The 'molecularly unstratified' patient: a focus for moral, psycho-social and societal research.

The biomedical paradigm of personalised precision medicine - identification of specific molecular targets for treatment of an individual patient - offers great potential for treatment of many diseases including cancer. This article provides a critical analysis of the promise, the hype and the pitfalls attending this approach. In particular, we focus on 'molecularly unstratified' patients - those who, for various reasons, are not eligible for a targeted therapy. For these patients, hope-laden therapeutic options are closed down, leaving them left out, and left behind, bobbing untidily about in the wake of technological and scientific 'advance'. This process creates a distinction between groups of patients on the basis of biomarkers and challenges our ability to provide equitable access to care for all patients. In broadening our consideration of these patients to include the research ecosystem that shapes their experience, we hypothesise that the combination of immense promise with significant complexity creates particular individual and organisational challenges for researchers. The novelty and complexity of their research consumes high levels of resource, possibly in parallel with undervaluing other 'low hanging fruit', and may be challenging current regulatory thinking. We outline future research to consider the societal, psycho-social and moral issues relating to 'molecularly unstratified' patients, and the impact of the drive towards personalisation on the research, funding, and regulatory ecosystem.

Pricing and reimbursement experiences and insights in the European Union and the United States: Lessons learned to approach adaptive payer pathways.

Earlier patient access to beneficial therapeutics that addresses unmet need is one of the main requirements of innovation in global healthcare systems already burdened by unsustainable budgets. "Adaptive pathways" encompass earlier cross-stakeholder engagement, regulatory tools, and iterative evidence generation through the life cycle of the medicinal product. A key enabler of earlier patient access is through more flexible and adaptive payer approaches to pricing and reimbursement that reflect the emerging evidence generated.

Burden of illness and factors associated with duration of illness in clinical campylobacteriosis.

A population-based study investigated the burden of illness, including the duration of illness associated with laboratory-confirmed cases of campylobacteriosis in two health unit areas. Questionnaire data were collected for 250 cases. The median duration of illness was 8 days and 66% of cases reported symptoms of moderate severity or greater. A Cox proportional hazards model identified antimicrobial use factors associated with a significantly increased rate of symptom resolution (shorter duration of illness): macrolides for less than the recommended number of days, ciprofloxacin for at least 3 days, and antimicrobials not recommended for campylobacteriosis. The impact of antimicrobial use was consistent regardless of when, during the course of illness, the antimicrobial use began. The effectiveness of ciprofloxacin in these results may be due to the low prevalence of resistance to ciprofloxacin in isolates from this study. The effect of antimicrobials not recommended for campylobacteriosis should be further investigated.

The role of individuality in collective group movement.

How different levels of biological organization interact to shape each other's function is a central question in biology. One particularly important topic in this context is how individuals' variation in behaviour shapes group-level characteristics. We investigated how fish that express different locomotory behaviour in an asocial context move collectively when in groups. First, we established that individual fish have characteristic, repeatable locomotion behaviours (i.e. median speeds, variance in speeds and median turning speeds) when tested on their own. When tested in groups of two, four or eight fish, we found individuals partly maintained their asocial median speed and median turning speed preferences, while their variance in speed preference was lost. The strength of this individuality decreased as group size increased, with individuals conforming to the speed of the group, while also decreasing the variability in their own speed. Further, individuals adopted movement characteristics that were dependent on what group size they were in. This study therefore shows the influence of social context on individual behaviour. If the results found here can be generalized across species and contexts, then although individuality is not entirely lost in groups, social conformity and group-size-dependent effects drive how individuals will adjust their behaviour in groups.

Age-related changes in parahippocampal white matter integrity: a diffusion tensor imaging study.

The axons in the parahippocampal white matter (PWM) region that includes the perforant pathway relay multimodal sensory information, important for memory function, from the entorhinal cortex to the hippocampus. Previous work suggests that the integrity of the PWM shows changes in individuals with amnestic mild cognitive impairment and is further compromised as Alzheimer's disease progresses. The present study was undertaken to determine the effects of healthy aging on macro- and micro-structural alterations in the PWM. The study characterized in vivo white matter changes in the parahippocampal region that includes the perforant pathway in cognitively healthy young (YNG, n=21) compared to cognitively healthy older (OLD, n=21) individuals using volumetry, diffusion tensor imaging (DTI) and tractography. Results demonstrated a significant reduction in PWM volume in old participants, with further indications of reduced integrity of remaining white matter fibers. In logistic regressions, PWM volume, memory performance and DTI indices of PWM integrity were significant indicator variables for differentiating the young and old participants. Taken together, these findings suggest that age-related alterations do occur in the PWM region and may contribute to the normal decline in memory function seen in healthy aging by degrading information flow to the hippocampus.

Alzheimer-signature MRI biomarker predicts AD dementia in cognitively normal adults.

OBJECTIVE: Since Alzheimer disease (AD) neuropathology is thought to develop years before dementia, it may be possible to detect subtle AD-related atrophy in preclinical AD. Here we hypothesized that the "disease signature" of AD-related cortical thinning, previously identified in patients with mild AD dementia, would be useful as a biomarker to detect anatomic abnormalities consistent with AD in cognitively normal (CN) adults who develop AD dementia after longitudinal follow-up. METHODS: We studied 2 independent samples of adults who were CN when scanned. In sample 1, 8 individuals developing AD dementia (CN-AD converters) after an average of 11.1 years were compared to 25 individuals who remained CN (CN-stable). In sample 2, 7 CN-AD converters (average follow-up 7.1 years) were compared to 25 CN-stable individuals. RESULTS: AD-signature cortical thinning in CN-AD converters in both samples was remarkably similar, about 0.2 mm (p < 0.05). Despite this small absolute difference, Cohen d effect sizes for these differences were very large (> 1). Of the 11 CN individuals with baseline low AD-signature thickness (≥ 1 SD below cohort mean), 55% developed AD dementia over nearly the next decade, while none of the 9 high AD-signature thickness individuals (≥ 1 SD above mean) developed dementia. This marker predicted time to diagnosis of dementia (hazard ratio = 3.4, p < 0.0005); 1 SD of thinning increased dementia risk by 3.4. CONCLUSIONS: By focusing on cortical regions known to be affected in AD dementia, subtle but reliable atrophy is identifiable in asymptomatic individuals nearly a decade before dementia, making this measure a potentially important imaging biomarker of early neurodegeneration.

MRI-based volumetric measurement of the substantia innominata in amnestic MCI and mild AD.

The substantia innominata (SI) contains the nucleus basalis of Meynert, which provides the major cholinergic innervation to the entire cortical mantel and the amygdala; degeneration of nucleus basalis neurons correlates with cognitive decline in Alzheimer's disease (AD). However, whether SI atrophy occurs in individuals with amnestic mild cognitive impairment (aMCI) has not been examined thoroughly in vivo. In the present study, we developed a new protocol to measure volumetric changes in the SI from magnetic resonance imaging (MRI) scans. Participants consisted of 27 elderly controls with no cognitive impairment (NCI); 33 individuals with aMCI; and 19 patients with mild AD. SI volumes were traced on three consecutive gapless 1mm thick coronal slices. Results showed that SI volume was significantly reduced in the mild AD group compared to both NCI and aMCI participants; however, the NCI and aMCI groups did not differ from each other. Furthermore, a decrease in SI volume was related to impaired performance on declarative memory tasks even when attention was controlled.

Rate of entorhinal and hippocampal atrophy in incipient and mild AD: relation to memory function.

In the present study, as part of a more extensive longitudinal investigation of the in vivo anatomical markers of early and incipient AD in our laboratory, three groups of elderly participants were followed with yearly clinical evaluations and high resolution MRI scans over a 6-year period (baseline and 5 years of follow-up). At baseline, participants consisted of: (1) 35 old subjects with no cognitive impairment (controls); (2) 33 participants with amnestic mild cognitive impairment (MCI); and (3) 14 patients with very mild AD. 11 participants with amnestic MCI received a diagnosis of AD over the follow-up period and 9 controls declined in cognitive function. T1 weighted MRI scans were acquired using a 3D SPGR pulse sequence. At baseline, both the amnestic MCI and mild AD groups differed from the controls in hippocampal and entorhinal cortex volume, but not from each other. Longitudinal analyses showed that the rate of atrophy of the entorhinal cortex and hippocampus for the stable controls differed significantly from MCI participants who converted to AD and the AD groups. Furthermore, longitudinal decreases in hippocampal and entorhinal volume were related to longitudinal decline in declarative memory performance. These findings suggest that the rate of atrophy of mesial temporal lobe structures can differentiate healthy from pathological aging.

Changes in parahippocampal white matter integrity in amnestic mild cognitive impairment: a diffusion tensor imaging study.

In the present study, changes in the parahippocampal white matter (PWM), in the region that includes the perforant path, were investigated, in vivo, in 14 individuals with amnestic mild cognitive impairment (aMCI) compared to 14 elderly controls with no cognitive impairment (NCI). For this purpose, (1) volumetry; (2) diffusion tensor imaging (DTI) derived measures of mean diffusivity (MD) and fractional anisotropy (FA); and (3) tractography were used. In addition, regression models were utilized to examine the association of PWM measurements with memory decline. The results from this study confirm previous findings in our laboratory and others, showing that compared to controls, individuals with aMCI have PWM volume loss. In addition to volume reduction, participants with aMCI demonstrated a significant increase in MD, but no difference in FA, both in the PWM region and in fibers modeled to pass through the PWM region. Further, the DTI metric of MD was associated with declarative memory performance, suggesting it may be a sensitive marker for memory dysfunction. These results indicate that there is general tissue loss and degradation (decreased volume; increased MD) in individuals with aMCI compared to older people with normal cognitive function. However, the microstructural organization of remaining fibers, as determined by measures of anisotropic diffusion, is not significantly different from that of controls.

Baseline differences between vascular cognitive impairment no dementia reverters and non-reverters.

BACKGROUND: The underlying factors of reversion from cognitive impairment to normal cognitive functioning in stroke are not well understood. We compare demographic, cognitive and imaging factors in Vascular Cognitive Impairment, No Dementia (Vascular CIND) patients who revert to normal cognitive functioning to Vascular CIND patients who do not revert. METHODS: Thirty-one ischaemic stroke patients, who met classification criteria for Vascular CIND, were >49.5 years old, met NINDS stroke criteria, and were free from additional neurological illness, completed baseline and 1-year examinations. Forty-five per cent of the Vascular CIND participants reverted to no cognitive impairment at 1-year follow-up examination. RESULTS: There was greater cognitive impairment in non-reverters on a summary score spanning several neuropsychological domains and on psychomotor and working memory summary scores. There were no differences on demographic factors or in stroke severity between reverters and non-reverters. Structural MRI analyses revealed no baseline differences in number of strokes, stroke volume or stroke location. However, there was greater frontal white matter hyperintensity load in the non-reverter group. CONCLUSIONS: These results suggest that Vascular CIND reversion may be a function of a combination of baseline neuropsychological function and location of cerebrovascular disease.

RISK-SENSITIVE ANTIPREDATOR BEHAVIOR IN THE TRINIDADIAN GUPPY, POECILIA RETICULATA.

The comparative approach has become a powerful tool for understanding how predation has shaped prey behavior. In this study we recorded the occurrence of common aquatic predator species and their densities in seven natural populations of Trinidadian guppies, Poecilia reticulata. We then exposed shoals of guppies from each of these populations to a series of predator treatments. Predator treatments differed in the species of predator used (pike cichlids, Crenicichla frenata; rivulus, Rivulus hartii; and freshwater prawns, Macrobrachium carcinus) and thus in the level of risk posed. We recorded the antipredator responses of guppies in each of these predator treatments. The strength of antipredator behavior shown by guppies was affected by both the type of predator they were exposed to and the level of predation risk they experienced naturally in the wild. Importantly, we found that guppies from high-risk populations showed a heightened response, compared to those from lower risk populations, only when exposed to the predator species that posed the greatest risk. Our results show the importance of individual predator species in shaping the behavioral traits of prey species at the population level. This has implications for prey movement between habitats that are geographically close but differ greatly in predator fauna.

MRI predictors of risk of incident Alzheimer disease: a longitudinal study.

OBJECTIVE: To determine if baseline entorhinal and hippocampal volumes and their rate of atrophy could predict the risk of incident Alzheimer disease (AD). METHODS: The authors used proportional odds models to assess the relationship between entorhinal and hippocampal size and risk of incident AD among 58 nondemented elderly people. All participants were followed with annual clinical evaluations and structural MRI scans for up to 5 years (baseline and 5 years of follow-up). At baseline, 23 of 58 participants received a diagnosis of amnestic mild cognitive impairment (MCI) and 35 of 58 were healthy control subjects with no cognitive impairment. Structural MRI scans were acquired with a T1-weighted three-dimensional spoiled gradient-recalled echo pulse sequence in a 1.5 T scanner. Entorhinal and hippocampal volumes were derived from 1.6-mm gapless coronal images reformatted to be perpendicular to the long axis of the hippocampus and were normalized by dividing with intracranial volume. RESULTS: Fourteen of 58 nondemented participants developed AD during the follow-up period. Initial diagnosis of MCI was a significant predictor of incident AD. In addition, both baseline entorhinal volume and its slope of decline were independent predictors of incident AD, but initial hippocampal size and its rate of decline were not, after controlling for entorhinal volume. CONCLUSION: In nondemented individuals, entorhinal cortex atrophy is associated with risk of Alzheimer disease.

Spatial memory in aged rats is related to PKCgamma-dependent G-protein coupling of the M1 receptor.

In the present study, individual differences in spatial memory in aged Fischer 344 (F344) rats were associated with the extent of G-protein coupling of the M1 muscarinic receptor and the dendritic-to-somal ratio of hippocampal PKCgamma (d/sPKCgamma) immunogenicity. Following testing in the eight-arm radial maze task, 7 young and 13 aged rat brains were sectioned through the dorsal hippocampal formation (HF). G-protein coupling of the M1 receptor was assessed autoradiographically using competition binding studies in the presence and absence of a G-protein uncoupler to determine high (K(H)) and low (K(L)) affinity states for agonist in the HF, neocortex, and amygdala. In aged animals, a relationship between choice accuracy in the maze and K(H), a measure of M1 receptor-G-protein coupling was seen in the dentate gyrus, CA3, CA1, and neocortex. Furthermore, choice accuracy and d/sPKCgamma immunogenicity showed a significant relationship in CA1. Lastly, a correlation was seen in the CA1 of aged animals between K(H) and d/sPKCgamma. These relationships did not hold for the amygdala. Thus, individual differences in a naturally occurring age-dependent disruption of cholinergic-PKCgamma signal transduction is associated with spatial memory dysfunction.

Outpatient clinic: where is the delay?

In outpatient clinics, consultation times are often eroded by extraneous activities. We measured the components of each outpatient episode in 167 patients attending a general urology follow-up clinic. 41% of time in the clinic was spent away from the patient-administration 17%, disturbances 15%, finding results 9%. The inefficiencies had changed little since a study in the same setting thirteen years earlier. Since then, parallel nurse-practitioner-run clinics have been introduced in the hope of giving consultants longer with the patient; however, time with each patient is now 4.8 min compared with a previous 7.6 min. The most easily addressed inefficiencies are those relating to missing information, such as radiology reports.

MRI of human entorhinal cortex: a reliable protocol for volumetric measurement.

A new protocol for measuring the volume of the entorhinal cortex (EC) from magnetic resonance images (MRI) was developed specifically to measure the EC from oblique coronal sections used in hippocampal volumetric studies. The relative positions of the anatomic landmarks demarcating EC boundaries were transposed from standard coronal sections to oblique ones. The lateral EC border, which is the most controversial among anatomists, was defined in a standard and conservative manner at the medial edge of the collateral sulcus. Two raters measured the EC twice for 78 subjects (healthy aged individuals, very mild AD patients, and elderly patients who did not meet criteria for dementia) to study intra- and inter-rater reproducibility and reliability of measurements. The level of accuracy achieved (coefficients of reproducibility of 1.40-3.86%) and reliability of measurements (intraclass correlation coefficients of 0.959-0.997) indicated that this method provides a feasible tool for measuring the volume of the EC in vivo.

MRI-derived entorhinal and hippocampal atrophy in incipient and very mild Alzheimer's disease.

With high resolution, quantitative magnetic resonance imaging (MRI) techniques, it is now possible to examine alterations in brain anatomy in vivo and to identify regions affected in the earliest stages of Alzheimer's disease (AD). In this study, we compared MRI-derived entorhinal and hippocampal volume in healthy elderly controls, patients who presented at the clinic with cognitive complaints, but did not meet criteria for dementia (non-demented), and patients with very mild AD. The two patient groups differed significantly from controls in entorhinal volume, but not from each other; in contrast, they differed from each other, as well as from controls, in hippocampal volume, with the mild AD cases showing the greatest atrophy. Follow-up clinical evaluations available on 23/28 non-demented patients indicated that 12/23 had converted to AD within 12-77 months from the baseline MRI examination. Converters could be best differentiated from non-converters on the basis of entorhinal, but not hippocampal volume. These data suggest that although both the EC and hippocampal formation degenerate before the onset of overt dementia, EC volume is a better predictor of conversion.

Surgical resection for intractable epilepsy in "double cortex" syndrome yields inadequate results.

PURPOSE: To analyze the results of surgical treatment of intractable epilepsy in patients with subcortical band heterotopia, or double cortex syndrome, a diffuse neuronal migration disorder. METHODS: We studied eight patients (five women) with double cortex syndrome and intractable epilepsy. All had a comprehensive presurgical evaluation including prolonged video-EEG recordings and magnetic resonance imaging (MRI). RESULTS: All patients had partial seizures, with secondary generalization in six of them. Neurologic examination was normal in all. Three were of normal intelligence, and five were mildly retarded. Six patients underwent invasive EEG recordings, three of them with subdural grids and three with stereotactic implanted depth electrodes (SEEG). Although EEG recordings showed multilobar epileptic abnormalities in most patients, regional or focal seizure onset was recorded in all. MRI showed bilateral subcortical band heterotopia, asymmetric in thickness in three. An additional area of cortical thickening in the left frontal lobe was found in one patient. Surgical procedures included multiple subpial transections in two patients, frontal lesionectomy in one, temporal lobectomy with amygdalohippocampectomy in five, and an additional anterior callosotomy in one. Five patients had no significant improvement, two had some improvement, and one was greatly improved. CONCLUSION: Our results do not support focal surgical removal of epileptogenic tissue in patients with double cortex syndrome, even in the presence of a relatively localized epileptogenic area.

From healthy aging to early Alzheimer's disease: in vivo detection of entorhinal cortex atrophy.

Using quantitative structural MRI protocols, we examined the effects of age on alterations in entorhinal cortex (EC) volume. The left EC was found to be smaller than the right in both young and healthy aged subjects. More importantly, the right EC, but not the left, was significantly smaller in elderly participants compared to young controls. In an attempt to determine the earliest sites of involvement in mild and incipient Alzheimer's disease (AD), we compared entorhinal and hippocampal volume in (1) healthy elderly controls, (2) patients with very mild AD, and (3) elderly patients who were evaluated for cognitive complaints, but did not meet criteria for dementia. Both patient groups differed from controls in EC volume, but not from each other. In contrast, the two patient groups differed in hippocampal volume from controls, as well as from each other, with the mild AD cases showing the greatest atrophy. These results suggest that degeneration of the EC and hippocampal formation occurs before the onset of overt dementia. In fact, follow-up clinical evaluations available on 23 of 28 nondemented patients indicated that 12 of 23 had converted to AD. Converters could be best differentiated from nonconverters on the basis of entorhinal volume.

Hemispheric differences in hippocampal volume predict verbal and spatial memory performance in patients with Alzheimer's disease.

Atrophy of the hippocampal formation, a region important for the acquisition of new declarative knowledge, has been well-documented in Alzheimer's disease (AD), although the relation of such atrophy to the extent of memory dysfunction in these patients has been less clear. In the present study, 18 patients with a clinical diagnosis of probable AD were studied with a high-resolution, quantitative magnetic resonance imaging (MRI) protocol, as well as the verbal and spatial versions of the Buschke controlled learning task. The volumes of the hippocampal formation and, as a control for generalized atrophy, parahippocampal gyrus and temporal neocortex were computed from gapless coronal slices taken perpendicular to the long axis of the hippocampus. To correct for individual differences in brain size, volumes of regions of interest were divided by total intracranial volume. Separate stepwise regression analyses (with age, right and left hippocampal, parahippocampal gyrus, and temporal lobe volumes as the independent variables) showed that left hippocampal volume was the best predictor of free recall and delayed free recall of verbal information (P = 0.0042 and P < 0.0001, respectively). Recall and delayed recall of the spatial location of verbal items were best predicted by right hippocampal volume (P = 0.0054 and P = 0.0118, respectively). Memory scores did not correlate either with parahippocampal gyrus or temporal lobe volume. Furthermore, the relation between hippocampal volume and memory function observed in cases with AD did not hold for healthy aged control subjects.