BACKGROUND:The objective of this study was to examine the effects of aerobic exercise on evoked dopamine release and activity of the ventral striatum using positron emission tomography and functional magnetic resonance imaging in Parkinson's disease (PD). METHODS:Thirty-five participants were randomly allocated to a 36-session aerobic exercise or control intervention. Each participant underwent an functional magnetic resonance imaging scan while playing a reward task before and after the intervention to determine the effect of exercise on the activity of the ventral striatum in anticipation of reward. A subset of participants (n = 25) completed [11 C] raclopride positron emission tomography scans to determine the effect of aerobic exercise on repetitive transcranial magnetic stimulation-evoked release of endogenous dopamine in the dorsal striatum. All participants completed motor (MDS-UPDRS part III, finger tapping, Timed-up-and-go) and nonmotor assessments (Starkstein Apathy Scale, Beck Depression Inventory, reaction time, Positive and Negative Affect Schedule, Trail Making Test [A and B], and Montreal Cognitive Assessment) before and after the interventions. RESULTS:The aerobic group exhibited increased activity in the ventral striatum during functional magnetic resonance imaging in anticipation of 75% probability of reward (P = 0.01). The aerobic group also demonstrated increased repetitive transcranial magnetic stimulation-evoked dopamine release in the caudate nucleus (P = 0.04) and increased baseline nondisplaceable binding potential in the posterior putamen of the less affected repetitive transcranial magnetic stimulation-stimulated hemisphere measured by position emission tomography (P = 0.03). CONCLUSIONS:Aerobic exercise alters the responsivity of the ventral striatum, likely related to changes to the mesolimbic dopaminergic pathway, and increases evoked dopamine release in the caudate nucleus. This suggests that the therapeutic benefits of exercise are in part related to corticostriatal plasticity and enhanced dopamine release. © 2019 International Parkinson and Movement Disorder Society.

BACKGROUND Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common genetic risk factor for Parkinson's disease (PD). While the corresponding pathogenic mechanisms remain largely unknown, LRRK2 has been implicated in the immune system. OBJECTIVE To assess whether LRRK2 mutations alter the sensitivity to a single peripheral inflammatory trigger, with ultimate impact on dopaminergic integrity, using a longitudinal imaging-based study design. METHODS Rats carrying LRRK2 p.G2019S and non-transgenic (NT) littermates were treated peripherally with lipopolysaccharide (LPS). They were monitored over 10 months with PET markers for neuroinflammation and dopaminergic integrity, and with behavioral testing. Tyrosine hydroxylase and CD68 expression were assessed postmortem, 12 months after LPS treatment, in the striatum and substantia nigra. RESULTS Longitudinal [11C]PBR28 PET imaging revealed that LPS treatment caused inflammation in the brain, increasing over time, as compared to saline (corrected p = 0.008). LPS treated LRRK2 animals exhibited significantly increased neuroinflammation in the cortex and ventral-regions compared to saline treated animals (LRRK2 and NT) at 10 months post treatment, with the increase in [11C]PBR28 binding from baseline averaging 0.128±0.045 g/mL. For LPS treated NT animals, the increase was not significant. CD68 immunohistochemistry data supported the imaging results, but without reaching statistical significance. No dopaminergic degeneration was observed. CONCLUSION A single peripheral inflammatory trigger elicited long lasting, progressive neuroinflammation. A trend for an exacerbated inflammatory response in LRRK2 animals compared to NT controls was observed. Translationally, this implies that repeated exposure to inflammatory triggers may be needed for LRRK2 mutation carriers to develop active PD.

ABSTRACTBackgroundThe benefits of exercise in PD have been linked to enhanced dopamine (DA) transmission in the striatum.ObjectiveTo examine differences in DA release, reward signaling, and clinical features between habitual exercisers and sedentary subjects with PD.MethodsEight habitual exercisers and 9 sedentary subjects completed [11C]raclopride PET scans before and after stationary cycling to determine exercise‐induced release of endogenous DA in the dorsal striatum. Additionally, functional MRI assessed ventral striatum activation during reward anticipation. All participants completed motor (UPDRS III; finger tapping; and timed‐up‐and‐go) and nonmotor (Beck Depression Inventory; Starkstein Apathy Scale) assessments.Results[11C]Raclopride analysis before and after stationary cycling demonstrated greater DA release in the caudate nuclei of habitual exercisers compared to sedentary subjects (P < 0.05). Habitual exercisers revealed greater activation of ventral striatum during the functional MRI reward task (P < 0.05) and lower apathy (P < 0.05) and bradykinesia (P < 0.05) scores versus sedentary subjects.ConclusionsHabitual exercise is associated with preservation of motor and nonmotor function, possibly mediated by increased DA release. This study formulates a foundation for prospective, randomized controlled studies. © 2018 International Parkinson and Movement Disorder Society

Reward-related stimuli can potently influence behavior; for example, exposure to drug-paired cues can trigger drug use and relapse in people with addictions. Psychological mechanisms that generate such outcomes likely include cue-induced cravings and attentional biases. Recent animal data suggest another candidate mechanism: reward-paired cues can enhance risky decision making, yet whether this translates to humans is unknown. Here, we examined whether sensory reward-paired cues alter decision making under uncertainty and risk, as measured respectively by the Iowa Gambling Task and a two-choice lottery task. In the cued versions of both tasks, gain feedback was augmented with reward-concurrent audiovisual stimuli. Healthy human volunteers (53 males, 78 females) performed each task once, one with and the other without cues (cued Iowa Gambling Task/uncued Vancouver Gambling Task: n = 63; uncued Iowa Gambling Task/cued Vancouver Gambling Task: n = 68), with concurrent eye-tracking. Reward-paired cues did not affect choice on the Iowa Gambling Task. On the two-choice lottery task, the cued group displayed riskier choice and reduced sensitivity to probability information. The cued condition was associated with reduced eye fixations on probability information shown on the screen and greater pupil dilation related to decision and reward anticipation. This pupil effect was unrelated to the risk-promoting effects of cues: the degree of pupil dilation for risky versus risk-averse choices did not differ as a function of cues. Together, our data show that sensory reward cues can promote riskier decisions and have additional and distinct effects on arousal.SIGNIFICANCE STATEMENT Animal data suggest that reward-paired cues can promote maladaptive reward-seeking by biasing cost-benefit decision making. Whether this finding translates to humans is unknown. We examined the effects of salient reward-paired audiovisual cues on decision making under risk and uncertainty in human volunteers. Cues had risk-promoting effects on a risky choice task and independently increased task-related arousal as measured by pupil dilation. By demonstrating risk-promoting effects of cues in human participants, our data identify a mechanism whereby cue reactivity could translate into maladaptive behavioral outcomes in people with addictions.

BACKGROUND:Markers of neuroinflammation are increased in some patients with LRRK2 Parkinson's disease compared with individuals with idiopathic Parkinson's disease, suggesting possible differences in disease pathogenesis. Previous PET studies have suggested amplified dopamine turnover and preserved serotonergic innervation in LRRK2 mutation carriers. We postulated that patients with LRRK2 mutations might show abnormalities of central cholinergic activity, even before the diagnosis of Parkinson's disease.METHODS:Between June, 2009, and December, 2015, we recruited participants from four movement disorder clinics in Canada, Norway, and the USA. Patients with Parkinson's disease were diagnosed by movement disorder neurologists on the basis of the UK Parkinson's Disease Society Brain Bank criteria. LRRK2 carrier status was confirmed by bidirectional Sanger sequencing. We used the PET tracer N-11C-methyl-piperidin-4-yl propionate to scan for acetylcholinesterase activity. The primary outcome measure was rate of acetylcholinesterase hydrolysis, calculated using the striatal input method. We compared acetylcholinesterase hydrolysis rates between groups using ANCOVA, with adjustment for age based on the results of linear regression analysis.FINDINGS:We recruited 14 patients with LRRK2 Parkinson's disease, 16 LRRK2 mutation carriers without Parkinson's disease, eight patients with idiopathic Parkinson's disease, and 11 healthy controls. We noted significant between-group differences in rates of acetylcholinesterase hydrolysis in cortical regions (average cortex p=0·009, default mode network-related regions p=0·006, limbic network-related regions p=0·020) and the thalamus (p=0·008). LRRK2 mutation carriers without Parkinson's disease had increased acetylcholinesterase hydrolysis rates compared with healthy controls in the cortex (average cortex, p=0·046). Patients with LRRK2 Parkinson's disease had significantly higher acetylcholinesterase activity in some cortical regions (average cortex p=0·043, default mode network-related regions p=0·021) and the thalamus (thalamus p=0·004) compared with individuals with idiopathic disease. Acetylcholinesterase hydrolysis rates in healthy controls were correlated inversely with age.INTERPRETATION:LRRK2 mutations are associated with significantly increased cholinergic activity in the brain in mutation carriers without Parkinson's disease compared with healthy controls and in LRRK2 mutation carriers with Parkinson's disease compared with individuals with idiopathic disease. Changes in cholinergic activity might represent early and sustained attempts to compensate for LRRK2-related dysfunction, or alteration of acetylcholinesterase in non-neuronal cells.FUNDING:Michael J Fox Foundation, National Institutes of Health, and Pacific Alzheimer Research Foundation.

Background: As individuals age, they are more likely to experience increasing frailty and more frequent use of hospital services. First, we explored whether initiating home-based primary care in a frail homebound cohort, influenced hospital use. Second, we explored whether initiating regular home care support for personal care with usual primary care, in a second somewhat less frail cohort, influenced hospital use. Methods: This was a before-after retrospective cohort study of two frail populations in Vancouver, Canada using administrative data to assess the influence of two different services started in two different cohorts over the same time period. The participants were 246 recipients of integrated home-based primary care and 492 recipients of home care followed between July 1st, 2008 and June 30th, 2013 before and after starting their respective services. Individuals in each group were linked to their hospital emergency department visit and discharge abstract records. The main outcome measures were mean emergency department visit and hospital admission rates per 1000 patient days for 21 months before versus the period after receipt of services, and the adjusted incidence rate ratios (IRRs) on these outcomes post receipt of service. Results: Before versus after starting integrated home-based primary care, emergency department visit rates per 1000 patient days (95% confidence intervals) were 4.1 (3.8, 4.4) versus 3.7 (3.3, 4.1), and hospital admissions rates were 2.3 (2.1, 2.5) versus 2.2 (1.9, 2.5). Before versus after starting home care, emergency department visit rates per 1000 patient days (95% confidence intervals) were 3.0 (2.8, 3.2) versus 4.0 (3.7, 4.3) visits and hospital admissions rates were 1.3 (1.2, 1.4) versus 1.9 (1.7, 2.1). Home-based primary care IRRs were 0.91 (0.72, 1.15) and 0.99 (0.76, 1.27) and home care IRRs were 1.34 (1.15, 1.56) and 1.46 (1.22, 1.74) for emergency department visits and hospital admissions respectively. Conclusions: After enrollment in integrated home-based primary care, emergency department visit and hospital admission rates stabilized. After starting home care with usual primary care, emergency department visit and hospital admission rates continued to rise.

BACKGROUND:People with Parkinson's disease can show premotor neurochemical changes in the dopaminergic and non-dopaminergic systems. Using PET, we assessed whether dopaminergic and serotonin transporter changes are similar in LRRK2 mutation carriers with Parkinson's disease and individuals with sporadic Parkinson's disease, and whether LRRK2 mutation carriers without motor symptoms show PET changes. METHODS:We did two cross-sectional PET studies at the Pacific Parkinson's Research Centre in Vancouver, BC, Canada. We included LRRK2 mutation carriers with or without manifest Parkinson's disease, people with sporadic Parkinson's disease, and age-matched healthy controls, all aged 18 years or older. People with Parkinson's disease were diagnosed by a neurologist with movement disorder training, in accordance with the UK Parkinson's Disease Society Brain Bank criteria. LRRK2 carrier status was confirmed by bidirectional Sanger sequencing. In the first study, LRRK2 mutation carriers with or without manifest Parkinson's disease who were referred for investigation between July, 1999, and January, 2012, were scanned with PET tracers for the membrane dopamine transporter, and dopamine synthesis and storage (18F-6-fluoro-L-dopa; 18F-FDOPA). We compared findings with those in people with sporadic Parkinson's disease and age-matched healthy controls. In the second study, distinct groups of LRRK2 mutation carriers, individuals with sporadic Parkinson's disease, and age-matched healthy controls seen from November, 2012, to May, 2016, were studied with tracers for the serotonin transporter and vesicular monoamine transporter 2 (VMAT2). Striatal dopamine transporter binding, VMAT2 binding, 18F-FDOPA uptake, and serotonin transporter binding in multiple brain regions were compared by ANCOVA, adjusted for age. FINDINGS:Between January, 1997, and January, 2012, we obtained data for our first study from 40 LRRK2 mutation carriers, 63 individuals with sporadic Parkinson's disease, and 35 healthy controls. We identified significant group differences in striatal dopamine transporter binding (all age ranges in caudate and putamen, p<0·0001) and 18F-FDOPA uptake (in caudate: age ≤50 years, p=0·0002; all other age ranges, p<0·0001; in putamen: all age ranges, p<0·0001). LRRK2 mutation carriers with manifest Parkinson's disease (n=15) had reduced striatal dopamine transporter binding and 18F-FDOPA uptake, comparable with amounts seen in individuals with sporadic Parkinson's disease of similar duration. LRRK2 mutation carriers without manifest Parkinson's disease (n=25) had greater 18F-FDOPA uptake and dopamine transporter binding than did individuals with sporadic Parkinson's disease, with 18F-FDOPA uptake comparable with controls and dopamine transporter binding lower than in controls. Between November, 2012, and May, 2016, we obtained data for our second study from 16 LRRK2 mutation carriers, 13 individuals with sporadic Parkinson's disease, and nine healthy controls. Nine LRRK2 mutation carriers without manifest Parkinson's disease had significantly elevated serotonin transporter binding in the hypothalamus (compared with controls, individuals with LRRK2 Parkinson's disease, and people with sporadic Parkinson's disease, p<0·0001), striatum (compared with people with sporadic Parkinson's disease, p=0·02), and brainstem (compared with LRRK2 mutation carriers with manifest Parkinson's disease, p=0·01), after adjustment for age. Serotonin transporter binding in the cortex did not differ significantly between groups after age adjustment. Striatal VMAT2 binding was reduced in all individuals with manifest Parkinson's disease and reduced asymmetrically in one LRRK2 mutation carrier without manifest disease. INTERPRETATION:Dopaminergic and serotonergic changes progress in a similar fashion in LRRK2 mutation carriers with manifest Parkinson's disease and individuals with sporadic Parkinson's disease, but LRRK2 mutation carriers without manifest Parkinson's disease show increased serotonin transporter binding in the striatum, brainstem, and hypothalamus, possibly reflecting compensatory changes in serotonergic innervation preceding the motor onset of Parkinson's disease. Increased serotonergic innervation might contribute to clinical differences in LRRK2 Parkinson's disease, including the emergence of non-motor symptoms and, potentially, differences in the long-term response to levodopa. FUNDING:Canada Research Chairs, Michael J Fox Foundation, National Institutes of Health, Pacific Alzheimer Research Foundation, Pacific Parkinson's Research Institute, National Research Council of Canada.

Introduction Following the investigation of the mother’s preceding pregnancies on fetal development and postnatal survival of the neonate, we turned our attention to an earlier period, that is the interval separating the onset of the current pregnancy from the end of the preceding one. The objectives of this study is to investigate the variations of interpregnancy interval length associated to the mother’s preceding pregnancies.Methods A population of 7773 neonates, alive at the time of hospital discharge, were divided into cohorts according to the current neonate’s sex and number and sex of the mother’s preceding pregnancies. Interpregnancy interval average of each cohort of same neonate’s sex and mother’s parity, but different configuration of preceding pregnancies, were measured and compared.Results A positive association was found between mother’s preceding pregnancies and length of interpregnancy interval when current pregnancy and preceding pregnancy were of the same sex, and a negative association when they were of opposite sex.Discussion Interpregnancy interval length follows a pattern regarding the gravida’s preceding pregnancy similar to the other early life indicators pattern, birth weight, placenta weight, gestation length and neonatal survival. Our results confirm and complete an immunological explanation of the indicators variations associated to the gravida’s preceding pregnancy.

Neuroinflammation in the aging rat brain was investigated using [ 11 C]PBR28 microPET (positron emission tomography) imaging. Normal rats were studied alongside LRRK2 p.G2019S transgenic rats; this mutation increases the risk of Parkinson's disease in humans. Seventy [ 11 C]PBR28 PET scans were acquired. Arterial blood sampling enabled tracer kinetic modeling and estimation of V T . In vitro autoradiography was also performed. PBR28 uptake increased with age, without differences between nontransgenic and transgenic rats. In 12 months of aging (4 to 16 months), standard uptake value (SUV) increased by 56% from 0.44 to 0.69 g/mL, whereas V T increased by 91% from 30 to 57 mL/cm 3 . Standard uptake value and V T were strongly correlated (r = 0.52, 95% confidence interval (CI) = 0.31 to 0.69, n = 37). The plasma free fraction, f p , was 0.21 ± 0.03 (mean ± standard deviation, n = 53). In vitro binding increased by 19% in 16 months of aging (4 to 20 months). The SUV was less variable across rats than V T ; coefficients of variation were 13% ( n = 27) and 29% ( n = 12). The intraclass correlation coefficient for SUV was 0.53, but was effectively zero for V T . These data show that [ 11 C]PBR28 brain uptake increases with age, implying increased microglial activation in the aged brain.

Introduction. A number of epidemiological studies on various diseases have drawn attention to relationships between fetal life events, as measured by health indicators and pathological events later in life. This accounts for the renewed interest in fetal health indicators. The objective of this retrospective study is to investigate the relationship between the sex of conceptuses of the mother’s preceding pregnancies and the gestation length of the current pregnancy. Methods. A population of 7773 neonates were divided into cohorts, according to the sex of the current neonate and number and sex of the mother’s preceding pregnancies. Average gestation lengths for each cohort were measured and compared between different configurations of preceding pregnancies. Results. There a positive association between the length of gestation of the neonate and its mother’s preceding pregnancies of same sex as its own. Gestation length increases with the number of conceptuses of same sex among the preceding pregnancies. Likewise, there is a negative association between the length of gestation of the neonate and its mother’s preceding pregnancies of opposite sex to its own. Gestation length decreases with the number of conceptuses of opposite sex among the preceding pregnancies. Discussion. The results of our study are compatible with the immunological hypothesis, based on the sex-linked concepto-gravidic antigenic dissimilarity, proposed to explain the association between preceding pregnancy and fetal development. The influence of the preceding pregnancy is significant enough to be taken into account for effective management of current pregnancies as well as for efficient clinical trial analysis.

OBJECTIVE: To investigate whether there is a difference in the progression of dopaminergic dysfunction in the caudate in sporadic Parkinson9s disease (PD) between men and women. BACKGROUND: PD is a clinically heterogeneous disorder and is more common in men. There is a paucity of information on the gender difference in the progression of dopaminergic dysfunction in the parkinsonian caudate. DESIGN/METHODS: PD subjects (n=78; 58 men and 20 women) underwent positron emission tomography (PET) scans using [ 11 C](±)dihydrotetrabenazine (DTBZ), a presynaptic dopamine marker that estimates the density of striatal vesicular monoamine transporter type 2. Subjects were scanned at the initial visit and again after 4 and 8 years of follow-up. Non-linear multivariate regression analyses with random effects, of the form BP ND (t) = a*e (-bt-dA) +c (BP ND = tissue input derived binding potential; a,b,c,d were constants to be estimated; t=symptom duration; A=age at symptom onset) were utilized to model the temporal changes in DTBZ binding in the more severely affected caudate in the two groups (men and women). RESULTS: The study comprised a total of 156 DTBZ scans. Between the two groups, there were no statistically significant differences in either the loss of caudate DTBZ binding at symptom onset or the rate of decline in tracer binding over the entire 25 years of symptom duration. CONCLUSIONS: To the extent that DTBZ scan provides a reliable estimate of loss of dopamine terminal density, our findings suggest similar rates of progression of dopaminergic dysfunction in the parkinsonian caudate in men and women. Study Supported by: The Canadian Institutes of Health Research, the Michael Smith Foundation for Health Research and the Canada Research Chairs. Disclosure: Dr. Ramachandiran has nothing to disclose. Dr. Schulzer has nothing to disclose. Dr. Kuramoto has nothing to disclose. Dr. Cragg has nothing to disclose. Dr. Sossi has nothing to disclose. Dr. de la Fuente-Fernandez has nothing to disclose. Dr. Stoessl has received personal compensation for activities with Teva Neuroscience, AbbVie, and UCB Pharma.

Introduction: We used positron emission tomography (PET) to assess dopaminergic and serotonergic terminal density in three subjects carrying a mutation in the DCT1 gene, two clinically affected with Perry syndrome.Methods: All subjects had brain imaging using 18F-6-fluoro-L-dopa (FDOPA, dopamine synthesis and storage), (1)-11C-dihydrotetrabenazine (DTBZ, vesicular monoamine transporter type 2), and 11C-raclopride (RAC, dopamine D2/D3 receptors). One subject also underwent PET with 11C-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB, serotonin transporter).Results: FDOPA-PET and DTBZ-PET in the affected individuals showed a reduction of striatal tracer uptake. Also, RAC-PET showed higher uptake in these area. DASB-PET showed significant uptake changes in left orbitofrontal cortex, bilateral anterior insula, left dorsolateral prefrontal cortex, left orbitofrontal cortex, left posterior cingulate cortex, left caudate, and left ventral striatum.Conclusions: Our data showed evidence of both striatal dopaminergic and widespread cortical/subcortical serotonergic dysfunctions in individuals carrying a mutation in the DCTN1 gene. (C) 2014 International Parkinson and Movement Disorder Society

This study examined how nursing home facility ownership and organizational characteristics relate to emergency department (ED) transfer rates. The sample included a retrospective cohort of nursing home residents in the Vancouver Coastal Health region (n = 13,140). Rates of ED transfers were compared between nursing home ownership types. Administrative data were further linked to survey-derived data of facility organizational characteristics for exploratory analysis. Crude ED transfer rates (transfers/100 resident years) were 69, 70, and 51, respectively, in for-profit, non-profit, and publicly owned facilities. Controlling for sex and age, public ownership was associated with lower ED transfer rates compared to for-profit and non-profit ownership. Results showed that higher total direct-care nursing hours per resident day, and presence of allied health staff - disproportionately present in publicly owned facilities - were associated with lower transfer rates. A number of other facility organizational characteristics - unrelated to ownership - were also associated with transfer rates.

Background To date, statistical methods that take into account fully the non-linear, longitudinal and multivariate aspects of clinical data have not been applied to the study of progression in Parkinson’s disease (PD). In this paper, we demonstrate the usefulness of such methodology for studying the temporal and spatial aspects of the progression of PD. Extending this methodology further, we also explore the presymptomatic course of this disease. Methods Longitudinal Positron Emission Tomography (PET) measurements were collected on 78 PD patients, from 4 subregions on each side of the brain, using 3 different radiotracers. Non-linear, multivariate, longitudinal random effects modelling was applied to analyze and interpret these data. Results The data showed a non-linear decline in PET measurements, which we modelled successfully by an exponential function depending on two patient-related covariates duration since symptom onset and age at symptom onset. We found that the degree of damage was significantly greater in the posterior putamen than in the anterior putamen throughout the disease. We also found that over the course of the illness, the difference between the less affected and more affected sides of the brain decreased in the anterior putamen. Younger patients had significantly poorer measurements than older patients at the time of symptom onset suggesting more effective compensatory mechanisms delaying the onset of symptoms. Cautious extrapolation showed that disease onset had occurred some 8 to 17 years prior to symptom onset. Conclusions Our model provides important biological insights into the pathogenesis of PD, as well as its preclinical aspects. Our methodology can be applied widely to study many other chronic progressive diseases.

Background —The NNT (number needed to treat) and NNH (number needed to harm) are useful in conveying the results of clinical trials because they emphasize the effort that must be expended to accomplish a single, tangible outcome. But NNT conveys the effort required to achieve a positive outcome without distinguishing between the presence or absence of treatment-related adverse events. Similarly, NNH conveys harm without accounting for the achievement or lack of achievement of the benefit of therapy. Consequently, a mathematical model was developed to extend the NNT and NNH to represent the effort required to achieve “unqualified success” (NNT US , treatment success without treatment-induced side effects) and “unmitigated failure” (NNH UF , lack of treatment success with treatment-induced side effects). Methods and Results —NNT US was calculated by adjusting the absolute risk reduction to allow for the probability of not incurring a treatment-related adverse event. NNH UF was similarly calculated by adjusting the absolute risk of incurring a treatment-related adverse event by the probability of not incurring any treatment-related benefit. The impact of conveying clinical trial data by the use of NNT, NNT US , NNH, and NNH UF is illustrated by means of 11 highly cited trials identified systematically from the cardiovascular literature. The treatment effort measured by the NNT US and the NNH UF was consistently higher than that given by the traditional NNT and NNH. These increments ranged from 1% to several hundred percent. Conclusions —The NNT US and the NNH UF represent the treatment effort required on average to achieve 1 unqualified success and 1 unmitigated failure. NNT US and NNH UF balance benefit and harm in an objective way and are relevant for making service delivery decisions.