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Extended oral antibiotic prophylaxis (EOA) has been shown to reduce infection after high-risk primary total hip arthroplasties (THAs) and reimplantations. However, data are limited regarding EOA after aseptic revision THAs. This study evaluated the impact of EOA on infection-related outcomes after aseptic revision THAs.We retrospectively identified 1,107 aseptic revision THAs performed between 2014 and 2019. Patients who received EOA24 hours perioperatively (n = 370) were compared to those who did not (n = 737) using an inverse probability of treatment weighting model. Their mean age was 65 years (range, 19-98 years), mean body mass index was 30 kg/mThe cumulative probability of any infection after aseptic revision THA was 2.3% at 90 days, 2.7% at 1 year, and 3.5% at 5 years. The cumulative probability of PJI was 1.7% at 90 days, 2.1% at 1 year, and 2.8% at 5 years. There was a trend toward an increased risk of any infection (hazards ratio [HR] = 2.6; P = .058), PJI (HR = 2.6; P = .085), and re-revision (HR = 6.5; P = .077) or reoperation (HR = 2.3; P = .095) for infection in patients who did not have EOA at the final clinical follow-up.EOA after aseptic revision THA was not associated with a statistically significant decreased risk of any infection, PJI, or re-revision or reoperation for infection at all time points.Level III.

Diabetes elevates endothelin-1 (ET-1) in the vitreous and enhances constriction of retinal venules to this peptide. However, mechanisms contributing to ET-1–induced constriction of retinal venules are incompletely understood. We examined roles of sodium-hydrogen exchanger 1 (NHE1), protein kinase C (PKC), mitogen-activated protein kinases (MAPKs), and extracellular calcium (Ca2+) in retinal venular constriction to ET-1 and the impact of diabetes on these signaling molecules. Retinal venules were isolated from control pigs and pigs with streptozocin-induced diabetes for in vitro studies. ET-1–induced vasoconstriction was abolished in the absence of extracellular Ca2+ and sensitive to c-Jun N-terminal kinase (JNK) inhibitor SP600125 but unaffected by extracellular signal–regulated kinase (ERK) inhibitor PD98059, p38 kinase inhibitor SB203580, or broad-spectrum PKC inhibitor Gö 6983. Diabetes (after 2 weeks) enhanced venular constriction to ET-1, which was insensitive to PD98059 and Gö 6983 but was prevented by NHE1 inhibitor cariporide, SB203580, and SP600125. In conclusion, extracellular Ca2+ entry and activation of JNK, independent of ERK and PKC, mediate constriction of retinal venules to ET-1. Diabetes activates p38 MAPK and NHE1, which cause enhanced venular constriction to ET-1. Treatments targeting these vascular molecules may lessen retinal complications in early diabetes.

We report the development of novel cannabinergic probes that can stabilize the cannabinoid receptors (CBRs) through tight binding interactions. Ligand design involves the introduction of select groups at a judiciously chosen position within the classical hexahydrocannabinol template (monofunctionalized probes). Such groups include the electrophilic isothiocyanato, the photoactivatable azido, and the polar cyano moieties. These groups can also be combined to produce bifunctionalized probes potentially capable of interacting at two distinct sites within the CBR-binding domains. These novel compounds display remarkably high binding affinities for CBRs and are exceptionally potent agonists. A key ligand (27a, AM11245) exhibits exceptionally high potency in both in vitro and in vivo assays and was designated as "megagonist," a property attributed to its tight binding profile. By acting both centrally and peripherally, 27a distinguishes itself from our previously reported "megagonist" AM841, whose functions are restricted to the periphery.

Supplemental Digital Content is Available in the Text. Estimated peak oxygen uptake (V˙o2peak) using 6-min Walk Test distance demonstrated poor agreement with measured V˙o2peak from a cardiopulmonary exercise test in patients with heart failure enrolled in cardiac rehabilitation., Purpose: We examined the agreement between peak oxygen uptake (V˙o2peak), estimated using prediction equations from the 6-min Walk Test (6MWT), and V˙o2peak measured using a cardiopulmonary exercise test (CPX) to estimate change in V˙o2peak in patients with heart failure (HF) enrolled in cardiac rehabilitation (CR). Methods: This was secondary analysis of 54 (including 9 women) patients with HF who completed a clinical CR program. Four previously published equations using 6MWT distance were used to estimate V˙o2peak and were compared with a CPX at baseline, follow-up, and change using the standard and modified Bland-Altman method. Analyses were repeated for quartiles of cardiorespiratory fitness (CRF) based on measured V˙o2peak from the CPX. Results: Bland-Altman plots revealed proportional bias between all prediction equations and the measured V˙o2peak. The difference between methods varied by the level of CRF, with overestimation of prediction equations at greater levels of CRF and underestimation at lower levels of CRF. This poor agreement remained when comparisons were made between the estimated and measured V˙o2peak values at quartiles of CRF, indicating prediction equations have limited ability to predict V˙o2peak at any level of CRF. Conclusion: Estimated V˙o2peak using 6MWT distance demonstrated poor agreement with measured V˙o2peak from a CPX. While distance ambulated on the 6MWT remains an important measure of physical performance in patients with HF, prediction equations using 6MWT distance are not appropriate to monitor changes in V˙o2peak following CR in patients with HF.

As a result of genetic selection, the modern broiler is more efficient, higher yielding, and faster growing than the bird of the 1950s. Unfortunately, as a result of improvement in growth rate, the modern broiler has the potential to struggle under heat stress conditions. The present study evaluates 3 different random bred populations and a common ancestor under both a thermal neutral and heat stress conditions after a 54-D grow-out period. The lines used in this study included the Athens Canadian Random Bred (ACRB), a 1995 Random Bred (95RAN), a 2015 Random Bred (MRB), and a Junglefowl (JF). Male chicks (n = 150/line) were placed by line in environmentally controlled chambers. An 8-h daily cyclic heat stress (36°C) was applied to half of the chambers beginning on day 28 (HS) and lasting until processing at day 55, while the remaining chambers remained thermal neutral (TN) at 26°C. Dock weights and carcass weights were lower in the HS-95RAN and HS-MRB, compared to their TN counterparts, while the ACRB and JF had no difference in dock and carcass weights regardless of environmental condition. The MRB line had the highest breast yield (27.79%) while the JF (12.79%) and ACRB (12.42%) had the lowest. The 95RAN line had the highest abdominal fat percentage (2.83%) while the MRB line had the lowest moisture uptake during chill. The HS exposure lowered overall breast yield and breast pH at 15 min and 4 h postmortem but did not have an impact on color (L∗) or 24 h breast drip loss. The MRB was scored for both woody breast and white striping. The TN-MRB group had a higher incidence of moderate and severe woody breast and white striping than the HS-MRB group. Based on the results of this study, it appears that HS has a greater negative impact on the higher yielding lines (MRB and 95RAN) than the ACRB and JF and that clear line differences exist between the random bred lines and their common ancestor.

Can a previously defined relationship between sperm capacitation and the probability of a man generating pregnancy within three cycles, prospectively predict male fertility in diverse clinical settings? A second study asked, what is the prevalence of impaired sperm fertilizing ability in men questioning their fertility (MQF), and does this relate to traditional semen analysis metrics?In the multicentric, prospective observational study, data (n = 128; six clinics) were analysed to test a published relationship between the percentage of fertilization-competent, capacitated spermatozoa (Cap-Score) and probability of generating pregnancy (PGP) within three cycles of intrauterine insemination. Logistic regression of total pregnancy outcomes (n = 252) assessed fit. In the cohort comparison, Cap-Scores of MQF (n = 2155; 22 clinics) were compared with those of 76 fertile men.New outcomes (n = 128) were rank-ordered by Cap-Score and divided into quintiles (25-26 per group); chi-squared testing revealed no difference between predicted and observed pregnancies (P = 0.809). Total outcomes (n = 252; 128 new + 124 previous) were pooled and the model recalculated, yielding an improved fit (P0.001). Applying the Akaike information criterion found that the optimal model used Cap-Score alone. Cap-Scores were performed on 2155 men (with semen analysis data available for 1948). To compare fertilizing ability, men were binned by PGP (≤19%, 20-29%, 30-39%, 40-49%, 50-59%, ≥60%). Distributions of PGP and the corresponding Cap-Scores were significantly lower in MQF versus fertile men (P0.001). Notably, 64% of MQF with normal volume, concentration and motility (757/1183) had PGP of 39% or less (Cap-Scores ≤31), versus 25% of fertile men.Sperm capacitation prospectively predicted male fertility. Impaired capacitation affects many MQF with normal semen analysis results, informing diagnosis versus idiopathic infertility.

Predictive approaches to assessing the toxicity of contaminant mixtures have been largely limited to chemicals that exert effects through the same biological molecular initiating event. However, by understanding specific pathways through which chemicals exert effects, it may be possible to identify shared "downstream" nodes as the basis for forecasting interactive effects of chemicals with different molecular initiating events. Adverse outcome pathway (AOP) networks conceptually support this type of analysis. We assessed the utility of a simple AOP network for predicting the effects of mixtures of an aromatase inhibitor (fadrozole) and an androgen receptor agonist (17β-trenbolone) on aspects of reproductive endocrine function in female fathead minnows. The fish were exposed to multiple concentrations of fadrozole and 17β-trenbolone individually or in combination for 48 or 96 h. Effects on 2 shared nodes in the AOP network, plasma 17β-estradiol (E2) concentration and vitellogenin (VTG) production (measured as hepatic vtg transcripts) responded as anticipated to fadrozole alone but were minimally impacted by 17β-trenbolone alone. Overall, there were indications that 17β-trenbolone enhanced decreases in E2 and vtg in fadrozole-exposed fish, as anticipated, but the results often were not statistically significant. Failure to consistently observe hypothesized interactions between fadrozole and 17β-trenbolone could be due to several factors, including lack of impact of 17β-trenbolone, inherent biological variability in the endpoints assessed, and/or an incomplete understanding of interactions (including feedback) between different pathways within the hypothalamic-pituitary-gonadal axis. Environ Toxicol Chem 2020;39:913-922. © 2020 SETAC.

BACKGROUND: Dermatologic surgery is associated with low postoperative infection rates, averaging from approximately 1% to 4.25%. Often, postoperative infections are treated empirically based on clinical diagnosis of infection, given it can take 48 to 72 hours for a wound culture to identify a pathogen. OBJECTIVE: We aimed to evaluate the efficacy of empiric antibiotics in dermatologic surgery postoperative infections and if wound cultures change postoperative antibiotic therapy. METHODS: A 7-center, retrospective analysis of postoperative infections, with culture data, in dermatologic surgery patients was performed. RESULTS: Of 91 cases of clinically diagnosed postoperative infection, 82.4% (n = 75) were successfully treated with empiric oral antibiotics (95% confidence interval [0.73–0.89], p < .0001). In 16 (17.6%) cases, initial empiric antibiotics were unsuccessful, and wound culture results altered antibiotic therapy in 9 cases (9.9%) with 6 (6.6%) of these cases requiring additional coverage for methicillin-resistant Staphylococcus aureus (MRSA). CONCLUSION: Empiric antibiotic treatment is usually appropriate for patients with postoperative surgical-site infections with wound cultures altering antibiotic management in a minority of cases. When empiric antibiotics fail, lack of MRSA coverage is usually the cause; therefore, providers should be aware of local MRSA prevalence and susceptibilities.

Extended oral antibiotic prophylaxis (EOA) has been shown to potentially reduce infection rates after high-risk primary total knee arthroplasties (TKAs) and reimplantations. However, data is limited regarding EOA after aseptic revision TKAs. This study evaluated the impact of EOA on infection-related outcomes after aseptic revision TKAs.904 aseptic revision TKAs from 2014-2019 were retrospectively identified. Patients who received EOA24 hours perioperatively (n = 267) were compared to those who did not (n = 637) using an inverse probability of treatment weighting model. Mean age was 66 years, mean BMI was 33 kg/mThe cumulative probability of any infection after aseptic revision TKA was 1.9% at 90 days, 3.5% at 1 year, and 8.1% at 5 years. Patients without EOA had a higher risk of any infection at 90 days (HR = 7.1; P = .01), but not other time points. The cumulative probability of PJI after aseptic revision TKA was 0.8% at 90 days, 2.3% at 1 year, and 6.5% at 5 years. Patients without EOA did not have an increased risk of PJI. There were no differences in re-revision or reoperation for infection at any time point between groups.Extended oral antibiotics after aseptic revision TKA were associated with a 7-fold decreased risk of any infection at 90 days. The results suggest a potential role for EOA after aseptic revision TKA and warrant additional prospective studies.Level III.

The ability of a ligand to preferentially promote engagement of one signaling pathway over another downstream of GPCR activation has been referred to as signaling bias, functional selectivity, and biased agonism. The presentation of ligand bias reflects selectivity between active states of the receptor, which may result in the display of preferential engagement with one signaling pathway over another. In this study, we provide evidence that the G protein–biased mu opioid receptor (MOR) agonists SR-17018 and SR-14968 stabilize the MOR in a wash-resistant yet antagonist-reversible G protein–signaling state. Furthermore, we demonstrate that these structurally related biased agonists are noncompetitive for radiolabeled MOR antagonist binding, and while they stimulate G protein signaling in mouse brains, partial agonists of this class do not compete with full agonist activation. Importantly, opioid antagonists can readily reverse their effects in vivo. Given that chronic treatment with SR-17018 does not lead to tolerance in several mouse pain models, this feature may be desirable for the development of long-lasting opioid analgesics that remain sensitive to antagonist reversal of respiratory suppression.

Background Prescription opioids play a large role in the opioid epidemic. Even short-term prescriptions provided postoperatively can lead to dependence. Objective To provide opioid prescription recommendations after Mohs micrographic surgery (MMS) and reconstruction. Methods This was a multi-institutional Delphi consensus study consisting of a panel of members of the American College of Mohs Surgery from various practice settings. Participants were first asked to describe scenarios in which they prescribe opioids at various frequencies. These scenarios then underwent 2 Delphi ratings rounds that aimed to identify situations in which opioid prescriptions should, or should not, be routinely prescribed. Consensus was set at ≥80% agreement. Prescription recommendations were then distributed to the panelists for feedback and approval. Results Twenty-three Mohs surgeons participated in the study. There was no scenario in which consensus was met to routinely provide an opioid prescription. However, there were several scenarios in which consensus were met to not routinely prescribe an opioid. Conclusion Opioids should not be routinely prescribed to every patient undergoing MMS. Prescription recommendations for opioids after MMS and reconstruction may decrease the exposure to these drugs and help combat the opioid epidemic.

ObjectiveBystander cardiopulmonary resuscitation (CPR) after out-of-hospital cardiac arrest (OHCA) improves survival and neurological outcomes. Nonetheless, many OHCA patients do not receive bystander CPR during a witnessed arrest. Our aim was to identify potential barriers to bystander CPR.MethodsParticipants at CPR training events conducted in the USA between February and May 2018 answered a 14-question survey prior to training. Respondents were asked about their overall comfort level performing CPR, and about potential concerns specific to performing CPR on a middle-aged female, a geriatric male, and male and female adolescent patients. Open-ended responses were analysed qualitatively by categorising responses into themes.ResultsOf the 677 participants, 582 (86.0%) completed the survey, with 509 (88.1%) between 18 and 29 years of age, 341 (58.6%) without prior CPR training and 556 (96.0%) without prior CPR experience. Across all four scenarios of patients in cardiac arrest, less than 65% of respondents reported that they would be ‘Extremely Likely’ (20.6%–29.1%) or ‘Moderately Likely’ (26.9%–34.8%) to initiate CPR. The leading concerns were ‘causing injury to patient’ for geriatric (n=193, 63.1%), female (n=51, 20.5%) and adolescent (n=148, 50.9%) patients. Lack of appropriate skills was the second leading concern when the victim was a geriatric (n=41, 13.4%) or adolescent (n=68, 23.4%) patient, whereas for female patients, 35 (14.1%) were concerned about exposing the patient or the patient’s breasts interfering with performance of CPR and 15 (6.0%) were concerned about being accused of sexual assault. Significant differences were observed in race, ethnicity and age regarding the likelihood of starting to perform CPR on female and adolescent patients.ConclusionsParticipants at CPR training events have multiple concerns and fears related to performing bystander CPR. Causing additional harm and lack of skills were among the leading reservations reported. These findings should be considered for improved CPR training and public education.

It has been demonstrated that opioid agonists that preferentially act at μ-opioid receptors to activate G protein signaling over βarrestin2 recruitment produce antinociception with less respiratory suppression. However, most of the adverse effects associated with opioid therapeutics are realized after extended dosing. Therefore, we tested the onset of tolerance and dependence, and assessed for neurochemical changes associated with prolonged treatment with the biased agonist SR-17018. When chronically administered to mice, SR-17018 does not lead to hot plate antinociceptive tolerance, receptor desensitization in periaqueductal gray, nor a super-sensitization of adenylyl cyclase in the striatum, which are hallmarks of opioid neuronal adaptations that are seen with morphine. Interestingly, substitution with SR-17018 in morphine-tolerant mice restores morphine potency and efficacy, whereas the onset of opioid withdrawal is prevented. This is in contrast to buprenorphine, which can suppress withdrawal, but produces and maintains morphine antinociceptive tolerance. Biased agonists of this nature may therefore be useful for the treatment of opioid dependence while restoring opioid antinociceptive sensitivity.

One emerging strategy to address the opioid crisis is the development of mu opioid receptor (MOR) ligands that preferentially signal the G-protein vs. β-arrestin pathway. The present study compared the relative potency and effectiveness of two G-protein biased (GPB)-MOR ligands TRV130 and SR-14968 to five unbiased MOR ligands (NAQ, nalbuphine, buprenorphine, morphine, and methadone) on therapeutic-related (e.g. antinociception) and abuse-related (e.g. discriminative stimulus effects) endpoints. Male and female rats were tested in a warm water tail-withdrawal procedure (50 °C) or trained to discriminate fentanyl (0.04 mg/kg, SC) from saline in a two-lever food-reinforced discrimination procedure. TRV130 and SR-14968 were approximately two-fold more potent to produce fentanyl stimulus effects vs. antinociception. Morphine, fentanyl, and methadone were significantly more potent in the fentanyl discrimination vs. tail withdrawal procedure. In addition, maximum antinociceptive and discriminative stimulus effects of fixed-proportion fentanyl/naltrexone mixtures (1:0.018, 1:0.054, 1:0.18, 1:0.3, and 1:0.54) were used to quantify 1) the relative in vivo efficacy of the two GPB-MOR agonists and five unbiased MOR ligands, and 2) potential species differences in MOR ligand effects between rats and monkeys. The efficacy-effect function generated from the fentanyl/naltrexone mixtures stratified the five unbiased ligands consistent with agonist-stimulated GTPγS binding (NAQ = nalbuphine buprenorphine morphine methadone). However, TRV130 and SR-14968 produced greater antinociception and less fentanyl-like stimulus effects than was predicted. Furthermore, there was a significant positive correlation between rat and monkey antinociceptive effects. Overall, these results demonstrate GPB-MOR agonists produce undesirable abuse-related effects, albeit with slightly better potency and efficacy ratios compared to unbiased agonists. This article is part of the Special Issue entitled 'Opioid Neuropharmacology: Advances in treating pain and opioid addiction'.

Summary Classic bladder exstrophy in the female results in an exstrophic bladder and urethra, an anterior introitus with a bifid clitoris and short labia minora. During closure, the lower abdominal wall is closed and the bifid clitori are brought into close apposition, but are often not completely closed to prevent injury to the clitoral bodies, thus leaving a persistent gap between the clitoral bodies that grows over time. We demonstrate a vertical z plasty closure to provide a 2 layer closure of the mons that decreases tension and improves cosmetic appearance by recreating a clitoral hood that provides a more normal appearance of the external genitalia for girls with bladder exstrophy.

This study aims to examine contemporary practice patterns and compare short-term outcomes for vesicoureteral reflux procedures (ureteral reimplant/endoscopic injection) using National Surgical Quality Improvement Program-Pediatric data.Procedure-specific variables for antireflux surgery were developed to capture data not typically collected in National Surgical Quality Improvement Program-Pediatric (eg vesicoureteral reflux grade, urine cultures, 31-60-day followup). Descriptive statistics were performed, and logistic regression assessed associations between patient/procedural factors and outcomes (urinary tract infection, readmissions, unplanned procedures).In total, 2,842 patients (median age 4 years; 76% female; 68% open reimplant, 6% minimally invasive reimplant, 25% endoscopic injection) had procedure-specific variables collected from July 2016 through June 2018. Among 88 hospitals, a median of 24.5 procedures/study period were performed (range 1-148); 95% performed ≥1 open reimplant, 30% ≥1 minimally invasive reimplant, and 70% ≥1 endoscopic injection, with variability by hospital. Two-thirds of patients had urine cultures sent preoperatively, and 76% were discharged on antibiotics. Outcomes at 30 days included emergency department visits (10%), readmissions (4%), urinary tract infections (3%), and unplanned procedures (2%). Over half of patients (55%) had optional 31-60-day followup, with additional outcomes (particularly urinary tract infections) noted. Patients undergoing reimplant were younger, had higher reflux grades, and more postoperative occurrences than patients undergoing endoscopic injections.Contemporary data indicate that open reimplant is still the most common antireflux procedure, but procedure distribution varies by hospital. Emergency department visits are common, but unplanned procedures are rare, particularly for endoscopic injection. These data provide basis for comparing short-term complications and developing standardized perioperative pathways for antireflux surgery.

The mu opioid receptor-selective agonist, SR-17018, preferentially activates GTPγS binding over βarrestin2 recruitment in cellular assays, thereby demonstrating signaling bias. In mice, SR-17018 stimulates GTPγS binding in brainstem and produces antinociception with potencies similar to morphine. However, it produces much less respiratory suppression and mice do not develop antinociceptive tolerance in the hot plate assay upon repeated dosing. Herein we evaluate the effects of acute and repeated dosing of SR-17018, oxycodone and morphine in additional models of pain-related behaviors. In the mouse warm water tail immersion assay, an assessment of spinal reflex to thermal nociception, repeated administration of SR-17018 produces tolerance as does morphine and oxycodone. SR-17018 retains efficacy in a formalin-induced inflammatory pain model upon repeated dosing, while oxycodone does not. In a chemotherapeutic-induced neuropathy pain model SR-17018 is more potent and efficacious than morphine or oxycodone, moreover, this efficacy is retained upon repeated dosing of SR-17018. These findings demonstrate that, with the exception of the tail flick test, SR-17018 retains efficacy upon chronic treatment across several pain models.

BACKGROUND AND AIMS: Serotonin (5HT) is a neuroendocrine hormone synthetized in the central nervous system (CNS) as well as enterochromaffin cells of the gastrointestinal tract. Tryptophan hydroxylase (TPH1) and monoamine oxidase (MAO-A) are the key enzymes for the synthesis and catabolism of 5HT, respectively. Previous studies demonstrated that 5-hydroxytryptamine receptor (5HTR)1A/1B receptor agonists inhibit biliary hyperplasia in bile-duct ligated (BDL) rats, whereas 5HTR2B receptor antagonists attenuate liver fibrosis (LF) in mice. Our aim was to evaluate the role of 5HTR2A/2B/2C agonists/antagonists in cholestatic models. APPROACH AND RESULTS: While in vivo studies were performed in BDL rats and the multidrug resistance gene 2 knockout (Mdr2(−/−)) mouse model of PSC, in vitro studies were performed in cell lines of cholangiocytes and hepatic stellate cells (HSCs). 5HTR2A/2B/2C and MAO-A/TPH1 are expressed in cholangiocytes and HSCs from BDL rats and Mdr2(−/−) mice. Ductular reaction, LF, as well as the mRNA expression of proinflammatory genes increased in normal, BDL rats, and Mdr2(−/−) mice following treatment 5HTR2A/2B/2C agonists, but decreased when BDL rats and Mdr2(−/−) mice were treated with 5HTR2A/2B/2C antagonists compared to BDL rats and Mdr2(−/−) mice, respectively. 5HT levels increase in Mdr2(−/−) mice and in PSC human patients compared to their controls and decrease in serum of Mdr2(−/−) mice treated with 5HTR2A/2B/2C antagonists compared to untreated Mdr2(−/−) mice. In vitro, cell lines of murine cholangiocytes and human HSCs express 5HTR2A/2B/2C and MAO-A/TPH1; treatment of these cell lines with 5HTR2A/2B/2C antagonists or TPH1 inhibitor decreased 5HT levels as well as expression of fibrosis and inflammation genes compared to controls. CONCLUSIONS: Modulation of the TPH1/MAO-A/5HT/5HTR2A/2B/2C axis may represent a therapeutic approach for management of cholangiopathies, including PSC.

Bumble bees thrive in cold climates including high latitude and high altitude regions around the world, yet cold tolerance strategies are largely unknown for most species. To determine bumble bee cold tolerance strategy, we exposed bumble bees to a range of low temperatures and measured survival 72 h post-exposure. All bees that froze died within 72 h while only one bee died without freezing, suggesting that bumble bees are generally freeze-avoiding insects and may be slightly chill susceptible. We then assessed whether temperatures that cause internal ice formation (supercooling points, SCP) varied among bumble bee castes (drones, workers, and queens), or across queen life stages, collection elevation, species, or season. Males froze at significantly lower temperatures than workers or queens. Queens in pre-overwintering or overwintering states froze at significantly lower temperatures than queens stimulated to initiate ovary development by CO

Lower-extremity musculoskeletal injuries are common in sports such as basketball and soccer. Athletes competing in sports of this nature must maneuver in response to the actions of their teammates, opponents, etc. This limits their ability to preplan movements. The purpose of this study was to compare impact accelerations during preplanned versus unplanned lateral cutting. A total of 30 subjects (15 males and 15 females) performed preplanned and unplanned cuts while the authors analyzed impact accelerations using an accelerometer secured to their tibia. For the preplanned condition, subjects were aware of the movement to perform before initiating a trial. For the unplanned condition, subjects initiated their movement and then reacted to the illumination of one of 3 visual stimuli which dictated whether they would cut, land, or land-and-jump. A mixed-model analysis of variance with a between factor of sex (male and female) and a within factor of condition (preplanned and unplanned) was used to analyze the magnitude and variability of the impact accelerations for the cutting trials. Both males and females demonstrated higher impact accelerations (P = .01) and a trend toward greater intertrial variability (P = .07) for the unplanned cutting trials (vs preplanned cuts). Unplanned cutting may place greater demands on the musculoskeletal system.

BACKGROUND: The natural history of post-injury among elderly trauma patients has not been well described. We hypothesized that elderly trauma patients would have lower admission hemoglobin (Hb) levels, higher transfusion rates, and worse outcomes than young trauma patients. METHODS: We performed a propensity-matched retrospective cohort analysis comparing elderly (age ≥65 years) to young (age 18–64) trauma patients matched by sex, mechanism of injury, Injury Severity Score, base deficit, comorbidities, operative blood loss, and phlebotomy blood loss (n=41/group). Outcomes included Hb trends, packed red blood cell (PRBC) transfusion, length of stay, and mortality. RESULTS: Elderly patients had lower admission Hb (11.3 vs. 10.2 g/dL, p=0.012), received more PRBC transfusions within 24 hours (3.6 vs. 1.8 units, p=0.046) and during admission (6.9 vs. 4.3 units, p=0.008). Despite receiving more PRBC transfusions and having similar operative and phlebotomy blood loss, elderly subjects had lower discharge Hb (9.0 vs. 9.7 g/dL, p=0.013). Elderly subjects had fewer ICU-free days (2.0 vs. 6.0 days, p

It is unknown whether ketamine administered via patient-controlled analgesia (PCA) provides adequate analgesia while reducing opioid consumption in the traumatically injured patient. Differences in opioid consumption, pain scores, and adverse effects between ketamine and hydromorphone PCA were studied.This is an investigator-initiated, single-center, double-blinded, randomized, pilot trial conducted from 2014 to 2016 at a level 1 trauma center. Nonintubated trauma patients in intensive care, who were receiving PCA, were randomized to ketamine or hydromorphone PCA plus opioid analgesics for breakthrough pain.Twenty subjects were randomized. There was no difference in median daily breakthrough opioid use (10 [0.63-19.38] mg versus 10 [4.38-22.5] mg, P = 0.55). Subjects in the ketamine group had lower median cumulative opioid use on therapy day 1 than the hydromorphone group (4.6 [2.5-15] mg versus 41.8 [31.8-50] mg, P 0.001), as well as in the first 48 h (10 [3.3-15] mg versus 48.5 [32.1-67.5] mg, P 0.001) and first 72 h (10 [4.2-15] mg versus 42.5 [31.7-65.2] mg, P 0.001) of therapy. Daily oxygen supplementation requirements were lower in the ketamine group (0.5 [0-1.5] L/min versus 2 [0.5-3] L/min, P = 0.020). Hallucinations occurred more frequently in the ketamine group (40% versus 0%, P = 0.090).Ketamine PCA led to lower cumulative opioid consumption and lower oxygen supplementation requirements, though hallucinations occurred more frequently with use of ketamine. Additional studies are needed to investigate the tolerability of ketamine as an alternative to traditional opioid-based PCA.

Objectives: To examine non-local muscle fatigue (NLMF) in both contralateral homologous and non-related heterogonous muscles for both sexes. Methods: Ten men and nine women participated in this study. After the familiarization visit, subjects completed four separate randomly sequenced experimental visits, during which the fatiguing interventions (six sets of 30-second maximal isometric contractions) were performed on either their right elbow flexors or knee extensors. Before (Pre-) and after (Post-) the fatiguing interventions, the isometric strength and the corresponding surface electromyographic (EMG) amplitude were measured for the non-exercised left elbow flexors or knee extensors. Results: For the non-exercised elbow flexors, the isometric strength decreased for both sexes (sex combined mean±SE: Pre vs. Post=339.67±18.02 N vs. 314.41±16.37 N; p

On October 6, 2017, an outbreak of cholera was declared in Zambia after laboratory confirmation of Vibrio cholerae O1, biotype El Tor, serotype Ogawa, from stool specimens from two patients with acute watery diarrhea. The two patients had gone to a clinic in Lusaka, the capital city, on October 4. Cholera cases increased rapidly, from several hundred cases in early December 2017 to approximately 2,000 by early January 2018 (Figure). In collaboration with partners, the Zambia Ministry of Health (MoH) launched a multifaceted public health response that included increased chlorination of the Lusaka municipal water supply, provision of emergency water supplies, water quality monitoring and testing, enhanced surveillance, epidemiologic investigations, a cholera vaccination campaign, aggressive case management and health care worker training, and laboratory testing of clinical samples. In late December 2017, a number of water-related preventive actions were initiated, including increasing chlorine levels throughout the city's water distribution system and placing emergency tanks of chlorinated water in the most affected neighborhoods; cholera cases declined sharply in January 2018. During January 10-February 14, 2018, approximately 2 million doses of oral cholera vaccine were administered to Lusaka residents aged ≥1 year. However, in mid-March, heavy flooding and widespread water shortages occurred, leading to a resurgence of cholera. As of May 12, 2018, the outbreak had affected seven of the 10 provinces in Zambia, with 5,905 suspected cases and a case fatality rate (CFR) of 1.9%. Among the suspected cases, 5,414 (91.7%), including 98 deaths (CFR = 1.8%), occurred in Lusaka residents.

Extrarenal Wilms tumor is rare. We describe the first reported case of primary paratesticular extrarenal Wilms tumor with regional metastasis in 8-month old male with left undescended testis. Patient underwent left radical orchiectomy with regional lymph node excision. The inguinal node and paratesticular mass demonstrated the classic Wilms triphasic pattern, stained positively for WT-1 and demonstrated no loss of heterozygosity of chromosomes 1p and 16q. Work-up was negative for primary renal Wilms tumor or distant metastasis. Patient underwent adjuvant chemoradiation therapy for stage III disease. Patient is currently 2 years of age with no evidence of recurrence or metastatic disease.

Background We hypothesized that packed red blood cell (PRBC) transfusions from older donors would be associated with fewer nosocomial infections among trauma patients. Methods We performed a four-year retrospective analysis of 264 consecutive adult trauma patients who received ≥1 PRBC transfusion during admission. The capacity of donor age to predict nosocomial infection was assessed by logistic regression. Results Thirty-three percent of all patients developed a nosocomial infection. Donor age was significantly higher among patients with nosocomial infection (40.3 vs. 37.6 years, p = 0.035), and the incidence of infection was directly proportional to donor age. The association between donor age and infection was strongest among recipients age ≥60 years, and was significant on multivariate regression for this cohort (OR 1.07 (95% CI 1.01–1.13), p = 0.024). Conclusions Among trauma patients receiving PRBC transfusions, blood from older donors may be associated with increased risk for nosocomial infection.

Background: New hepatitis C virus (HCV) therapies report cure rates of ~90% but are expensive. Identification of predictors for treatment failure could help decrease health care costs, limit unnecessary drug exposure and adverse events, and prevent drug-drug interactions. Failure to achieve rapid viral response (RVR), defined as detectable viral load at 4 weeks, has previously been identified as a predictor of treatment failure with some previous HCV therapies. Objective: To evaluate RVR, and other potential variables, as predictors of treatment failure in patients treated with ledipasvir and sofosbuvir (LDV/SOF). Methods: A retrospective, case-control analysis of adult veterans treated with LDV/SOF was conducted. Included patients had a viral load obtained between weeks 3 and 6 of therapy (RVR) and between weeks 12 and 16 after the end of therapy for sustained viral response (SVR12) evaluation. Identified SVR12 failures (viral load detectable) constituted the case population. The control population was randomly selected in a 1:4 case: control ratio from all identified SVR12 successes. Results: In all, 12 SVR12 failures were identified; 48 of 144 SVR12 successes were randomly selected for inclusion. Overall failure rate was 7.7% (12/156). Univariate analysis identified histamine-2 receptor antagonist, previous treatment failure, and pretreatment creatinine clearance (CrCl; Cockcroft-Gault) >90 mL/min as potential predictors of SVR12 failure; these variables were included in the regression model with RVR per protocol. In multivariate analysis, pretreatment CrCl >90 mL/min was independently associated with SVR12 failure (odds ratio = 7.27; 95% CI = 1.33 to 39.72; P = 0.022). Conclusions: Patients with pretreatment CrCl >90 mL/min were more likely to fail SVR12 than patients with CrCl

We sought to determine mercury (Hg) and other trace metal concentrations in Adélie (Pygoscelis adeliae) and emperor penguin (Aptenodytes forsteri) breast feathers from the Ross Sea, Antarctica, and relate those concentrations to the trophic position and the habitats in which each of these species forage. Adélie penguin feathers from the southern Ross Sea colonies were higher in Hg than those sampled further north in the Ross Sea, potentially due to greater exposure to local sources, such as volcanism. Female Adélie penguins had lower feather total Hg concentrations than males. This may reflect female penguin's capacity to eliminate Hg through the egg development and laying process, or the larger and/or older prey items that male birds can consume, reflected by their higher trophic position. Emperor penguins have higher Hg concentrations than Adélie penguins which is also partially explained by Adélie penguins feeding at lower trophic levels than emperor penguins.

As an approach to organizational change, trauma-informed care is contextualized within the broader organizational literature by examining the associations between organizational conditions (i.e., psychological experiences of choice and collaboration in the work environment) with precursors to organizational effectiveness (i.e., affective commitment and burnout). The study occurred within a large public hospital's behavioral health department located in the Western New York region (N = 197). Structural regression analyses were conducted, and the primary findings, while nuanced, include support for choice and collaboration's prediction of employee commitment and burnout. Organizational interventions that improve worker's experiences of choice and collaboration may result in increased commitment, reduced burnout, and possibly improved effectiveness. Future research should employ longitudinal designs to further examine the condition-performance relationship and include direct measures of clinical effectiveness.

OBJECTIVES: Opioid-exposed neonates (OENs) are a population at risk for postdischarge complications. Our objective was to improve completion of a discharge bundle to connect patients with outpatient resources to mitigate postdischarge risks. METHODS: Team Hope, a hospital-wide initiative to improve the care of OENs, examined the completion of a discharge bundle from September 2017 through February 2019. A complete discharge bundle was defined as referral to a primary care physician, referral to early intervention services, referral to in-home nursing assessment and educational services, referral to the development clinic if diagnosed with neonatal abstinence syndrome, and referral to the gastroenterology or infectious disease clinic if exposed to hepatitis C virus. After obtaining baseline data, simple interventions were employed as education of providers, social workers, and case management; reminder notes in the electronic health record; and biweekly reminders to resident physicians. A statistical process control chart was used to analyze our primary measure, with special cause variation resulting in a shift indicated by 8 consecutive points above or below the mean line. RESULTS: One hundred nineteen OENs were examined with an initial discharge bundle completion of 2.6% preimplementation. Referral to early intervention services and the development clinic were the least successfully completed elements before intervention implementation. After the development of the discharge bundle in July 2018, special cause variation was achieved, resulting in a mean-line shift with 60.3% now having a complete bundle for 83 OENs. CONCLUSIONS: We implemented a standardized discharge bundle that improved our discharge processes for OENs.

Background Opioid overprescribing is a major contributor to the opioid crisis. The lack of procedure-specific guidelines contributes to the vast differences in prescribing practices. Objective Create opioid-prescribing consensus guidelines for common dermatologic procedures. Methods We utilized a four-step modified Delphi method to conduct a systematic discussion among a panel of providers in the fields of general dermatology, dermatologic surgery, and cosmetics/phlebology to develop opioid-prescribing guidelines for some of the most common dermatologic procedural scenarios. Guidelines were developed for opioid-naive patients undergoing routine procedures. Opioid tablets were defined as oxycodone 5-mg oral equivalents. Results Postoperative pain after most uncomplicated procedures (76%) can be adequately managed with acetaminophen and/or ibuprofen. Group consensus identified no specific dermatological scenario that routinely requires more than 15 oxycodone 5-mg oral equivalents to manage postoperative pain. Group consensus found that 23 percent of the procedural scenarios routinely require 1-10 opioid tablets, while only one routinely requires 1-15 opioid tablets. Limitations These recommendations are based on expert consensus in lieu of quality evidence-based outcomes research. These recommendations must be individualized to accommodate patients’ comorbidities. Conclusions Procedure-specific opioid-prescribing guidelines may serve as a foundation to produce effective and responsible postoperative pain management strategies after dermatologic interventions.

OBJECTIVE This study was undertaken to characterize structural and pharmacological properties of the pig popliteal artery in order to develop a novel system for the examination of lower limb blood flow regulation in a variety of cardiovascular pathologies, such as diabetes-induced peripheral artery disease. METHODS Popliteal arteries were isolated from streptozocin-induced diabetic pigs or age-matched saline-injected control pigs for morphological study using transmission electron microscopy and for examination of vasoreactivity to pharmacological agents using wire myography. RESULTS Transmission electron microscopy of the porcine popliteal artery wall revealed the presence of endothelial cell-smooth muscle cell interactions (myoendothelial junctions) and smooth muscle cell-smooth muscle cell interactions, for which we have coined the term "myo-myo junctions." These myo-myo junctions were shown to feature plaques indicative of connexin expression. Further, the pig popliteal artery was highly responsive to a variety of vasoconstrictors including norepinephrine, phenylephrine, and U46619, and vasodilators including acetylcholine, adenosine 5'-[β-thio] diphosphate, and bradykinin. Finally, 2 weeks after streptozocin-induced diabetes, the normalized vasoconstriction of the pig popliteal artery to norepinephrine was unaltered compared to control. CONCLUSIONS The pig popliteal artery displays structural and pharmacological properties that might prove useful in future studies of diabetes-associated peripheral artery disease and other lower limb cardiovascular diseases.

Novel molecular data from both mitochondrial ( cytochrome c oxidase subunit 1) and ribosomal regions ( 18S, ITS1-5.8S, ITS2, and 28S) are provided for Sebekia mississippiensis Overstreet, Self,Vliet, 1985 , a pentastome infecting the American alligator, Alligator mississippiensis Daudin, 1801, and the spotted gar, Lepisosteus oculatus Winchell, 1864. Adult and nymphal pentastomes are described from the lungs and liver of the type host, A. mississippiensis, collected from Mississippi, while additional nymphs are described from the esophageal lining of L. oculatus specimens collected from Louisiana. This sequencing data will facilitate more accurate identification of various life cycle stages of S. mississippiensis, enabling future work to resolve many ambiguities in the literature regarding this species. Additionally, histopathological data are provided from both the definitive and intermediate hosts.

Cannabinoid receptor 1 (CB(1)) is a potential therapeutic target for the treatment of pain, obesity and obesity-related metabolic disorders, and addiction. The crystal structure of human CB(1) has been determined in complex with the stabilizing antagonist AM6538. In the present study, we characterize AM6538 as a tight-binding/irreversible antagonist of CB(1), as well as two derivatives of AM6538 (AM4112 and AM6542) as slowly dissociating CB(1) antagonists across binding simulations and cellular signaling assays. The long-lasting nature of AM6538 was explored in vivo wherein AM6538 continues to block CP55,940-mediated behaviors in mice up to 5 days after a single injection. In contrast, the effects of SR141716A abate in mice 2 days after injection. These studies demonstrate the functional outcome of CB(1) antagonist modification and open the path for development of long-lasting CB(1) antagonists.

Determining the thermal tolerance of an organism is important when assessing its activity time and survival rate in a given environment. However, thermal tolerance is not a static trait and may be influenced by a number of environmental and organismal factors. We report the results of three experiments investigating the effects of environmental temperature, exposure duration, age, sex, and nutrient availability on the upper thermal tolerance of the adult secondary screwworm, Cochliomyia macellaria. The probability of knockdown and survival was determined using a static method for different environmental temperatures (22, 40, 42, 44, or 45 °C), exposure durations (1, 2, 4, or 6 h), and nutrient availabilities (no food or water, water only, or both food and water) for both sexes and two age classes (young = 7–9 days post pupal emergence, old = 10–12 days post pupal emergence). In general, environmental temperature and exposure duration had the greatest effects on both the probability of knockdown and survival. As temperature or duration increased, the probability of knockdown increased while the probability of survival decreased. The availability of nutrients (water only or food and water) increased thermal tolerance at moderate temperatures (42 and 44 °C), but had no effect at 45 °C. Female flies were more thermally tolerant than males, regardless of nutrient availability. And age exhibited negligible effects on the probabilities of knockdown or survival, regardless of nutrient availability. These data show multiple environmental factors affected the thermal tolerance of C. macellaria. Thus, such aspects of basic thermal biology should feature more prominently in applied fields using blow flies, including but not limited to forensic entomology, disease ecology, and pollination ecology.

Diabetes is associated with hyperglycemia and impairment of retinal microvascular function. However, the impact of hyperglycemia on retinal venular constriction remains unknown. We examined retinal venular responsiveness to endogenous vasoconstrictors and the contribution of the reverse-mode sodium-calcium exchanger (NCX) to these responses during hyperglycemia. Retinal venules were isolated from pigs with streptozocin-induced diabetes (2 weeks, in vivo hyperglycemia) and age-matched control pigs for vasoreactivity and molecular studies. For in vitro hyperglycemia, vessels from euglycemic pigs were exposed to high glucose (25 mmol/L) for 2 h, and 5 mmol/L glucose served as the control. Constrictions of venules from euglycemic pigs to endothelin-1 (ET-1), thromboxane analog U46619, and norepinephrine were mediated by ETA, thromboxane, and α2-adrenergic receptors, respectively, and were insensitive to reverse-mode NCX blockade (KB-R7943). In vivo hyperglycemia enhanced these vasoconstrictions without altering respective receptor mRNA expression. Similarly, in vitro hyperglycemia augmented venular constrictions. Enhanced vasoconstrictions during hyperglycemia were prevented by KB-R7943, while mRNA expression of venular NCX isoforms was unaltered. In vivo hyperglycemia increased vitreous levels of ET-1 but not thromboxane B2. In conclusion, both in vitro and in vivo hyperglycemia enhance retinal venular responses to endogenous vasoconstrictors by activating reverse-mode NCX. Therapies targeting this vascular molecule may alleviate retinal complications during diabetes.

OBJECTIVES Typical carcinoids (TCs) are rare, slow-growing neoplasms, usually characterized by satisfactory surgical outcomes. Due to the rarity of TCs, international guidelines for the management of particular clinical presentations currently do not exist. In particular, non-anatomical resections (wedges) are sometimes advocated for Stage 1 TCs because of their indolent behaviour. The aim of this paper was to evaluate the most effective type of surgery for Stage 1 TCs, using the European Society of Thoracic Surgeons retrospective database of the Neuroendocrine Tumors of the Lung Working Group. METHODS We analysed the effect of surgical procedure on the survival of patients with Stage 1 TCs. Overall survival (OS) was calculated from the date of intervention. The cumulative incidence of cause-specific death (tumour- and non-tumour-related) was also estimated. The impact of the surgical procedure (i.e. lobectomy vs segmentectomy vs wedge resection) on survival was investigated using the Cox model with shared frailty (for OS, accounting for the within-centre correlation) and the Fine and Gray model (for cause-specific mortality) using the approach based on the multinomial propensity score. Effects were estimated including in the model the logit-transformed propensity scores of segmentectomy and wedge resection as covariates. RESULTS A total of 876 patients with Stage 1 TCs (569 women, 65%) were included in this study. The median age was 60 years (interquartile range 47–69). At the last follow-up, 66 patients had died: The 5-year OS rate was 94.3% [95% confidence interval (CI) 92.2–95.9]. The 5-year cumulative incidences of tumour- and non-tumour-related deaths were 2.4% (95% CI 1.4–3.9) and 3.9% (95% CI 2.5–5.6%), respectively. The analysis performed using the multinomial propensity score approach confirmed the significantly worse survival of patients treated with a wedge resection compared to those treated with a lobectomy (hazard ratio 2.01, 95% CI 1.09–3.69; P = 0.024). Similar effects of wedge resection are detectable for cause-specific deaths: tumour-related (hazard ratio 2.28, 95% CI 0.86–6.02; P = 0.096) and non-tumour-related (hazard ratio 1.74, 95% CI 0.89–3.40; P = 0.105). CONCLUSIONS In a large cohort of patients, we were able to demonstrate the superiority of anatomical surgical resection in Stage 1 TCs in terms of OS. This result should therefore be considered for future clinical guidelines for the management of TCs.

Summary Introduction/background: Bladder exstrophy patients have a high prevalence of inguinal hernia that often become clinically evident following bladder closure. Understanding when the bladder exstrophy patient is under greatest risk of developing an inguinal hernia following bladder closure is important, since incarceration resulting in strangulation of intra-abdominal contents can lead to significant morbidity if not addressed in a timely fashion. Although the incidence and risk factors of inguinal hernia have been reported, the timing of occurrence is not well understood. Objective: The primary objective of this study was to assess the timing of inguinal hernia following complete primary repair of bladder exstrophy (CPRE). In addition, we aimed to evaluate possible risk factors associated with inguinal hernia, including sex, age at bladder closure and iliac osteotomy status. Study Design: A multi-institutional retrospective review identified patients with bladder exstrophy repaired by CPRE under 6 months of age while excluding those who underwent inguinal hernia repair before or during bladder closure. Timing of inguinal hernia following bladder closure was evaluated using Kaplan–Meier methods. Cox proportional hazards model was used to investigate association of sex, age at bladder closure, and osteotomy on the risk of developing of inguinal hernia while clustering for institution. Results: 91 subjects were included in our analysis with median follow-up time of 6.5 years. 34 of 53 males (64.2%) and 2 of 38 females (5.3%) underwent inguinal hernia repair. The median time to inguinal hernia was 4.7 months following closure. The greatest hazard of inguinal hernia was within the first six months following closure. In multivariate analysis, male sex was strongly associated with inguinal hernia (HR = 19.00, p = 0.0038). Osteotomy and delay in closure were not significantly associated with inguinal hernia. 7 of 36 patients (19.4%) who underwent inguinal hernia repair presented with recurrence on the ipsilateral side. Discussion: Our results suggest that the greatest risk of inguinal hernia is within the first six months following bladder closure. The decreased risk of inguinal hernia after one year of follow-up may reflect anatomic stability that is reached following major reconstruction of the pelvis. While male bladder exstrophy patients are significantly more susceptible to inguinal hernias following CPRE, osteotomy and delayed bladder closure do not appear to be protective factors for inguinal hernia development following initial bladder closure. Conclusions: There is a heightened risk of inguinal hernia in the first six months following closure. The rate of recurrence following inguinal hernia repair is significantly elevated compared to the general pediatric population. Download : Download high-res image (250KB) Download : Download full-size image Summary Figure . Kaplan–Meier curves for overall probability of inguinal hernia repair for males and females

Critical Care Air Transport Teams (CCATTs) are integral to the U.S. Air Force aeromedical evacuation paradigm. The current study was conducted to evaluate predictors of nontechnical skills (NOTECHS) in CCATT trainees.Sixteen CCATTs were studied over a 6-month period. Team members completed a biographical survey and teams were videotaped during a simulated CCATT mission. Teams and individuals were assigned a "red flag score" using a validated assessment tool for NOTECHS. Salivary cortisol levels were measured at baseline and pre- and postsimulation exercises.63% of participants reported regular intensive care unit (ICU) experience and 67% had flown real-world CCATT missions. Sixteen simulated missions were reviewed, with 69 crisis events identified. Task saturation was observed in 42% of crisis events. Average team red flag score correlated with task saturation during the simulated missions (odds ratio = 0.5). Daily ICU experience (p0.03) and previous deployment (p0.04) correlated with NOTECHS performance. Cortisol levels increased from baseline as the result of the simulation (p0.01) but did not correlate with red flag scores or biographical data.Task saturation occurred frequently and correlated with performance of NOTECHS. Previous real-world CCATT experience and daily ICU care correlated with improved performance of NOTECHS.

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License., PURPOSE: Although endothelium-dependent nitric oxide (NO)-mediated dilation of retinal arterioles has been well described, the role of endothelium-derived hyperpolarizing factor (EDHF) in the retinal arteriolar response remains unclear. In the current study, we examined the contribution of EDHF to the retinal arteriolar dilation to the inflammatory agent histamine and investigated the signaling mechanisms underlying this vasomotor activity. METHODS: Porcine retinal arterioles were isolated, cannulated, and pressurized without flow for functional study by using video microscopic techniques. The immunohistochemical staining was performed to determine histamine receptor subtypes. RESULTS: Histamine (0.1-30 μM) produced concentration-dependent dilation of retinal arterioles in a manner sensitive to H1- and H2-receptor antagonists chlorpheniramine and famotidine, respectively. Histamine-induced vasodilation was almost abolished after endothelial removal. In the intact vessels, vasodilation to histamine was partially inhibited by the inhibitors of cyclooxygenase (indomethacin), NO synthase (NG-nitro-L-arginine methyl ester, L-NAME), or Ca2+ -activated K+ (KCa) channels (apamin plus charybdotoxin). Combination of the above inhibitors abolished histamine-induced vasodilation. Residual vasodilation in the presence of indomethacin and L-NAME was further reduced by the cytochrome P450 enzyme inhibitor sulfaphenazole but not by the gap junction inhibitor carbenoxolone or the hydrogen peroxide scavenger catalase. Immunohistochemical signals for H1- and H2-receptor expression were found only in the endothelium. CONCLUSIONS: The endothelium plays an essential role in the dilation of porcine retinal arterioles to histamine via H1- and H2-receptor activation. The EDHF derived from cytochrome P450 contributed in part to this vasodilation via KCa channel activation, in addition to the endothelial release of NO and prostanoids.

Purpose Hyperglycemia, a hallmark of diabetes mellitus, is associated with retinal inflammation and impairment of endothelium-dependent nitric oxide (NO)–mediated dilation of retinal arterioles. However, molecular mechanisms involved in this diminished endothelial vasodilator function remain unclear. We examined whether inflammatory stress-activated kinases, c-Jun N-terminal kinase (JNK) and p38, contribute to retinal arteriolar dysfunction during exposure to acute and chronic hyperglycemia. Methods Retinal arterioles were isolated from streptozocin-induced diabetic pigs (2 weeks; chronic hyperglycemia, 471 ± 23 mg/dL) or age-matched control pigs (euglycemia, 79 ± 5 mg/dL), and then cannulated and pressurized for vasoreactivity study. For acute hyperglycemia study, vessels from nondiabetic pigs were exposed intraluminally to high glucose (25 mM ≈ 450 mg/dL) for 2 hours, and normal glucose (5 mM ≈ 90 mg/dL) served as the control. Results Endothelium-dependent vasodilation to bradykinin was reduced in a similar manner after exposure to acute or chronic hyperglycemia. Administration of NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) nearly abolished vasodilations either in control (euglycemia and normal glucose) or hyperglycemic (acute and chronic) vessels. Treatment of either acute or chronic hyperglycemic vessels with JNK inhibitor SP600125 or JNK-interacting protein-1 (JIP1) inhibitor BI-78D3, but not p38 inhibitor SB203580, preserved bradykinin-induced dilation in an L-NAME–sensitive manner. By contrast, endothelium-independent vasodilation to sodium nitroprusside was unaffected by acute or chronic hyperglycemia. Conclusions Activation of JIP1/JNK signaling in retinal arterioles during exposure to acute or chronic hyperglycemia leads to selective impairment of endothelium-dependent NO-mediated dilation. Therapeutic targeting of the vascular JNK pathway may improve retinal endothelial vasodilator function during early diabetes.

There have been recent attempts to characterize the mechanisms associated with fatigue-induced task failure. We compared the time to failure and the corresponding changes in the surface electromyogram (EMG) during sustained maximal and submaximal isometric force tasks. EMG activity was measured from the biceps brachii of 18 male participants as they sustained either a maximal or submaximal (60 % MVC) isometric contraction of the dominant elbow flexors until force could not be maintained above 55 % MVC. Intensity-dependent patterns of change were observed for EMG amplitude and mean power frequency (MNF) between the two force tasks. Interestingly, the only significant predictor of failure time was the rate of change in EMG MNF during the submaximal task (r 2 = 0.304). In addition, EMG amplitude at submaximal failure was significantly lower (p

A series of in vivo and in vitro assays were conducted to characterize the pharmacological effects of the first generation abused synthetic cannabinoid CP47,497, a racemic bicyclic cannabinoid that is similar in structure to the potent, high-efficacy synthetic cannabinoid CP55,940. CP47,497 was less efficacious than CP55,940 in activating G-proteins and dose-dependently produced common CB1 receptor-dependent pharmacological effects (i.e. catalepsy, hypothermia, antinociception, and hypolocomotion). CP47,497 also substituted for Δ9-tetrahydrocannabinol (THC) in the mouse drug discrimination, indicating that both drugs elicited a similar interceptive stimulus. The pharmacological effects of CP47,497 underwent tolerance following repeated administration and showed cross-tolerance following repeated THC administration, further suggesting a common cannabimimetic mechanism of action. Finally, the CB1 receptor antagonist rimonabant precipitated similar magnitudes of somatic withdrawal responses in mice treated repeatedly with THC or CP47,497. Taken together, these data verify the acute cannabimimetic effects of CP47,497, and indicate tolerance and dependence following repeated administration. The assays used here provide a straightforward approach to characterize the emerging next generation of abused synthetic cannabinoids.

Serious clinical liabilities associated with the prescription of opiates for pain control include constipation, respiratory depression, pruritus, tolerance, abuse, and addiction. A recognized strategy to circumvent these side effects is to combine opioids with other antinociceptive agents. The combination of opiates with the primary active constituent of cannabis (Δ(9)-tetrahydrocannabinol) produces enhanced antinociceptive actions, suggesting that cannabinoid receptor agonists can be opioid sparing. Here, we tested whether elevating the endogenous cannabinoid 2-arachidonoylglycerol through the inhibition of its primary hydrolytic enzyme monoacylglycerol lipase (MAGL), will produce opioid-sparing effects in the mouse chronic constriction injury (CCI) of the sciatic nerve model of neuropathic pain. The dose-response relationships of i.p. administration of morphine and the selective MAGL inhibitor 2,5-dioxopyrrolidin-1-yl 4-(bis(4-chlorophenyl)methyl)piperazine-1-carboxylate (MJN110) were tested alone and in combination at equieffective doses for reversal of CCI-induced mechanical allodynia and thermal hyperalgesia. The respective ED50 doses (95% confidence interval) of morphine and MJN110 were 2.4 (1.9-3.0) mg/kg and 0.43 (0.23-0.79) mg/kg. Isobolographic analysis of these drugs in combination revealed synergistic antiallodynic effects. Acute antinociceptive effects of the combination of morphine and MJN110 required μ-opioid, CB1, and CB2 receptors. This combination did not reduce gastric motility or produce subjective cannabimimetic effects in the drug discrimination assay. Importantly, combinations of MJN110 and morphine given repeatedly (i.e., twice a day for 6 days) continued to produce antiallodynic effects with no evidence of tolerance. Taken together, these findings suggest that MAGL inhibition produces opiate-sparing events with diminished tolerance, constipation, and cannabimimetic side effects.

Purpose Retinal vasomotor activity can be regulated by two major endothelial enzymes, nitric oxide synthase (NOS) and cyclooxygenase (COX). The vascular arginase also consumes a NOS substrate and thus impedes NOS-mediated vasodilation. Diabetes mellitus exhibits vascular complications in the retina with elevated oxidative stress and compromised NOS-mediated vasodilation. However, the underlying molecular mechanisms remain unclear, and the effect of diabetes on COX-mediated vasodilation is unknown. Herein, we examined the relative impact of diabetes on retinal arteriolar dilations to COX and NOS activation and the roles of arginase and superoxide in diabetes-induced vasomotor dysfunction. Methods Retinal arterioles were isolated from streptozocin-induced diabetic pigs (2 weeks of hyperglycemia, 433 ± 27 mg/dL) or age-matched control pigs (97 ± 4 mg/dL). The vasodilations to bradykinin (NOS activator) and histamine (NOS/COX activator) were examined in vitro. Results Retinal arteriolar dilations to histamine and bradykinin were significantly reduced after 2 weeks of diabetes. The NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) attenuated the dilations of control vessels, but not diabetic vessels, to histamine. In the presence of L-NAME and COX inhibitor indomethacin, histamine-induced dilations of control and diabetic vessels were reduced similarly. Treatment of diabetic vessels with arginase inhibitor nor-NOHA, but not superoxide dismutase mimetic TEMPOL, preserved both histamine- and bradykinin-induced dilations in an L-NAME-sensitive manner. Conclusions Arginase, rather than superoxide, impairs endothelium-dependent NOS-mediated dilation of retinal arterioles during diabetes, whereas vasodilation mediated by COX remains intact. Blockade of vascular arginase may improve endothelial function of retinal arterioles during early onset of diabetes.

The participation of children and adolescents in wilderness and extreme environment sports is increasing. Engaging in these activities is not without risk of injury, illness, or death. To date, there is limited research investigating pediatric and adolescent injuries in wilderness and extreme environments. With the intent of creating awareness within the sports medicine field, this review begins by examining the growth in popularity of outdoor sports in wilderness and extreme environments and the injury impact they are registering. The review then examines reported pediatric and adolescent injuries in multiple wilderness and extreme environments. Close examination is paid to youth adventuring on global expeditions and entering high altitude environments. Future studies acquiring denominator data to help establish injury rates while keeping pace with the rapidly diversifying outdoor and extreme wilderness sport trends are necessary.