Treatment variation from observational data has been used to estimate patient-specific treatment effects. Causal Forest Algorithms (CFAs) developed for this task have unknown properties when ...treatment effect heterogeneity from unmeasured patient factors influences treatment choice - essential heterogeneity.
We simulated eleven populations with identical treatment effect distributions based on patient factors. The populations varied in the extent that treatment effect heterogeneity influenced treatment choice. We used the generalized random forest application (CFA-GRF) to estimate patient-specific treatment effects for each population. Average differences between true and estimated effects for patient subsets were evaluated.
CFA-GRF performed well across the population when treatment effect heterogeneity did not influence treatment choice. Under essential heterogeneity, however, CFA-GRF yielded treatment effect estimates that reflected true treatment effects only for treated patients and were on average greater than true treatment effects for untreated patients.
Patient-specific estimates produced by CFAs are sensitive to why patients in real-world practice make different treatment choices. Researchers using CFAs should develop conceptual frameworks of treatment choice prior to estimation to guide estimate interpretation ex post.
One patient for whom an MR-guided focused ultrasound (MRgFUS) pallidotomy was attempted was discovered to have multiple new skull lesions with the appearance of infarcts on the MRI scan 3 months ...after his attempted treatment. The authors conducted a retrospective review of the first 30 patients treated with MRgFUS to determine the incidence of skull lesions in patients undergoing these procedures and to consider possible causes.
A retrospective review of the MRI scans of the first 30 patients, 1 attempted pallidotomy and 29 ventral intermediate nucleus thalamotomies, was conducted. The correlation of the mean skull density ratio (SDR) and the maximum energy applied in the production or attempted production of a brain lesion was examined.
Of 30 patients treated with MRgFUS for movement disorders, 7 were found to have new skull lesions that were not present prior to treatment and not visible on the posttreatment day 1 MRI scan. Discomfort was reported at the time of treatment by some patients with and without skull lesions. All patients with skull lesions were completely asymptomatic. There was no correlation between the mean SDR and the presence or absence of skull lesions, but the maximum energy applied with the Exablate system was significantly greater in patients with skull lesions than in those without.
It is known that local skull density, thickness, and SDR vary from location to location. Sufficient energy transfer resulting in local heating sufficient to produce a bone lesion may occur in regions of low SDR. A correlation of lesion location and local skull properties should be made in future studies.
•Ongoing severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection may occur in immunocompromised hosts.•Sequencing of repeat samples demonstrated an increasing repertoire of ...mutations.•Viral culture can be used to confirm the presence of infectious SARS-CoV-2.
This article reports a case of a 21-year-old woman with refractory B-cell acute lymphocytic leukaemia who presented with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). She remained positive for SARS-CoV-2 by viral culture for 78 days and by polymerase chain reaction (PCR) for 97 days. Sequencing of repeat samples over time demonstrated an increasing and dynamic repertoire of mutations.
Rats readily switch between foraging and more complex navigational behaviors such as pursuit of other rats or prey. These tasks require vastly different tracking of multiple behaviorally significant ...variables including self-motion state. To explore whether navigational context modulates self-motion tracking, we examined self-motion tuning in posterior parietal cortex neurons during foraging versus visual target pursuit. Animals performing the pursuit task demonstrate predictive processing of target trajectories by anticipating and intercepting them. Relative to foraging, pursuit yields multiplicative gain modulation of self-motion tuning and enhances self-motion state decoding. Self-motion sensitivity in parietal cortex neurons is, on average, history dependent regardless of behavioral context, but the temporal window of self-motion integration extends during target pursuit. Finally, many self-motion-sensitive neurons conjunctively track the visual target position relative to the animal. Thus, posterior parietal cortex functions to integrate the location of navigationally relevant target stimuli into an ongoing representation of past, present, and future locomotor trajectories.
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•Rats pursue moving visual targets and make predictions about their paths•Pursuit behavior enhances self-motion coding in parietal cortex via gain modulation•Pursuit increases timescale of instantaneous trajectory mappings in parietal cortex•Parietal cortex neurons conjunctively code self-motion and egocentric target position
Alexander et al. examine rats pursuing visual targets and characterize emergent predictive behaviors. Relative to free exploration, pursuit elicits enhanced coding of self-motion in the parietal cortex over extended temporal durations. A subset of parietal cortex neurons code for self-motion state and egocentric position of the pursuit target simultaneously.
Life history trade‐offs are ubiquitous across species and place constraints on the timing of life history events, including the optimal age at first reproduction. However, studies on lifetime ...breeding success of male mammals are rare due to sex‐biased dispersal and the requirement for genetic paternity inferences. We studied the correlates and apparent fitness consequences of early life reproduction among males in a free‐living population of Soay sheep (Ovis aries) on St Kilda, Scotland. We investigated the factors associated with early breeding success and the apparent consequences of early success for survival and future reproduction. We used genetic paternity inferences, population data, and individual morphology measurements collected over 30 years. We found that individuals born in years with low‐density population size had the highest early life breeding success and singletons were more likely to be successful than twins. Individuals that bred successfully at 7 months were more likely to survive their first winter. For individuals that survived their first winter, early breeding success was not associated with later breeding success. As individual heterogeneity affects breeding success, we believe that variation in individual quality masks the costs of early reproduction in this population. Our findings provide no evidence for selection for delayed age at reproduction in male Soay sheep.
We investigated the factors associated with early breeding success in male Soay sheep and the consequences of this for survival and future reproduction. We found that individuals born into low‐density populations had the highest early life breeding success. Individuals that bred in their first year were more likely to survive their first winter but breeding early had no effect on their future reproductive success.
Mutations in the chromodomain helicase DNA binding protein 2 (CHD2) gene are associated with neurodevelopmental disorders. However, mechanisms by which CHD2 regulates human brain development remain ...largely uncharacterized. Here, we used a human embryonic stem cell model of cortical interneuron (hcIN) development to elucidate its roles in this process. We identified genome-wide CHD2 binding profiles during hcIN differentiation, defining direct CHD2 targets related to neurogenesis in hcIN progenitors and to neuronal function in hcINs. CHD2 bound sites were frequently coenriched with histone H3 lysine 27 acetylation (H3K27ac) and associated with high gene expression, indicating roles for CHD2 in promoting gene expression during hcIN development. Binding sites for different classes of transcription factors were enriched at CHD2 bound regions during differentiation, suggesting transcription factors that may cooperatively regulate stage-specific gene expression with CHD2. We also demonstrated that CHD2 haploinsufficiency altered CHD2 and H3K27ac coenrichment on chromatin and expression of associated genes, decreasing acetylation and expression of cell cycle genes while increasing acetylation and expression of neuronal genes, to cause precocious differentiation. Together, these data describe CHD2 direct targets and mechanisms by which CHD2 prevents precocious hcIN differentiation, which are likely to be disrupted by pathogenic CHD2 mutation to cause neurodevelopmental disorders.
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