Beyond high-risk: analysis of the outcomes of extreme-risk patients in the National Emergency Laparotomy Audit.

Patients who require emergency laparotomy are defined as high risk if their 30-day predicted risk of mortality is ≥ 5%. Despite a large difference in the characteristics of patients with a mortality risk score of between 5% and 50%, these outcomes are aggregated by the National Emergency Laparotomy Audit (NELA). Our aim was to describe the outcomes of the cohort of patients at extreme risk of death, which we defined as having a NELA-predicted 30-day mortality of ≥ 50%. All patients enrolled in the NELA database between December 2012 and 2020 were included. We compared patient characteristics; length of hospital stay; rates of unplanned return to the operating theatre; and 90-day survival in extreme-risk groups (predicted ≥ 50%) and high-risk patients (predicted 5-49%). Of 161,337 patients, 5193 (3.2%) had a predicted mortality of ≥ 50%. When patients were further subdivided, 2437 (47%) had predicted mortality of 50-59% (group 50-59); 1484 (29%) predicted mortality of 60-69% (group 60-69); 840 (16%) predicted mortality of 70-79% (group 70-79); and 423 (8%) predicted mortality of ≥ 80% (group 80+). Extreme-risk patients were significantly more likely to have been admitted electively than high-risk patients (p < 0.001). Length of stay increased from a median (IQR [range]) of 26 (16-43 [0-271]) days in group 50-59 to 35 (21-56 [0-368]) days in group 80+, compared with 17 (10-30 [0-1136]) days for high-risk patients. Rates of unplanned return to the operating theatre were higher in extreme-risk groups compared with high-risk patients (11% vs. 8%). The 90-day survival was 43% in group 50-59, 34% in group 60-69, 27% in group 70-79 and 17% in group 80+. These data underscore the need for a differentiated approach when discussing risk with patients at extreme risk of mortality following an emergency laparotomy. Clinicians should focus on patient priorities on quantity and quality of life during informed consent discussions before surgery. Future work should extend beyond the immediate postoperative period to encompass the longer-term outcomes (survival and function) of patients who have emergency laparotomies.

Development and validation of a prognostic model for death 30 days after adult emergency laparotomy.

The probability of death after emergency laparotomy varies greatly between patients. Accurate pre-operative risk prediction is fundamental to planning care and improving outcomes. We aimed to develop a model limited to a few pre-operative factors that performed well irrespective of surgical indication: obstruction; sepsis; ischaemia; bleeding; and other. We derived a model with data from the National Emergency Laparotomy Audit for patients who had emergency laparotomy between December 2016 and November 2018. We tested the model on patients who underwent emergency laparotomy between December 2018 and November 2019. There were 4077/40,816 (10%) deaths 30 days after surgery in the derivation cohort. The final model had 13 pre-operative variables: surgical indication; age; blood pressure; heart rate; respiratory history; urgency; biochemical markers; anticipated malignancy; anticipated peritoneal soiling; and ASA physical status. The predicted mortality probability deciles ranged from 0.1% to 47%. There were 1888/11,187 deaths in the test cohort. The scaled Brier score, integrated calibration index and concordance for the model were 20%, 0.006 and 0.86, respectively. Model metrics were similar for the five surgical indications. In conclusion, we think that this prognostic model is suitable to support decision-making before emergency laparotomy as well as for risk adjustment for comparing organisations.

Quantitative futility in emergency laparotomy: an exploration of early-postoperative death in the National Emergency Laparotomy Audit.

BACKGROUND: Quantitative futility is an appraisal of the risk of failure of a treatment. For those who do not survive, a laparotomy has provided negligible therapeutic benefit and may represent a missed opportunity for palliation. The aim of this study was to define a timeframe for quantitative futility in emergency laparotomy and investigate predictors of futility using the National Emergency Laparotomy Audit (NELA) database. METHODS: A two-stage methodology was used; stage one defined a timeframe for futility using an online survey and steering group discussion; stage two applied this definition to patients enrolled in NELA December 2013-December 2020 for analysis. Futility was defined as all-cause mortality within 3 days of emergency laparotomy. Baseline characteristics of this group were compared to all others. Multilevel logistic regression was carried out with potentially clinically important predictors defined a priori. RESULTS: Quantitative futility occurred in 4% of patients (7442/180,987). Median age was 74 years (range 65-81 years). Median NELA risk score was 32.4% vs. 3.8% in the surviving cohort (p < 0.001). Early mortality patients more frequently presented with sepsis (p < 0.001). Significant predictors of futility included age, arterial lactate and cardiorespiratory co-morbidity. Frailty was associated with a 38% increased risk of early mortality (95% CI 1.22-1.55). Surgery for intestinal ischaemia was associated with a two times greater chance of futile surgery (OR 2.67; 95% CI 2.50-2.85). CONCLUSIONS: Quantitative futility after emergency laparotomy is associated with quantifiable risk factors available to decision-makers preoperatively. These findings should be incorporated qualitatively by the multidisciplinary team into shared decision-making discussions with extremely high-risk patients.

Clinical risk prediction model for 30-day all-cause re-hospitalisation or mortality in patients hospitalised with heart failure.

BACKGROUND: This study aimed to develop a risk prediction model (AUS-HF model) for 30-day all-cause re-hospitalisation or death among patients admitted with acute heart failure (HF) to inform follow-up after hospitalisation. The model uses routinely collected measures at point of care. METHODS: We analyzed pooled individual-level data from two cohort studies on acute HF patients followed for 30-days after discharge in 17 hospitals in Victoria, Australia (2014-2017). A set of 58 candidate predictors, commonly recorded in electronic medical records (EMR) including demographic, medical and social measures were considered. We used backward stepwise selection and LASSO for model development, bootstrap for internal validation, C-statistic for discrimination, and calibration slopes and plots for model calibration. RESULTS: The analysis included 1380 patients, 42.1% female, median age 78.7 years (interquartile range = 16.2), 60.0% experienced previous hospitalisation for HF and 333 (24.1%) were re-hospitalised or died within 30 days post-discharge. The final risk model included 10 variables (admission: eGFR, and prescription of anticoagulants and thiazide diuretics; discharge: length of stay>3 days, systolic BP, heart rate, sodium level (<135 mmol/L), >10 prescribed medications, prescription of angiotensin converting enzyme inhibitors or angiotensin receptor blockers, and anticoagulants prescription. The discrimination of the model was moderate (C-statistic = 0.684, 95%CI 0.653, 0.716; optimism estimate = 0.062) with good calibration. CONCLUSIONS: The AUS-HF model incorporating routinely collected point-of-care data from EMRs enables real-time risk estimation and can be easily implemented by clinicians. It can predict with moderate accuracy risk of 30-day hospitalisation or mortality and inform decisions around the intensity of follow-up after hospital discharge.

Failure to rescue patients after emergency laparotomy for large bowel perforation: analysis of the National Emergency Laparotomy Audit (NELA).

BACKGROUND: Past studies have highlighted variation in in-hospital mortality rates among hospitals performing emergency laparotomy for large bowel perforation. The aim of this study was to investigate whether failure to rescue (FTR) contributes to this variability. METHODS: Patients aged 18 years or over requiring surgery for large bowel perforation between 2013 and 2016 were extracted from the National Emergency Laparotomy Audit (NELA) database. Information on complications were identified using linked Hospital Episode Statistics data and in-hospital deaths from the Office for National Statistics. The FTR rate was defined as the proportion of patients dying in hospital with a recorded complication, and was examined in hospitals grouped as having low, medium or high overall postoperative mortality. RESULTS: Overall, 6413 patients were included with 1029 (16.0 per cent) in-hospital deaths. Some 3533 patients (55.1 per cent) had at least one complication: 1023 surgical (16.0 per cent) and 3332 medical (52.0 per cent) complications. There were 22 in-hospital deaths following a surgical complication alone, 685 deaths following a medical complication alone, 150 deaths following both a surgical and medical complication, and 172 deaths with no recorded complication. The risk of in-hospital death was high among patients who suffered either type of complication (857 deaths in 3533 patients; FTR rate 24.3 per cent): 172 deaths followed a surgical complication (FTR-surgical rate 16.8 per cent) and 835 deaths followed a medical complication (FTR-medical rate of 25.1 per cent). After adjustment for patient characteristics and hospital factors, hospitals grouped as having low, medium or high overall postoperative mortality did not have different FTR rates (P = 0.770). CONCLUSION: Among patients having emergency laparotomy for large bowel perforation, efforts to reduce the risk of in-hospital death should focus on reducing avoidable complications. There was no evidence of variation in FTR rates across National Health Service hospitals in England.

The management of adult appendicitis during the COVID-19 pandemic: an interim analysis of a UK cohort study.

BACKGROUND: Acute appendicitis (AA) is the most common general surgical emergency. Early laparoscopic appendicectomy is the gold-standard management. SARS-CoV-2 (COVID-19) brought concerns of increased perioperative mortality and spread of infection during aerosol generating procedures: as a consequence, conservative management was advised, and open appendicectomy recommended when surgery was unavoidable. This study describes the impact of the first weeks of the pandemic on the management of AA in the United Kingdom (UK). METHODS: Patients 18 years or older, diagnosed clinically and/or radiologically with AA were eligible for inclusion in this prospective, multicentre cohort study. Data was collected from 23rd March 2020 (beginning of the UK Government lockdown) to 1st May 2020 and included: patient demographics, COVID status; initial management (operative and conservative); length of stay; and 30-day complications. Analysis was performed on the first 500 cases with 30-day follow-up. RESULTS: The patient cohort consisted of 500 patients from 48 sites. The median age of this cohort was 35 [26-49.75] years and 233 (47%) of patients were female. Two hundred and seventy-one (54%) patients were initially treated conservatively; with only 26 (10%) cases progressing to an operation. Operative interventions were performed laparoscopically in 44% (93/211). Median length of hospital stay was significantly reduced in the conservatively managed group (2 [IQR 1-4] days vs. 3 [2-4], p < 0.001). At 30 days, complications were significantly higher in the operative group (p < 0.001), with no deaths in any group. Of the 159 (32%) patients tested for COVID-19 on admission, only 6 (4%) were positive. CONCLUSION: COVID-19 has changed the management of acute appendicitis in the UK, with non-operative management shown to be safe and effective in the short-term. Antibiotics should be considered as the first line during the pandemic and perhaps beyond.

Trainee-led emergency laparotomy operating.

BACKGROUND: To achieve completion of training in general surgery, trainees are required to demonstrate competency in common procedures performed at emergency laparotomy. The aim of this study was to describe the patterns of trainee-led emergency laparotomy operating and the association between postoperative outcomes. METHODS: Data on all patients who had an emergency laparotomy between December 2013 and November 2017 were extracted from the National Emergency Laparotomy Audit database. Patients were grouped by grade of operating surgeon: trainee (specialty registrar) or consultant (including post-Certificate of Completion of Training fellows). Trends in trainee operating by deanery, hospital size and time of day of surgery were investigated. Univariable and adjusted regression analyses were performed for the outcomes 90-day mortality and return to theatre, with analysis of patients in operative subgroups segmental colectomy, Hartmann's procedure, adhesiolysis and repair of perforated peptic ulcer disease. RESULTS: The study cohort included 87 367 patients. The 90-day mortality rate was 15·1 per cent in the consultant group compared with 11·0 per cent in the trainee group. There were no increased odds of death by 90 days or of return to theatre across any of the operative groups when the operation was performed with a trainee listed as the most senior surgeon in theatre. Trainees were more likely to operate independently in high-volume centres (highest- versus lowest-volume centres: odds ratio (OR) 2·11, 95 per cent c.i. 1·91 to 2·33) and at night (00.00 to 07.59 versus 08.00 to 11.59 hours; OR 3·20, 2·95 to 3·48). CONCLUSION: There is significant variation in trainee-led operating in emergency laparotomy by geographical area, hospital size and by time of day. However, this does not appear to influence mortality or return to theatre.

ANTECEDENTES: Para completar la formación en cirugía general, se requiere que los aspirantes demuestren solvencia en la práctica de los procedimientos comunes efectuados por laparotomía de urgencia. El objetivo de este estudio fue describir los esquemas de formación de los aspirantes en laparotomía de urgencia y su asociación con los resultados postoperatorios. MÉTODOS: Todos los pacientes a los que se realizó una laparotomía de urgencia entre diciembre del 2013 y noviembre del 2017 se obtuvieron a partir de la base de datos de la Auditoría Nacional de Laparotomía de Urgencia (National Emergency Laparotomy Audit, NELA). Los pacientes se agruparon según la experiencia del cirujano; cirujanos en periodo de formación (residentes, speciality registrar) o consultores (incluyendo los que habían completado la especialidad). Se investigaron las tendencias entre los residentes por universidad, tamaño del hospital y hora del día de la cirugía. Se realizaron análisis de regresión univariable y ajustados para la mortalidad a los 90 días y la reoperación, así como análisis de subgrupos para los procedimientos quirúrgicos de colectomía segmentaria, intervención de Hartmann, liberación de bridas y la sutura de una úlcera péptica perforada. RESULTADOS: La cohorte de estudio incluyó 87.367 pacientes. La mortalidad a los 90 días en el grupo de consultores fue del 15% en comparación con el 11% en el grupo de residentes. No hubo aumento del riesgo de mortalidad a los 90 días o de reoperación en ninguno de los subgrupos de las diferentes operaciones cuando la cirugía era efectuada por el residente considerado como el más senior en las listas de quirófano. Los residentes tenían más probabilidades de operar solos en centros de alto volumen (en comparación con centros de bajo volumen; razón de oportunidades, odds ratio (OR) 2,11, i.c. del 95% 1,91-2,33) o durante la noche (00:00-07:59 horas en comparación con 08:00-11:59; OR 3,20; i.c. del 95% 2,95-3,48). CONCLUSIÓN: Existen diferencias significativas en la formación que reciben los residentes en laparotomía de urgencia según el área geográfica, el tamaño del hospital y la hora del día. Sin embargo, estas diferencias no parecen afectar a la mortalidad ni a la tasa de reoperaciones.

A review of surgical and peri-operative factors to consider in emergency laparotomy care.

Patients undergoing emergency laparotomy are a heterogeneous group with regard to comorbidity, pre-operative physiological state and surgical pathology. There are many factors to consider in the peri-operative period for these patients. Surgical duration should be as short as possible for adequate completion of the procedure. This is of particular importance in the elderly and comorbid population. To date, there are limited data addressing the role of damage control surgery in emergency general surgery. Dual consultant-led care in all stages of emergency laparotomy care is increasing, with increased presence out of hours and also for high-risk patients. The role of the stoma care team should be actively encouraged in all patients who may require a stoma. Due to the emergent and unpredictable nature of surgical emergencies, healthcare teams may need to employ novel strategies to ensure early input from the stoma care team. It is important for all members of the medical teams to ensure that patients have given consent for both anaesthesia and surgery before emergency laparotomy. Small studies suggest that patients and their families are not aware of the high risk of morbidity and mortality following emergency laparotomy before operative intervention. Elderly patients should have early involvement from geriatric specialists and careful attention paid to assessment of frailty due to its association with mortality and morbidity. Additionally, the use of enhanced recovery programmes in emergency general surgery has been shown to have some impact in reducing length of stay in emergency surgical patients. However, the emergent nature of this surgery has been shown to be a detrimental factor in full implementation of enhanced recovery programmes. The use of a national database to collect data on patients undergoing emergency laparotomy and their processes of care has led to reduced mortality and length of stay in the UK. However, internationally, fewer data are available to draw conclusions.

Delay in Source Control in Perforated Peptic Ulcer Leads to 6% Increased Risk of Death Per Hour: A Nationwide Cohort Study.

BACKGROUND: Delay to theatre for patients with intra-abdominal sepsis is cited as a particular risk factor for death. Our aim was to evaluate the potential relationship between hourly delay from admission to surgery and post-operative mortality in patients with perforated peptic ulcer (PPU). METHODS: All patients entered in the National Emergency Laparotomy Audit who had an emergency laparotomy for PPU within 24 h of admission from December 2013 to November 2017 were included. Time to theatre from admission was modelled as a continuous variable in hours. Outcome was 90-day mortality. Logistic regression adjusting for confounding factors was performed. RESULTS: 3809 patients were included, and 90-day mortality rate was 10.61%. Median time to theatre was 7.5 h (IQR 5-11.6 h). The odds of death increased with time to operation once adjustment for confounding variables was performed (per hour after admission adjusted OR 1.04 95% CI 1.02-1.07). In patients who were physiologically shocked (N = 334), there was an increase of 6% in risk-adjusted odds of mortality for every hour Em Lap was delayed after admission (OR 1.06 95% CI 1.01-1.11). CONCLUSION: Hourly delay to theatre in patients with PPU is independently associated with risk of death by 90 days. Therefore, we suggest that surgical source control should occur as soon as possible after admission regardless of time of day.

Machine learning models for predicting the use of different animal breeding services in smallholder dairy farms in Sub-Saharan Africa.

This study is concerned with developing predictive models using machine learning techniques to be used in identifying factors that influence farmers' decisions, predict farmers' decisions, and forecast farmers' demands relating to breeding service. The data used to develop the models comes from a survey of small-scale dairy farmers from Tanzania (n = 3500 farmers), Kenya (n = 6190 farmers), Ethiopia (n = 4920 farmers), and Uganda (n = 5390 farmers) and more than 120 variables were identified to influence breeding decisions. Feature engineering process was used to reduce the number of variables to a practical level and to identify the most influential ones. Three algorithms were used for feature selection, namely: logistic regression, random forest, and Boruta. Subsequently, six predictive models, using features selected by feature selection method, were tested for each country-neural network, logistic regression, K-nearest neighbor, decision tree, random forest, and Gaussian mixture model. A combination of decision tree and random forest algorithms was used to develop the final models. Each country model showed high predictive power (up to 93%) and are ready for practical use. The use of ML techniques assisted in identifying the key factors that influence the adoption of breeding method that can be taken and prioritized to improve the dairy sector among countries. Moreover, it provided various alternatives for policymakers to compare the consequences of different courses of action which can assist in determining which alternative at any particular choice point had a high probability to succeed, given the information and alternatives pertinent to the breeding decision. Also, through the use of ML, results to the identification of different clusters of farmers, who were classified based on their farm, and farmers' characteristics, i.e., farm location, feeding system, animal husbandry practices, etc. This information had significant value to decision-makers in finding the appropriate intervention for a particular cluster of farmers. In the future, such predictive models will assist decision-makers in planning and managing resources by allocating breeding services and capabilities where they would be most in demand.

Characterisation of peripheral and central components of the rat monoiodoacetate model of Osteoarthritis.

OBJECTIVE: Pain is the main reason patients report Osteoarthritis (OA), yet current analgesics remain relatively ineffective. This study investigated both peripheral and central mechanisms that lead to the development of OA associated chronic pain. DESIGN: The monoiodoacetate (MIA) model of OA was investigated at early (2-6 days post injection) and late (>14 days post injection) time points. Pain-like behaviour and knee histology were assessed to understand the extent of pain due to cartilage degradation. Electrophysiological single-unit recordings were taken from spinal wide dynamic range (WDR) neurons to investigate Diffuse Noxious Inhibitory Controls (DNIC) as a marker of potential changes in descending controls. Immunohistochemistry was performed on dorsal root ganglion (DRG) neurons to assess any MIA induced neuronal damage. Furthermore, qPCR was used to measure levels of glia cells and cytokines in the dorsal horn. RESULTS: Both MIA groups develop pain-like behaviour but only late phase (LP) animals display extensive cartilage degradation. Early phase animals have a normally functioning DNIC system but there is a loss of DNIC in LP animals. We found no evidence for neuronal damage caused by MIA in either group, yet an increase in IL-1ß mRNA in the dorsal horn of LP animals. CONCLUSION: The loss of DNIC in LP MIA animals suggests an imbalance in inhibitory and facilitatory descending controls, and a rise in the mRNA expression of IL-1ß mRNA suggest the development of central sensitisation. Therefore, the pain associated with OA in LP animals may not be attributed to purely peripheral mechanisms.

An investigation into the noradrenergic and serotonergic contributions of diffuse noxious inhibitory controls in a monoiodoacetate model of osteoarthritis.

Osteoarthritis (OA) is a debilitating conditioning with pain as the major clinical symptom. Understanding the mechanisms that drive OA-associated chronic pain is crucial for developing the most effective analgesics. Although the degradation of the joint is the initial trigger for the development of chronic pain, the discordance between radiographic joint damage and the reported pain experience in patients, coupled with clinical features that cannot be explained by purely peripheral mechanisms, suggest there are often other factors at play. Therefore, this study considers the central contributions of chronic pain, using a monoiodoacetate (MIA) model of OA. Particularly, this study explores the functionality of descending controls over the course of the model by assessing diffuse noxious inhibitory controls (DNIC). Early-phase MIA animals have a functional DNIC system, whereas DNIC are abolished in late-phase MIA animals, indicating a dysregulation in descending modulation over the course of the model. In early-phase animals, blocking the actions of spinal α2-adrenergic receptors completely abolishes DNIC, whereas blocking the actions of spinal 5-HT7 receptors only partially decreases the magnitude of DNIC. However, activating the spinal α2-adrenergic or 5-HT7 receptors in late-phase MIA animals restored DNIC-induced neuronal inhibition. This study confirms that descending noradrenergic signaling is crucial for DNIC expression. Furthermore, we suggest a compensatory increase in descending serotonergic inhibition acting at 5-HT7 receptors as the model progresses such that receptor activation is sufficient to override the imbalance in descending controls and mediate neuronal inhibition. NEW & NOTEWORTHY This study showed that there are both noradrenergic and serotonergic components contributing to the expression of diffuse noxious inhibitory controls (DNIC). Furthermore, although a tonic descending noradrenergic tone is always crucial for the expression of DNIC, variations in descending serotonergic signaling over the course of the model mean this component plays a more vital role in states of sensitization.

Technologies for Measuring Pharmacokinetic Profiles.

The creation of a pharmacokinetic (PK) curve, which follows the plasma concentration of an administered drug as a function of time, is a critical aspect of the drug development process and includes such information as the drug's bioavailability, clearance, and elimination half-life. Prior to a drug of interest gaining clearance for use in human clinical trials, research is performed during the preclinical stages to establish drug safety and dosing metrics from data obtained from the PK studies. Both in vivo animal models and in vitro platforms have limitations in predicting human reaction to a drug due to differences in species and associated simplifications, respectively. As a result, in silico experiments using computer simulation have been implemented to accurately predict PK parameters in human studies. This review assesses these three approaches (in vitro, in vivo, and in silico) when establishing PK parameters and evaluates the potential for in silico studies to be the future gold standard of PK preclinical studies.

Relationships among temperament, acute and chronic cortisol and testosterone concentrations, and breeding soundness during performance testing of Angus bulls.

The aim of this study was to examine relationships among temperament, endocrinology, and reproductive parameters of bulls enrolled in an 84-day performance test. Angus bulls (n = 60) were housed in six pens grouped by age and weight. Pen scores (PS; 1 = docile to 5 = very aggressive) were assigned on Days -1, 27, 55, and 83 of the performance test. On the following day, blood and hair samples were collected, and body weight (BW) and exit velocity (EV) were recorded. Bulls were split into two categories based on; Day -1 PS (PScalm = PS 1 or 2; PSexcitable = PS 3 or 4) and Day 0 EV (EVcalm = slowest 20 bulls; EVexcitable = fastest 20 bulls). Cortisol and testosterone concentrations in serum and hair did not differ (P > 0.10) between PS or EV temperament categories. Sampling day differences (P < 0.01) occurred for serum testosterone, hair cortisol, and hair testosterone concentration; however, serum cortisol concentration did not differ (P > 0.10) over the sampling days. Serum testosterone concentration increased (P < 0.01) from Day 0 to 28, decreased from Day 28 to 56, but Day 84 did not differ from Day 0, 28, or 56. Hair cortisol concentration was greatest (P < 0.01) on Day 0, decreased from Day 28 to 56 but did not differ from Day 56 to 84. Hair testosterone concentration was greatest (P < 0.01) on Day 0 and remained constant from Day 28 to 84. Bulls categorized as PScalm had a greater (P < 0.01) percentage of normal sperm and secondary defects (P < 0.01) when compared with PSexcitable bulls. However, EVcalm bulls had fewer (P < 0.01) primary defects but more (P < 0.01) secondary defects than EVexcitable bulls. In conclusion, bulls exhibited physiological evidence of acclimation during the test as indicated by a reduction in hair cortisol concentration. In addition, the ability of the bulls to acclimate while residing at the testing center may have contributed to little differences observed during the breeding soundness examination portion of the performance test.

An investigation into the inhibitory function of serotonin in diffuse noxious inhibitory controls in the neuropathic rat.

BACKGROUND: Following neuropathy α2-adrenoceptor-mediated diffuse noxious inhibitory controls (DNIC), whereby a noxious conditioning stimulus inhibits the activity of spinal wide dynamic range (WDR) neurons, are abolished, and spinal 5-HT7 receptor densities are increased. Here, we manipulate spinal 5-HT content in spinal nerve ligated (SNL) animals and investigate which 5-HT receptor mediated actions predominate. METHODS: Using in vivo electrophysiology we recorded WDR neuronal responses to von frey filaments applied to the hind paw before, and concurrent to, a noxious ear pinch (the conditioning stimulus) in isoflurane-anaesthetised rats. The expression of DNIC was quantified as a reduction in WDR neuronal firing in the presence of conditioning stimulus and was investigated in SNL rats following spinal application of (1) selective serotonin reuptake inhibitors (SSRIs) citalopram or fluoxetine, or dual application of (2) SSRI plus 5-HT7 receptor antagonist SB269970, or (3) SSRI plus α2 adrenoceptor antagonist atipamezole. RESULTS: DNIC were revealed in SNL animals following spinal application of SSRI, but this effect was abolished upon joint application of SSRI plus SB269970 or atipamezole. CONCLUSIONS: We propose that in SNL animals the inhibitory actions (quantified as the presence of DNIC) of excess spinal 5-HT (presumed present following application of SSRI) were mediated via 5-HT7 receptors. The anti-nociception depends upon an underlying tonic noradrenergic inhibitory tone via the α2-adrenoceptor. SIGNIFICANCE: Following neuropathy enhanced spinal serotonin availability switches the predominant spinal 5-HT receptor-mediated actions but also alters noradrenergic signalling. We highlight the therapeutic complexity of SSRIs and monoamine modulators for the treatment of neuropathic pain.

Relationships among temperament, behavior, and growth during performance testing of bulls.

Excitable cattle are dangerous to personnel and have reduced individual performance. The aim of this study was to 1) identify objective criteria for evaluating bull temperament and 2) examine relationships among temperament, behavior, and performance of bulls during an 84-d performance test. Angus bulls ( = 60) were reared in 6 pens based on BW and age. Pen scores (PS; 1 = docile and 5 = very aggressive) were assigned on d -1, 27, 55, and 83. Exit velocity (EV), BW, time to exit the chute, and order through the chute were recorded on d 0, 28, 56, and 84. The ADG was calculated for the 84-d test period, and ultrasound data and frame score calculations were recorded on d 84. Dataloggers measured steps taken, lying time, number of lying bouts, and lying bout duration of bulls ( = 27; 3 pens) from d 3 to 28 and d 59 to 84. Bulls with a d -1 PS of 1 or 2 were categorized as calm (PScalm; = 40), whereas bulls with a PS of 3 or 4 were categorized as excitable (PSexcitable; = 20). Bulls were separated into 2 groups based on the bottom 20 EV (EVcalm) and top 20 EV (EVexcitable) on d 0. Mixed model ANOVA (SAS 9.3) was used to compare groups for the two temperament assessment methods, behavior, and growth performance. Mean EV decreased ( < 0.05) by d 84. Total lying time from d 3 to 28 was greater ( < 0.05) for PScalm bulls when compared with PSexcitable bulls. However, total lying time from d 59 to 84 was greater ( < 0.05) for EVexcitable bulls when compared with EVcalm bulls. Regardless of initial contemporary group assignment, all bulls exited the chute slower ( < 0.001) on d 84 than on d 0. The PSexcitable bulls had greater ( < 0.01) frame scores and greater ADG than PScalm bulls. The PSexcitable bulls had more ( < 0.01) backfat than PScalm bulls. However, ribeye area was smaller ( < 0.01) in EVexcitable bulls than EVcalm bulls. Based on these results, bulls appeared to have habituated over the testing period. Additionally, the potential lack of innate temperament variation may have attributed to the little difference seen among the behavioral and performance data. Therefore, temperament should be reassessed within a novel environment with new handlers to differentiate between the bull's true temperament and its ability to habituate.