Enhancing medical image segmentation with a multi-transformer U-Net.

Various segmentation networks based on Swin Transformer have shown promise in medical segmentation tasks. Nonetheless, challenges such as lower accuracy and slower training convergence have persisted. To tackle these issues, we introduce a novel approach that combines the Swin Transformer and Deformable Transformer to enhance overall model performance. We leverage the Swin Transformer's window attention mechanism to capture local feature information and employ the Deformable Transformer to adjust sampling positions dynamically, accelerating model convergence and aligning it more closely with object shapes and sizes. By amalgamating both Transformer modules and incorporating additional skip connections to minimize information loss, our proposed model excels at rapidly and accurately segmenting CT or X-ray lung images. Experimental results demonstrate the remarkable, showcasing the significant prowess of our model. It surpasses the performance of the standalone Swin Transformer's Swin Unet and converges more rapidly under identical conditions, yielding accuracy improvements of 0.7% (resulting in 88.18%) and 2.7% (resulting in 98.01%) on the COVID-19 CT scan lesion segmentation dataset and Chest X-ray Masks and Labels dataset, respectively. This advancement has the potential to aid medical practitioners in early diagnosis and treatment decision-making.

Reconsideration of the Benefits of Pharmacological Interventions for the Attenuation of the Cognitive Adverse Effects of Electroconvulsive Therapy.

The cognitive adverse effects (AEs) of electroconvulsive therapy (ECT) limit the wider use of the treatment. These AEs can be attenuated by changing the way ECT is administered; however, such changes may reduce the response rate, the speed of response, or both. A recent systematic review and meta-analysis identified more than a dozen pharmacologic interventions in 26 randomized controlled trials (RCTs) that sought to reduce ECT-induced cognitive AEs. Because of large differences across RCTs, only a few outcomes for a few interventions could be pooled in meta-analysis, and most pooled analyses included only 2-3 RCTs. Important findings were that acetylcholinesterase inhibitors, ketamine, memantine, and liothyronine were associated with improved global cognitive functioning at 1-14 days post-ECT. Anti-inflammatory treatments and opioid receptor antagonists were not associated with improvement in general cognitive outcome at 1-14 days post-ECT. Meta-analysis was not possible for the remaining interventions, including piracetam, melatonin, pemoline, nortriptyline, herbal agents, drugs acting on the cortisol pathway, opioid receptor antagonists, l-tryptophan, vasopressin analogs, calcium channel blockers, and others; in individual RCTs, some of these interventions attenuated some cognitive measures as some time points after ECT. Regrettably, none of the RCTs examined clinically meaningful outcomes such as subjective cognitive impairment, impairments in daily life, and persistent autobiographical memory deficits. Future research should study such clinically meaningful outcomes (rather than laboratory tests), using pharmacologic interventions, perhaps in combination, for ECT procedures that are associated with higher cognitive AE burden. A risk is that whatever attenuates ECT-induced cognitive AEs may also attenuate ECT-related therapeutic benefits.

The Pemoline Model of Self-Injurious Behavior: An Update.

Neurodevelopmental disorders typically comprise a complex constellation of behavioral symptoms and neurochemical abnormalities. However, many of the symptoms are inconsistently expressed within any one particular patient group or overlap between patient groups. In other words, there is usually heterogeneity of symptoms between diagnostic groups, and there is often partial homogeneity of symptoms across these groups. These include cognitive deficits, emotional lability, and perseverative or aberrant behaviors. Animal models of neurodevelopmental disorders typically reproduce or mimic specific genetic, neurochemical, and/or behavioral sequelae, although they typically fail to replicate the entire spectrum of biological and behavioral characteristics. Indeed, it may be impractical or even impossible to model the entire spectrum of characteristics of a disorder in any single animal model. A focus on one or more specific behavioral characteristics that occur in multiple neurodevelopmental disorders (e.g., self-injury) may be a fruitful strategy. The development of these behaviorally focused models may yield increased understanding of the endogenous and environmental factors that confer vulnerability for aberrant behaviors that commonly occur in these disorders. One such behaviorally focused animal model is the pemoline model of self-injurious behavior.

The role of neurotensin in vulnerability for self-injurious behaviour: studies in a rodent model.

BACKGROUND: Self-injurious behaviour is a debilitating characteristic that is commonly expressed in people with autism and other neurodevelopmental disorders, but the neurobiological basis of this maladaptive behaviour is not understood. Abnormal dopaminergic and glutamatergic neurotransmission has been implicated, especially in relation to basal ganglia and mesocorticolimbic circuits. As neurotensin is an important modulator of dopamine and glutamate in these circuits, we investigated its potential role in vulnerability for self-injury, using the pemoline model in rats. METHODS: Male Long-Evans rats were injected once daily with the psychostimulant pemoline or peanut oil vehicle on each of five consecutive days. Self-injury was quantified by measuring the area of injuries for each rat on each day of the experiment. Each brain was harvested on the sixth day, and the striatum and ventral tegmentum were dissected. Neurotensin-like immunoreactivity was quantified by radioimmunoassay from the dissected brain regions of some of the rats. Membrane and intracellular neurotensin receptor NTS1 were assayed from the striata of the remaining pemoline-treated or vehicle-treated rats by Western blot. In an additional experiment, male Long-Evans rats were treated with daily injections of vehicle or pemoline, and the NTS1 neurotensin receptor agonist PD149163 or the NTS1 receptor antagonist SR48692 (or respective vehicle solutions) was co-administered twice daily throughout the pemoline treatment regimen. The areas of injured tissue were measured, and the duration of self-injurious oral contact was quantified by video-recorded time samples throughout each day. RESULTS: Striatal neurotensin immunoreactivity was found to be significantly higher in pemoline-treated than in vehicle-treated rats. Moreover, both membrane-bound and intracellular levels of NTS1 receptor were significantly higher in the striata of pemoline-treated rats than in the striata of the vehicle-treated controls. When the NTS1 receptor agonist PD149163 was co-administered during the pemoline treatment regimen, it prolonged the daily durations of self-injurious oral contact and increased the severity of the injuries in the self-injurious rats. Conversely, co-administration of the NTS1 receptor antagonist SR48692 diminished the daily durations of self-injurious oral contact and decreased the severity of the injuries. CONCLUSIONS: The elevation of striatal neurotensin immunoreactivity during pemoline treatment, coupled with the effects of the NTS1 agonist and antagonist, suggests that neurotensin transmission in the striatum may be an important modulator of self-injurious behaviour in the pemoline model. Overall, the convergence of the behavioural and biochemical findings suggests that neurotensin signalling could be an important target for pharmacotherapeutic interventions for self-injurious behaviour.

Pharmacological treatments for fatigue in patients with multiple sclerosis: A systematic review and meta-analysis.

BACKGROUND: Multiple sclerosis (MS) is a chronic immune-mediated inflammatory disease. Fatigue is the most common symptom of MS patients, affecting >80% subjects. Medical treatment is an important method for managing fatigue. Currently, although many drugs have been tested in treatment of MS fatigue, the efficacy of these drugs remain largely unclear. METHODS: We researched available literatures in PubMed, Embase, Medline, Google Scholar, Cochrane Library (August 31, 2016). Search terms included multiple sclerosis, fatigue, medication treatments, amantadine, modafinil, aspirin, acetyl-l-carnitine, pemoline, 4-aminopyridine and randomized controlled trial (RCT). Two researchers were required to independently assess the quality of literatures, and finish data extraction. Meta-analysis was conducted using RevMan 5.3 software. FINDINGS: A total of 11 RCTs involving 723 patients were included. The therapeutic effects were quantified by different scales, such as Modified Fatigue Impact Scale (MFIS) or Fatigue Severity Scale (FSS). Here, meta-analysis suggested that amantadine, not modafinil, was effective for treating the fatigue in MS. Moreover, two studies implied that l-carnitine might have similar therapeutic effect with amantadine. However, the reliability of this finding was greatly weakened by the limited sample sizes. Additionally, current data could not answer whether treatment of MS fatigue using aspirin or 4-aminopyridine was beneficial. Finally, we found that all drugs except pemoline were relatively safe for treating MS fatigue. CONCLUSIONS: Current limited data suggest that amantadine may be the only drug that has relatively sufficient evidences in treatment of fatigue symptoms in MS. Further RCT studies recruiting larger samples sizes are required to validate the therapeutic effect of these candidate drugs.

The role of anxiety in vulnerability for self-injurious behaviour: studies in a rodent model.

Self-injurious behaviour (SIB) is a debilitating characteristic that is highly prevalent in autism and other neurodevelopmental disorders. Pathological anxiety is also common, and there are reports of comorbid anxiety and self-injury in some children. We have investigated potential interactions between anxiety and self-injury, using a rat model of pemoline-induced self-biting. In one experiment, rats were pre-screened for trait anxiety by measuring expression of anxiety-related behaviour on the elevated plus maze and open field emergence test. The rats were then treated with pemoline once daily for ten days, and vulnerability for pemoline-induced self-injury was evaluated. This revealed modest correlations between innate levels of anxiety-related behaviour in the open field test (time in the start box, and latency to enter the open field), and vulnerability for pemoline-induced self-biting (total duration of self-injurious oral contact, and total size of tissue injury). Measures in the elevated plus maze were not significantly correlated with vulnerability for pemoline-induced self-injury. In a second experiment, rats were treated with the beta-carboline FG 7142 twice daily, during 5days of treatment with pemoline. The rats that were treated with this anxiogenic drug exhibited greater duration of self-injurious oral contact, and larger injuries than vehicle-treated controls did. Overall, these results suggest that anxiety may contribute to the etiology and/or expression of self-injurious behaviour, and indicate that further research is warranted.

Patterns of concurrent substance use among adolescent nonmedical ADHD stimulant users.

OBJECTIVES: There are growing concerns about nonmedical use of ADHD stimulants among adolescents; yet, little is known whether there exist heterogeneous subgroups among adolescents with nonmedical ADHD stimulant use according to their concurrent substance use. METHODS: We used latent class analysis (LCA) to examine patterns of past-year problematic substance use (meeting any criteria for abuse or dependence) in a sample of 2203 adolescent participants from the National Surveys on Drug Use and Health 2006-2011 who reported past-year nonmedical use of ADHD stimulants. Multivariable latent regression was used to assess the association of socio-demographic characteristics, mental health and behavioral problems with the latent classes. RESULTS: The model fit indices favored a four-class model, including a large class with frequent concurrent use of alcohol and marijuana (Alcohol/marijuana class; 41.2%), a second large class with infrequent use of other substances (Low substance class, 36.3%), a third class characterized by more frequent misuse of prescription drugs as well as other substances (Prescription drug+class; 14.8%), and finally a class characterized by problematic use of multiple substances (Multiple substance class; 7.7%). Compared with individuals in Low substance class, those in the other three classes were all more likely to report mental health problems, deviant behaviors and substance abuse service use. CONCLUSIONS: Adolescent nonmedical ADHD stimulants users are a heterogeneous group with distinct classes with regard to concurrent substance use, mental health and behavioral problems. The findings have implications for planning of tailored prevention and treatment programs to curb stimulant use for this age group.

Pharmacological treatments for fatigue associated with palliative care.

BACKGROUND: This review updates the original review, 'Pharmacological treatments for fatigue associated with palliative care' and also incorporates the review 'Drug therapy for the management of cancer-related fatigue'.In healthy individuals, fatigue is a protective response to physical or mental stress, often relieved by rest. By contrast, in palliative care patients' fatigue can be severely debilitating and is often not counteracted with rest, thereby impacting daily activity and quality of life. Fatigue frequently occurs in patients with advanced disease (e.g. cancer-related fatigue) and modalities used to treat cancer can often contribute. Further complicating issues are the multidimensionality, subjective nature and lack of a consensus definition of fatigue. The pathophysiology is not fully understood and evidence-based treatment approaches are needed. OBJECTIVES: To evaluate the efficacy of pharmacological treatments for fatigue in palliative care, with a focus on patients at an advanced stage of disease, including patients with cancer and other chronic diseases. SEARCH METHODS: For this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PsycINFO and EMBASE, and a selection of cancer journals up to 28 April 2014. We searched the references of identified articles and contacted authors to obtain unreported data. To validate the search strategy we selected sentinel references. SELECTION CRITERIA: We considered randomised controlled trials (RCTs) concerning adult palliative care with a focus on pharmacological treatment of fatigue compared to placebo, application of two drugs, usual care or a non-pharmacological intervention. The primary outcome had to be non-specific fatigue (or related terms such as asthenia). We did not include studies on fatigue related to antineoplastic treatment (e.g. chemotherapy, radiotherapy, surgical intervention). We also included secondary outcomes that were assessed in fatigue-related studies (e.g. exhaustion, tiredness). DATA COLLECTION AND ANALYSIS: Two review authors (MM and MC) independently assessed trial quality and extracted data. We screened the search results and included studies if they met the selection criteria. If we identified two or more studies that investigated a specific drug with the same dose in a population with the same disease and using the same assessment instrument or scale, we conducted meta-analysis. In addition, we compared the type of drug investigated in specific populations, as well as the frequent adverse effects of fatigue treatment, by creating overview tables. MAIN RESULTS: For this update, we screened 1645 publications of which 45 met the inclusion criteria (20 additional studies to the previous reviews). In total, we analysed data from 18 drugs and 4696 participants. There was a very high degree of statistical and clinical heterogeneity in the trials and we discuss the reasons for this in the review. There were some sources of potential bias in the included studies, including a lack of description of the methods of blinding and allocation concealment, and the small size of the study populations. We included studies investigating pemoline and modafinil in participants with multiple sclerosis (MS)-associated fatigue and methylphenidate in patients suffering from advanced cancer and fatigue in meta-analysis. Treatment results pointed to weak and inconclusive evidence for the efficacy of amantadine, pemoline and modafinil in multiple sclerosis and for carnitine and donepezil in cancer-related fatigue. Methylphenidate and pemoline seem to be effective in patients with HIV, but this is based only on one study per intervention, with only a moderate number of participants in each study. Meta-analysis shows an estimated superior effect for methylphenidate in cancer-related fatigue (standardised mean difference (SMD) 0.49, 95% confidence interval (CI) 0.15 to 0.83). Therapeutic effects could not be described for dexamphetamine, paroxetine or testosterone. There were a variety of results for the secondary outcomes in some studies. Most studies had low participant numbers and were heterogeneous. In general, adverse reactions were mild and had little or no impact. AUTHORS' CONCLUSIONS: Based on limited evidence, we cannot recommend a specific drug for the treatment of fatigue in palliative care patients. Fatigue research in palliative care seems to focus on modafinil and methylphenidate, which may be beneficial for the treatment of fatigue associated with palliative care although further research about their efficacy is needed. Dexamethasone, methylprednisolone, acetylsalicylic acid, armodafinil, amantadine and L-carnitine should be further examined. Consensus is needed regarding fatigue outcome parameters for clinical trials.

Determination of levamisole, aminorex, and pemoline in plasma by means of liquid chromatography-mass spectrometry and application to a pharmacokinetic study of levamisole.

Levamisole is an anti-helminthic drug and gained forensic interest after it was found that it was used as a cocaine adulterant. A liquid chromatography-mass spectrometry (LC-MS) method for the determination of levamisole and its metabolite aminorex in human plasma is described. Selectivity is given; calibration curves were linear within a calibration range of 1 ng/mL-500 ng/mL. Limits of detection and quantification (LODs, LOQs) were 0.85 ng/mL for levamisole and 0.09 ng/mL, and 0.34 ng/mL for aminorex, respectively. Precision data was in accordance with the GTFCh guidelines. The validated method was successfully applied to study the pharmacokinetics of levamisole after administration of 100 mg of levamisole orally. Levamisole could be detected up to 36 h after ingestion in serum, while aminorex never exceeded the LOQ. A one-compartment model best described levamisole pharmacokinetics. The following parameters were calculated: ka = 1.2 [1/h], CL/F = 52 l/h, V/F = 347 l, f (renal) = 0.0005, t ½ = 2.0 h, AUC = 1923 ng/mL*h, cmax = 214 ng/mL, tmax = 1.98 h. Levamisole could be quantified in 42.5% of cocaine--positive plasma samples (2.2 to 224 ng/mL). Aminorex was positive in only 11.3% of the cases; however, it was never found higher than the LOQ. Pemoline, another stimulant detected in horse urine samples after administration of levamisole, was not found either in serum or in urine of this pharmacokinetic study. In post-mortem cases, levamisole and aminorex could be detected in femoral blood and the urine of cocaine users. Pemoline was not detected.

Trends in office-based treatment of adults with stimulants in the United States.

OBJECTIVE: The authors investigated trends and patterns in stimulant treatment of adults visiting office-based medical practices in the United States. METHOD: A time series analysis of data from the 1994 to 2009 National Ambulatory Medical Care Surveys (no. of visits = 372,702) was performed, focusing on adult (aged ≥ 18 years) visits in which stimulant medications (amphetamine salts, methylphenidate, or pemoline) were prescribed. The authors computed trends in the percentage of visits in which a stimulant was prescribed stratified by background and clinical patient characteristics. Results are reported as odds ratios (ORs) over the 1994 to 2009 period. The authors also compare visits to psychiatrists and nonpsychiatrist physicians that yielded a stimulant prescription to an adult. RESULTS: The percentage of visits in which stimulants were prescribed increased from 0.11% (1994-1997) to 0.70% (2006-2009) (OR = 13.72, 95% confidence interval [CI], 9.40-20.03). Among adults aged 18 to 29 years, the corresponding increase in stimulant visits was from 0.17% to 1.83% (OR = 30.14, 95% CI, 15.84-57.36). Stimulant prescriptions increased significantly more rapidly among visits without a clinical ADHD diagnosis (OR = 11.86, 95% CI, 7.49-18.80) than among visits with such a diagnosis (OR = 5.45, 95% CI, 2.96-10.04) (interaction P = .04) and among visits to nonpsychiatrist physicians (OR = 21.54, 95% CI, 12.84-36.12) than psychiatrists (OR = 10.64, 95% CI, 6.72-16.86) (interaction P = .03). By 2006-2009, nonpsychiatrist physicians provided most (57.7%) of the stimulant prescriptions linked to adult office-based visits. As compared with psychiatrists, nonpsychiatrist physicians diagnosed ADHD in a significantly smaller proportion of their adult visits in which stimulants were prescribed (62.5% vs 34.4%, P < .0001). CONCLUSIONS: Between 1994 and 2009, there was a substantial increase in stimulant prescriptions during adult outpatient visits, especially during visits of younger adults. The increase in stimulant treatment occurred significantly more rapidly in the practices of nonpsychiatrist physicians than in those of psychiatrists.

Fatigue in multiple sclerosis - a brief review.

Fatigue is the most common and debilitating symptom in multiple sclerosis (MS) and is believed to be distinctly different from fatigue seen in other chronic conditions. It can affect a patient's mood, sleep and have a detrimental effect on their quality of life. In the recent years much literature has emerged in an attempt to elucidate the potential causes and treatment of this common symptom. This review article aims to examine the most recent theories on the pathophysiology of fatigue in MS as well as its association with sleep and depression. We describe the pharmacological and non-pharmacological approaches to its treatment and propose a multidisciplinary, patient enabled and individualised manner to the management of fatigue in MS.

Self-injurious behavior vs. nonsuicidal self-injury: the CNS stimulant pemoline as a model of self-destructive behavior.

BACKGROUND: Historically, the field of self-injury has distinguished between the behaviors exhibited among individuals with a developmental disability (self-injurious behaviors; SIB) and those present within a normative population (nonsuicidal self-injury; NSSI),which typically result as a response to perceived stress. More recently, however, conclusions about NSSI have been drawn from lines of animal research aimed at examining the neurobiological mechanisms of SIB. Despite some functional similarity between SIB and NSSI, no empirical investigation has provided precedent for the application of SIB-targeted animal research as justification for pharmacological interventions in populations demonstrating NSSI. AIMS: The present study examined this question directly, by simulating an animal model of SIB in rodents injected with pemoline and systematically manipulating stress conditions in order to monitor rates of self-injury. METHODS: Sham controls and experimental animals injected with pemoline (200 mg/kg) were assigned to either a low stress (discriminated positive reinforcement) or high stress (discriminated avoidance) group and compared on the dependent measures of self-inflicted injury prevalence and severity. RESULTS: The manipulation of stress conditions did not impact the rate of self-injury demonstrated by the rats. The results do not support a model of stress-induced SIB in rodents. CONCLUSIONS: Current findings provide evidence for caution in the development of pharmacotherapies of NSSI in human populations based on CNS stimulant models. Theoretical implications are discussed with respect to antecedent factors such as preinjury arousal level and environmental stress.

Animal models of self-injurious behaviour: an overview.

Self-injurious behaviour is highly prevalent in neurodevelopmental disorders. Interestingly, it is not restricted to any individual diagnostic group. Rather, it is exhibited in various forms across patient groups with distinct genetic defects and classifications of disorders. This suggests that there may be shared neuropathology that confers vulnerability. Convergent evidence from clinical pharmacotherapy, brain imaging studies, postmortem neurochemical analyses, and animal models indicates that dopaminergic insufficiency is a key culprit. This chapter provides an overview of studies in which animal models have been used to investigate the biochemical basis of self-injury, and highlights the convergence in findings between these models and expression of self-injury in humans.

The pemoline model of self-injurious behaviour.

Traditional models of neuropsychiatric disorders consist of attempts to replicate the broad spectrum of behavioural and neurochemical sequelae that characterize a specific disorder. However, these disorders comprise complex constellations of symptoms, including emotional instability, perseverative thoughts, and aberrant behaviours. Close examination often reveals heterogeneity of symptom expression within patient groups and homogeneity in expression of specific symptoms across diagnostic categories. Accordingly, it may not be possible to model the entire spectrum of characteristics for any one of these disorders in any single animal model. A focus on one or more specific behavioural characteristics (e.g. self-injury) may be a more fruitful strategy. Development of behaviourally focused models yields increased understanding of the genetic basis and biochemical abnormalities that underlie specific psychiatric dysfunctions. Furthermore, by revealing pathophysiology that underlies specific disease characteristics, behaviourally focused models improve translational power and help to identify targets for effective pharmacotherapies. One such behaviourally focused animal model is the pemoline model of self-injurious behaviour.

Self-injurious behaviour: limbic dysregulation and stress effects in an animal model.

BACKGROUND: Self-injurious behaviour (SIB) is prevalent in neurodevelopmental disorders, but its expression is highly variable within, and between diagnostic categories. This raises questions about the factors that contribute to aetiology and expression of SIB. Expression of SIB is generally described in relation to social reinforcement. However, variables that predispose vulnerability have not been as clearly characterised. This study reports the aetiology and expression of self-injury in an animal model of pemoline-induced SIB. It describes changes in gross neuronal activity in selected brain regions after chronic treatment with pemoline, and it describes the impact that a history of social defeat stress has on the subsequent expression of SIB during pemoline treatment. METHODS: Experiment 1--Male Long-Evans rats were injected on each of five consecutive days with pemoline or vehicle, and the expression of SIB was evaluated using a rating scale. The brains were harvested on the morning of the sixth day, and were assayed for expression of cytochrome oxidase, an index of sustained neuronal metabolic activity. Experiment 2--Male Long-Evans rats were exposed to a regimen of 12 daily sessions of social defeat stress or 12 daily sessions of handling (i.e. controls). Starting on the day after completion of the social defeat or handling regimen, each rat was given five daily injections of pemoline. The durations of self-injurious oral contact and other stereotyped behaviours were monitored, and the areas of tissue injury were quantified. RESULTS: Experiment 1--Neuronal metabolic activity was significantly lower in a variety of limbic and limbic-associated brain structures in the pemoline-treated rats, when compared with activity in the same regions of vehicle-treated controls. In addition, neuronal activity was low in the caudate-putamen, and in subfields of the hypothalamus, but did not differ between groups for a variety of other brain regions, including nucleus accumbens, substantia nigra, ventral tegmentum, thalamus, amygdala, and cortical regions. Experiment 2--All the pemoline-treated rats exhibited SIB, and whereas the social defeat regimen did not alter the total amount of self-injurious oral contact or other stereotyped behaviours, it significantly increased the severity of tissue injury. CONCLUSIONS: A broad sampling of regional metabolic activity indicates that the pemoline regimen produces enduring changes that are localised to specific limbic, hypothalamic and striatal structures. The potential role of limbic function in aetiology of SIB is further supported by the finding that pemoline-induced self-injury is exacerbated by prior exposure to social defeat stress. Overall, the results suggest brain targets that should be investigated further, and increase our understanding of the putative role that stress plays in the pathophysiology of SIB.

Safety assessment in pediatric studies.

It typically takes many years before an association of a drug with a rare, serious adverse reaction is established. As related to pediatric drug use, evidence is even more erratic, as most drugs are used off labels. To enhance child safety, there is an urgent need to develop robust and rapid methods to identify such associations in as timely a manner as possible. In this chapter, several novel methods, both clinically based pharmacoepidemiological approaches and laboratory-based methods, are described.

Stimulant adherence and academic performance in urban youth with attention-deficit/hyperactivity disorder.

OBJECTIVE: This analysis assessed whether stimulant adherence was associated with improvement in academic grade point average (GPA) among children diagnosed with and treated for attention-deficit/hyperactivity disorder (ADHD). METHOD: Medicaid claims were merged with academic records from Philadelphia public schools of Medicaid-eligible children in first through eighth grades who were diagnosed with ADHD and who had filled one or more stimulant prescription. Students diagnosed with mental retardation, autism, or speech, hearing, visual, or language impairments were excluded. Marking periods were scored for GPA (range: 0-4.0) based on English, mathematics, social studies, and science grades and for stimulant adherence (medication possession ratio ≥ 0.70). Random and fixed-effects models estimated the effects of stimulant adherence on GPA, between all adherent and nonadherent marking periods in aggregate and within individual student's marking periods, respectively. RESULTS: A total of 3,543 students contributed 29,992 marking periods, of which 18.6% were adherent. Mean GPA was significantly higher during stimulant-adherent (2.18) than stimulant-nonadherent (1.99) marking periods in aggregate (p < .0001). The regression coefficient representing within-student association between stimulant adherence and GPA over time was 0.108 (p < .0001), indicating that adherence was associated with a 0.108 increase in GPA. In stratified analyses, analogous coefficients were 0.106 for boys, 0.111 for girls, 0.078 for elementary students, and 0.118 for middle school students (all p < .0001). The association was stronger among students with (0.139) than without (0.088) comorbid disruptive behavior disorders (both p < .0001). CONCLUSIONS: Stimulant adherence, although found to be low among urban elementary and middle school students diagnosed with ADHD, was associated with a marginal improvement in GPA.

Individual differences in vulnerability for self-injurious behavior: studies using an animal model.

Self-injurious behavior (SIB) is a debilitating characteristic that is prevalent across a broad spectrum of neurodevelopmental disorders. In most of these disorders, some individuals exhibit SIB, whereas others do not. However, the neurobiological mechanisms that confer vulnerability are virtually unexplored. We examined innate characteristics that contribute to vulnerability or resistance for SIB in an animal model of the behavioral pathology. Eighteen outbred Long-Evans rats were screened for behavioral responsiveness to the mild stress of a novel environment. The rats were then categorized as high responders (HR; those rats that had the highest locomotor counts) or low responders (LR; those rats that had lower locomotor counts) by median split. All the rats were then given daily injections of the indirect monoamine agonist pemoline (150 mg/kg/day) for 10 days, and self-injury was evaluated. All 9 HR rats and 5 of the 9 LR rats exhibited self-injury. The HR rats spent more time self-injuring, injured more body sites, and caused larger areas of tissue damage than the LR rats did. Furthermore, the behavioral responsiveness to novelty stress was significantly correlated with each of these measures of self-injury. The HR rats did not exhibit substantially enhanced responses on other measures of psychostimulant action (stereotypy, grooming, locomotion, rearing). Accordingly, vulnerability to develop pemoline-induced SIB is positively correlated with, and can be predicted based upon, a behavioral measure of innate stress responsiveness. These findings suggest that characteristics that are common in developmental disorders may help predispose afflicted individuals to self-injure. The findings also extend the variety of behavioral pathologies (e.g. drug addiction) for which the HR/LR model predicts vulnerability.

Pharmacological treatments for fatigue associated with palliative care.

BACKGROUND: In healthy individuals, fatigue is a protective response to physical or mental stress, often relieved by rest. By contrast, in palliative care patients fatigue can be severely debilitating, thereby impacting daily activity and quality of life, often with rest not counteracting fatigue. Fatigue frequently occurs in patients with advanced disease and modalities treating cancer often contribute or cause fatigue. Further complicating issues are its multidimensionality, subjective nature, and lack of a consensus definition of fatigue. Pathophysiology is not fully understood and evidence-based treatment approaches are needed. OBJECTIVES: The objective was to determine efficacy of pharmacological treatments on non-specific fatigue in palliative care. The focus was on patients at an advanced stage of disease, including cancer and other chronic diseases associated with fatigue, aiming to relieve fatigue. Studies aiming at curative treatment (e.g. surgical intervention for early breast cancer) were not included. SEARCH STRATEGY: We searched EMBASE; Psych Lit, CENTRAL and MEDLINE to June 2009. SELECTION CRITERIA: We considered randomised controlled trials (RCTs) concerning adult palliative care with focus on pharmacological treatment of fatigue. The primary outcome had to be non-specific fatigue (or related terms such as asthenia). DATA COLLECTION AND ANALYSIS: Results were screened and included if they met the selection criteria. If two or more studies were identified that investigated a specific drug in a population with the same disease, meta-analysis was conducted. In addition, comparison of type of drug investigated in a specific population as well as comparison of frequent adverse effects of fatigue treatment was done by creating overview tables. MAIN RESULTS: More than 2000 publications were screened, and 22 met inclusion criteria. In total, data from 11 drugs and 1632 participants were analysed. Studies investigating amantadine, pemoline, and modafinil in participants with Multiple Sclerosis (MS)-associated fatigue and methylphenidate in patients suffering from advanced cancer and fatigue could be used for meta-analysis. Amantadine in MS and methylphenidate in cancer patients showed a superior effect. Most studies had low participant numbers and were heterogenous. AUTHORS' CONCLUSIONS: Based on limited evidence, we cannot recommend a specific drug for treatment of fatigue in palliative care patients. Surprisingly, corticosteroids have not been a research focus for fatigue treatment, although these drugs are frequently used. Recent fatigue research seems to focus on modafinil, which may be beneficial although there is no evidence currently. Amantadine and methylphenidate should be further examined. Consensus regarding fatigue assessment in advanced disease is needed.