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An adaptive response to unexpected perturbations requires near-term and long-term adjustments over time. We used multifractal analysis to test how nonlinear interactions across timescales might support an adaptive response following an unpredictable perturbation. We reanalyzed torque data from 44 young and 24 older adults who performed a single-leg squat task challenged by an unexpected mechanical perturbation and a secondary visual-cognitive task. We report three findings: (a) multifractal nonlinearity interacted with pre-perturbation torque production and task error to presage greater pre-voluntary feedforward increases and greater voluntary reductions, respectively, in post-perturbation task error; (b) multifractal nonlinearity presaged relatively smaller task error than standard deviations of both pre-perturbation torques and pre-perturbation task error; and (c) increased task demand (e.g., age-related changes in dexterity and dual-task settings) led to multifractal nonlinearity presaging reduced task error. All these results were consistent with our expectations, except that a pre-perturbation knee torque-dependent increase in post-perturbation task error appeared later for older than for younger participants. This correlational multifractal modeling offered theoretical clarity on the possible roles of nonlinear interactions across timescales, moderating both feedforward and feedback processes, and presaging greater stability when the standard deviation is relatively large and task demands are strong. Thus, multifractal nonlinearity usefully describes movement variability even when paired with classical descriptors like the standard deviation. We discuss potential insights from these findings for understanding suprapostural dexterity and developing rehabilitative interventions.

Deuterostomes are the major division of animal life which includes sea stars, acorn worms, and humans, among a wide variety of ecologically and morphologically disparate taxa. However, their early evolution is poorly understood, due in part to their disparity, which makes identifying commonalities difficult, as well as their relatively poor early fossil record. Here, we review the available morphological, palaeontological, developmental, and molecular data to establish a framework for exploring the origins of this important and enigmatic group. Recent fossil discoveries strongly support a vermiform ancestor to the group Hemichordata, and a fusiform active swimmer as ancestor to Chordata. The diverse and anatomically bewildering variety of forms among the early echinoderms show evidence of both bilateral and radial symmetry. We consider four characteristics most critical for understanding the form and function of the last common ancestor to Deuterostomia: Hox gene expression patterns, larval morphology, the capacity for biomineralization, and the morphology of the pharyngeal region. We posit a deuterostome last common ancestor with a similar antero-posterior gene regulatory system to that found in modern acorn worms and cephalochordates, a simple planktonic larval form, which was later elaborated in the ambulacrarian lineage, the ability to secrete calcium minerals in a limited fashion, and a pharyngeal respiratory region composed of simple pores. This animal was likely to be motile in adult form, as opposed to the sessile origins that have been historically suggested. Recent debates regarding deuterostome monophyly as well as the wide array of deuterostome-affiliated problematica further suggest the possibility that those features were not only present in the last common ancestor of Deuterostomia, but potentially in the ur-bilaterian. The morphology and development of the early deuterostomes, therefore, underpin some of the most significant questions in the study of metazoan evolution.

To demonstrate improvements in the precision of inverse probability-weighted estimators by use of auxiliary variables, i.e., determinants of the outcome that are independent of treatment, missingness or selection.First with simulated data, and then with public data from the National Health and Nutrition Examination Survey (NHANES), we estimated the mean of a continuous outcome using inverse probability weights to account for informative missingness. We assessed gains in precision resulting from the inclusion of auxiliary variables in the model for the weights. We compared the performance of robust and nonparametric bootstrap variance estimators in this setting.We found that the inclusion of auxiliary variables reduced the empirical variance of inverse probability-weighted estimators. However, that reduction was not captured in standard errors computed using the robust variance estimator, which is widely used in weighted analyses due to the non-independence of weighted observations. In contrast, a nonparametric bootstrap estimator properly captured the precision gain.Epidemiologists can leverage auxiliary data to improve the precision of weighted estimators by using bootstrap variance estimation, or a closed-form variance estimator that properly accounts for the estimation of the weights, in place of the standard robust variance estimator.

To advance methods for bioaccumulation assessment of organic substances in air-breathing organisms, the present study developed an in vitro approach for screening neutral hydrophobic organic substances for their bioaccumulation potential in air-breathing organisms consisting of (1) depletion assays for chemicals in rat liver S9 subcellular fractions, (2) in vitro-in vivo extrapolation, and (3) whole-organism bioaccumulation modeling to assess the biomagnification potential of neutral organic substances in the rat. Testing of the in vitro method on 14 test chemicals of potentially biomagnifying substances showed that the bioassays could be conducted with a high level of reproducibility and that in vitro-derived elimination rate constants were in good agreement with in vivo-determined elimination rate constants in the rat. Exploring the potential of the in vitro approach for screening organic chemicals for bioaccumulation in air-breathing organisms indicated that chemical substances that exhibit a depletion rate constant in the S9 in vitro bioassay ≥0.3 h

The purpose of this descriptive study was to evaluate the presence of telehealth content on chiropractic state board websites compared with websites from the medical and physical therapy professions during the early COVID-19 pandemic.State board websites for chiropractic, medicine, and physical therapy for each of the 50 United States and the District of Columbia were searched for the word "tele" to determine if there was a link on the homepage for content related to telehealth guidance. If there was none, the homepage was queried for the word "COVID" to determine if there was a link for COVID-19-related guidance. If yes, that linked COVID-19 page was queried for the word "tele." Consensus of 4 of 5 reviewers was sought. Binary results were entered into a separate spreadsheet for each profession (telehealth content easily accessible, yes or no). Easily accessible was defined as information found within 1 or 2 clicks. This search was performed between January 1, 2021, and March 1, 2021.There were 11 of 51 (21%) chiropractic state board websites that provided content regarding telehealth on the main page, 8 of 51 (16%) provided content on a separate COVID-19-related page, and 32 of 51 (63%) did not provide content that was accessible within 1 or 2 clicks. Comparatively, 9 of 51 (18%) medical state board websites provided content regarding telehealth on the main page, 20 of 51 (39%) provided content on a COVID-19-related page, and 22 of 51 (43%) did not provide content that was accessible within 1 or 2 clicks. Lastly, 10 of 51 (20%) physical therapy state board websites provided content regarding telehealth on the main page, 19 of 51 (37%) provided content on a COVID-19-related page, and 22 of 51 (43%) did not provide content that was accessible within 1 or 2 clicks.Telehealth content was more readily available on medical and physical therapy state board websites compared with chiropractic state board websites in the early stages of the COVID-19 pandemic.

A covariate-adjusted estimate of an exposure-outcome association may be biased if the exposure variable suffers measurement error. We propose an approach to correct for exposure measurement error in a covariate-adjusted estimate of the association between a continuous exposure variable and outcome of interest. Our proposed approach requires data for a reference population in which the exposure was a priori set to some known level (e.g., 0, and is therefore unexposed); however, our approach does not require an exposure validation study or replicate measures of exposure, which are typically needed when addressing bias due to exposure measurement error. A key condition for this method, which we refer to as “partial population exchangeability,” requires that the association between a measured covariate and outcome in the reference population equals the association between that covariate and outcome in the target population in the absence of exposure. We illustrate the approach using simulations and an example.

Electrical brain stimulation has become an essential treatment option for more than one third of epilepsy patients who are resistant to pharmacological therapy and are not candidates for surgical resection. However, currently approved stimulation paradigms achieve only moderate success, on average providing approximately 75% reduction in seizure frequency and extended periods of seizure freedom in nearly 20% of patients. Outcomes from electrical stimulation may be improved through the identification of novel anatomical targets, particularly those with significant anatomical and functional connectivity to the epileptogenic zone. Multiple studies have investigated the medial septal nucleus (i.e., medial septum) as such a target for the treatment of mesial temporal lobe epilepsy. The medial septum is a small midline nucleus that provides a critical functional role in modulating the hippocampal theta rhythm, a 4-7-Hz electrophysiological oscillation mechanistically associated with memory and higher order cognition in both rodents and humans. Elevated theta oscillations are thought to represent a seizure-resistant network activity state, suggesting that electrical neuromodulation of the medial septum and restoration of theta-rhythmic physiology may not only reduce seizure frequency, but also restore cognitive comorbidities associated with mesial temporal lobe epilepsy. Here, we review the anatomical and physiological function of the septohippocampal network, evidence for seizure-resistant effects of the theta rhythm, and the results of stimulation experiments across both rodent and human studies, to argue that deep brain stimulation of the medial septum holds potential to provide an effective neuromodulation treatment for mesial temporal lobe epilepsy. We conclude by discussing the considerations necessary for further evaluating this treatment paradigm with a clinical trial.

Selection bias remains a subject of controversy. Existing definitions of selection bias are ambiguous. To improve communication and the conduct of epidemiologic research focused on estimating causal effects, we propose to unify the various existing definitions of selection bias in the literature by considering any bias away from the true causal effect in the referent population (the population before the selection process), due to selecting the sample from the referent population, as selection bias. Given this unified definition, selection bias can be further categorized into two broad types: type 1 selection bias owing to restricting to one or more level(s) of a collider (or a descendant of a collider) and type 2 selection bias owing to restricting to one or more level(s) of an effect measure modifier. To aid in explaining these two types-which can co-occur-we start by reviewing the concepts of the target population, the study sample, and the analytic sample. Then, we illustrate both types of selection bias using causal diagrams. In addition, we explore the differences between these two types of selection bias, and describe methods to minimize selection bias. Finally, we use an example of "M-bias" to demonstrate the advantage of classifying selection bias into these two types.

“Fusion” study designs combine data from different sources to answer questions that could not be answered (as well) by subsets of the data. Studies that augment main study data with validation data, as in measurement-error correction studies or generalizability studies, are examples of fusion designs. Fusion estimators, here solutions to stacked estimating functions, produce consistent answers to identified research questions using data from fusion designs. In this paper, we describe a pair of examples of fusion designs and estimators, one where we generalize a proportion to a target population and one where we correct measurement error in a proportion. For each case, we present an example motivated by human immunodeficiency virus research and summarize results from simulation studies. Simulations demonstrate that the fusion estimators provide approximately unbiased results with appropriate 95% confidence interval coverage. Fusion estimators can be used to appropriately combine data in answering important questions that benefit from multiple sources of information.

The union of distinct covariate sets, or the superset, is often used in proofs for the identification or the statistical consistency of an estimator when multiple sources of bias are present. However, the use of a superset can obscure important nuances. Here, we provide two illustrative examples: one in the context of missing data on outcomes, and one in which the average causal effect is transported to another target population. As these examples demonstrate, the use of supersets may indicate a parameter is not identifiable when the parameter is indeed identified. Furthermore, a series of exchangeability conditions may lead to successively weaker conditions. Future work on approaches to address multiple biases can avoid these pitfalls by considering the more general case of nonoverlapping covariate sets.

BACKGROUND: Genetically predicted leukocyte telomere length (LTL) has been evaluated in several studies of childhood and adult cancer. We test whether genetically predicted longer LTL is associated with germ cell tumours (GCT) in children and adults. METHODS: Paediatric GCT samples were obtained from a Children’s Oncology Group study and state biobank programs in California and Michigan (N = 1413 cases, 1220 biological parents and 1022 unrelated controls). Replication analysis included 396 adult testicular GCTs (TGCT) and 1589 matched controls from the UK Biobank. Mendelian randomisation was used to look at the association between genetically predicted LTL and GCTs and TERT variants were evaluated within GCT subgroups. RESULTS: We identified significant associations between TERT variants reported in previous adult TGCT GWAS in paediatric GCT: TERT/rs2736100-C (OR = 0.82; P = 0.0003), TERT/rs2853677-G (OR = 0.80; P = 0.001), and TERT/rs7705526-A (OR = 0.81; P = 0.003). We also extended these findings to females and tumours outside the testes. In contrast, we did not observe strong evidence for an association between genetically predicted LTL by other variants and GCT risk in children or adults. CONCLUSION: While TERT is a known susceptibility locus for GCT, our results suggest that LTL predicted by other variants is not strongly associated with risk in either children or adults.

Sensitization, defined as the presence of circulating antibodies, presents challenges, particularly in patients undergoing heart transplantation (HTx) bridged with durable mechanical circulatory support (MCS). We aimed to investigate the post-transplantation outcomes of sensitized MCS patients.Among 889 consecutively enrolled heart transplant (HTx) recipients between 2010 and 2018, 86 (9.7%) sensitized MCS patients (Group A) were compared with sensitized non-MCS patients (Group B, n = 189), non-sensitized MCS patients (Group C, n = 162), and non-sensitized non-MCS patients (Group D, n = 452) regarding post-HTx outcomes, including the incidence of primary graft dysfunction (PGD), 1-year survival, and 1-year freedom from antibody-mediated rejection (AMR).Sensitized MCS patients (Group A) showed comparable rates of PGD, 1-year survival, and 1-year freedom from AMR with Groups C and D. However, Group A showed significantly higher rates of 1-year freedom from AMR (95.3% vs 85.7%, p = 0.02) and an earlier decline in panel-reactive antibody (PRA) levels (p0.01) than sensitized non-MCS patients (Group B). Desensitization therapy effectively reduced the levels of PRA in both Groups A and B. When Group A was further divided according to the presence of preformed donor-specific antibodies (DSA), patients with preformed DSA showed significantly lower rates of 1-year freedom from AMR than those without (84.2% vs 98.5%, p = 0.01).Sensitized MCS patients showed significantly lower rates of AMR and an earlier decline in PRA levels following HTx than sensitized non-MCS patients. Removal of MCS at the time of transplantation might underlie these observations.

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