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Adaptive genetic divergence occurs when selection imposed by the environment causes the genomic component of the phenotype to differentiate. However, genomic signatures of natural selection are usually identified without information on which trait is responding to selection by which selective agent(s). Here, we integrate whole-genome sequencing with phenomics and measures of putative selective agents to assess the extent of adaptive divergence in threespine stickleback occupying the highly heterogeneous lake MATIN SMALL LETTER Y WITH ACUTEvatn, NE Iceland. We find negligible genome wide divergence, yet multiple traits (body size, gill raker structure and defence traits) were divergent along known ecological gradients (temperature, predatory bird densities and water depth). SNP based heritability of all measured traits was high (h(2) = 0.42-0.65), indicating adaptive potential for all traits. Environment-association analyses further identified thousands of loci putatively involved in selection, related to genes linked to, for instance, neuron development and protein phosphorylation. Finally, we found that loci linked to water depth were concurrently associated with pelvic spine length variation - supporting the conclusion that divergence in pelvic spine length occurred in the face of gene flow. Our results suggest that whilst there is substantial genetic variation in the traits measured, phenotypic divergence of MATIN SMALL LETTER Y WITH ACUTEvatn stickleback is mostly weakly associated with environmental gradients, potentially as a result of substantial gene flow. Our study illustrates the value of integrative studies that combine genomic assays of multivariate trait variation with landscape genomics., Molecular Ecology, 32 (7), ISSN:0962-1083, ISSN:1365-294X

Metformin is used for the management of type 2 diabetes mellitus (T2DM) and is being tested clinically as an anticancer agent. Metformin concentrations safely achievable in human solid tissues including tumours are unknown. This study was designed to determine metformin concentration in tissue compartments as a function of dose to inform rational dosing in preclinical models and interpretation of clinical results."Subjects with solid tumours to be treated by resection and either (A) willingness to take metformin for 7-10 days before surgery or (B) taking metformin for T2DM were eligible. Whole blood, plasma, tumour, tumour-adjacent uninvolved tissue and subcutaneous adipose tissue were obtained for liquid chromatography with tandem mass spectrometry to measure metformin concentrations.All subjects had primary lung tumours. Metformin dose was significantly correlated with drug concentrations in all tissues analysed. Intersubject metformin concentrations varied by over two orders of magnitude. Metformin concentrations were significantly higher in tumour tissues and lower in adipose tissues compared to other tissues. Concentrations in blood and plasma were significantly correlated with concentrations in solid tissues.Metformin accumulates in cellular compartments. Concentrations observed in plasma, blood, lung and tumour tissues in subjects treated with US Food and Drug Administration-approved doses for T2DM are lower than those typically used in tissue culture studies. However, such tissue concentrations are in line with those found within cultured cells treated with supra-pharmacological doses of metformin. Given the large intersubject variability in metformin concentrations, it is imperative to determine whether there is an association between tissue metformin concentration and anticancer activity in humans.

Quantifying temporal variation in demographic rates is a central goal of population ecology. In this study, we analyzed a multidecadal age-structured time series of Arctic char (Salvelinus alpinus) abundance in Lake Mývatn, Iceland, to infer the time-varying demographic response of the population to reduced harvest in the wake of the fishery’s collapse. Our analysis shows that while survival probability of adults increased following the alleviation of harvesting pressure, per capita recruitment consistently declined over most of the study period, until the final three years when it began to increase. The countervailing demographic trends resulted in only limited directional change in the total population size and population growth rate. Rather, the population dynamics were dominated by large interannual variability and a shift towards an older age distribution. Our results are indicative of a slow recovery of the population after its collapse, despite the rising number of adults following relaxed harvest. This underscores the potential for heterogeneous demographic responses to management efforts due to the complex ecological context in which such efforts take place.

The continual rise of affective polarization in the United States harms trust in democratic institutions. Scholars cite processes of ideological and social sorting of the partisan coalitions in the electorate as contributing to the rise of affective polarization, but how do these processes relate to one another? Most scholarship implicitly assumes period effects—that people change their feelings toward the parties uniformly and contemporaneously as they sort. However, it is also possible that sorting and affective polarization link with one another as a function of age or cohort effects. In this paper, I estimate age, period and cohort effects on affective polarization, partisan strength, and ideological sorting. I find that affective polarization increases over time, but also as people age. Age-related increases in affective polarization occur as a function of increases in partisan strength, and for Republicans, social sorting. Meanwhile, sorting only partially explains period effects. These effects combine such that each cohort enters the electorate more affectively polarized than the last.

Widespread misperceptions about COVID-19 and the novel coronavirus threaten to exacerbate the severity of the pandemic. We conducted preregistered survey experiments in the United States, Great Britain, and Canada examining the effectiveness of fact-checks that seek to correct these false or unsupported misperceptions. Across three countries with differing levels of political conflict over the COVID-19 response, we demonstrate that fact-checks reduce targeted misperceptions, especially among the groups who are most vulnerable to these claims, and have minimal spillover effects on the accuracy of other beliefs about COVID-19. However, the positive effects of fact-checks on the accuracy of respondents’ beliefs fail to persist over time in panel data even after repeated exposure. These results suggest that fact-checks can successfully change the beliefs of the people who would benefit from them most but that their effects are disappointingly ephemeral.

Population cycles can be caused by consumer-resource interactions. Confirming the role of consumer-resource interactions, however, can be challenging due to an absence of data for the resource candidate. For example, interactions between midge larvae and benthic algae likely govern the high-amplitude population fluctuations of Tanytarsus gracilentus in Lake Mývatn, Iceland, but there are no records of benthic resources concurrent with adult midge population counts. Here, we investigate consumer population dynamics using the carbon stable isotope signatures of archived T. gracilentus specimens collected from 1977 to 2015, under the assumption that midge δ

Coevolution of competitors can lead to niche partitioning promoting coexistence or to heightened conflicts promoting competitive exclusion. If both are possible, when should coevolution favor coexistence versus exclusion? We investigated this question with a general eco-evolutionary model in which species can reduce the interspecific competition they experience through evolutionary investments in two types of competitive traits: partitioning traits that promote coexistence and conflict traits that promote exclusion. We found that communities were generally mixed, consisting of species investing in both trait types or mixtures of species specializing in one type. For each species, its competitors’ abundances and investments determined its experienced competition, and stronger competition begot greater competitive trait investment. Species investing in conflict traits strengthened competition for other species both directly and indirectly, whereas partitioning traits only weakened competition via direct effects. Conflict traits were therefore the stronger driver of community-wide investments in all traits. However, species investing most in conflict traits experienced less competition, so they ultimately evolved least investment, making them most likely to be excluded by the next invader. Thus, coevolution may provide an open door for species that play nice and a revolving door of exclusion for those that do not.

Previous work identified that routine preoperative type and screen (TS) testing before elective thoracic surgery is overutilized. We hypothesized that instituting a quality improvement (QI) initiative to change practice would significantly reduce this unnecessary testing, reduce costs, and improve healthcare efficiency.A QI initiative was developed at a single, academic center to reduce empiric TS ordering before elective anatomic lung resections. Two interventions were implemented: 1) education based on current institutional data and 2) an electronic medical record order set modification. Utilization of TS testing, blood transfusion data, and perioperative outcomes were tracked and compared between a preintervention group (2015-2018) and a postintervention group (2020-2021). Cost data were derived from institutional charges and Centers for MedicareMedicaid Services fee schedules.Of the 553 patients included: 420 were in the preintervention group and 133 were in the postintervention group. The rate of routine TSs significantly dropped after implementing the QI initiative (97 versus 20%, P ≤ 0.001). Additionally, no difference in blood transfusion rate was observed (4.3 versus 2.3%, P = 0.29), and there were no differences noted in postoperative complications (P = 0.82), 30-day readmission (P = 0.29), or mortality (P = 0.96). Based on current volumes of ∼200 anatomic lung resections/year, estimated cost savings from reducing TS testing from 97 to 20% would be at least $40,000 a year.Our QI initiative significantly reduced the use of routine TS testing. This practice change was achieved while maintaining excellent outcomes demonstrating routine preoperative TS testing can be safely reduced in most elective thoracic surgery.

Does information about how other people feel about COVID-19 vaccination affect immunization intentions? We conducted preregistered survey experiments in Great Britain (5,456 respondents across 3 survey waves from September 2020 to February 2021), Canada (1,315 respondents in February 2021), and the state of New Hampshire in the United States (1,315 respondents in January 2021). The experiments examine the effects of providing accurate public opinion information to people about either public support for COVID-19 vaccination (an injunctive norm) or public beliefs that the issue is contentious. Across all 3 countries, exposure to this information had minimal effects on vaccination intentions even among people who previously held inaccurate beliefs about support for COVID-19 vaccination or its perceived contentiousness. These results suggest that providing information on public opinion about COVID vaccination has limited additional effect on people’s behavioral intentions when public discussion of vaccine uptake and intentions is highly salient.

Background Previous work has identified that inpatient post-thoracic surgery chest x-ray films (CXR) are overutilized. Methods A three-phase rapid cycle quality improvement initiative was performed to reduce empiric post-thoracic surgery CXR use by 25% over 1 year. We adapted evidence-based guidelines and implemented “plan-do-study-act” (PDSA) cycle methodology. The PDSA cycles included (1) education with literature and preintervention statistics; (2) electronic medical record order-set modification; and (3) audit and feedback with monthly status reports. Each cycle lasted 3 months. Use of CXR was tracked in the post-anesthesia care unit and as a daily rate of non–post-anesthesia care unit CXRs. Cost data were estimated from Centers for Medicare & Medicaid Services fees. Results During the initiative, 292 thoracic surgery inpatients were monitored. Before intervention, 99% of patients (69 of 70) received a post-anesthesia care unit CXR, and the daily rate of other CXRs was 1.6. Overall, there was a significant reduction in CXR utilization (P Conclusions Implementation of our quality improvement initiative safely and systematically reduced empiric CXR use after inpatient thoracic surgery. Results will be used in future quality improvement initiatives to reduce unnecessary postoperative testing.

Preoperative type and screen (TS) is routinely performed before elective thoracic surgery. We sought to evaluate the utility of this practice by examining our institutional data related to intraoperative and postoperative transfusions for two common, complex procedures.A single-center, retrospective review of a prospective thoracic surgery database was performed. Patients who underwent consecutive elective anatomic lung resection (ALR) and esophagectomy from January 2015 to April 2018 were included. Perioperative characteristics between patients who received transfusion of packed red blood cells and those who did not were compared. The rates of emergent and nonemergent transfusions were evaluated. Cost data were derived from institutional charges and Centers for MedicareMedicaid Services fee schedules.Of 370 patients, 16 (4.3%) received a transfusion and four (1.1%) were deemed emergent by the surgeons and 0 (0%) by blood bank criteria. For ALR (n = 321), 13 (4.0%) received a transfusion, and four (1.2%) were emergent. For esophagectomies (n = 49), three (6.1%) received a transfusion, and none were emergent. Patients who underwent ALR requiring a transfusion had a lower preoperative hemoglobin (11.7 versus 13.4 gm/dL, P = 0.001), higher estimated blood loss (1325 versus 196 mL, P 0.001), and longer operative time (291 versus 217 min, P = 0.003) than nontransfused patients. Based on current volumes, eliminating TS in these patients would save at least an estimated $60,100 per year.Emergent transfusion in ALR and esophagectomy is rare. Routine preoperative TS is most likely unnecessary for these cases. These results will be used in a quality improvement initiative to change practice at our institution.

Individuals within a population often behave differently and these differences can be consistent over time and/or context, also termed "animal personality". Animal personality has been commonly classified into five axes with studies aiming to validate these axes. One subject that has surprisingly not received full attention yet is the difference between the two personality axes "activity" and "exploration-avoidance", i.e. behaviour in a known vs an unknown environment. Despite this clear difference in definition, many studies measure activity in an unknown environment and term it activity, while underlying motivations between the two environments are different. This study aimed to detect the two personality traits "activity" and "exploration" in Atlantic cod juveniles, and to investigate whether they support the distinctive definitions proposed by previous authors. This study showed significant consistency in locomotion variation in both environments, i.e. personality. In addition, the two environments clearly elicited different behaviours; Atlantic cod juvenile behaviour was more repeatable and they moved more in the known vs the unknown environment, and no correlation of the proportional locomotion between the two was found. This demonstrates that locomotion in both environments, i.e. the personality axes "activity" and "exploration", should not be confused nor treated as if they reflect the same personality trait.

This paper reports the findings of two studies conducted in Lebanon aimed at developing a new scale to measure multiple dimensions of individuals' support for collective violence.

The abundances of competing species may show positive correlations in time and space if they rely on a shared resource. Such positive correlations might obscure resource partitioning that facilitates coexistence of competitors and affects their abundances, spatial distributions, and population dynamics. Here, we examine the potential for resource partitioning between two ecologically similar midge species (Diptera: Chironomidae) in Lake Mývatn, Iceland. Tanytarsus gracilentus and Chironomus islandicus larvae coexist at high abundances in benthic habitats, and they have been previously described as feeding upon diatoms and detritus. Furthermore, both species show large, roughly synchronized population fluctuations, implying potential reliance on a shared fluctuating resource and posing the question of how these species coexist at high abundances. We first considered spatial partitioning of larvae; across multiple sites, abundances of both species were positively correlated. Thus, spatial partitioning across different sites in the lake did not appear to be strong. We then inferred differences in dietary resource use with stable carbon isotopes. T. gracilentus larvae had higher δ13C values than C. islandicus (mean difference = 5.39 ± 1.84‰), suggesting interspecific differences in resource use. Differences in resource selectivity, tube-building behavior, and feeding styles may facilitate resource partitioning between these two species. Relative to surface sediments, T. gracilentus had higher δ13C values (1.84 ± 0.96‰), suggesting that they selectively graze on 13C-enriched resources such as productive algae from the surface of their tubes. In contrast, C. islandicus had lower δ13C values than surface sediments (−2.87 ± 1.95‰), suggesting reliance on isotopically depleted resources, which may include detrital organic matter and associated microbes that larvae selectively consume from the sediment surface or within their tube walls. Overall, our study illustrates that coexisting and ecologically similar species may show positive correlations in space and time while using different resources at fine spatial scales.

Vitreoretinal mechanics plays an important role in retinal trauma and many sight-threatening diseases. In age-related pathologies, such as posterior vitreous detachment and vitreomacular traction, lingering vitreoretinal adhesions can lead to macular holes, epiretinal membranes, retinal tears and detachment. In age-related macular degeneration, vitreoretinal traction has been implicated in the acceleration of the disease due to the stimulation of vascular growth factors. Despite this strong mechanobiological influence on trauma and disease in the eye, fundamental understanding of the mechanics at the vitreoretinal interface is limited. Clarification of adhesion mechanisms and the role of vitreoretinal mechanics in healthy eyes and disease is necessary to develop innovative treatments for these pathologies. In this review, we evaluate the existing literature on the structure and function of the vitreoretinal interface to gain insight into age- and region-dependent mechanisms of vitreoretinal adhesion. We explore the role of vitreoretinal adhesion in ocular pathologies to identify knowledge gaps and future research areas. Finally, we recommend future mechanics-based studies to address the critical needs in the field, increase fundamental understanding of vitreoretinal mechanisms and disease, and inform disease treatments.

Background Smoking cessation programs for patients with cancer suggest 6-mo quit rates between 22% and 40%, and 1-y rates of 33%. We sought to investigate the long-term outcomes of an intensive, preoperative smoking cessation program in patients undergoing lung resection. Material and methods A retrospective analysis of an IRB-approved, prospective database was performed. Elective lung resections between January 1, 2015 and June 30, 2017 were identified. Demographics, smoking status, pack years, occurrence of smoking cessation counseling, complications, and quit date were obtained. Smoking cessation included face-to-face motivational interviewing, choice of nicotine replacement therapy, discussion that surgery may be canceled or delayed without cessation, and follow-up as needed. Results A total of 340 patients underwent lung resection. Of these, 82 patients were classified as current smokers. All were advised to quit and encouraged to meet with a certified tobacco treatment specialist. Sixty-three patients met with a tobacco treatment specialist and 19 did not. Overall, 60 patients (73%) were able to quit before surgery. At 2 y postoperatively, 15 (18%) were lost to follow-up and 9 (11%) had died. Excluding deaths and censoring those lost to follow-up, cessation rates at 6, 12, and 24 mo postoperatively were 55.3%, 55.6%, and 51.7%, respectively. Conclusions Implementation of an intensive smoking cessation program in the preoperative period demonstrated high initial, mid-term, and long-term success rates. The preoperative period, particularly one centered around lung cancer, is an effective time for smoking cessation intervention and can lead to a high rate of cessation up to 2 y after surgery.

The extraordinary demands of managing the COVID-19 pandemic has disrupted the world's ability to care for patients with thoracic malignancies. As a hospital's COVID-19 population increases and hospital resources are depleted, the ability to provide surgical care is progressively restricted, forcing surgeons to prioritize among their cancer populations. Representatives from multiple cancer, surgical, and research organizations have come together to provide a guide for triaging patients with thoracic malignancies as the impact of COVID-19 evolves as each hospital.

Dual-task gait can be a useful biomarker for cognitive decline and a sensitive predictor of future neurodegeneration in certain clinical populations, such as patients with idiopathic rapid eye movement sleep behavior disorder. Objectives The objective of this cross-sectional study was to determine the neural signature of dual-tasking deficits in idiopathic rapid eye movement sleep behavior disorder using a validated gait paradigm. Methods Fifty-eight participants (28 controls; 30 idiopathic rapid eye movement sleep behavior disorder patients) were recruited; 52 participants had functional MRI scans as they performed a validated dual-task virtual reality gait paradigm using foot pedals. Forty-one participants completed single- and dual-task "overground walking" on a pressure sensor carpet. Results Idiopathic rapid eye movement sleep behavior disorder patients showed deficits in dual-tasking (i.e., greater mean step time) compared to controls during "overground walking." Functional MRI revealed that idiopathic rapid eye movement sleep behavior disorder patients had reduced blood-oxygen-level-dependent signal change in the dorsal caudate nucleus, and significantly different corticostriatal functional connectivity patterns from controls, when dual-tasking in high versus low cognitive load. While controls showed greater connectivity between frontoparietal and motor networks, idiopathic rapid eye movement sleep behavior disorder patients exhibited less change in this connectivity as a function of cognitive load. Conclusions These findings demonstrate evidence of dual-task gait deficits in idiopathic rapid eye movement sleep behavior disorder patients, underpinned by disrupted corticostriatal connectivity. Minimal differences in the level of functional connectivity between dual-tasking conditions of high and low cognitive load suggest that idiopathic rapid eye movement sleep behavior disorder patients recruit cognitive networks to control gait even when the cognitive demands are low. This may indicate a compensatory strategy for early cognitive decline in idiopathic rapid eye movement sleep behavior disorder. © 2020 International Parkinson and Movement Disorder Society.

Background Routine chest x-rays (CXRs) ordered on thoracic surgery inpatients are common, costly, and of unclear clinical utility. We sought to investigate CXR ordering practices and their impact on clinical care. Materials and methods A single-center, retrospective cohort study of adult patients admitted after undergoing thoracic surgery with an intraoperative chest tube (CT) placed was performed over a 1-y period. Our primary outcome was a CXR-driven change in care. We evaluated routine CXR orders immediately after surgery in the postanesthesia care unit (PACU) and after final CT removal. “Routine” was defined as not ordered during a workup for a clinical concern. Patients were excluded if they underwent pleurodesis, were discharged with a CT, or had an immediate post-CT removal clinical change prompting intervention. Results A total of 241 patients met inclusion. All patients received a routine PACU CXR, and 48% (117) had abnormal radiographic findings (e.g., pneumothorax, consolidation, effusion, etc). Secondary to this CXR, one patient (0.4%) experienced a change in care: a repeat CXR only. All patients received a routine final CT removal CXR, and 58% (140) had abnormal radiographic findings. After this CXR, 33 patients (14%) experienced a change in care: 32 underwent repeat CXR and one was clinically observed. Overall, no patients experienced a procedural intervention. Conclusions Routine post-thoracic surgery CXRs in the PACU and after CT removal have limited clinical impact. Quality initiatives should be pursued to decrease empiric CXR use and reserve ordering for specific clinical concerns.

Vaccine hesitancy is a significant impediment to global efforts to vaccinate against the SARS-CoV-2 virus at levels that generate herd immunity. In this article, we show the utility of an inductive approach – latent class analysis (LCA) – that allows us to characterize the size and nature of different vaccine attitude groups; and to compare how these groups differ across countries as well as across demographic subgroups within countries. We perform this analysis using original survey data collected in the US, UK, and Canada. We also show that these classes are strongly associated with SARS-CoV-2 vaccination intent and perceptions of the efficacy and safety of the COVID-19 vaccines, suggesting that attitudes about vaccines to fight the novel coronavirus pandemic are well explained by latent vaccine attitudes that precede the pandemic. More specifically, we find four substantive classes of vaccine attitudes: strong supporters, supporters with concerns, vaccine hesitant, and “anti-vax” as well as a fifth measurement error class. The strong “anti-vax” sentiment class is small in all three countries, while the strong supporter class is the largest across all three countries. We observe different distributions of class assignments in different demographic groups – most notably education and political leaning (partisanship and ideology).

BACKGROUND: Nutritional status is related to treatment outcomes for esophageal cancer. Residing in a food desert (FD) has been associated with worse outcomes in breast and colon cancer. We assessed the association of residing in a FD on 30-day outcomes of esophageal cancer patients who received tri-modality therapy. METHODS: A retrospective review of patients who underwent esophagectomy (1/2015 to 7/2020, in New Hampshire, USA) was performed. Patients were excluded if they did not undergo neo-adjuvant treatment, required treatment outside of standard Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) protocol, or lacked both pre and post neo-adjuvant treatment computed tomography (CT) scans for review. Demographics, nutrition parameters, treatment characteristics, 30-day complications and 90-day mortality were reviewed. FD status was defined by the United States Department of Agriculture (USDA) Food Access Research Atlas and cross-referenced with patients’ home zip code. Readmission was defined as readmission to any hospital for any reason within 30-day of discharge. Univariable analysis was conducted using Student’s t-test or Wilcoxon rank-sum for continuous variables, and Fisher’s exact test for categorical variables. Multivariable logistic regression was then used to model readmission status on FD status adjusted for measures statistically associated with readmission status at the P

Widespread misperceptions about COVID-19 and the novel coronavirus threaten to exacerbate the severity of the pandemic. We conducted preregistered survey experiments in the United States, Great Britain, and Canada examining the effectiveness of fact-checks that seek to correct these false or unsupported misperceptions. Across three countries with differing levels of political conflict over the COVID-19 response, we demonstrate that fact-checks reduce targeted misperceptions, especially among the groups who are most vulnerable to these claims, and have minimal spillover effects on the accuracy of other beliefs about COVID-19. However, the positive effects of fact-checks on the accuracy of respondents' beliefs fail to persist over time in panel data even after repeated exposure. These results suggest that fact-checks can successfully change the beliefs of the people who would benefit from them most but that their effects are disappointingly ephemeral.

Widespread misperceptions about COVID-19 and the novel coronavirus threaten to exacerbate the severity of the pandemic. We conducted preregistered survey experiments in the United States, Great Britain and Canada examining the effectiveness of fact-checks that seek to correct these false or unsupported beliefs. Across three countries with differing levels of political conflict over the pandemic response, we demonstrate that fact-checks reduce targeted misperceptions, especially among the groups who are most vulnerable to these claims, and have minimal spillover effects on the accuracy of related beliefs. However, these reductions in COVID-19 misperception beliefs do not persist over time in panel data even after repeated exposure. These results suggest that fact-checks can successfully change the COVID-19 beliefs of the people who would benefit from them most but that their effects are ephemeral.

Cognitive fluctuations are a characteristic and distressing disturbance of attention and consciousness seen in patients with Dementia with Lewy bodies and Parkinson's disease dementia. It has been proposed that fluctuations result from disruption of key neuromodulatory systems supporting states of attention and wakefulness which are normally characterised by temporally variable and highly integrated functional network architectures. In this study, patients with DLB (n = 25) and age-matched controls (n = 49) were assessed using dynamic resting state fMRI. A dynamic network signature of reduced temporal variability and integration was identified in DLB patients compared to controls. Reduced temporal variability correlated significantly with fluctuation-related measures using a sustained attention task. A less integrated (more segregated) functional network architecture was seen in DLB patients compared to the control group, with regions of reduced integration observed across dorsal and ventral attention, sensorimotor, visual, cingulo-opercular and cingulo-parietal networks. Reduced network integration correlated positively with subjective and objective measures of fluctuations. Regions of reduced integration and unstable regional assignments significantly matched areas of expression of specific classes of noradrenergic and cholinergic receptors across the cerebral cortex. Correlating topological measures with maps of neurotransmitter/neuromodulator receptor gene expression, we found that regions of reduced integration and unstable modular assignments correlated significantly with the pattern of expression of subclasses of noradrenergic and cholinergic receptors across the cerebral cortex. Altogether, these findings demonstrate that cognitive fluctuations are associated with an imaging signature of dynamic network impairment linked to specific neurotransmitters/neuromodulators within the ascending arousal system, highlighting novel potential diagnostic and therapeutic approaches for this troubling symptom.

Background Although motor abnormalities have been flagged as potentially the most sensitive and specific clinical features for predicting the future progression to Parkinson's disease, little work has been done to characterize gait and balance impairments in idiopathic rapid eye movement sleep behavior disorder (iRBD). Objective The objective of this study was to quantitatively determine any static balance as well as gait impairments across the 5 independent domains of gait in polysomnography-confirmed iRBD patients using normal, fast-paced, and dual-task walking conditions. Methods A total of 38 participants (24 iRBD, 14 healthy controls) completed the following 5 different walking trials across a pressure sensor carpet: (1) normal pace, (2) fast pace, (3) while counting backward from 100 by 1s, (4) while naming as many animals as possible, (5) while subtracting 7s from 100. Results Although no gait differences were found between the groups during normal walking, there were significant differences between groups under the fast-paced and dual-task gait conditions. Specifically, in response to the dual tasking, healthy controls widened their step width without changing step width variability, whereas iRBD patients did not widen their step width but, rather, significantly increased their step width variability. Similarly, changes between the groups were observed during fast-paced walking wherein the iRBD patients demonstrated greater step length asymmetry when compared with controls. Conclusions This study demonstrates that iRBD patients have subtle gait impairments, which likely reflect early progressive degeneration in brainstem regions that regulate both REM sleep and gait coordination. Such gait assessments may be useful as a diagnostic preclinical screening tool for future fulminant gait abnormalities for trials of disease-preventive agents. © 2019 International Parkinson and Movement Disorder Society.

There is emerging evidence indicating that color discrimination impairments can predict the development of Lewy body dementia in patients with rapid eye movement sleep behavior disorder, Parkinson disease, and in patients with mild cognitive impairment. Despite this clear relationship, color vision deficits are not seen uniformly in patients with dementia with Lewy bodies (DLB), suggesting a more nuanced association with the underlying neuropathology. Visual hallucinations represent a discriminating feature of DLB, and recent evidence implicates visual pathway dysfunction as a significant contributor to this phenomenon. In this study, we examined the relationship between color vision impairment and visual hallucinations, along with other clinical and neuropsychological features in 24 well-characterized patients with DLB alongside 25 healthy controls. Color discrimination impairment was seen in 16 (67%) of 24 DLB participants with a higher error score relative to controls ( P = .001). We demonstrate for the first time a strong association between color discrimination errors on the Farnsworth-Munsell 100 hue test and both the presence and severity of hallucinatory symptoms in DLB based on clinician-derived ( P = .008) and questionnaire-derived ( P = .03) measures. Correlation with clinical and neuropsychological variables revealed that color discrimination is significantly related to visuospatial difficulties measured by the clock-drawing task ( P = .02) but not to global measures of cognition, motor severity, age, or disease duration in our cohort. Factor analysis confirmed a unique relationship between color discrimination, visual hallucinations, and visuospatial function. Our results suggest that color discrimination does not simply relate to dementia but rather indexes higher order perceptual deficits that may predict visual hallucinations in Lewy body disorders and share a common pathophysiological substrate.

Development of a small volume continuous process that used a combination of batch and flow unit operations to manufacture the small molecule oncolytic candidate merestinib is described. Continuous processing was enabled following the identification and development of suitable chemical transformations and unit operations. Aspects of the nascent process control strategy were evaluated in the context of a 20 kg laboratory demonstration campaign, executed in walk-in fume hoods at a throughput of 5–10 kg of active pharmaceutical ingredient per day. The process comprised an automated Suzuki–Miyaura cross-coupling reaction, a nitro-group hydrogenolysis, a continuous amide bond formation, and a continuous deprotection. Three of the four steps were purified using mixed-suspension, mixed-product removal crystallizations. Process analytical technology enabled real-time or nearly real-time process diagnostics. Findings from the demonstration campaign informed a second process development cycle as well as decision mak...