Dynamics of hydraulic and contractile wave-mediated fluid transport during Drosophila oogenesis.

From insects to mice, oocytes develop within cysts alongside nurse-like sister germ cells. Prior to fertilization, the nurse cells' cytoplasmic contents are transported into the oocyte, which grows as its sister cells regress and die. Although critical for fertility, the biological and physical mechanisms underlying this transport process are poorly understood. Here, we combined live imaging of germline cysts, genetic perturbations, and mathematical modeling to investigate the dynamics and mechanisms that enable directional and complete cytoplasmic transport in Drosophila melanogaster egg chambers. We discovered that during "nurse cell (NC) dumping" most cytoplasm is transported into the oocyte independently of changes in myosin-II contractility, with dynamics instead explained by an effective Young-Laplace law, suggesting hydraulic transport induced by baseline cell-surface tension. A minimal flow-network model inspired by the famous two-balloon experiment and motivated by genetic analysis of a myosin mutant correctly predicts the directionality, intercellular pattern, and time scale of transport. Long thought to trigger transport through "squeezing," changes in actomyosin contractility are required only once NC volume has become comparable to nuclear volume, in the form of surface contractile waves that drive NC dumping to completion. Our work thus demonstrates how biological and physical mechanisms cooperate to enable a critical developmental process that, until now, was thought to be mainly biochemically regulated.

Pathogenic alleles in microtubule, secretory granule and extracellular matrix-related genes in familial keratoconus.

Keratoconus is a common corneal defect with a complex genetic basis. By whole exome sequencing of affected members from 11 multiplex families of European ancestry, we identified 23 rare, heterozygous, potentially pathogenic variants in 8 genes. These include nonsynonymous single amino acid substitutions in HSPG2, EML6 and CENPF in two families each, and in NBEAL2, LRP1B, PIK3CG and MRGPRD in three families each; ITGAX had nonsynonymous single amino acid substitutions in two families and an indel with a base substitution producing a nonsense allele in the third family. Only HSPG2, EML6 and CENPF have been associated with ocular phenotypes previously. With the exception of MRGPRD and ITGAX, we detected the transcript and encoded protein of the remaining genes in the cornea and corneal cell cultures. Cultured stromal cells showed cytoplasmic punctate staining of NBEAL2, staining of the fibrillar cytoskeletal network by EML6, while CENPF localized to the basal body of primary cilia. We inhibited the expression of HSPG2, EML6, NBEAL2 and CENPF in stromal cell cultures and assayed for the expression of COL1A1 as a readout of corneal matrix production. An upregulation in COL1A1 after siRNA inhibition indicated their functional link to stromal cell biology. For ITGAX, encoding a leukocyte integrin, we assayed its level in the sera of 3 affected families compared with 10 unrelated controls to detect an increase in all affecteds. Our study identified genes that regulate the cytoskeleton, protein trafficking and secretion, barrier tissue function and response to injury and inflammation, as being relevant to keratoconus.

What's in it for me?: A value assessment of gynecologic cancer clinical trials for Black women.

OBJECTIVE: Underrepresented groups may be dissuaded from clinical trial participation without perceived value. We therefore comprehensively assessed gynecologic cancer clinical trial protocols for the inclusion of items of value most important to Black individuals. METHODS: ClinicalTrials.gov was queried for NCI-sponsored gynecologic cancer clinical trials in the US between Jan.1994 and Nov.2021. Pre-specified return of value (ROV) items were abstracted from each protocol. Inclusion proportions were calculated for each ROV item and temporal changes assessed with chi-square tests. Temporality of proportional trends was further assessed by slope and departure from linearity calculations. RESULTS: 279 gynecologic cancer clinical trials were included. Most commonly trials had first accrual in 2001-2007 (37%) and involved ovarian cancer (48%), phase II studies (53%), and chemotherapy (60%) or targeted therapy (34%). Trials often included ROV items in basic information (99%), medical record information (99%), and imaging (82%). 41% of trials included ROV items in biomarker testing, 20% genetic testing, and 20% in patient-reported outcome questionnaires. Over time, there were significant increases in the proportion of trials that included genetic (3% to 51%; p < 0.001) and biomarker testing (14 to 78%, p < 0.001). Information on lifestyle risk factors was rare (1%). No trials included ROV items in ancestry, how to connect with other participants, or remuneration. CONCLUSIONS: Gynecologic cancer clinical trials include few design elements that provide high value to Black individuals like lifestyle risk factors, ancestry, and remuneration. In any multi-pronged effort to improve diversity in clinical trial enrollment, inclusion of items valued by Black individuals should be considered.

Centering race in procedural justice theory: Structural racism and the under- and overpolicing of Black communities.

OBJECTIVE: We assessed the factors that legitimized the police in the United States at an important moment of history, just after the police killing of George Floyd in 2020. We also evaluated one way of incorporating perceptions of systemic racism into procedural justice theory. HYPOTHESES: We tested two primary hypotheses. The first hypothesis was that perceptions of police procedural justice, distributive justice, and bounded authority were important to the legitimization of the police. The second hypothesis was that perceptions of the under- and overpolicing of Black communities also mattered to the delegitimization of the institution, especially for people who identified with the Black Lives Matter movement. METHOD: A cross-sectional quota sample survey of 1,500 U.S. residents was conducted in June 2020. Data were analyzed using confirmatory factor analysis, structural equation modeling, and latent moderated structural equation modeling. RESULTS: People who viewed the police as legitimate also tended to believe that police treated people with respect and dignity, made decisions in unbiased ways, fairly allocated their finite resources across groups in society, and respected the limits of their rightful authority. Moreover, people who believed that Black communities were underpoliced and overpoliced also tended to question the legitimacy of the police, especially if they identified with the Black Lives Matter movement. These results held among Black and White study participants alike. CONCLUSIONS: At the time of the study, systemic racism in policing may have delegitimized the institution in a way that transcended the factors that procedural justice theory focuses on, such as procedural justice. This was especially so for individuals who identified with a social movement, Black Lives Matter, that had an extremely high profile in 2020. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Artificial fairness? Trust in algorithmic police decision-making.

Objectives: Test whether (1) people view a policing decision made by an algorithm as more or less trustworthy than when an officer makes the same decision; (2) people who are presented with a specific instance of algorithmic policing have greater or lesser support for the general use of algorithmic policing in general; and (3) people use trust as a heuristic through which to make sense of an unfamiliar technology like algorithmic policing. Methods: An online experiment tested whether different decision-making methods, outcomes and scenario types affect judgements about the appropriateness and fairness of decision-making and the general acceptability of police use of this particular technology. Results: People see a decision as less fair and less appropriate when an algorithm decides, compared to when an officer decides. Yet, perceptions of fairness and appropriateness were strong predictors of support for police use of algorithms, and being exposed to a successful use of an algorithm was linked, via trust in the decision made, to greater support for police use of algorithms. Conclusions: Making decisions solely based on algorithms might damage trust, and the more police rely solely on algorithmic decision-making, the less trusting people may be in decisions. However, mere exposure to the successful use of algorithms seems to enhance the general acceptability of this technology. Supplementary Information: The online version contains supplementary material available at 10.1007/s11292-021-09484-9.

Putting participants and study partners FIRST when clinical trials end early.

Between 2018 and 2019, multiple clinical trials ended earlier than planned, resulting in calls to improve communication with and support for participants and their study partners ("dyads"). The multidisciplinary Participant Follow-Up Improvement in Research Studies and Trials (Participant FIRST) Work Group met throughout 2021. Its goals were to identify best practices for communicating with and supporting dyads affected by early trial stoppage. The Participant FIRST Work Group identified 17 key recommendations spanning the pre-trial, mid-trial, and post-trial periods. These focus on prospectively allocating sufficient resources for orderly closeout; developing dyad-centered communication plans; helping dyads build and maintain support networks; and, if a trial stops, informing dyads rapidly. Participants and study partners invest time, effort, and hope in their research participation. The research community should take intentional steps toward better communicating with and supporting participants when clinical trials end early. The Participant FIRST recommendations are a practical guide for embarking on that journey.

Relational and instrumental perspectives on compliance with the law among people experiencing homelessness.

OBJECTIVE: We conducted an exploratory study testing procedural justice theory with a novel population. We assessed the extent to which police procedural justice, effectiveness, legitimacy, and perceived risk of sanction predict compliance with the law among people experiencing homelessness. HYPOTHESES: We did not develop formal a priori hypotheses but examined five general research questions. First, are there positive associations between police procedural justice, police legitimacy, and compliance? Second, do procedural justice and legitimacy differentially predict compliance, depending on the particular type of offending? Third, are there positive associations between police effectiveness, perceived risk of sanction, and compliance? Fourth, does the perceived risk of sanction differentially predict compliance, depending on the particular type of offending? And fifth, are there positive associations between moral judgments about different offending behaviors and compliance? METHOD: Two hundred people (87% male, 49% aged 45-64, 37% White British) experiencing homelessness on the streets of an inner London borough completed a survey that included measures of procedural justice, police legitimacy, perceived risk of sanction, morality, and compliance with the law. RESULTS: Procedural justice and police legitimacy were only weakly (and not significantly) associated with any of the three types of compliance (compliance with laws prohibiting low-level crimes, behaviors specific to the street population, and high-level crimes). Police effectiveness positively predicted compliance via perceived risk of sanction, but only for street-population-specific offenses that can be important for survival on the streets, such as begging and sleeping in certain localities. Morality was positively associated with all three types of compliance behaviors. Supplementary analyses suggested a small amount of instability in the results, however, possibly because of the relatively small sample size. CONCLUSIONS: The lack of relevant relational connections to legal authority may explain why procedural fairness and perceptions of police legitimacy were not particularly important predictors of compliance in this context. More research is needed into the types of marginalized communities for whom structural factors of alienation and lack of access to resources may serve to reduce normative group connections. Future work should test whether the need to survive on the streets leads people to discount some social and relational constraints to behavior, making people (almost by definition) more instrumental in relation to law and law enforcement. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Psychological aspects of living with an artificial eye.

PURPOSE: Artificial eye clinics address physical and aesthetic aspects of orbital prostheses, but psychological effects may not be formally addressed. In general, without effective coping mechanisms, stress can lead to anxiety and depression. This study aims to determine, in the context of having an artificial eye, whether coping strategies, as well as perception of illness and other demographic and clinical variables are associated with anxiety or depression. METHODS: Consecutive patients attending two artificial eye clinics were invited to participate in this audit. Participants completed questionnaires: HADS, Brief IPQ and Brief COPE. Variables with a correlation coefficient of ≥0.2 with anxiety or depression were included in regression modeling. The extent to which the participants' emotional and cognitive representations of their artificial eye related to feelings of anxiety and depression was determined. RESULTS: In the cohort of 208, clinically significant anxiety was present in 29.5% and clinically significant depression was present in 8.4%. Perceptions of the impact of the artificial eye and self-blame as a coping strategy were correlated with anxiety. Depression levels were higher when participants believed that their artificial eye had a greater impact on their life, when they lived alone, and when they used substances as a coping strategy. CONCLUSION: Significant levels of anxiety exist in those living with artificial eyes, with various coping strategies used. Addressing this and offering alternative coping strategies may improve patient well being and overall satisfaction.

Association of anxiety with subcortical amyloidosis in cognitively normal older adults.

Late-life anxiety has been associated with increased progression from normal cognition to amnestic MCI, suggesting that anxiety may be a neuropsychiatric symptom of Alzheimer's disease (AD) pathological changes and a possible marker of anatomical progression in preclinical AD. This study examined whether cortical or subcortical amyloidosis, indicating earlier or later stages of preclinical AD, was associated with greater self-reported anxiety among 118 cognitively normal volunteers, aged 65-90 years, and whether this association was stronger in APOEε4 carriers. Participants underwent Pittsburgh Compound B Positron Emission Tomography (PiB-PET) to assess fibrillar amyloid-ß burden in cortical and subcortical regions, and measurement of anxiety using the Hospital Anxiety and Depression Scale-anxiety subscale. Higher PiB-PET measures in the subcortex (striatum, amygdala, and thalamus), but not in the cortex, were associated with greater anxiety, adjusting for demographics, cognition, and depression. Findings were similar using a cortico-striatal staging system and continuous PET measurements. Anxiety was highest in APOEε4 carriers with subcortical amyloidosis. This work supports in vivo staging of amyloid-ß deposition in both cortical and subcortical regions as a promising approach to the study of neuropsychiatric symptoms such as anxiety in cognitively normal older individuals. Elevated anxiety symptoms in combination with high-risk biological factors such as APOEε4 and subcortical amyloid-ß may identify participants closest to MCI for secondary prevention trials.

Correction: Association of anxiety with subcortical amyloidosis in cognitively normal older adults.

This Article was originally published under Nature Research's License to Publish, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the Article have been modified accordingly.

Test-Retest Reliability of Concussion Baseline Assessments in United States Service Academy Cadets: A Report from the National Collegiate Athletic Association (NCAA)-Department of Defense (DoD) CARE Consortium.

OBJECTIVE: In response to advancing clinical practice guidelines regarding concussion management, service members, like athletes, complete a baseline assessment prior to participating in high-risk activities. While several studies have established test stability in athletes, no investigation to date has examined the stability of baseline assessment scores in military cadets. The objective of this study was to assess the test-retest reliability of a baseline concussion test battery in cadets at U.S. Service Academies. METHODS: All cadets participating in the Concussion Assessment, Research, and Education (CARE) Consortium investigation completed a standard baseline battery that included memory, balance, symptom, and neurocognitive assessments. Annual baseline testing was completed during the first 3 years of the study. A two-way mixed-model analysis of variance (intraclass correlation coefficent (ICC)3,1) and Kappa statistics were used to assess the stability of the metrics at 1-year and 2-year time intervals. RESULTS: ICC values for the 1-year test interval ranged from 0.28 to 0.67 and from 0.15 to 0.57 for the 2-year interval. Kappa values ranged from 0.16 to 0.21 for the 1-year interval and from 0.29 to 0.31 for the 2-year test interval. Across all measures, the observed effects were small, ranging from 0.01 to 0.44. CONCLUSIONS: This investigation noted less than optimal reliability for the most common concussion baseline assessments. While none of the assessments met or exceeded the accepted clinical threshold, the effect sizes were relatively small suggesting an overlap in performance from year-to-year. As such, baseline assessments beyond the initial evaluation in cadets are not essential but could aid concussion diagnosis.

COVID-19: The regional impact of COVID-19 on the certification of vision impairment in Northern Ireland.

PURPOSE: In this paper we highlight the impact which the disruption of secondary care ophthalmic services, resulting from COVID-19, has had on Sight Impairment (SI) and Severe Sight Impairment (SSI) certification in Northern Ireland. METHODS: Regional data on SI and SSI certification in the period after the onset of the lockdown (19 March 2020-18 June 2020) were compared to the period immediately before lockdown (1 January 2020-18 March 2020) and to the same periods in 2019. Change documented was compared to post-lockdown reductions in primary and secondary ophthalmic care activity. RESULTS: In 2019, during the 3-month period (19 March 2019-18 June 2019), 115 individuals were certified as sight impaired (SI 36, SSI 75, unspecified 4). Of those certified, 65 were female, 49 male. Principal causes of certification were: Age-related macular degeneration (AMD) (N = 45), glaucoma (N = 20) and diabetic eye disease (DED) (N = 10). Mean VA, recorded from the better eye of those certified, was 0.96 LogMAR. In the 3 months following the onset of lockdown (19 March 2020-18 June 2020), only 37 individuals were certified (SI 6, SSI 31), 12 female and 25 male. AMD was the most frequent cause of sight impairment (N = 20). There were only two DED certifications and one due to glaucoma. Mean VA in the better eye of those certified was 1.15LogMAR. The numbers of CVI certifications completed following the introduction of COVID-19 lockdown fell by 68%, compared to the 2019 data. There was a significant reduction in the proportion of female certifications (p = 0.01), and in certifications due to glaucoma (p = 0.02). The proportion of those certified as SSI as opposed to SI in the period after the onset of lockdown rose from 68% in 2019 to 84% in 2020. The mean VA of those certified in the period after the onset of lockdown, when compared to those certified in the other three periods, was worse by between 0.21 and 0.19 LogMAR (p = 0.06). Reductions reflected change in overall primary and secondary ophthalmic care activity. CONCLUSIONS: It is inconceivable that COVID-19 has reduced the incidence of sight-threatening eye disease. We must therefore assume that a flood of newly presenting sight loss will present once the pandemic has passed. New presentations will include those who would normally have attended during the lockdown period, and patients who, had they accessed ophthalmic care at the appropriate time, would have been saved from severe levels of blindness. The implications of the predicted increase in demand for medical, social and low vision related services are huge.

Return to Sport After Nonoperative Management of Medial Ulnar Collateral Ligament Injuries About the Elbow in Non-throwing Athletes.

There is a paucity of literature published on management of acute medial ulnar collateral ligament injuries in the non-throwing athlete and when these athletes may expect to safely return to sport. Non-overhead throwing athletes that sustained medial ulnar collateral ligament (MUCL) injuries treated conservatively with brace immobilization and therapy can successfully return to sport in a relatively short duration. A radiographic query of Magnetic Resonance Images (MRIs) was performed to identify patients sustaining elbow MUCL injury. Only those participating as intercollegiate athletes were included. Medical charts and documents were reviewed to determine time away from sport and rehabilitation protocol. A total of 17 patient-athletes were identified as having sustained MUCL injuries that met inclusion criteria. There was a 100% return to sport rate, averaging 5 weeks from date of injury. Non-overhead throwing athletes competing at the intercollegiate level who sustained acute MUCL injury were effectively treated nonoperatively. (Journal of Surgical Orthopaedic Advances 30(3):136-139, 2021).

The impact of amyloid-beta and tau on prospective cognitive decline in older individuals.

OBJECTIVES: Amyloid-beta (Aß) and tau pathologies are commonly observed among clinically normal older individuals at postmortem and can now be detected with in vivo neuroimaging. The association and interaction of these proteinopathies with prospective cognitive decline in normal aging and preclinical Alzheimer's disease (AD) remains to be fully elucidated. METHODS: One hundred thirty-seven older individuals (age = 76.3 ± 6.22 years) participating in the Harvard Aging Brain Study underwent Aß (11 C-Pittsburgh compound B) and tau (18 F-flortaucipir) positron emission tomography (PET) with prospective neuropsychological assessments following PET imaging (mean number of cognitive visits = 2.8 ± 1.1). Tau and Aß PET measures were assessed in regions of interest (ROIs) as well as vertex-wise map analyses. Cognitive change was evaluated with Memory and Executive Function composites. RESULTS: Higher levels of Aß and tau were both associated with greater memory decline, but not with change in executive function. Higher cortical Aß was associated with higher tau levels in all ROIs, independent of age, and very elevated levels of tau were observed primarily in clinically normal with elevated Aß. A significant interaction between tau and Aß was observed in both ROI and map-level analyses, such that rapid prospective memory decline was observed in participants who had high levels of both pathologies. INTERPRETATION: Our results are consistent with the supposition that both Aß and tau are necessary for memory decline in the preclinical stages of AD. These findings may be relevant for disambiguating aging and early cognitive manifestations of AD, and to inform secondary prevention trials in preclinical AD. Ann Neurol 2019;00:1-3 ANN NEUROL 2019;85:181-193.

On the importance of a procedurally fair organizational climate for openness to change in law enforcement.

OBJECTIVE: Drawing on recent work in policing and organizational psychology, we examined factors related to openness to organizational change and to adopting evidence-based interview techniques among law enforcement investigators. HYPOTHESES: We hypothesized that a procedurally fair organizational climate would predict outcomes tied to organizational change, mediated by organizational identification and perceived legitimacy. We also predicted that procedural justice factors would be stronger predictors than outcome-oriented factors (i.e., rewards and sanctions). METHOD: Study 1 surveyed law enforcement investigators (N = 711) about their attitudes toward and behaviors within their organization (i.e., perceived procedural fairness of one's organization, identification, legitimacy, compliance, empowerment, and extra-role behavior). Study 2 conceptually extended this survey to interviewers (N = 71) trained in a new, evidence-based interviewing approach adding likelihood of future use of the novel interviewing approach as an outcome. RESULTS: In Study 1, the more investigators thought their organization had a procedurally fair climate, the more they identified with the organization and perceived it as legitimate. Framing compliance, empowerment and extra-role behavior as associated with openness to change, we found that legitimacy predicted compliance and tendency toward extra-role behavior (i.e., going "above and beyond"), while level of identification predicted feelings of empowerment and extra-role behavior. Study 2 partially replicated findings from Study 1 and found that motivation to attend the training also predicted likelihood of future use. CONCLUSIONS: These studies highlight the value of a procedurally just organizational climate framework in understanding law enforcement interrogators' propensity toward implementing new evidence-based interrogation techniques. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Severe Hepatotoxicity of Mithramycin Therapy Caused by Altered Expression of Hepatocellular Bile Transporters.

Mithramycin demonstrates preclinical anticancer activity, but its therapeutic dose is limited by the development of hepatotoxicity that remains poorly characterized. A pharmacogenomics characterization of mithramycin-induced transaminitis revealed that hepatotoxicity is associated with germline variants in genes involved in bile disposition: ABCB4 (multidrug resistance 3) rs2302387 and ABCB11 [bile salt export pump (BSEP)] rs4668115 reduce transporter expression (P < 0.05) and were associated with ≥grade 3 transaminitis developing 24 hours after the third infusion of mithramycin (25 mcg/kg, 6 hours/infusion, every day ×7, every 28 days; P < 0.0040). A similar relationship was observed in a pediatric cohort. We therefore undertook to characterize the mechanism of mithramycin-induced acute transaminitis. As mithramycin affects cellular response to bile acid treatment by altering the expression of multiple bile transporters (e.g., ABCB4, ABCB11, sodium/taurocholate cotransporting polypeptide, organic solute transporter α/ß) in several cell lines [Huh7, HepaRG, HepaRG BSEP (-/-)] and primary human hepatocytes, we hypothesized that mithramycin inhibited bile-mediated activation of the farnesoid X receptor (FXR). FXR was downregulated in all hepatocyte cell lines and primary human hepatocytes (P < 0.0001), and mithramycin inhibited chenodeoxycholic acid- and GW4046-induced FXR-galactose-induced gene 4 luciferase reporter activity (P < 0.001). Mithramycin promoted glycochenodeoxycholic acid-induced cytotoxicity in ABCB11 (-/-) cells and increased the overall intracellular concentration of bile acids in primary human hepatocytes grown in sandwich culture (P < 0.01). Mithramycin is a FXR expression and FXR transactivation inhibitor that inhibits bile flow and potentiates bile-induced cellular toxicity, particularly in cells with low ABCB11 function. These results suggest that mithramycin causes hepatotoxicity through derangement of bile acid disposition; results also suggest that pharmacogenomic markers may be useful to identify patients who may tolerate higher mithramycin doses. SIGNIFICANCE STATEMENT: The present study characterizes a novel mechanism of drug-induced hepatotoxicity in which mithramycin not only alters farnesoid X receptor (FXR) and small heterodimer partner gene expression but also inhibits bile acid binding to FXR, resulting in deregulation of cellular bile homeostasis. Two novel single-nucleotide polymorphisms in bile flow transporters are associated with mithramycin-induced liver function test elevations, and the present results are the rationale for a genotype-directed clinical trial using mithramycin in patients with thoracic malignancies.

A Global Public Health Perspective: Facilitating Access to Assistive Technology.

SIGNIFICANCE: Clinicians should not overlook vulnerable populations with limited access to assistive technology (AT), the importance of collaboration in multidisciplinary teams, advocacy for enabling environments, and supportive health systems. Resources, a model of care, and recommendations can assist clinicians in contributing to changing attitudes, expanding knowledge, and improving the lives of many.The increasing availability of innovative advances in AT can immeasurably enhance the quality of life of people with disabilities. Clinicians will undoubtedly welcome the prospect of having cutting-edge AT available to prescribe to individuals who consult them. Arguably, though, the development of innovative strategies to improve access to AT, especially to underserved people "left behind," is equally urgent. Current efforts are inadequate, with millions of people with disabilities not being reached. Particularly at risk are women, children, and the elderly, as well as poorer people who live in resource-poor and remote areas, especially in low- and middle-income countries. Not only must physical access be facilitated, but also quality services must be available. Good-quality, affordable AT, which is appropriate and acceptable to the user, would ideally be provided by competent personnel, working in multidisciplinary teams, offering comprehensive, person-centered services, including rehabilitation, fully integrated into the various levels of the health system. Clinicians can contribute to improving access to quality services, participate in initiatives aiming to increase the knowledge of health personnel and the public, engage in advocacy to change attitudes, influence legislation, and raise awareness of universal health coverage-ultimately facilitating access to AT for all.

Bounded authority: Expanding "appropriate" police behavior beyond procedural justice.

This paper expands previous conceptualizations of appropriate police behavior beyond procedural justice. The focus of the current study is on the notion of bounded authority-that is, acting within the limits of one's rightful authority. According to work on legal socialization, U.S. citizens come to acquire three dimensions of values that determine how authorities ought to behave: (a) neutral, consistent, and transparent decision-making; (b) interpersonal treatment that conveys respect, dignity, and concern; and (c) respecting the limits of one's rightful power. Using survey data from a nationally representative sample of U.S. adults, we show that concerns over bounded authority, respectful treatment, and neutral decision-making combine to form a strong predictor of police and legal legitimacy. We also find that legal legitimacy is associated with greater compliance behavior, controlling for personal morality and perceived likelihood of sanctions. We discuss the implications of a boundary perspective with respect to ongoing debates over the appropriate scope of police power and the utility of concentrated police activities. We also highlight the need for further research specifically focused on the psychological mechanisms underlying the formation of boundaries and why they shape the legitimacy of the police and law. (PsycINFO Database Record

Three Cases of Neurologic Syndrome Caused by Donor-Derived Microsporidiosis.

In April 2014, a kidney transplant recipient in the United States experienced headache, diplopia, and confusion, followed by neurologic decline and death. An investigation to evaluate the possibility of donor-derived infection determined that 3 patients had received 4 organs (kidney, liver, heart/kidney) from the same donor. The liver recipient experienced tremor and gait instability; the heart/kidney and contralateral kidney recipients were hospitalized with encephalitis. None experienced gastrointestinal symptoms. Encephalitozoon cuniculi was detected by tissue PCR in the central nervous system of the deceased kidney recipient and in renal allograft tissue from both kidney recipients. Urine PCR was positive for E. cuniculi in the 2 surviving recipients. Donor serum was positive for E. cuniculi antibodies. E. cuniculi was transmitted to 3 recipients from 1 donor. This rare presentation of disseminated disease resulted in diagnostic delays. Clinicians should consider donor-derived microsporidial infection in organ recipients with unexplained encephalitis, even when gastrointestinal manifestations are absent.

Prediction of Clinically Relevant Herb-Drug Clearance Interactions Using Sandwich-Cultured Human Hepatocytes: Schisandra spp. Case Study.

The Schisandraceae family is reported to have a range of pharmacological activities, including anti-inflammatory effects. As with all herbal preparations, extracts of Schisandra species are mixtures composed of >50 lignans, especially schizandrins, deoxyschizandrins, and gomisins. In China, Schisandra sphenanthera extract (SSE) is often coadministered with immunosuppressant treatment of transplant recipients. In cases of coadministration, the potential for herb-drug interactions (HDIs) increases. Clinical studies have been used to assess HDI potential of SSE. Results demonstrated that chronic SSE administration reduced midazolam (MDZ) clearance by 52% in healthy volunteers. Although clinical studies are definitive and considered the "gold standard," these studies are impractical for routine HDI assessments. Alternatively, in vitro strategies can be used to reduce the need for clinical studies. Transporter-certified sandwich-cultured human hepatocytes (SCHHs) provide a fully integrated hepatic cell system that maintains drug clearance pathways (metabolism and transport) and key regulatory pathways constitutive active/androstane receptor and pregnane X receptor (CAR/PXR) necessary for quantitative assessment of HDI potential. Mechanistic studies conducted in SCHHs demonstrated that SSE and the more commonly used dietary supplement Schisandra chinensis extract (SCE) inhibited CYP3A4/5-mediated metabolism and induced CYP3A4 mRNA in a dose-dependent manner. SSE and SCE reduced MDZ clearance to 0.577- and 0.599-fold of solvent control, respectively, in chronically exposed SCHHs. These in vitro results agreed with SSE clinical findings and predicted a similar in vivo HDI effect with SCE exposure. These findings support the use of an SCHH system that maintains transport, metabolic, and regulatory functionality for routine HDI assessments to predict clinically relevant clearance interactions.