A genotyping array for the globally invasive vector mosquito, Aedes albopictus.

BACKGROUND: Although whole-genome sequencing (WGS) is the preferred genotyping method for most genomic analyses, limitations are often experienced when studying genomes characterized by a high percentage of repetitive elements, high linkage, and recombination deserts. The Asian tiger mosquito (Aedes albopictus), for example, has a genome comprising up to 72% repetitive elements, and therefore we set out to develop a single-nucleotide polymorphism (SNP) chip to be more cost-effective. Aedes albopictus is an invasive species originating from Southeast Asia that has recently spread around the world and is a vector for many human diseases. Developing an accessible genotyping platform is essential in advancing biological control methods and understanding the population dynamics of this pest species, with significant implications for public health. METHODS: We designed a SNP chip for Ae. albopictus (Aealbo chip) based on approximately 2.7 million SNPs identified using WGS data from 819 worldwide samples. We validated the chip using laboratory single-pair crosses, comparing technical replicates, and comparing genotypes of samples genotyped by WGS and the SNP chip. We then used the chip for a population genomic analysis of 237 samples from 28 sites in the native range to evaluate its usefulness in describing patterns of genomic variation and tracing the origins of invasions. RESULTS: Probes on the Aealbo chip targeted 175,396 SNPs in coding and non-coding regions across all three chromosomes, with a density of 102 SNPs per 1 Mb window, and at least one SNP in each of the 17,461 protein-coding genes. Overall, 70% of the probes captured the genetic variation. Segregation analysis found that 98% of the SNPs followed expectations of single-copy Mendelian genes. Comparisons with WGS indicated that sites with genotype disagreements were mostly heterozygotes at loci with WGS read depth < 20, while there was near complete agreement with WGS read depths > 20, indicating that the chip more accurately detects heterozygotes than low-coverage WGS. Sample sizes did not affect the accuracy of the SNP chip genotype calls. Ancestry analyses identified four to five genetic clusters in the native range with various levels of admixture. CONCLUSIONS: The Aealbo chip is highly accurate, is concordant with genotypes from WGS with high sequence coverage, and may be more accurate than low-coverage WGS.

Adaptive auditory assistance for stride length cadence modification in older adults and people with Parkinson's.

Gait rehabilitation using auditory cues can help older adults and people with Parkinson's improve walking performance. While auditory cues are convenient and can reliably modify gait cadence, it is not clear if auditory cues can reliably modify stride length (SL), another key gait performance metric. Existing algorithms also do not address habituation or fluctuation in motor capability, and have not been evaluated with target populations or under dual-task conditions. In this study, we develop an adaptive auditory cueing framework that aims to modulate SL and cadence. The framework monitors the gait parameters and learns a personalized cue-response model to relate the gait parameters to the input cues. The cue-response model is represented using a multi-output Gaussian Process (MOGP) and is used during optimization to select the cue to provide. The adaptive cueing approach is benchmarked against the fixed approach, where cues are provided at a fixed cadence. The two approaches are tested under single and dual-task conditions with 13 older adults (OA) and 8 people with Parkinson's (PwP). The results show that more than half of the OA and PwP in the study can change both SL and cadence using auditory cues. The fixed approach is best at changing people's gait without secondary task, however, the addition of the secondary task significantly degrades effectiveness at changing SL. The adaptive approach can maintain the same level of SL change regardless of the presence of the secondary task. A separate analysis is conducted to identify factors that influence the performance of the adaptive framework. Gait information from the previous time step, along with the previous input cue, can improve its prediction accuracy. More diversity in the initialization data can also improve the GP model. Finally, we did not find a strong correlation between stride length and cadence when the parameters are contingent upon input cues.

Auditory cueing strategy for stride length and cadence modification: a feasibility study with healthy adults.

People with Parkinson's Disease experience gait impairments that significantly impact their quality of life. Visual, auditory, and tactile cues can alleviate gait impairments, but they can become less effective due to the progressive nature of the disease and changes in people's motor capability. In this study, we develop a human-in-the-loop (HIL) framework that monitors two key gait parameters, stride length and cadence, and continuously learns a person-specific model of how the parameters change in response to the feedback. The model is then used in an optimization algorithm to improve the gait parameters. This feasibility study examines whether auditory cues can be used to influence stride length in people without gait impairments. The results demonstrate the benefits of the HIL framework in maintaining people's stride length in the presence of a secondary task.Clinical relevance- This paper proposes a gait rehabilitation framework that provides a personalized cueing strategy based on the person's real-time response to cues. The proposed approach has potential application to people with Parkinson's Disease.

Are Abnormal Muscle Biomechanics and Patient-reported Outcomes Associated in Patients With Hip Dysplasia?

BACKGROUND: Developmental dysplasia of the hip (DDH) is a major risk factor for the early development of hip osteoarthritis. Recent studies have demonstrated how DDH alters hip muscle moment arms and elevates muscle-induced biomechanical variables such as joint reaction forces and acetabular edge loads. Understanding the link between abnormal biomechanics and patient-reported outcome measures (PROMs) is important for evidence-based clinical interventions that improve patient symptoms and functional outcomes. To our knowledge, there are no reports of the relationships between muscle-induced biomechanics and PROMs. QUESTIONS/PURPOSES: (1) Are there associations between PROMs and muscle-induced hip biomechanics during gait for patients with DDH and controls? (2) Are there associations among PROMs and separately among biomechanical variables? METHODS: Participants in this prospective cross-sectional comparative study included 20 female patients with DDH who had no prior surgery or osteoarthritis and 15 female individuals with no evidence of hip pathology (controls) (age: median 23 years [range 16 to 39 years]; BMI: median 22 kg/m 2 [range 17 to 27 kg/m 2 ]). Muscle-induced biomechanical variables for this cohort were reported and had been calculated from patient-specific musculoskeletal models, motion data, and MRI. Biomechanical variables included joint reaction forces, acetabular edge loads, hip center lateralization, and gluteus medius muscle moment arm lengths. PROMs included the Hip Disability and Osteoarthritis Outcome Score (HOOS), the WOMAC, International Hip Outcome Tool-12, National Institutes of Health Patient-Reported Outcome Measure Information System (PROMIS) Pain Interference and Physical Function subscales, and University of California Los Angeles activity scale. Associations between PROMs and biomechanical variables were tested using Spearman rank-order correlations and corrected for multiple comparisons using the Benjamini-Yekutieli method. For this study, associations between variables were considered to exist when correlations were statistically significant (p < 0.05) and were either strong (ρ ≥ 0.60) or moderate (ρ = 0.40 to 0.59). RESULTS: Acetabular edge load impulses (the cumulative acetabular edge load across the gait cycle), medially directed joint reaction forces, and hip center lateralization most commonly demonstrated moderate or strong associations with PROMs. The strongest associations were a negative correlation between acetabular edge load impulse on the superior acetabulum and the HOOS function in daily living subscale (ρ = -0.63; p = 0.001), followed by a negative correlation between hip center lateralization and the HOOS pain subscale (ρ = -0.6; p = 0.003), and a positive correlation between hip center lateralization and the PROMIS pain subscale (ρ = 0.62; p = 0.002). The University of California Los Angeles activity scale was the only PROM that did not demonstrate associations with any biomechanical variable. All PROMs, aside from the University of California Los Angeles activity scale, were associated with one another. Although most of the biomechanical variables were associated with one another, these relationships were not as consistent as those among PROMs. CONCLUSION: The associations with PROMs detected in the current study suggest that muscle-induced biomechanics may have wide-reaching effects not only on loads within the hip, but also on patients' perceptions of their health and function. As the treatment of DDH evolves, patient-specific joint preservation strategies may benefit from targeting the underlying causes of biomechanical outcomes associated with PROMs. LEVEL OF EVIDENCE: Level III, prognostic study.

Adaptive cueing strategy for gait modification: A case study using auditory cues.

People with Parkinson's (PwP) experience gait impairments that can be improved through cue training, where visual, auditory, or haptic cues are provided to guide the walker's cadence or step length. There are two types of cueing strategies: open and closed-loop. Closed-loop cueing may be more effective in addressing habituation and cue dependency, but has to date been rarely validated with PwP. In this study, we adapt a human-in-the-loop framework to conduct preliminary analysis with four PwP. The closed-loop framework learns an individualized model of the walker's responsiveness to cues and generates an optimized cue based on the model. In this feasibility study, we determine whether participants in early stages of Parkinson's can respond to the novel cueing framework, and compare the performance of the framework to two alternative cueing strategies (fixed/proportional approaches) in changing the participant's cadence to two target cadences (speed up/slow down). The preliminary results show that the selection of the target cadence has an impact on the participant's gait performance. With the appropriate target, the framework and the fixed approaches perform similarly in slowing the participants' cadence. However, the proposed framework demonstrates better efficiency, explainability, and robustness across participants. Participants also have the highest retention rate in the absence of cues with the proposed framework. Finally, there is no clear benefit of using the proportional approach.

Demystifying borderline personality disorder in primary care.

Borderline personality disorder (BPD) is a common mental health diagnosis observed in the primary care population and is associated with a variety of psychological and physical symptoms. BPD is a challenging disorder to recognize due to the limitations of accurate diagnosis and identification in primary care settings. It is also difficult to treat due to its complexity (e.g., interpersonal difficulties and patterns of unsafe behaviors, perceived stigma) and healthcare professionals often feel overwhelmed when treating this population. The aim of this article is to describe the impact of BPD in primary care, review current state of knowledge, and provide practical, evidence-based treatment approaches for these patients within this setting. Due to the lack of evidence-based pharmacological treatments, emphasis is placed on describing the framework for treatment, identifying psychotherapeutic opportunities, and managing responses to difficult clinical scenarios. Furthermore, we discuss BPD treatment as it relates to populations of special interest, including individuals facing societal discrimination and adolescents. Through this review, we aim to highlight gaps in current knowledge around managing BPD in primary care and provide direction for future study.

Neural correlates of risky decision making in Parkinson's disease patients with impulse control disorders.

Some patients with Parkinson's disease (PD) experience impulse control disorders (ICDs), characterized by deficient voluntary control over impulses, drives, or temptations regarding excessive hedonic behavior. The present study aimed to better understand the neural basis of impulsive, risky decision making in PD patients with ICDs by disentangling potential dysfunctions in decision and outcome mechanisms. We collected fMRI data from 20 patients with ICDs and 28 without ICDs performing an information gathering task. Patients viewed sequences of bead colors drawn from hidden urns and were instructed to infer the majority bead color in each urn. With each new bead, they could choose to either seek more evidence by drawing another bead (draw choice) or make an urn-inference (urn choice followed by feedback). We manipulated risk via the probability of bead color splits (80/20 vs. 60/40) and potential loss following an incorrect inference ($10 vs. $0). Patients also completed the Barratt Impulsiveness Scale (BIS) to assess impulsivity. Patients with ICDs showed greater urn choice-specific activation in the right middle frontal gyrus, overlapping the dorsal premotor cortex. Across all patients, fewer draw choices (i.e., more impulsivity) were associated with greater activation during both decision making and outcome processing in a variety of frontal and parietal areas, cerebellum, and bilateral striatum. Our findings demonstrate that ICDs in PD are associated with differences in neural processing of risk-related information and outcomes, implicating both reward and sensorimotor dopaminergic pathways.

Environmental exposures and sleep outcomes: A review of evidence, potential mechanisms, and implications.

Environmental exposures and poor sleep outcomes are known to have consequential effects on human health. This integrative review first seeks to present and synthesize existing literature investigating the relationship between exposure to various environmental factors and sleep health. We then present potential mechanisms of action as well as implications for policy and future research for each environmental exposure. Broadly, although studies are still emerging, empirical evidence has begun to show a positive association between adverse effects of heavy metal, noise pollution, light pollution, second-hand smoke, and air pollution exposures and various sleep problems. Specifically, these negative sleep outcomes range from subjective sleep manifestations, such as general sleep quality, sleep duration, daytime dysfunction, and daytime sleepiness, as well as objective sleep measures, including difficulties with sleep onset and maintenance, sleep stage or circadian rhythm interference, sleep arousal, REM activity, and sleep disordered breathing. However, the association between light exposure and sleep is less clear. Potential toxicological mechanisms are thought to include the direct effect of various environmental toxicants on the nervous, respiratory, and cardiovascular systems, oxidative stress, and inflammation. Nevertheless, future research is required to tease out the exact pathways of action to explain the associations between each environmental factor and sleep, to inform possible therapies to negate the detrimental effects, and to increase efforts in decreasing exposure to these harmful environmental factors to improve health.

Utilization of Prophylactic Antibiotics After Nasal Packing for Epistaxis.

BACKGROUND: There have been few investigations examining the benefits, consequences, and patterns of use for prophylactic antibiotics for nasal packing in the emergency department setting. Given the frequency of epistaxis in the emergency department, it is an ideal setting to study the efficacy and utilization patterns of prophylactic antibiotics in nasal packing. OBJECTIVE: Our aim was to assess both rates of utilization and evidence of benefit for prophylactic antibiotics in patients with nasal packing for epistaxis. METHODS: A single-institution retrospective review of 275 cases of anterior nasal packing in an urban emergency department between September 2013 and April 2017 was performed. Chi-square statistical analysis was used to evaluate results. RESULTS: Among 275 cases studied, there were no instances of toxic shock syndrome. Roughly 73% of patients with nonabsorbable packing received prophylactic antibiotics. Only one (1.1%) case of sinusitis was noted among the nonabsorbable packing with prophylaxis group, with no such complication in the nonprophylaxis group. In contrast, 95% of patients with absorbable nasal packing were not given prophylactic antibiotics. Analysis of all cases given prophylactic antibiotics vs. no prophylaxis, regardless of packing type, revealed no statistically significant difference in the development of acute sinusitis (1% vs. 0.56%; p = 0.6793). CONCLUSIONS: There was no observed advantage or disadvantage to using prophylactic antibiotics in anterior nasal packing in the emergency department, regardless of whether patients received absorbable or nonabsorbable packing. However, patients who receive nonabsorbable nasal packing were more likely to receive antibiotic prophylaxis.

Acute stroke care in a New York City comprehensive stroke center during the COVID-19 pandemic.

BACKGROUND AND PURPOSE: The coronavirus disease-2019 (COVID-19) pandemic caused unprecedented demand and burden on emergency health care services in New York City. We aim to describe our experience providing acute stroke care at a comprehensive stroke center (CSC) and the impact of the pandemic on the quality of care for patients presenting with acute ischemic stroke (AIS). METHODS: We retrospectively analyzed data from a quality improvement registry of consecutive AIS patients at New York University Langone Health's CSC between 06/01/2019-05/15/2020. During the early stages of the pandemic, the acute stroke process was modified to incorporate COVID-19 screening, testing, and other precautionary measures. We compared stroke quality metrics including treatment times and discharge outcomes of AIS patients during the pandemic (03/012020-05/152020) compared with a historical pre-pandemic group (6/1/2019-2/29/2020). RESULTS: A total of 754 patients (pandemic-120; pre-pandemic-634) were admitted with a principal diagnosis of AIS; 198 (26.3%) received alteplase and/or mechanical thrombectomy. Despite longer median door to head CT times (16 vs 12 minutes; p = 0.05) and a trend towards longer door to groin puncture times (79.5 vs. 71 min, p = 0.06), the time to alteplase administration (36 vs 35 min; p = 0.83), door to reperfusion times (103 vs 97 min, p = 0.18) and defect-free care (95.2% vs 94.7%; p = 0.84) were similar in the pandemic and pre-pandemic groups. Successful recanalization rates (TICI≥2b) were also similar (82.6% vs. 86.7%, p = 0.48). After adjusting for stroke severity, age and a prior history of transient ischemic attack/stroke, pandemic patients had increased discharge mortality (adjusted OR 2.90 95% CI 1.77 - 7.17, p = 0.021) CONCLUSION: Despite unprecedented demands on emergency healthcare services, early multidisciplinary efforts to adapt the acute stroke treatment process resulted in keeping the stroke quality time metrics close to pre-pandemic levels. Future studies will be needed with a larger cohort comparing discharge and long-term outcomes between pre-pandemic and pandemic AIS patients.

The Effectiveness of Collaborative Care on Depression Outcomes for Racial/Ethnic Minority Populations in Primary Care: A Systematic Review.

BACKGROUND: Racial/ethnic minorities experience a greater burden of mental health problems than white adults in the United States. The collaborative care model is increasingly being adopted to improve access to services and to promote diagnosis and treatment of psychiatric diseases. OBJECTIVE: This systematic review seeks to summarize what is known about collaborative care on depression outcomes for racial/ethnic minorities in the United States. METHODS: This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses method. Collaborative care studies were included if they comprised adults from at least one racial/ethnic minority group, were located in primary care clinics in the United States, and had depression outcome measures. Core principles described by the University of Washington Advancing Integrated Mental Health Solutions Center were used to define the components of collaborative care. RESULTS: Of 398 titles screened, 169 full-length articles were assessed for eligibility, and 19 studies were included in our review (10 randomized controlled trials, 9 observational). Results show there is potential that collaborative care, with or without cultural/linguistic tailoring, is effective in improving depression for racial/ethnic minorities, including those from low socioeconomic backgrounds. CONCLUSIONS: Collaborative care should be explored as an intervention for treating depression for racial/ethnic minority patients in primary care. Questions remain as to what elements of cultural adaptation are most helpful, factors behind the difficulty in recruiting minority patients for these studies, and how the inclusion of virtual components changes access to and delivery of care. Future research should also recruit individuals from less studied populations.

Air pollution exposure and adverse sleep health across the life course: A systematic review.

An increasing number of epidemiological studies have examined air pollution as a possible contributor to adverse sleep health, but results are mixed. The aims of this systematic review are to investigate and summarize the associations between exposures to air pollutants and various sleep measures across the lifespan. PubMed, CINAHL, Cochrane, Scopus, Web of Science, and PsycInfo were searched through October 2019 to identify original data-based research examining direct epidemiological associations between ambient and indoor air pollution exposures and various sleep health measures, including sleep quality, sleep duration, sleep disturbances, and daytime sleepiness. Twenty-two articles from 2010 to 2019 were selected for inclusion in this review, including a wide range of study populations (from early childhood to elderly) and locations (10 Asian, 4 North American, 3 European, 5 other). Due to variation in both exposure and outcome assessments, conducting a meta-analysis was not plausible. Twenty-one studies reported a generally positive association between exposure and poor sleep quality. While most studies focused on ambient air pollutants, five assessed the specific effect of indoor exposure. In children and adolescents, increased exposure to both ambient and indoor pollutants is associated with increased respiratory sleep problems and a variety of additional adverse sleep outcomes. In adults, air pollution exposure was most notably related to sleep disordered breathing. Existing literature generally shows a negative relationship between exposures to air pollution and sleep health in populations across different age groups, countries, and measures. While many associations between air pollution and sleep outcomes have been investigated, the mixed study methods and use of subjective air pollution and sleep measures result in a wide range of specific associations. Plausible toxicological mechanisms remain inconclusive. Future studies utilizing objective sleep measures and controlling for all air pollution exposures and individual encounters may help ameliorate variability in the results reported by current published literature.

Quantitative Thermal Imaging Biomarkers to Detect Acute Skin Toxicity From Breast Radiation Therapy Using Supervised Machine Learning.

PURPOSE: Radiation-induced dermatitis is a common side effect of breast radiation therapy (RT). Current methods to evaluate breast skin toxicity include clinical examination, visual inspection, and patient-reported symptoms. Physiological changes associated with radiation-induced dermatitis, such as inflammation, may also increase body-surface temperature, which can be detected by thermal imaging. Quantitative thermal imaging markers were identified and used in supervised machine learning to develop a predictive model for radiation dermatitis. METHODS AND MATERIALS: Ninety patients treated for adjuvant whole-breast RT (4250 cGy/fx = 16) were recruited for the study. Thermal images of the treated breast were taken at 4 intervals: before RT, then weekly at fx = 5, fx = 10, and fx = 15. Parametric thermograms were analyzed and yielded 26 thermal-based features that included surface temperature (°C) and texture parameters obtained from (1) gray-level co-occurrence matrix, (2) gray-level run-length matrix, and (3) neighborhood gray-tone difference matrix. Skin toxicity was evaluated at the end of RT using the Common Terminology Criteria for Adverse Events (CTCAE) guidelines (Ver.5). Binary group classes were labeled according to a CTCAE cut-off score of ≥2, and thermal features obtained at fx = 5 were used for supervised machine learning to predict skin toxicity. The data set was partitioned for model training, independent testing, and validation. Fifteen patients (∼17% of the whole data set) were randomly selected as an unseen test data set, and 75 patients (∼83% of the whole data set) were used for training and validation of the model. A random forest classifier with leave-1-patient-out cross-validation was employed for modeling single and hybrid parameters. The model performance was reported using receiver operating characteristic analysis on patients from an independent test set. RESULTS: Thirty-seven patients presented with adverse skin effects, denoted by a CTCAE score ≥2, and had significantly higher local increases in skin temperature, reaching 36.06°C at fx = 10 (P = .029). However, machine-learning models demonstrated early thermal signals associated with skin toxicity after the fifth RT fraction. The cross-validated model showed high prediction accuracy on the independent test data (test accuracy = 0.87) at fx = 5 for predicting skin toxicity at the end of RT. CONCLUSIONS: Early thermal markers after 5 fractions of RT are predictive of radiation-induced skin toxicity in breast RT.

Personalized Breast Cancer Treatments Using Artificial Intelligence in Radiomics and Pathomics.

Progress in computing power and advances in medical imaging over recent decades have culminated in new opportunities for artificial intelligence (AI), computer vision, and using radiomics to facilitate clinical decision-making. These opportunities are growing in medical specialties, such as radiology, pathology, and oncology. As medical imaging and pathology are becoming increasingly digitized, it is recently recognized that harnessing data from digital images can yield parameters that reflect the underlying biology and physiology of various malignancies. This greater understanding of the behaviour of cancer can potentially improve on therapeutic strategies. In addition, the use of AI is particularly appealing in oncology to facilitate the detection of malignancies, to predict the likelihood of tumor response to treatments, and to prognosticate the patients' risk of cancer-related mortality. AI will be critical for identifying candidate biomarkers from digital imaging and developing robust and reliable predictive models. These models will be used to personalize oncologic treatment strategies, and identify confounding variables that are related to the complex biology of tumors and diversity of patient-related factors (ie, mining "big data"). This commentary describes the growing body of work focussed on AI for precision oncology. Advances in AI-driven computer vision and machine learning are opening new pathways that can potentially impact patient outcomes through response-guided adaptive treatments and targeted therapies based on radiomic and pathomic analysis.

Prolonged mobile phone use is associated with depressive symptoms in Chinese adolescents.

BACKGROUND: Prolonged screen time has negative impacts on health and well-being. This study examined the association between the duration of mobile phone use (DMPU) and depressive symptoms in a large sample of Chinese adolescents. METHODS: 11,831 adolescent students participated in the baseline Shandong Adolescent Behavior and Health Cohort (SABHC) survey in Shandong, China in 2015. A self-administered questionnaire was used to measure DMPU on weekdays and the weekend, sleep, mental health, and family environment. The Center for Epidemiologic Studies Depression Scale (CES-D) and Youth Self-Report (YSR) depression scales were used to assess depressive symptoms. RESULTS: The mean age of participants was 15.0 (SD = 1.5) and 51% were male. The prevalence of depressive symptoms increased with prolonged DMPU. After adjusting for adolescent and family covariates, DMPU ≥ 2 h/day on weekdays (OR = 1.78, 95%CI = 1.48-2.15) and ≥ 5 h/day on the weekend (OR = 1.67, 95%CI = 1.41-1.98) was associated with increased risk of depressive symptoms as assessed by CES-D. The DMPU-depression association was found to be partially mediated by short sleep duration or insomnia. Similar associations were observed for depression as assessed by YSR. STUDY LIMITATION: This is a cross-sectional survey. Mobile phone use and depressive symptoms were measured by self-report. CONCLUSIONS: Prolonged mobile phone use of ≥ 2 h on weekdays and ≥ 5 h on the weekend is associated with an increased risk of depressive symptoms. The association appears to be partially mediated by sleep disturbances.

Impulsivity in Parkinson's Disease Is Associated With Alterations in Affective and Sensorimotor Striatal Networks.

A subset of patients with Parkinson's disease (PD) experiences problems with impulse control, characterized by a loss of voluntary control over impulses, drives, or temptations regarding excessive hedonic behavior. The present study aimed to better understand the neural basis of such impulse control disorders (ICDs) in PD. We collected resting-state functional connectivity and structural MRI data from 21 PD patients with ICDs and 30 patients without such disorders. To assess impulsivity, all patients completed the Barratt Impulsiveness Scale and performed an information-gathering task. MRI results demonstrated substantial differences in neural characteristics between PD patients with and without ICDs. Results showed that impulsivity was linked to alterations in affective basal ganglia circuitries. Specifically, reduced frontal-striatal connectivity and GPe volume were associated with more impulsivity. We suggest that these changes affect decision making and result in a preference for risky or inappropriate actions. Results further showed that impulsivity was linked to alterations in sensorimotor striatal networks. Enhanced connectivity within this network and larger putamen volume were associated with more impulsivity. We propose that these changes affect sensorimotor processing such that patients have a greater propensity to act. Our findings suggest that the two mechanisms jointly contribute to impulsive behaviors in PD.

Association Between Academic Medical Center Pharmaceutical Detailing Policies and Physician Prescribing.

IMPORTANCE: In an effort to regulate physician conflicts of interest, some US academic medical centers (AMCs) enacted policies restricting pharmaceutical representative sales visits to physicians (known as detailing) between 2006 and 2012. Little is known about the effect of these policies on physician prescribing. OBJECTIVE: To analyze the association between detailing policies enacted at AMCs and physician prescribing of actively detailed and not detailed drugs. DESIGN, SETTING, AND PARTICIPANTS: The study used a difference-in-differences multivariable regression analysis to compare changes in prescribing by physicians before and after implementation of detailing policies at AMCs in 5 states (California, Illinois, Massachusetts, Pennsylvania, and New York) that made up the intervention group with changes in prescribing by a matched control group of similar physicians not subject to a detailing policy. EXPOSURES: Academic medical center implementation of policies regulating pharmaceutical salesperson visits to attending physicians. MAIN OUTCOMES AND MEASURES: The monthly within-drug class market share of prescriptions written by an individual physician for detailed and nondetailed drugs in 8 drug classes (lipid-lowering drugs, gastroesophageal reflux disease drugs, diabetes drugs, antihypertensive drugs, hypnotic drugs approved for the treatment of insomnia [sleep aids], attention-deficit/hyperactivity disorder drugs, antidepressant drugs, and antipsychotic drugs) comparing the 10- to 36-month period before implementation of the detailing policies with the 12- to 36-month period after implementation, depending on data availability. RESULTS: The analysis included 16 121 483 prescriptions written between January 2006 and June 2012 by 2126 attending physicians at the 19 intervention group AMCs and by 24 593 matched control group physicians. The sample mean market share at the physician-drug-month level for detailed and nondetailed drugs prior to enactment of policies was 19.3% and 14.2%, respectively. Exposure to an AMC detailing policy was associated with a decrease in the market share of detailed drugs of 1.67 percentage points (95% CI, -2.18 to -1.18 percentage points; P < .001) and an increase in the market share of nondetailed drugs of 0.84 percentage points (95% CI, 0.54 to 1.14 percentage points; P < .001). Associations were statistically significant for 6 of 8 study drug classes for detailed drugs (lipid-lowering drugs, gastroesophageal reflux disease drugs, antihypertensive drugs, sleep aids, attention-deficit/hyperactivity disorder drugs, and antidepressant drugs) and for 9 of the 19 AMCs that implemented policies. Eleven of the 19 AMCs regulated salesperson gifts to physicians, restricted salesperson access to facilities, and incorporated explicit enforcement mechanisms. For 8 of these 11 AMCs, there was a significant change in prescribing. In contrast, there was a significant change at only 1 of 8 AMCs that did not enact policies in all 3 areas. CONCLUSIONS AND RELEVANCE: Implementation of policies at AMCs that restricted pharmaceutical detailing between 2006 and 2012 was associated with modest but significant reductions in prescribing of detailed drugs across 6 of 8 major drug classes; however, changes were not seen in all of the AMCs that enacted policies.

Characterizing the effect of multiple Fc glycan attributes on the effector functions and FcγRIIIa receptor binding activity of an IgG1 antibody.

N-linked Fc glycosylation of IgG1 monoclonal antibody therapeutics can directly influence their mechanism of action by impacting IgG effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Therefore, identification and detailed characterization of Fc glycan critical quality attributes (CQAs) provides important information for process design and control. A two-step approach was used to identify and characterize the Fc glycan CQAs for an IgG1 Mab with effector function. First, single factor experiments were performed to identify glycan critical quality attributes that influence ADCC and CDC activities. Next, a full-factorial design of experiment (DOE) to characterize the possible interactions and relative effect of these three glycan species on ADCC, CDC, and FcγRIIIa binding was employed. Additionally, the DOE data were used to develop models to predict ADCC, CDC, and FcγRIIIa binding of a given configuration of the three glycan species for this IgG1 molecule. The results demonstrate that for ADCC, afuco mono/bi has the largest effect, followed by HM and ß-gal, while FcγRIIIa binding is affected by afuco mono/bi and ß-gal. CDC, in contrast, is affected by ß-gal only. This type of glycan characterization and modeling can provide valuable information for development, manufacturing support and process improvements for IgG products that require effector function for efficacy. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:1181-1192, 2016.