Naked mole rat ovaries allow investigation of ovarian reserve, in vitro germ cell expansion, and oocyte in vitro maturation within a single sample.

Recently, we described that in the naked mole rat ovary it is possible to study the ovarian reserve and the mitotic expansion of the germ cell postnatally. Herein, we show oocyte in vitro maturation and in vitro germ cell expansion using the same ovary.

Neuropsychiatric symptoms and brain morphology in patients with mild cognitive impairment, cerebrovascular disease and Parkinson disease: A cross sectional and longitudinal study.

OBJECTIVES: Neuropsychiatric symptoms (NPS) increase risk of developing dementia and are linked to various neurodegenerative conditions, including mild cognitive impairment (MCI due to Alzheimer's disease [AD]), cerebrovascular disease (CVD), and Parkinson's disease (PD). We explored the structural neural correlates of NPS cross-sectionally and longitudinally across various neurodegenerative diagnoses. METHODS: The study included individuals with MCI due to AD, (n = 74), CVD (n = 143), and PD (n = 137) at baseline, and at 2-years follow-up (MCI due to AD, n = 37, CVD n = 103, and PD n = 84). We assessed the severity of NPS using the Neuropsychiatric Inventory Questionnaire. For brain structure we included cortical thickness and subcortical volume of predefined regions of interest associated with corticolimbic and frontal-executive circuits. RESULTS: Cross-sectional analysis revealed significant negative correlations between appetite with both circuits in the MCI and CVD groups, while apathy was associated with these circuits in both the MCI and PD groups. Longitudinally, changes in apathy scores in the MCI group were negatively linked to the changes of the frontal-executive circuit. In the CVD group, changes in agitation and nighttime behavior were negatively associated with the corticolimbic and frontal-executive circuits, respectively. In the PD group, changes in disinhibition and apathy were positively associated with the corticolimbic and frontal-executive circuits, respectively. CONCLUSIONS: The observed correlations suggest that underlying pathological changes in the brain may contribute to alterations in neural activity associated with MBI. Notably, the difference between cross-sectional and longitudinal results indicates the necessity of conducting longitudinal studies for reproducible findings and drawing robust inferences.

White matter hyperintensity burden predicts cognitive but not motor decline in Parkinson's disease: results from the Ontario Neurodegenerative Diseases Research Initiative.

BACKGROUND AND PURPOSE: The pathophysiology of Parkinson's disease (PD) negatively affects brain network connectivity, and in the presence of brain white matter hyperintensities (WMHs) cognitive and motor impairments seem to be aggravated. However, the role of WMHs in predicting accelerating symptom worsening remains controversial. The objective was to investigate whether location and segmental brain WMH burden at baseline predict cognitive and motor declines in PD after 2 years. METHODS: Ninety-eight older adults followed longitudinally from Ontario Neurodegenerative Diseases Research Initiative with PD of 3-8 years in duration were included. Percentages of WMH volumes at baseline were calculated by location (deep and periventricular) and by brain region (frontal, temporal, parietal, occipital lobes and basal ganglia + thalamus). Cognitive and motor changes were assessed from baseline to 2-year follow-up. Specifically, global cognition, attention, executive function, memory, visuospatial abilities and language were assessed as were motor symptoms evaluated using the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III, spatial-temporal gait variables, Freezing of Gait Questionnaire and Activities Specific Balance Confidence Scale. RESULTS: Regression analysis adjusted for potential confounders showed that total and periventricular WMHs at baseline predicted decline in global cognition (p < 0.05). Also, total WMH burden predicted the decline of executive function (p < 0.05). Occipital WMH volumes also predicted decline in global cognition, visuomotor attention and visuospatial memory declines (p < 0.05). WMH volumes at baseline did not predict motor decline. CONCLUSION: White matter hyperintensity burden at baseline predicted cognitive but not motor decline in early to mid-stage PD. The motor decline observed after 2 years in these older adults with PD is probably related to the primary neurodegenerative process than comorbid white matter pathology.

Secondary thalamic atrophy related to brain infarction may contribute to post-stroke cognitive impairment.

BACKGROUND AND PURPOSE: The thalamus is a key brain hub that is globally connected to many cortical regions. Previous work highlights thalamic contributions to multiple cognitive functions, but few studies have measured thalamic volume changes or cognitive correlates. This study investigates associations between thalamic volumes and post-stroke cognitive function. METHODS: Participants with non-thalamic brain infarcts (3-42 months) underwent MRI and cognitive testing. Focal infarcts and thalami were traced manually. In cases with bilateral infarcts, the side of the primary infarct volume defined the hemisphere involved. Brain parcellation and volumetrics were extracted using a standardized and previously validated neuroimaging pipeline. Age and gender-matched healthy controls provided normal comparative thalamic volumes. Thalamic atrophy was considered when the volume exceeded 2 standard deviations greater than the controls. RESULTS: Thalamic volumes ipsilateral to the infarct in stroke patients (n=55) were smaller than left (4.4 ± 1.4 vs. 5.4 ± 0.5 cc, p < 0.001) and right (4.4 ± 1.4 vs. 5.5 ± 0.6 cc, p < 0.001) thalamic volumes in the controls. After controlling for head-size and global brain atrophy, infarct volume independently correlated with ipsilateral thalamic volume (ß= -0.069, p=0.024). Left thalamic atrophy correlated significantly with poorer cognitive performance (ß = 4.177, p = 0.008), after controlling for demographics and infarct volumes. CONCLUSIONS: Our results suggest that the remote effect of infarction on ipsilateral thalamic volume is associated with global post-stroke cognitive impairment.

Maternal effects in mammals: Broadening our understanding of offspring programming.

The perinatal period is a sensitive time in mammalian development that can have long-lasting consequences on offspring phenotype via maternal effects. Maternal effects have been most intensively studied with respect to two major conditions: maternal diet and maternal stress. In this review, we shift the focus by discussing five major additional maternal cues and their influence on offspring phenotype: maternal androgen levels, photoperiod (melatonin), microbiome, immune regulation, and milk composition. We present the key findings for each of these topics in mammals, their mechanisms of action, and how they interact with each other and with the maternal influences of diet and stress. We explore their impacts in the contexts of both predictive adaptive responses and the developmental origins of disease, identify knowledge gaps and research opportunities in the field, and place a particular emphasis on the application and consideration of these effects in non-model species and natural ecological systems.

Deep Bayesian networks for uncertainty estimation and adversarial resistance of white matter hyperintensity segmentation.

White matter hyperintensities (WMHs) are frequently observed on structural neuroimaging of elderly populations and are associated with cognitive decline and increased risk of dementia. Many existing WMH segmentation algorithms produce suboptimal results in populations with vascular lesions or brain atrophy, or require parameter tuning and are computationally expensive. Additionally, most algorithms do not generate a confidence estimate of segmentation quality, limiting their interpretation. MRI-based segmentation methods are often sensitive to acquisition protocols, scanners, noise-level, and image contrast, failing to generalize to other populations and out-of-distribution datasets. Given these concerns, we propose a novel Bayesian 3D convolutional neural network with a U-Net architecture that automatically segments WMH, provides uncertainty estimates of the segmentation output for quality control, and is robust to changes in acquisition protocols. We also provide a second model to differentiate deep and periventricular WMH. Four hundred thirty-two subjects were recruited to train the CNNs from four multisite imaging studies. A separate test set of 158 subjects was used for evaluation, including an unseen multisite study. We compared our model to two established state-of-the-art techniques (BIANCA and DeepMedic), highlighting its accuracy and efficiency. Our Bayesian 3D U-Net achieved the highest Dice similarity coefficient of 0.89 ± 0.08 and the lowest modified Hausdorff distance of 2.98 ± 4.40 mm. We further validated our models highlighting their robustness on "clinical adversarial cases" simulating data with low signal-to-noise ratio, low resolution, and different contrast (stemming from MRI sequences with different parameters). Our pipeline and models are available at: https://hypermapp3r.readthedocs.io.

Hormones do not maketh the mole-rat: No steroid hormone signatures of subordinate behavioral phenotypes.

In some cooperatively breeding groups, individuals have distinct behavioral characteristics that are often stable and predictable across time. However, in others, as in the eusocial naked mole-rat, evidence for behavioral phenotypes is ambiguous. Here, we study whether the naked mole-rat can be divided into discrete phenotypes and if circulating hormone concentrations underpin these differences. Naked mole-rat colonies consist of a single breeding female and large numbers of non-reproductive subordinates that in some cases can exceed several hundred in a colony. The subordinates can potentially be divided into soldiers, who defend the colony; workers, who maintain it; and dispersers, who want to leave it. We established six colonies de novo, tracked them over three years, and assessed the behavior and hormone concentrations of the subordinates. We found that soldiers tended to be from earlier litters and were higher ranked compared to workers, whereas dispersers were distributed throughout litters and rankings. There was no difference in estradiol, testosterone, or dehydroepiandrosterone (DHEA) concentrations among phenotypes. Progesterone concentrations were higher in soldiers, but this difference appeared to be driven by a few individuals. Principal component analysis demonstrated that soldiers separated into a discrete category relative to workers/dispersers, with the highest ranked loadings being age, body mass, and testosterone concentrations. However, the higher testosterone in soldiers was correlated with large body size instead of strictly behavioral phenotype. Workers and dispersers have more overlap with each other and no hormonal differences. Thus the behavioral variation in subordinate naked mole-rats is likely not driven by circulating steroid hormone concentrations, but rather it may stem from alternative neural and/or neuroendocrine mechanisms.

Effect of a Home-Based, Walking Exercise Behavior Change Intervention vs Usual Care on Walking in Adults With Peripheral Artery Disease: The MOSAIC Randomized Clinical Trial.

Importance: Home-based walking exercise interventions are recommended for people with peripheral artery disease (PAD), but evidence of their efficacy has been mixed. Objective: To investigate the effect of a home-based, walking exercise behavior change intervention delivered by physical therapists in adults with PAD and intermittent claudication compared with usual care. Design, Setting, and Participants: Multicenter randomized clinical trial including 190 adults with PAD and intermittent claudication in 6 hospitals in the United Kingdom between January 2018 and March 2020; final follow-up was September 8, 2020. Interventions: Participants were randomized to receive a walking exercise behavior change intervention delivered by physical therapists trained to use a motivational approach (n = 95) or usual care (n = 95). Main Outcomes and Measures: The primary outcome was 6-minute walking distance at 3-month follow-up (minimal clinically important difference, 8-20 m). There were 8 secondary outcomes, 3 of which were the Walking Estimated Limitation Calculated by History (WELCH) questionnaire (score range, 0 [best performance] to 100), the Brief Illness Perceptions Questionnaire (score range, 0 to 80 [80 indicates negative perception of illness]), and the Theory of Planned Behavior Questionnaire (score range, 3 to 21 [21 indicates best attitude, subjective norms, perceived behavioral control, or intentions]); a minimal clinically important difference was not defined for these instruments. Results: Among 190 randomized participants (mean age 68 years, 30% women, 79% White race, mean baseline 6-minute walking distance, 361.0 m), 148 (78%) completed 3-month follow-up. The 6-minute walking distance changed from 352.9 m at baseline to 380.6 m at 3 months in the intervention group and from 369.8 m to 372.1 m in the usual care group (adjusted mean between-group difference, 16.7 m [95% CI, 4.2 m to 29.2 m]; P = .009). Of the 8 secondary outcomes, 5 were not statistically significant. At 6-month follow-up, baseline WELCH scores changed from 18.0 to 27.8 in the intervention group and from 20.7 to 20.7 in the usual care group (adjusted mean between-group difference, 7.4 [95% CI, 2.5 to 12.3]; P = .003), scores on the Brief Illness Perceptions Questionnaire changed from 45.7 to 38.9 in the intervention group and from 44.0 to 45.8 in the usual care group (adjusted mean between-group difference, -6.6 [95% CI, -9.9 to -3.4]; P < .001), and scores on the attitude component of the Theory of Planned Behavior Questionnaire changed from 14.7 to 15.4 in the intervention group and from 14.6 to 13.9 in the usual care group (adjusted mean between-group difference, 1.4 [95% CI, 0.3 to 2.5]; P = .02). Thirteen serious adverse events occurred in the intervention group, compared with 3 in the usual care group. All were determined to be unrelated or unlikely to be related to the study. Conclusions and Relevance: Among adults with PAD and intermittent claudication, a home-based, walking exercise behavior change intervention, compared with usual care, resulted in improved walking distance at 3 months. Further research is needed to determine the durability of these findings. Trial Registrations: ISRCTN Identifier: 14501418; ClinicalTrials.gov Identifier: NCT03238222.

Germ cell nests in adult ovaries and an unusually large ovarian reserve in the naked mole-rat.

The naked mole-rat (NMR, Heterocephalus glaber) is renowned for its eusociality and exceptionally long lifespan (> 30 y) relative to its small body size (35-40 g). A NMR phenomenon that has received far less attention is that females show no decline in fertility or fecundity into their third decade of life. The age of onset of reproductive decline in many mammalian species is closely associated with the number of germ cells remaining at the age of sexual maturity. We quantified ovarian reserve size in NMRs at the youngest age (6 months) when subordinate females can begin to ovulate after removal from the queen's suppression. We then compared the NMR ovarian reserve size to values for 19 other mammalian species that were previously reported. The NMR ovarian reserve at 6 months of age is exceptionally large at 108,588 ± 69,890 primordial follicles, which is more than 10-fold larger than in mammals of a comparable size. We also observed germ cell nests in ovaries from 6-month-old NMRs, which is highly unusual since breakdown of germ cell nests and the formation of primordial follicles is generally complete by early postnatal life in other mammals. Additionally, we found germ cell nests in young adult NMRs between 1.25 and 3.75 years of age, in both reproductively activated and suppressed females. The unusually large NMR ovarian reserve provides one mechanism to account for this species' protracted fertility. Whether germ cell nests in adult ovaries contribute to the NMR's long reproductive lifespan remains to be determined.

Social Behavior in Naked Mole-Rats: Individual Differences in Phenotype and Proximate Mechanisms of Mammalian Eusociality.

Naked mole-rats (Heterocephalus glaber) are small rodents native to east Africa, living in subterranean colonies of up to 300 individuals. Within each colony, reproduction is restricted to a single breeding female and 1-3 breeding males; all other colony members are reproductively suppressed and socially subordinate unless removed from the suppressive cues of the colony. Due to their striking reproductive skew, naked mole-rats are often considered eusocial mammals. Consistent with this idea, there are behavioral specializations and at least some evidence for morphological distinctions within and between the breeding and non-breeding members of the colony. Importantly, naked mole-rats show plasticity in their behavioral phenotype whereby changes in the social environment influence expression of both type and amount of social behavior. Thus, naked mole-rats provide the opportunity to examine the proximate mechanisms controlling individual differences in social behavior, shedding light on how mammals live in complex social groups.

Neuropeptidergic and Neuroendocrine Systems Underlying Eusociality and the Concomitant Social Regulation of Reproduction in Naked Mole-Rats: A Comparative Approach.

The African mole-rat family (Bathyergidae) includes the first mammalian species identified as eusocial: naked mole-rats. Comparative studies of eusocial and solitary mole-rat species have identified differences in neuropeptidergic systems that may underlie the phenomenon of eusociality. These differences are found in the oxytocin, vasopressin and corticotrophin-releasing factor (CRF) systems within the nucleus accumbens, amygdala, bed nucleus of the stria terminalis and lateral septal nucleus. As a corollary of their eusociality, most naked mole-rats remain pre-pubertal throughout life because of the presence of the colony's only reproductive female, the queen. To elucidate the neuroendocrine mechanisms that mediate this social regulation of reproduction, research on the hypothalamo-pituitary-gonadal axis in naked mole-rats has identified differences between the many individuals that are reproductively suppressed and the few that are reproductively mature: the queen and her male consorts. These differences involve gonadal steroids, gonadotrophin-releasing hormone-1 (GnRH-1), kisspeptin, gonadotrophin-inhibitory hormone/RFamide-related peptide-3 (GnIH/RFRP-3) and prolactin. The comparative findings in eusocial and solitary mole-rat species are assessed with reference to a broad range of studies on other mammals.

Adult Neural Plasticity in Naked Mole-Rats: Implications of Fossoriality, Longevity and Sociality on the Brain's Capacity for Change.

Naked mole-rats (Heterocephalus glaber) are small African rodents that have many unique behavioral and physiological adaptations well-suited for testing hypotheses about mammalian neural plasticity. In this chapter, we focus on three features of naked mole-rat biology and how they impact neural plasticity in this species: (1) their fossorial lifestyle, (2) their extreme longevity with a lack of demonstrable senescence, and (3) their unusual social structure. Critically, each of these features requires some degree of biological flexibility. First, their fossorial habitat situates them in an environment with characteristics to which the central nervous system is particularly sensitive (e.g., oxygen content, photoperiod, spatial complexity). Second, their long lifespan requires adaptations to combat senescence and declines in neural functioning. Finally, their extreme reproductive skew and sustained ability for release from reproductive suppression indicates remarkable neural sensitivity to the sociosexual environment that is distinct from chronological age. These three features of naked mole-rat life are not mutually exclusive, but they do each offer unique considerations for the possibilities, constraints, and mechanisms associated with adult neural plasticity.

Some Exciting Future Directions for Work on Naked Mole-Rats.

The naked mole-rat is a species of growing research interest. Recent focus on this species from both a biomedical and zoological perspective has led to important discoveries regarding eusociality and ecophysiological and sensory traits associated with life below ground as well as natural protection from variable oxygen availability, acid-induced pain, and the vagaries of aging. These features serve to remind us that many foundational discoveries have arisen using extremophilic organisms and elucidating the mechanisms they employ to survive the harsh environmental conditions they encounter. Investigating these evolved features also facilitates a better understanding of several human disease states that share features with this harsh subterranean milieu. Here, we provide an overview of some unanswered questions and future directions to advance this field, alongside discussion of the tools that could facilitate accelerated progression of research using this enigmatic model.

Naked mole-rats lack cold sensitivity before and after nerve injury.

Neuropathic pain is a chronic disease state resulting from injury to the nervous system. This type of pain often responds poorly to standard treatments and occasionally may get worse instead of better over time. Patients who experience neuropathic pain report sensitivity to cold and mechanical stimuli. Since the nociceptive system of African naked mole-rats contains unique adaptations that result in insensitivity to some pain types, we investigated whether naked mole-rats may be resilient to sensitivity following nerve injury. Using the spared nerve injury model of neuropathic pain, we showed that sensitivity to mechanical stimuli developed similarly in mice and naked mole-rats. However, naked mole-rats lacked sensitivity to mild cold stimulation after nerve injury, while mice developed robust cold sensitivity. We pursued this response deficit by testing behavior to activators of transient receptor potential (TRP) receptors involved in detecting cold in naïve animals. Following mustard oil, a TRPA1 activator, naked mole-rats responded similarly to mice. Conversely, icilin, a TRPM8 agonist, did not evoke pain behavior in naked mole-rats when compared with mice. Finally, we used RNAscope to probe for TRPA1 and TRPM8 messenger RNA expression in dorsal root ganglia of both species. We found increased TRPA1 messenger RNA, but decreased TRPM8 punctae in naked mole-rats when compared with mice. Our findings likely reflect species differences due to evolutionary environmental responses that are not easily explained by differences in receptor expression between the species.

Hippocampal segmentation for brains with extensive atrophy using three-dimensional convolutional neural networks.

Hippocampal volumetry is a critical biomarker of aging and dementia, and it is widely used as a predictor of cognitive performance; however, automated hippocampal segmentation methods are limited because the algorithms are (a) not publicly available, (b) subject to error with significant brain atrophy, cerebrovascular disease and lesions, and/or (c) computationally expensive or require parameter tuning. In this study, we trained a 3D convolutional neural network using 259 bilateral manually delineated segmentations collected from three studies, acquired at multiple sites on different scanners with variable protocols. Our training dataset consisted of elderly cases difficult to segment due to extensive atrophy, vascular disease, and lesions. Our algorithm, (HippMapp3r), was validated against four other publicly available state-of-the-art techniques (HippoDeep, FreeSurfer, SBHV, volBrain, and FIRST). HippMapp3r outperformed the other techniques on all three metrics, generating an average Dice of 0.89 and a correlation coefficient of 0.95. It was two orders of magnitude faster than some of the tested techniques. Further validation was performed on 200 subjects from two other disease populations (frontotemporal dementia and vascular cognitive impairment), highlighting our method's low outlier rate. We finally tested the methods on real and simulated "clinical adversarial" cases to study their robustness to corrupt, low-quality scans. The pipeline and models are available at: https://hippmapp3r.readthedocs.ioto facilitate the study of the hippocampus in large multisite studies.

Parkinson's Disease, NOTCH3 Genetic Variants, and White Matter Hyperintensities.

BACKGROUND: White matter hyperintensities (WMH) on magnetic resonance imaging may influence clinical presentation in patients with Parkinson's disease (PD), although their significance and pathophysiological origins remain unresolved. Studies examining WMH have identified pathogenic variants in NOTCH3 as an underlying cause of inherited forms of cerebral small vessel disease. METHODS: We examined NOTCH3 variants, WMH volumes, and clinical correlates in 139 PD patients in the Ontario Neurodegenerative Disease Research Initiative cohort. RESULTS: We identified 13 PD patients (~9%) with rare (<1% of general population), nonsynonymous NOTCH3 variants. Bayesian linear modeling demonstrated a doubling of WMH between variant negative and positive patients (3.1 vs. 6.9 mL), with large effect sizes for periventricular WMH (d = 0.8) and lacunes (d = 1.2). Negative correlations were observed between WMH and global cognition (r = -0.2). CONCLUSION: The NOTCH3 rare variants in PD may significantly contribute to increased WMH burden, which in turn may negatively influence cognition. © 2020 International Parkinson and Movement Disorder Society.

The stress of being alone: Removal from the colony, but not social subordination, increases fecal cortisol metabolite levels in eusocial naked mole-rats.

In many social species, hierarchical status within the group is associated with differences in basal adrenocortical activity. We examined this relationship in naked mole-rats (Heterocephalus glaber), eusocial rodents with arguably the most extreme social hierarchies of all mammals. This species lives in colonies where breeding is restricted to one socially dominant 'queen' and her male consorts, and all other individuals are reproductively suppressed 'subordinates'. The relationship between cortisol and social status in naked mole-rats has not fully been elucidated, as prior results on this topic have been contradictory. We used non-invasive feces sampling to measure baseline cortisol levels in eight laboratory colonies of naked mole-rats, to either replicate or reject rank differences. First, we successfully validated an assay to measure fecal cortisol metabolites (FCMs). Removal from the colony for the validation experiment, either alone or with an opposite sex conspecific, induced prolonged elevation of FCM levels on a scale of days to weeks. This increase in cortisol did not prevent the removed animals from sexually maturing. In colony-housed animals, we found no relationship between rank in the social hierarchy and FCM levels. Further, queens, breeding males, and reproductively suppressed subordinates all had equivalent FCM levels. We conclude that this species shows little evidence of the 'stress of dominance' or 'stress of subordination' and that reproductive suppression in naked mole-rats is not driven by elevated cortisol levels.

RFamide-related peptide-3 (RFRP-3) suppresses sexual maturation in a eusocial mammal.

Neuroendocrine mechanisms underlying social inhibition of puberty are not well understood. Here, we use a model exhibiting the most profound case of pubertal suppression among mammals to explore a role for RFamide-related peptide-3 [RFRP-3; mammalian ortholog to gonadotropin-inhibitory hormone (GnIH)] in neuroendocrine control of reproductive development. Naked mole rats (NMRs) live in sizable colonies where breeding is monopolized by two to four dominant animals, and no other members exhibit signs of puberty throughout their lives unless they are removed from the colony. Because of its inhibitory action on the reproductive axis in other vertebrates, we investigated the role of RFRP-3 in social reproductive suppression in NMRs. We report that RFRP-3 immunofluorescence expression patterns and RFRP-3/GnRH cross-talk are largely conserved in the NMR brain, with the exception of the unique presence of RFRP-3 cell bodies in the arcuate nucleus (Arc). Immunofluorescence comparisons revealed that central expression of RFRP-3 is altered by reproductive status, with RFRP-3 immunoreactivity enhanced in the paraventricular nucleus, dorsomedial nucleus, and Arc of reproductively quiescent NMRs. We further observed that exogenous RFRP-3 suppresses gonadal steroidogenesis and mating behavior in NMRs given the opportunity to undergo puberty. Together, our findings establish a role for RFRP-3 in preserving reproductive immaturity, and challenge the view that stimulatory peptides are the ultimate gatekeepers of puberty.

Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial.

BACKGROUND: Patients with relapsed or refractory FLT3 internal tandem duplication (FLT3-ITD)-positive acute myeloid leukaemia have a poor prognosis, including high frequency of relapse, poorer response to salvage therapy, and shorter overall survival than those with FLT3 wild-type disease. We aimed to assess whether single-agent quizartinib, an oral, highly potent and selective type II FLT3 inhibitor, improves overall survival versus salvage chemotherapy. METHODS: QuANTUM-R is a randomised, controlled, phase 3 trial done at 152 hospitals and cancer centres in 19 countries. Eligible patients aged 18 years or older with ECOG performance status 0-2 with relapsed or refractory (duration of first composite complete remission ≤6 months) FLT3-ITD acute myeloid leukaemia after standard therapy with or without allogeneic haemopoietic stem-cell transplantation were randomly assigned (2:1; permuted block size of 6; stratified by response to previous therapy and choice of chemotherapy via a phone-based and web-based interactive response system) to quizartinib (60 mg [30 mg lead-in] orally once daily) or investigator's choice of preselected chemotherapy: subcutaneous low-dose cytarabine (subcutaneous injection of cytarabine 20 mg twice daily on days 1-10 of 28-day cycles); intravenous infusions of mitoxantrone (8 mg/m2 per day), etoposide (100 mg/m2 per day), and cytarabine (1000 mg/m2 per day on days 1-5 of up to two 28-day cycles); or intravenous granulocyte colony-stimulating factor (300 µg/m2 per day or 5 µg/kg per day subcutaneously on days 1-5), fludarabine (intravenous infusion 30 mg/m2 per day on days 2-6), cytarabine (intravenous infusion 2000 mg/m2 per day on days 2-6), and idarubicin (intravenous infusion 10 mg/m2 per day on days 2-4 in up to two 28-day cycles). Patients proceeding to haemopoietic stem-cell transplantation after quizartinib could resume quizartinib after haemopoietic stem-cell transplantation. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02039726, and follow-up is ongoing. FINDINGS: Between May 7, 2014, and Sept 13, 2017, 367 patients were enrolled, of whom 245 were randomly allocated to quizartinib and 122 to chemotherapy. Four patients in the quizartinib group and 28 in the chemotherapy group were not treated. Median follow-up was 23·5 months (IQR 15·4-32·3). Overall survival was longer for quizartinib than for chemotherapy (hazard ratio 0·76 [95% CI 0·58-0·98; p=0·02]). Median overall survival was 6·2 months (5·3-7·2) in the quizartinib group and 4·7 months (4·0-5·5) in the chemotherapy group. The most common non-haematological grade 3-5 treatment-emergent adverse events (within ≤30 days of last dose or >30 days if suspected to be a treatment-related event) for quizartinib (241 patients) and chemotherapy (94 patients) were sepsis or septic shock (46 patients [19%] for quizartinib vs 18 [19%] for chemotherapy), pneumonia (29 [12%] vs eight [9%]), and hypokalaemia (28 [12%] vs eight [9%]). The most frequent treatment-related serious adverse events were febrile neutropenia (18 patients [7%]), sepsis or septic shock (11 [5%]), QT prolongation (five [2%]), and nausea (five [2%]) in the quizartinib group, and febrile neutropenia (five [5%]), sepsis or septic shock (four [4%]), pneumonia (two [2%]), and pyrexia (two [2%]) in the chemotherapy group. Grade 3 QT prolongation in the quizartinib group was uncommon (eight [3%] by central reading, ten [4%] by investigator report); no grade 4 events occurred. There were 80 (33%) treatment-emergent deaths in the quizartinib group (31 [13%] of which were due to adverse events) and 16 (17%) in the chemotherapy group (nine [10%] of which were due to adverse events). INTERPRETATION: Treatment with quizartinib had a survival benefit versus salvage chemotherapy and had a manageable safety profile in patients with rapidly proliferative disease and very poor prognosis. Quizartinib could be considered a new standard of care. Given that there are only a few available treatment options, this study highlights the value of targeting the FLT3-ITD driver mutation with a highly potent and selective FLT3 inhibitor. FUNDING: Daiichi Sankyo.

Are Walking Treatment Beliefs and Illness Perceptions Associated With Walking Intention and 6-Min Walk Distance in People With Intermittent Claudication? A Cross-Sectional Study.

Intermittent claudication is debilitating leg pain affecting older people with peripheral arterial disease, which is improved by regular walking. This study evaluated associations between psychosocial variables and 6-min walk distance (6MWD) to identify factors that motivate walking. A total of 142 individuals with intermittent claudication (116 males; Mage = 66.9 years [SD = 10.2]) completed cross-sectional assessments of sociodemographics, walking treatment beliefs and intention (Theory of Planned Behaviour), illness perceptions (Revised Illness Perceptions Questionnaire), and 6MWD. Multiple linear regression was used to evaluate relationships among psychosocial variables (treatment beliefs and illness perceptions) and outcomes (walking intention and 6MWD). Theory of planned behavior constructs were associated with intention (R = .72, p < .001) and 6MWD (R = .08, p < .001). Illness perceptions were associated with 6MWD only (R = .27, p < .001). Intention (ß = 0.26), treatment control (ß = -0.27), personal control (ß = 0.32), coherence (ß = 0.18), and risk factor attributions (ß = 0.22; all ps < .05) were independently associated with 6MWD. Treatment beliefs and illness perceptions associated with intention and 6MWD in people with intermittent claudication are potential intervention targets.