapI and PSMs and BCR. Reporting of possible areas of CapI on the operation note, or marking areas of concern on the specimen, are critical to assist CapI recognition by the pathologist.

The evolution of donation after circulatory death renal transplantation: a decade of experience.

BACKGROUND: This study compared long-term outcomes of renal transplantation from donors following donation after circulatory death (DCD) with those following donation after brain death (DBD) from one of the largest centres in the UK. METHOD: Recipients of renal transplants from deceased donors between 2002 and 2014 were identified from a prospectively maintained database. Outcomes were compared between DCD (468) and DBD (905) donors and between standard criteria donors (SCDs) and extended criteria donors (ECDs). RESULTS: Graft survival (GS) and patient survival (PS) from DCD and DBD donors were comparable up to 10 years (GS: 61 versus 55%, P = 0.780; PS: 78 versus 71%, P = 0.285, respectively). Graft function was comparable after 3 months. GS and function were worse in the ECD groups, with no difference between EC-DBD and EC-DCD. PS in the ECD groups was worse than the SCD groups and PS in the EC-DCD group was worse than in the EC-DBD group. DCD donors were an independent risk factor for delayed graft function. Post-operative complications and EC-DCD donation were independent risk factors for reduced GS and PS. CONCLUSION: This study supports the use of DCD renal grafts with comparable long-term survival and function to DBD grafts. The use of EC-DCD grafts is justified in selected recipients and provides acceptable function and survival advantages over dialysis.

Adolescent Intermittent Ethanol Increases the Sensitivity to the Reinforcing Properties of Ethanol and the Expression of Select Cholinergic and Dopaminergic Genes within the Posterior Ventral Tegmental Area.

BACKGROUND: Although not legally allowed to consume alcohol, adolescents account for 11% of all alcohol use in the United States and approximately 90% of adolescent intake is in the form of an alcohol binge. The adolescent intermittent ethanol (AIE) model developed by the NADIA consortium produces binge-like EtOH exposure episodes. The current experiment examined the effects of AIE on the reinforcing properties of EtOH and genetic expression of cholinergic and dopaminergic factors within the posterior ventral tegmental area (pVTA) in Wistar male and female rats and in male alcohol-preferring (P) rats. METHODS: Rats were exposed to the AIE or water during adolescence, and all testing occurred during adulthood. Wistar control and AIE rats were randomly assigned to groups that self-administered 0 to 200 mg% EtOH. Male P rats self-administered 0 to 100 mg%. RESULTS: The data indicated that exposure to AIE in both Wistar male and female rats (and male P rats) resulted in a significant leftward shift in dose-response curve for EtOH self-administration into the pVTA. TaqMan array indicated that AIE exposure had divergent effects on the expression of nicotinic receptors (increased a7, reduction in a4 and a5). There were also sex-specific effects of AIE on gene expression; male only reduction in D3 receptors. CONCLUSION: Binge-like EtOH exposure during adolescence enhances the sensitivity to the reinforcing properties of EtOH during adulthood which could be part of biological sequelae that are the basis for the deleterious effects of adolescent alcohol consumption on the rate of alcoholism during adulthood.