Capacity to consent to treatment in psychiatry inpatients - a systematic review.

BACKGROUND: Mental capacity for treatment decisions in psychiatry inpatients is an important ethical and legal concern, especially in light of changes in mental capacity legislation in many jurisdictions. AIMS: To conduct a systematic review of literature examining the prevalence of mental capacity for treatment decisions among voluntary and involuntary psychiatry inpatients, and to assess any correlations between research tools used to measure mental capacity and binary judgements using criteria such as those in capacity legislation. METHOD: We searched PsycINFO, Ovid MEDLINE and EMBASE for studies assessing mental capacity for treatment decisions in people admitted voluntarily and involuntarily to psychiatric hospitals. RESULTS: Forty-five papers emanating from 33 studies were identified. There was huge variability in study methods and often selective populations, but the prevalence of decision-making capacity varied between 5% and 83.7%. These figures resulted from studies using cut-off scores or categorical criteria only. The prevalence of decision-making capacity among involuntary patients ranged from 7.7% to 42%, and among voluntary patients ranged from 29% to 97.9%. Two papers showed positive correlations between clinicians' judgement of decision-making capacity and scores on the MacArthur Competence Assessment Tool for Treatment; two papers showed no such correlation. CONCLUSIONS: Not all voluntary psychiatry inpatients possess mental capacity and many involuntary patients do. This paradox needs to be clarified and resolved in mental health legislation; supported decision-making can help with this task.Key PointsLegislative changes for mental capacity are taking place in many jurisdictions.This is an important human rights issue for many people, including psychiatry inpatients.In our review, we found the prevalence of decision-making capacity varies between 5% and 83.7% in psychiatry inpatients.Not all voluntary inpatients have decision-making capacity.Many involuntary inpatients have mental capacity to make decisions.Supported decision-making can help those with impairments in their mental capacity.

Exercise training for adults hospitalized with an acute respiratory condition: a systematic scoping review.

OBJECTIVE: In adults hospitalized with an acute or chronic respiratory condition, to determine what has been reported regarding exercise programmes in terms of content, tolerability, evaluation and adverse events. DATA SOURCES: A systematic search was conducted of electronic databases (PubMed, EMBASE, CINAHL, PEDro, The Cochrane Library), trial registries and conference abstracts (Thoracic Society of Australia and New Zealand Annual Scientific Meeting, the European Respiratory Society Congress, the American Thoracic Society International Conference). REVIEW METHODS: Studies were included if they (1) recruited adults hospitalized with an acute or chronic respiratory condition, (2) described an exercise programme that targeted peripheral muscles and (3) reported that ⩾80% of the sample had initiated training within 72 hours of hospitalization. RESULTS: The last search was conducted on 2 June 2019. Of the 6282 records identified, 20 met the study criteria. These described 18 separate studies (2018 participants). Studies were conducted in adults hospitalized with an exacerbation of chronic obstructive pulmonary disease or with community-acquired pneumonia. The content of exercise programmes included aerobic and/or resistance training, neuromuscular electrical stimulation, whole-body vibration or movement out of bed. In eight studies (44%), the initial session was prescribed using objective measures of exercise capacity, peripheral muscle force and the ability to undertake activities of daily living. Across 7420 training sessions, seven adverse events were reported. CONCLUSION: Methods used to prescribe and titrate exercise programmes in adults hospitalized with an acute or an exacerbation of a chronic respiratory condition were disparate. When reported, programmes were well tolerated and adverse events were infrequent.

Evaluation for learning and improvement at the right time: an example from the field.

Evaluation expertise to assist with identifying improvements, sourcing relevant literature and facilitating learning from project implementation is not routinely available or accessible to not-for-profit organisations. The right information, at the right time and in an appropriate format, is not routinely available to program managers. Program management team members who were implementing The Fred Hollows Foundation's Indigenous Australia Program's Trachoma Elimination Program required information about what was working well and what required improvement. This article describes a way of working where the program management team and an external evaluation consultancy collaboratively designed and implemented an utilisation-focused evaluation, informed by a developmental evaluation approach. Additionally, principles of knowledge translation were embedded in this process, thereby supporting the evaluation to translate knowledge into practice. The lessons learned were that combining external information and practice-based knowledge with local knowledge and experience is invaluable; it is useful to incorporate evaluative information from inception and for the duration of a program; a collaborative working relationship can result in higher quality information being produced and it is important to communicate findings to different audiences in different formats.

Sublingual glyceryl trinitrate during colonoscopy and terminal ileal intubation: a randomized controlled trial.

Background and aims Sublingual glyceryl trinitrate has been used as an aid to cannulate the Sphincter of Oddi during endoscopic retrograde cholangiopancreatography. Its role in terminal ileal intubation during colonoscopy is unknown. This study examines the role of sublingual glyceryl trinitrate in terminal ileal intubation during colonoscopy. Methods A triple-blind randomized controlled trial comparing sublingual glyceryl trinitrate (800 µg) vs. placebo (saline) in relation to terminal ileal intubation during colonoscopy was performed. Following caecal intubation, participants received sublingual glyceryl trinitrate/placebo followed by a 2-min observation period before intubation was attempted. Data on time to intubate the terminal ileum and intubation rate were collected. Results A total of 110 patients (age: 58 years (18-75)) were recruited and randomised as per protocol: 54 received sublingual glyceryl trinitrate. Terminal ileal intubation was successful in all patients receiving sublingual glyceryl trinitrate and in 53 (94.6%) of those receiving saline ( p = 0.243: Fischer's exact). The median time taken for ileal intubation after application of spray was 72.5 (7-900) s in the glyceryl trinitrate group compared with 125 (5-900) s in the placebo group ( p = 0.150: Mann-Whitney). There were no major adverse events reported in either group. Conclusions Terminal ileal intubation rates and timing were very good in both groups. Routine sublingual glyceryl trinitrate was not proven to be beneficial in improving terminal ileal intubation or intubation success rates in the hands of experienced colonoscopists. However, trends in this small study might suggest that glyceryl trinitrate could be useful in the hands of less experienced colonoscopists or in difficult terminal ileal intubation cases.

The P2Y1 receptor antagonist MRS2500 prevents carotid artery thrombosis in cynomolgus monkeys.

Adenosine diphosphate directly induces platelet aggregation via the G-protein coupled P2Y1 and P2Y12 receptors. P2Y12, but not P2Y1, receptor antagonists are available in the clinic. The relevance of the P2Y1 receptor as an antiplatelet target has been studied in rodents, but not in higher species. We therefore examined effects of the pharmacological blockade of the P2Y1 receptor with its selective antagonist MRS2500 in monkey models of electrolytic-mediated arterial thrombosis (ECAT) and kidney bleeding time (KBT). Abciximab, a GPIIb-IIIa antagonist, and cangrelor, a P2Y12 antagonist, were utilized to validate these monkey models. Compounds were given IV at 15-60 min before thrombosis initiation in anesthetized monkeys. Scanning electron microscopy showed the luminal surface of thrombotic artery covered with platelet aggregates and fibrin network. Administration of abciximab at 0.25 and 0.7 mg/kg IV significantly reduced thrombus weight by 71 ± 1 and 100 ± 0 %, and increased KBT by 10.0 ± 0.1- and 10.1 ± 0-fold, respectively (n = 3/dose). Likewise, cangrelor at 0.6 and 2 mg/kg/h IV significantly reduced thrombus weight significantly by 72 ± 9 % and 100 ± 0 % and increased KBT by 2.1 ± 0.1- and 9.8 ± 0.2-fold, respectively (n = 3/dose). MRS2500 [mg/kg + mg/kg/h IV] at 0.09 + 0.14 and 0.45 + 0.68 significantly reduced thrombus weight by 57 ± 1 % and 88 ± 1 % and increased KBT by 2.1 ± 0.3- and 4.9 ± 0.6-fold, respectively (n = 4/dose). In summary, MRS2500 prevented occlusive arterial thrombosis at a dose that moderately prolonged KBT, indicating a role of P2Y1 receptors in arterial thrombosis and hemostasis in monkeys. Thus P2Y1 receptor antagonism provides a suitable target for drug discovery.

In vitro, antithrombotic and bleeding time studies of BMS-654457, a small-molecule, reversible and direct inhibitor of factor XIa.

BMS-654457 ((+) 3'-(6-carbamimidoyl-4-methyl-4-phenyl-1,2,3,4-tetrahydro-quinolin-2-yl)-4-carbamoyl-5'-(3-methyl-butyrylamino)-biphenyl-2-carboxylic acid) is a small-molecule factor XIa (FXIa) inhibitor. We evaluated the in vitro properties of BMS-654457 and its in vivo activities in rabbit models of electrolytic-induced carotid arterial thrombosis and cuticle bleeding time (BT). Kinetic studies conducted in vitro with a chromogenic substrate demonstrated that BMS-654457 is a reversible and competitive inhibitor for FXIa. BMS-654457 increased activated partial thromboplastin time (aPTT) without changing prothrombin time. It was equipotent in prolonging the plasma aPTT in human and rabbit, and less potent in rat and dog. It did not alter platelet aggregation to ADP, arachidonic acid and collagen. In vivo, BMS-654457 or vehicle was given IV prior to initiation of thrombosis or cuticle transection. Preservation of integrated carotid blood flow over 90 min (iCBF, % control) was used as a marker of antithrombotic efficacy. BMS-654457 at 0.37 mg/kg + 0.27 mg/kg/h produced almost 90 % preservation of iCBF compared to its vehicle (87 ± 10 and 16 ± 3 %, respectively, n = 6 per group) and increased BT by 1.2 ± 0.04-fold (P < 0.05). At a higher dose (1.1 mg/kg + 0.8 mg/kg/h), BMS-654457 increased BT by 1.33 ± 0.08-fold. This compares favorably to equivalent antithrombotic doses of reference anticoagulants (warfarin and dabigatran) and antiplatelet agents (clopidogrel and prasugrel) which produced four- to six-fold BT increases in the same model. In summary, BMS-654457 was effective in the prevention of arterial thrombosis in rabbits with limited effects on BT. This study supports inhibition of FXIa, with a small-molecule, reversible and direct inhibitor as a promising antithrombotic therapy with a wide therapeutic window.

The Business of Testing.

Theodore Millon was a brilliant man: erudite, thoughtful, confident, deliberate, and curious. He was an integrative thinker. It is widely known how these characteristics manifested themselves in his landmark work in the areas of personality theory, personality development, and personality assessment. What is likely less well known is that he displayed these same characteristics in and to the world of business; in particular, his relationships with those who published and distributed his assessment measures. This article traces those relationships. Various components are explored, ranging from product development to product marketing, from the protection of intellectual property to the development and execution of contracts, from deciding how and when to revise a test to ensuring that his legacy continues long into the future. Although the primary dynamic of these relationships was commercial, the reasons for their success were personal. Common goals, clarity of communication, persistence, respect, and trust allowed these relationships to develop, prosper, evolve, and endure.

Substance abuse treatment utilization, HIV risk behaviors, and recruitment among suburban injection drug users in Long Island, New York.

Prevention and treatment of injection drug use remains a public health concern. We used data from the 2005 Centers for Disease Control and prevention National HIV Behavioral Surveillance system to assess substance abuse treatment utilization, risk behaviors, and recruitment processes in a respondent driven sample of suburban injectors. Twelve service utilization and injection risk variables were analyzed using latent class analysis. Three latent classes were identified: low use, low risk; low use, high risk; and high use, moderate/high risk. In multivariate analysis, annual income <$15,000 (adjusted odds ratio (aOR) = 8.19 [95 % confidence interval (CI), 3.83-17.51]) and self-reported hepatitis C virus infection (aOR = 4.32, 95 % CI (1.84-10.17)) were significantly associated with class membership. Homophily, a measure of preferential recruitment showed that injectors with recent treatment utilization appear a more cohesive group than out-of-treatment injectors. Preferentially reaching injection drug users with high risk behaviors and no recent drug treatment history via respondent driven sampling will require future research.

Identification of novel functional and spatial associations between sphingosine kinase 1, sphingosine 1-phosphate receptors and other signaling proteins that affect prognostic outcome in estrogen receptor-positive breast cancer.

Sphingosine kinase is an enzyme that catalyses the phosphorylation of sphingosine to form sphingosine 1-phosphate. Sphingosine 1-phosphate is a bioactive lipid, which has been shown to have an important role in promoting the survival, growth and invasiveness of cancer cells. Sphingosine 1-phosphate binds to five different plasma membrane sphingosine 1-phosphate receptors (S1P(1-5) ) and can regulate intracellular target proteins. We have used immunohistochemical analysis to determine the concurrent expression levels of sphingosine kinase 1 or S1P receptors and other signaling proteins in estrogen receptor-positive breast cancer tumors and have then assessed the impact of these combinations on clinical outcome. This approach has enabled identification of (i) novel biomarkers and (ii) several spatially controlled associations between either sphingosine kinase 1 or S1P(1-3) and other signaling proteins whose combination affect prognosis. For instance, the translocation of sphingosine kinase 1 to the plasma membrane has been shown to be a critical determinant in cancer progression. However, our findings identify an additional novel role for the nuclear localization of sphingosine kinase 1 combined with either ERK-1/2 or SFK or LYN or AKT or NF-κB, which significantly shortens disease-specific survival and/or recurrence. We also demonstrate that nuclear S1P(2) receptor and c-SRC are associated with improved prognosis and this is linked with a reduction in the nuclear localization of sphingosine kinase 1. These findings identify potential novel biomarker associations, which might serve as new targets for drug intervention designed to improve treatment of estrogen receptor-positive breast cancer.

Discovery of diarylurea P2Y(1) antagonists with improved aqueous solubility.

Preclinical data suggests that P2Y1 antagonists, such as diarylurea compound 1, may provide antithrombotic efficacy similar to P2Y12 antagonists and may have the potential of providing reduced bleeding liabilities. This manuscript describes a series of diarylureas bearing solublizing amine side chains as potent P2Y1 antagonists. Among them, compounds 2l and 3h had improved aqueous solubility and maintained antiplatelet activity compared with compound 1. Compound 2l was moderately efficacious in both rat and rabbit thrombosis models and had a moderate prolongation of bleeding time in rats similar to that of compound 1.

Insidious Onset of Incarcerated Parastomal Hernia With Gastric Outlet Obstruction: A Case Report.

Although parastomal hernias have a high incidence in the general population, involvement of the stomach remains rare due to the numerous suspensory structures tethering this organ in its anatomical location. This case details a 75-year-old lady with a painless onset of a gastric parastomal hernia with progressive incarceration over a two-week period. The deteriorating clinical condition of the patient following weeks of stability indicated that the cause of symptoms is likely sinister. Imaging confirmed incarceration of the stomach within a parastomal hernia. Although this has been reported previously, there is little to suggest this condition exists with an insidious onset. Patients who are at high risk of gastric herniation and who fit this clinical vignette with a known parastomal hernia should be offered prompt investigations to ascertain the diagnosis and facilitate further management.

Research lessons during the COVID-19 pandemic: collecting longitudinal physical and mental health outcomes.

BACKGROUND: Participant enrolment, assessment and/or delivery of intervention in many clinical trials during the COVID-19 pandemic were severely impacted by public health measures limiting physical contact. This report describes the lessons learned in completing a repeated measures cohort study involving suspected and confirmed COVID-19 survivors at three sites in Perth, Western Australia. MAIN BODY: An observational analysis of the conduct and data completeness results of the LATER-19 trial. People with COVID19 symptoms who were tested between February and November 2020 were recruited. In both those who tested positive and those who tested negative (control group) for COVID19, data on physical function and mental health were collected at two time points up to eight months after COVID19 testing. Recruitment of the controls was targeted from hospital records for comparison, it was balanced for age and sex and for the non-hospitalised group also comorbidities. A sample of 344 participants was recruited: 155 (45.1%) COVID-19 positive. Taking the research design and environmental adaptations into account, we recorded > 90% participant engagement during the trial. Of the 637 planned assessments, objective measures were completed on 602 (94.5%) occasions; 543 (90.2%) were on-site and 59 (9.8%) were remote. A total of 577 (90.6%) mental health/symptoms surveys, 569 (89.3%) 1-min sit-to-stand tests, and 520 (81.6%) handgrip strength tests were completed. CONCLUSION: The sample size and high completion rate of planned assessments during the LATER-19 trial potentially increases the contextual, groupwise generalisability of the results. The results demonstrate the effectiveness of a simple, rapid, reproducible and adaptable battery of assessments, leveraging telehealth and digital solutions. TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trial Registration (ANZCTR): ACTRN12621001067864 .

Discovery of Two Novel Antiplatelet Clinical Candidates (BMS-986120 and BMS-986141) That Antagonize Protease-Activated Receptor 4.

Protease-activated receptor 4 (PAR4) is a G-protein coupled receptor that is expressed on human platelets and activated by the coagulation enzyme thrombin. PAR4 plays a key role in blood coagulation, and its importance in pathological thrombosis has been increasingly recognized in recent years. Herein, we describe the optimization of a series of imidazothiadiazole PAR4 antagonists to a first-in-class clinical candidate, BMS-986120 (43), and a backup clinical candidate, BMS-986141 (49). Both compounds demonstrated excellent antithrombotic efficacy and minimal bleeding time prolongation in monkey models relative to the clinically important antiplatelet agent clopidogrel and provide a potential opportunity to improve the standard of care in the treatment of arterial thrombosis.

High expression of sphingosine 1-phosphate receptors, S1P1 and S1P3, sphingosine kinase 1, and extracellular signal-regulated kinase-1/2 is associated with development of tamoxifen resistance in estrogen receptor-positive breast cancer patients.

Various studies in cell lines have previously demonstrated that sphingosine kinase 1 (SK1) and extracellular signal-regulated kinase 1/2 (ERK-1/2) interact in an estrogen receptor (ER)-dependent manner to influence both breast cancer cell growth and migration. A cohort of 304 ER-positive breast cancer patients was used to investigate the prognostic significance of sphingosine 1-phosphate (S1P) receptors 1, 2, and 3 (ie, S1P1, S1P2, and S1P3), SK1, and ERK-1/2 expression levels. Expression levels of both SK1 and ERK-1/2 were already available for the cohort, and S1P1, S1P2, and S1P3 levels were established by immunohistochemical analysis. High membrane S1P1 expression was associated with shorter time to recurrence (P=0.008). High cytoplasmic S1P1 and S1P3 expression levels were also associated with shorter disease-specific survival times (P=0.036 and P=0.019, respectively). Those patients with tumors that expressed high levels of both cytoplasmic SK1 and ERK-1/2 had significantly shorter recurrence times than those that expressed low levels of cytoplasmic SK1 and cytoplasmic ERK-1/2 (P=0.00008), with a difference in recurrence time of 10.5 years. Similarly, high cytoplasmic S1P1 and cytoplasmic ERK-1/2 expression levels (P=0.004) and high cytoplasmic S1P3 expression and cytoplasmic ERK-1/2 expression levels (P=0.004) were associated with shorter recurrence times. These results support a model in which the interaction between SK1, S1P1, and/or S1P3 and ERK-1/2 might drive breast cancer progression, and these findings, therefore, warrant further investigation.

A small-molecule factor XIa inhibitor produces antithrombotic efficacy with minimal bleeding time prolongation in rabbits.

BMS-262084 is a 4-carboxy-2-azetidinone-containing irreversible inhibitor of FXIa, which is selective over other coagulation proteases. We evaluated the in vitro and in vivo properties of BMS-262084 in rabbits. Studies were conducted in arteriovenous-shunt thrombosis (AVST), venous thrombosis (VT), electrolytic-mediated carotid arterial thrombosis (ECAT) and cuticle bleeding time (BT) models. BMS-262084 was infused IV from 1 h before thrombus induction or cuticle transection to the end of the experiment. In vitro, BMS-262084 prolonged activated partial thromboplastin time (aPTT) with EC(2x) (concentration required to double aPTT) of 10.6 µM in rabbit plasma, and did not prolong prothrombin time (PT), thrombin time (TT) and HepTest. In vivo, BMS-262084 produced dose-dependent antithrombotic effects in rabbits with antithrombotic ED(50) (dose that reduced thrombus weight or increased blood flow by 50% of the control) in AVST, VT and ECAT of 0.4, 0.7 and 1.5 mg/kg/h IV, respectively. BMS-262084 increased ex vivo aPTT dose-dependently without changes in PT and TT. The antithrombotic effect of BMS-262084 was significantly correlated with its ex vivo aPTT, supporting the use of ex vivo aPTT as a pharmacodynamic biomarker. BMS-262084 did not alter ex vivo rabbit platelet aggregation to ADP and collagen. BT (fold-increase) determined at 3 and 10 mg/kg/h of BMS-262084 were 1.17 ± 0.04 and 1.52 ± 0.07*, respectively (*P < 0.05 vs. control). This study demonstrated that BMS-262084 prevented experimental thrombosis at doses with low BT effects in rabbits, and suggests that a small molecule FXIa inhibitor may represent a promising antithrombotic therapy.

Modified Chester Step Test in a Healthy Adult Population: Measurement Properties and Development of a Regression Equation to Estimate Test Duration.

OBJECTIVE: Healthy working-aged adults performed the modified Chester Step Test (mCST) to (1) determine the effect of repetition on test duration, (2) report cardiorespiratory and symptom responses, (3) establish a regression equation to estimate duration, and (4) calculate the minimal detectable change of the test. METHODS: In this observational study conducted in a hospital physical therapy, adult participants aged 25 to 65 years who were healthy performed the mCST twice. This submaximal test required participants to step on and off a 20-cm step at a standardized cadence that increased every 2 minutes. The criteria for test completion were either a heart rate equal to 80% of age-predicted maximum or the onset of intolerable symptoms. The primary measure was time to test completion during the mCST (seconds). Cardiorespiratory and symptom responses were also collected during the mCST. RESULTS: A total of 83 participants (40 men, mean [SD] age = 44 [12] years) completed data collection. There was no systematic effect of test repetition with median test duration of the first test (522 seconds, range = 400-631 seconds) and second test (501 seconds, range = 403-631 seconds). The test elicited moderate symptoms of breathlessness and leg fatigue. In the multivariable model, age, sex, weight, and height were retained as significant predictors of test duration (R2 = 0.48). The minimal detectable change was 119 seconds. CONCLUSIONS: The mCST is a reliable and valid clinically applicable test of aerobic capacity in working-aged adults. Independent pretest predictors can be used to estimate the clinical time required to complete the test. IMPACT: The mCST was stable between test repetitions, suggesting no learning effect. For any given individual, a test duration change of 2 minutes represents change was beyond the natural variability. The mCST has good applicability to clinical settings.

Reduced Step Count and Clinical Frailty in Hospitalized Adults With Community-Acquired Pneumonia.

BACKGROUND: In adults hospitalized with community-acquired pneumonia (CAP), increasing ward-based walking may reduce length of stay (LOS). There are few data to describe ward-based walking in this population. In adults hospitalized with CAP, we aimed to report variables of walking and non-walking time, to determine whether demographic or clinical variables influenced daily step count, and to determine whether daily step count influenced LOS. METHODS: Following admission, daily step count and variables related to walking and non-walking time were quantified using the StepWatch Activity Monitor. Details regarding demographics, clinical characteristics, clinical care, and LOS were extracted from the medical records and hospital electronic data systems. Frailty was calculated via the 7-point Clinical Frailty Scale; disease severity was measured via the CURB-65 score. Health care utilization at 30 d following discharge was measured via telephone interview. RESULTS: Two hundred participants completed the study, of whom 121 contributed ≥ 24 h of data from the StepWatch Activity Monitor. The median (interquartile range (IQR)) number of daily steps was 926 (457-1706). These were accumulated over 66 (41-121) min/d, with a usual bout duration of 3 (2-4) min and 1-min peak cadence of 56 (43-74) steps/min. An average of 93% (89-96) of waking hours was spent in non-walking time. In the multivariable model, increased frailty was retained as a predictor of lower step count (incidence rate ratio [IRR] 0.59, 95% CI 0.41-0.85). For every increase in 500 steps/d, LOS reduced by 11% (IRR 0.89, 95% CI 0.80-0.99). CONCLUSIONS: Subjects hospitalized with CAP did very little walking, most of which was accumulated in short bouts at a low intensity. Compared with subjects with mild frailty, those with moderate to severe frailty took 59% fewer steps per day. Those with a higher daily step count had a shorter LOS.

Clopidogrel versus prasugrel in rabbits. Effects on thrombosis, haemostasis, platelet function and response variability.

The new P2Y(12) antagonist prasugrel produces greater inhibition of ADP-induced platelet aggregation (IPA) and reduction of thrombotic events in patients versus approved doses of clopidogrel, but increases major bleeding. We examined whether IPA level or P2Y(12) receptor occupancy (RO) could be optimized to better balance the efficacy and bleeding effects of these thienopyridines and reduce the response variability in rabbits. Rabbits were given three daily oral doses of clopidogrel (0.3-30 mg/kg/d), prasugrel (0.03-10 mg/kg/d) or vehicle (n = 6-40/group). Electrically-induced carotid artery thrombosis (AT, % thrombus weight reduction), cuticle bleeding time (BT, fold-increase over control), IPA to 20 microM ADP (% inhibition of peak light transmission) and RO (% inhibition of [(33)P]-2MeS-ADP binding to P2Y(1)-blocked platelets) were determined 2-3 hours after the last dose. ED(50) (doses for half-maximal effect, mg/kg/d) of AT, BT, IPA and RO were 1.6, 6.7, 1.9 and 1.4 for clopidogrel vs. 1.2, 1.9, 0.5 and 0.2 for prasugrel. IPA of 30-40% for both compounds produced the optimal balances of efficacy (AT: 50-60%) and BT of about 2-fold with significant RO of 70-80%. IPA of 50-60% achieved higher efficacy (AT: 60-80%), but with increased BT of five- to six-fold and >90% RO. Box-plot suggests no significant difference in the IPA and RO response variability between both compounds. Clopidogrel was 1.3-7 times less potent than prasugrel in rabbits, depending upon which biomarker was studied. The ratio of efficacy: bleeding was most favorable at a moderate IPA of 30% to 40%. Both compounds had similar IPA and RO response variability.

Survival outcomes following adrenalectomy for isolated metastases to the adrenal gland.

BACKGROUND: Adrenal metastases can arise from different primary sites. Surgical resection of the adrenal gland in patients with isolated metastases may offer improved survival in many of these patients. However, the benefit of surgery in this heterogenous group is often disputed. The aim of this study was to identify patients undergoing adrenalectomy for isolated metastases and to describe survival outcomes based on origin of the primary malignancy. METHODS: Patients undergoing surgery for isolated adrenal metastases were retrospectively analysed from a prospectively kept database. Data collected included the age of the patient, gender, size and functional status of the tumour and the site of the primary malignancy. Overall survival and survival based on the primary tumour were calculated using Kaplan-Meier survival analyses. RESULTS: 42 patients were included for analysis. The median tumour size was 40 mm. 91% (n = 38) of operations were performed laparoscopically. Metastases were from the following primary organs: kidney (n = 22), lung (n = 11), breast (n = 2), gastric (n = 1), skin (n = 3), liver (n = 2) and neuroendocrine (n = 1). Overall median survival was 56 (19-93) months with 95% of patients followed up for >6 months. There was a significant difference in median survival between primary organs of origin: 83(42-123), 14(9-18), 15 and 12(3-20) months (p < 0.05) for kidney, lung, breast and skin respectively. CONCLUSION: There is a potential survival benefit for patients undergoing surgery for isolated adrenal metastases; however this survival benefit is greater in patients undergoing resection for metastases arising from kidney primaries. A selective approach should be adopted to identify patients that will clearly benefit from surgery.

Adult neuroblastoma: a rare diagnosis of an adrenal mass.

A 22-year-old woman presented to her local district hospital with left-sided abdominal pain. She denied any urinary or gastrointestinal symptoms. She had a CT scan of her abdomen which showed a probable 8×5×8 cm left-sided adrenal mass. Functional tests for hormone excess were negative. She was referred to a tertiary referral centre and given the size of the adrenal mass; she consented for laparoscopic left adrenalectomy. During the operation, the mass was grossly adherent to the celiac axis, left renal pedicle and DJ flexure. A small nodule posterior to the renal vein was also identified. The operation was completed laparoscopically and she made an uneventful recovery. The specimen was reported as a poorly differentiated neuroblastoma. She had a postoperative MIBG scan which was negative for residual or metastatic disease. She was commenced on platinum-based chemotherapy with a plan for further radiological follow-up.