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HIV infection occlusive arteriopathies may result in neurological symptoms. We report a case of bilateral complete occlusion of the extracranial portions of the internal carotid arteries in a HIV+ve patient who presented with a syncopal episode due to intraventricular haemorrhage. Compensatory blood flow from the posterior cerebral circulation via the circle of Willis resulted in small telangiectatic vessels arising from the posterior cerebral circulation which probably accounted for this rare haemorrhagic complication of an occlusive arteriopathy.&nbsp

A middle-aged lady who presented with headaches and sudden onset of left cavernous sinus syndrome was found to have a left persistent primitive trigeminal artery (PPTA) on scans. The syndrome uniquely resolved spontaneously after a few days. Vascular variations in the region of the cavernous sinus should be actively sought in cross-sectional imaging performed for cavernous sinus syndrome.

Current retinal prostheses (RPs) have not achieved useful vision restoration, as their resolution is limited by power dissipation and complexity of interconnect. This article presents an inductively powered wireless system on a chip (SoC) for an electrically controlled, optically addressed retinal prosthetic system. The SoC interfaces to a co-fabricated nanoengineered photosensitive electrode array using only two wires. To reduce the thermal dissipation near sensitive retinal tissue, the proposed design pushes voltage regulation and charge-balanced stimulation control off the implant via a duty-cycled wireless charge metering technique. A calibration technique compensating for power fluctuation caused by eye movement is also presented. Implemented in 180-nm CMOS and delivering up to $3~\mu \text{C}$ of charge at 20-nC resolution, the SoC achieves 73% RF-to-stimulation power efficiency.

Environmental decision-making is recognised as requiring integration of biophysical and social knowledge, but integration of knowledges based in different epistemic assumptions is challenging. We used an action research approach to observe integration in the development of a landscape decision support system (DSS) for forest and fire management in Victoria, Australia. We found two different knowledge integration processes, conceptually-driven to shape the structure of the DSS and technically-driven through modelling. Project framing dominated by biophysical sciences and technically-driven integration presented a barrier to many potential social science contributions that could connect a DSS with the surrounding social and decision contexts. Nonetheless, some conceptually-driven integration occurred when social researchers contributed their analysis of values of the public to the DSS design. The need for this integration emerged through initial conflict over disciplinary understandings of ‘value’. While initially uncomfortable, this opened the way to differentiate knowledge related to the term and to negotiate some conceptual synthesis and an agreed multidisciplinary list of values to structure the DSS. Technically-driven integration occurred through incorporation of social and biophysical metrics in model software. Our research highlights that bridging concepts such as values and related frameworks act as boundary objects that help in overcoming barriers to integration between social and biophysical knowledge. Integration is itself a potential boundary object and early discussions to differentiate and clarify how the term is understood can help in designing interdisciplinary processes. Critically, projects need adequate time for interdisciplinary differentiation, tolerance amongst the team for uncomfortable conversations, and leadership that fosters interdisciplinary interactions to achieve a high degree of knowledge integration.

There are calls to consider the views of the diverse public in bushfire policy, planning, and management, yet those who do not typically participate in social research and/or government community engagement activities are generally under-represented. A mixed method research design was used, including a survey, intercept and in-depth interviews to study a diversity of views. Concepts of social values, knowledge and practices were drawn on first to examine participants’ relationship to bushfire and second to discuss bushfire engagement. We identified and analyzed three relationships to bushfire: Irrelevant to me; Terror at my door; A rural concern. Participants’ values were more focused on people, pets, and special things than in earlier research and they generally perceived bushfire as solely a domain for experts. There is an opportunity to find ways to resonate with their values and relationships to bushfire, and to shape bushfire research and practice.

Enthusiasm is high for expansion of robotic assisted surgery into right hemicolectomy. But data on outcomes and cost is lacking. Our objective was to determine the association between surgical approach and cost for minimally invasive right hemicolectomy. We hypothesized that a robot approach would have increased costs (both economic and opportunity) while achieving similar short-term outcomes. We performed a retrospective cohort analysis with a simulation of operating room utilization at a quaternary care, academic institution. We enrolled patients undergoing minimally invasive right hemicolectomy from November 2017 to August 2019. Patients were categorized by the intended approach- laparoscopic or robotic. The primary outcome was the technical variable direct cost. Secondary outcomes included total cost, supply cost, operating room utilization, operative time, conversion, length of stay and 30-day post-operative outcomes. 79 patients were included in the study. A robotic approach was used in 22% of the cohort. The groups differed significantly only in etiology of surgery. Robotic surgery was associated with a 1.5 times increase in the technical variable direct cost (p

OBJECTIVES To determine whether elimination of co-pays for prescription drugs affects medication adherence and total health care spending. STUDY DESIGN Retrospective comparative study. METHODS We conducted a difference-in-differences comparison in the year before and after expansion of a Zero Dollar Co-pay (ZDC) prescription drug benefit in commercially insured Louisiana residents. Blue Cross and Blue Shield of Louisiana members with continuous disease management program enrollment were analyzed, of whom 6463 were enrolled in the ZDC program and 1821 were controls who were ineligible because their employers did not opt in. RESULTS After ZDC expansion, medication adherence fell in the control group and rose in the ZDC group, with a relative increase of 2.1 percentage points (P = .002). Medical spending fell by $71 per member per month (PMPM) (P = .027) in the ZDC group relative to controls. Overall, there was no significant increase in the cost of drugs between treatment and controls. However, when drugs were further categorized, there was a significant increase of $8 PMPM for generic drugs and no significant difference for brand name drugs. Comparisons of medication adherence rates by household income showed the largest relative increase post ZDC expansion among low-income members. CONCLUSIONS Elimination of co-pays for drugs indicated to treat chronic illnesses was associated with increases in medication adherence and reductions in overall spending of $63. Benefit designs that eliminate co-pays for patients with chronic illnesses may improve adherence and reduce the total cost of care.

Increased regurgitant blood flow has been linked to endocardial cushion defects and resultant congenital heart diseases (CHDs). Prenatal alcohol exposure (PAE) has been shown to alter early blood flow resulting in abnormal endocardial cushions and CHDs. Compounds, including folic acid (FA), mitigate PAE effects and prevent CHDs, but few studies have assessed their effects on blood flow. We modeled binge drinking in quail embryos at gastrulation. Embryos were exposed to ethanol alone, FA (3.2 μg/egg) alone, and the two simultaneously. We quantified in cardiac looping stages (equivalent to 4 wk of human gestation), the regurgitant blood flow with Doppler optical coherence tomography (OCT) and endocardial cushion volumes using OCT imaging. Incidences of abnormal body curvature and heart rates were also measured. Embryos exposed to ethanol showed significantly increased regurgitant blood flow compared with controls, whereas embryos given FA with ethanol had significantly reduced regurgitant blood flow but without returning to control levels. Ethanol exposure led to significantly smaller, abnormal endocardial cushions, and the addition of FA improved their size, but they remained smaller than controls. Abnormal body curvatures after PAE were reduced in incidence but not fully prevented by FA. FA supplementation partially alleviated PAE-induced abnormal cardiovascular function and morphology. Normal blood flow and endocardial cushions are both required to produce a healthy four-chambered heart. These findings support that FA supplementation should begin early in pregnancy to prevent heart as well as neural tube defects. Investigations into the efficacy of combinations of compounds to prevent PAE-induced defects are warranted. NEW & NOTEWORTHY State-of-the-art biophotonic tools captured blood flow and endocardial cushion volumes in tiny beating quail embryo hearts, an accessible model for studying four-chambered heart development. Both hemodynamic flow and endocardial cushion volumes were altered with ethanol exposure but normalized when folic acid was introduced with ethanol. Folic acid supplementation preserved hemodynamic function that is intimately involved in sculpting the heart from the earliest stages of heart development.

There is currently a lack of consensus as to what defines exercise and resistance training in the cancer setting and whether current studies comply with exercise guidelines. This study aimed to quantify the available research studies using resistance training exercise interventions in the breast cancer setting for future clinical trial utilization. We systemically reviewed all available resistance exercise studies during and after breast cancer treatment in an attempt to quantify to the prescribed dose and whether regimens aligned with general exercise guidelines to improve functional mobility, body composition, and metabolic function. They were then compared with recommendations set forth by the national committees that create evidence-based exercise guidelines. Fifty studies met the initial criteria, with 35 meeting analysis criteria for evaluation. Fifteen studies evaluated an exercise regimen during cancer treatment, and 20 evaluated a regimen after treatment. The average adherence rates were 84% for all studies. Only 23 studies listed specific exercises used within the protocol. Most exercise regimens relied on open chain movements and machine exercises. Around half of studies met criteria to achieve hypertrophy, and 66% met American College of Sports Medicine exercise guidelines for cancer patients. A minority of breast cancer studies implementing a resistance training exercise regimen prescribed a regimen or specific dose that follows general exercise guidelines. This study highlights a potential deficiency in exercise programs designed for patients with breast cancer, and these findings should be considered in future study design.

Course-based undergraduate research experiences (CUREs) integrate authentic research into undergraduate chemistry laboratories, introducing students to research while simultaneously reinforcing fundamental concepts. Despite their ubiquitous nature in bioanalytical research, few CUREs have been published applying the fundamental techniques of separations, spectroscopy, quantification, and mass spectrometry. To engage students in learning these increasingly essential bioanalytical techniques, we designed and implemented a semester-long project-based course centered around the purification, quantification, and identification of heterologously expressed proteins in five succinct and adaptable modules. Instructors can use these modules to form the foundation of a CURE specific to their research interests. The extensive commercial availability of plasmids for transformation combined with the modular approach to laboratory experiments enables convenient customization to accommodate diverse research goals. Instructors can tailor the modules to meet the curricular requirements and instrumentation capabilities of their institutions and can easily extend the research goals to incorporate more specialized analytical techniques, as needed. Through the implementation of the five modules, students apply the fundaments of acid–base chemistry, statistics, quantification strategies, spectrophotometry, separations, and mass spectrometry, thus covering the material required in most undergraduate introductory analytical courses. Instructors can then use these modules as a backbone to support student-led discovery-based investigations for the remainder of the course. Students demonstrate their understanding through the completion of a comprehensive, publication-style laboratory report as well as a poster presentation at a university-wide undergraduate research symposium. Since first offering this course in 2016, student evaluations have been exceedingly positive, with over 75% of students indicating that the course both increased their scientific skills as well as their confidence in their ability to succeed in further science courses. Furthermore, 22% of students reported they were “much more” or “extremely more” likely to enroll in a Ph.D. program in science, math, or engineering following the courses, emphasizing the impact that project-based laboratories can have on undergraduate chemists’ career trajectories.

Tendon injuries are difficult to heal, in part, because intrinsic tendon healing, which is dominated by scar tissue formation, does not effectively regenerate the native structure and function of healthy tendon. Further, many current treatment strategies also fall short of producing regenerated tendon with the native properties of healthy tendon. There is increasing interest in the use of cell-instructive strategies to limit the intrinsic fibrotic response following injury and improve the regenerative capacity of tendon in vivo. We have established multifunctional, cell-instructive hydrogels for treating injured tendon that afford tunable control over the biomechanical, biochemical, and structural properties of the cell microenvironment. Specifically, we incorporated integrin-binding domains (RGDS) and assembled multifunctional collagen mimetic peptides that enable cell adhesion and elongation of stem cells within synthetic hydrogels of designed biomechanical properties and evaluated these materials using targeted success criteria developed for testing in mechanically demanding environments such as tendon healing. The in vitro and in situ success criteria were determined based on systematic reviews of the most commonly reported outcome measures of hydrogels for tendon repair and established standards for testing of biomaterials. We then showed, using validation experiments, that multifunctional and synthetic hydrogels meet these criteria. Specifically, these hydrogels have mechanical properties comparable to developing tendon; are noncytotoxic both in two-dimensional bolus exposure (hydrogel components) and three-dimensional encapsulation (full hydrogel); are formed, retained, and visualized within tendon defects over time (2-weeks); and provide mechanical support to tendon defects at the time of in situ gel crosslinking. Ultimately, the in vitro and in situ success criteria evaluated in this study were designed for preclinical research to rigorously test the potential to achieve successful tendon repair before in vivo testing and indicate the promise of multifunctional and synthetic hydrogels for continued translation. IMPACT STATEMENT: Tendon healing results in a weak scar that forms due to poor cell-mediated repair of the injured tissue. Treatments that tailor the instructions experienced by cells during healing afford opportunities to regenerate the healthy tendon. Engineered cell-instructive cues, including the biomechanical, biochemical, and structural properties of the cell microenvironment, within multifunctional synthetic hydrogels are promising therapeutic strategies for tissue regeneration. In this article, the preclinical efficacy of multifunctional synthetic hydrogels for tendon repair is tested against rigorous in vitro and in situ success criteria. This study indicates the promise for continued preclinical translation of synthetic hydrogels for tissue regeneration.

Background and Aims: In the REALM (Randomized, Observational Study of Entecavir to Assess Long-Term Outcomes Associated with Nucleoside/Nucleotide Monotherapy for Patients with Chronic HBV Infection) study, 12,378 patients with chronic hepatitis B virus (HBV) infection received up to 10 years of randomized therapy with entecavir or another HBV nucleos(t)ide analogue. Monitored clinical outcome events (COEs) included malignant neoplasms, HBV disease progression events, and deaths. An external event adjudication committee (EAC) was convened to provide real-time review of reported COEs to optimize data quality, and minimize potential adverse effects of the large cohort, interdisciplinary outcome assessments, geographic scope, and long duration. Methods: The EAC comprised an international group of hepatologists and oncologists with expertise in diagnosis of targeted COEs. The EAC reviewed and adjudicated COEs according to prospectively defined diagnostic criteria captured in the EAC charter. Operational processes, including data collection and query procedures, were implemented to optimize efficiency of data recovery to maximize capture of adjudicated COEs, the primary study outcome measure. Results: A total of 1724 COEs were reported and 1465 of these events were adjudicated by the EAC as reported by the investigators (85.0% overall concordance). Concordance by COE type varied: deaths, 99.6%; hepatocellular carcinoma (HCC), 83.3%; non-HCC malignancies, 88.0%; non-HCC HBV disease progression, 68.2%. Reasons for lack of concordance were most commonly lack of adequate supporting data to support an adjudicated diagnosis or evidence that the event pre-dated the study. Conclusions: The REALM EAC performed a critical role in ensuring data quality and consistency; EAC performance was facilitated by well-defined diagnostic criteria, effective data capture, and efficient operational processes. Trial registration: ClinicalTrials.gov NCT00388674.

Objectives To determine whether a program that eliminated pharmacy co-pays, the Blue Cross Blue Shield of Louisiana (BCBSLA) Zero Dollar Co-pay (ZDC) program, decreased health care spending. Previous studies have found that value-based insurance designs like the ZDC program have little or no impact on total health care spending. ZDC included an expansive set of medications related to 4 chronic diseases rather than a limited set of medications for 1 or 2 chronic diseases. Additionally, ZDC focused on the most at-risk patients. Study design ZDC began in 2014 and enrolled patients over time based on (1) when a patient answered a call from a nurse care manager and (2) when a patient or their employer changed the benefit structure to meet the program criteria. During 2015 and 2016, 265 patients with at least 1 chronic condition (asthma, diabetes, hypertension, mental illness) enrolled in ZDC. Methods Observational study using within-patient variation and variation in patient enrollment month to identify the impact of the ZDC program on health spending measures. We used 100% BCBSLA claims data from January 2015 to June 2018. Monthly level event studies were used to test for differential spending patterns prior to ZDC enrollment. Results We found that total spending decreased by $205.9 (P = .049) per member per month, or approximately 18%. We saw a decrease in medical spending ($195.0; P = .023) but did not detect a change in pharmacy spending ($7.59; P = .752). We found no evidence of changes in spending patterns prior to ZDC enrollment. Conclusions The ZDC program provides evidence that value-based insurance designs that incorporate a comprehensive set of medications and focus on populations with chronic disease can reduce spending.

Purpose: Patients with triple-negative breast cancer (TNBC) with homologous recombination deficient tumors achieve significantly higher pathologic complete response (pCR) rates when treated with neoadjuvant platinum-based therapy. Tumor-infiltrating lymphocytes (TIL) are prognostic and predictive of chemotherapy benefit in early stage TNBC. The relationship between TILs, BRCA1/2 mutation status, and homologous recombination deficiency (HRD) status in TNBC remains unclear. Experimental Design: We performed a pooled analysis of five phase II studies that included patients with TNBC treated with neoadjuvant platinum-based chemotherapy to evaluate the association of TILs with HRD status (Myriad Genetics) and tumor BRCA1/2 mutation status. Furthermore, the relationship between pathologic response assessed using the residual cancer burden (RCB) index and HRD status with adjustment for TILs was evaluated. Results: Among 161 patients, stromal TIL (sTIL) density was not significantly associated with HRD status (P = 0.107) or tumor BRCA1/2 mutation status (P = 0.391). In multivariate analyses, sTIL density [OR, 1.23; 95% confidence interval (CI), 0.94–1.61; P = 0.139] was not associated with pCR, but was associated with RCB 0/I status (OR 1.62; 95% CI, 1.20–2.28; P = 0.001). HRD was significantly associated with both pCR (OR 12.09; 95% CI, 4.11–44.29; P = 7.82 × 10−7) and RCB 0/I (OR 10.22; 95% CI, 4.11–28.75; P = 1.09 × 10−7) in these models. Conclusions: In patients with TNBC treated with neoadjuvant platinum-based therapy, TIL density was not significantly associated with either tumor BRCA1/2 mutation status or HRD status. In this pooled analysis, HRD and sTIL density were independently associated with treatment response, with HRD status being the strongest predictor.

Community-based management is an increasingly important form of governance and control of forests and other natural resources. In Indonesia, government policy aims to expand the role of communities in controlling and managing forests. Since the 1970s, many different forms of community forestry (CF) have been implemented in Indonesia but there has been little systematic analysis of these different approaches. This paper presents a typology of CF in Indonesia to present academic knowledge of CF in a form that is useful for practice. The typology acknowledges the networked nature of communities and was developed through qualitative analysis of 311 documents representing 112 cases of CF. Two dimensions emerged that illustrate the evolution of CF: a 'formality' dimension and a 'support' dimension. The former indicated the degree of government authorisation and the latter indicated the degree and type of support provided to communities from governments, businesses, NGOs or other external actors. Nine types of CF were identified, six formal, two partially formalised and one informal. An analysis of these types revealed there are mixed benefits for communities in formalising their access to forests and that the challenges, and therefore needs for support, differ markedly between communities. This study provides a systematic basis for researchers aiming to understand the processes of transition to CF, and for policy makers and practitioners aiming to implement CF in Indonesia and elsewhere.

One factor that contributes to the high prevalence of fetal alcohol spectrum disorder (FASD) is binge-like consumption of alcohol before pregnancy awareness. It is known that treatments are more effective with early recognition of FASD. Recent advances in retrospective motion correction for the reconstruction of three-dimensional (3D) fetal brain MRI have led to significant improvements in the quality and resolution of anatomical and diffusion MRI of the fetal brain. Here, a rhesus macaque model of FASD, involving oral self-administration of 1.5 g/kg ethanol per day beginning prior to pregnancy and extending through the first 60 d of a 168-d gestational term, was utilized to determine whether fetal MRI could detect alcohol-induced abnormalities in brain development. This approach revealed differences between ethanol-exposed and control fetuses at gestation day 135 (G135), but not G110 or G85. At G135, ethanol-exposed fetuses had reduced brainstem and cerebellum volume and water diffusion anisotropy in several white matter tracts, compared to controls. Ex vivo electrophysiological recordings performed on fetal brain tissue obtained immediately following MRI demonstrated that the structural abnormalities observed at G135 are of functional significance. Specifically, spontaneous excitatory postsynaptic current amplitudes measured from individual neurons in the primary somatosensory cortex and putamen strongly correlated with diffusion anisotropy in the white matter tracts that connect these structures. These findings demonstrate that exposure to ethanol early in gestation perturbs development of brain regions associated with motor control in a manner that is detectable with fetal MRI.

Differences in the mutation spectrum across ethnicities suggest the importance of identifying genes in addition to common high penetrant genes to estimate the associated breast cancer risk in China. A total of 1338 high-risk breast cancer patients who tested negative for germline BRCA1, BRCA2, TP53, and PTEN mutations between 2007 and 2017 were selected from the Hong Kong Hereditary Breast Cancer Family Registry. Patient samples were subjected to next-generation DNA sequencing using a multigene panel (Color Genomics). All detected pathogenic variants were validated by bidirectional DNA sequencing. The sequencing data were coanalyzed by a bioinformatics pipeline developed in-house. Sixty-one pathogenic variants (4.6%) were identified in this cohort in 11 cancer predisposition genes. Most carriers (77.1%) had early onset of breast cancer (age

Experience in applying research suggests that new knowledge requires development and change before it can be applied in everyday settings, but there has been little examination of how this occurs. Through two case studies of new knowledge about social values being developed for a bushfire agency in Victoria, Australia, we follow how pre-existing social research findings about “valued attributes” are shaped and changed as they were applied in two different organisational activities of planning guidance and community engagement. We form a conceptual framework of reduction and amplification, stretching, re-articulation, and crystallisation to observe how the social research findings were drawn on, modified, and incorporated into the future directions of the organisation. In finding that the social research was stretched and crystallised differently in the two case studies, we consider how organisational context and relationships influence how social research findings are shaped and changed. We consider implications for theory and practice in fostering integration between academic research and real-world application.

This study examined the association between the sleep environment and sleep disturbances in 44 low-income Latinx youth. Participants reported an average of 2.10 past-week ambient sleep disruptions....

Healthcare reimbursement is rapidly moving away from a fee-for-service model toward value-based purchasing. An integral component of this new focus on quality is patient-centered outcomes. One metric used to define patient satisfaction is the Press Ganey Patient Satisfaction Survey. Data are lacking to accurately benchmark these scores based on diagnosis. We sought to identify if different colorectal disease processes affected a patient’s perception of their healthcare experience. Adult colorectal patients seen between July 2015 and September 2016 in a tertiary hospital colorectal clinic were mailed a Press Ganey survey. Patients were stratified based on diagnosis: neoplasia, IBD, anorectal and benign colorectal disease. Survey scores were compared across the groups with adjustment for confounding variables. 312 patients responded and formed the cohort. The mean age was 61 (range 18–93) and 56% were women. The cohort breakdown was 38% neoplasia, 32% anorectal, 21% benign, and 9% IBD. In a multivariable model, there was a difference in PG scores by diagnosis; patients with neoplasia had higher Overall scores (β 10.2; Std Error 4.0; p = 0.01), Care Provider scores (β 8.5; Std Error 4.2; p = 0.04), Nurse Assistant scores (β 15.0; Std Error 5.7; p = 0.01), and Personal Issues scores (β 11.8; Std Error 5/0; p = 0.01). Press Ganey scores were found to vary significantly. Patients with a neoplasia diagnosis reported higher overall satisfaction, Care Provider, Nurse Assistant, and Personal Issues scores. Adjustment for disease condition is important when assessing patient satisfaction as an indicator of quality and as a metric for reimbursement. This study adds to increasing evidence about bias in these scores.

Contains fulltext : 225261.pdf (Publisher’s version ) (Closed access) Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome that is characterised by a high prevalence of diffuse gastric cancer and lobular breast cancer. It is largely caused by inactivating germline mutations in the tumour suppressor gene CDH1, although pathogenic variants in CTNNA1 occur in a minority of families with HDGC. In this Policy Review, we present updated clinical practice guidelines for HDGC from the International Gastric Cancer Linkage Consortium (IGCLC), which recognise the emerging evidence of variability in gastric cancer risk between families with HDGC, the growing capability of endoscopic and histological surveillance in HDGC, and increased experience of managing long-term sequelae of total gastrectomy in young patients. To redress the balance between the accessibility, cost, and acceptance of genetic testing and the increased identification of pathogenic variant carriers, the HDGC genetic testing criteria have been relaxed, mainly through less restrictive age limits. Prophylactic total gastrectomy remains the recommended option for gastric cancer risk management in pathogenic CDH1 variant carriers. However, there is increasing confidence from the IGCLC that endoscopic surveillance in expert centres can be safely offered to patients who wish to postpone surgery, or to those whose risk of developing gastric cancer is not well defined.

Special Issue: The ENIGMA Consortium: the first 10 years., Schizophrenia is associated with widespread alterations in subcortical brain structure. While analytic methods have enabled more detailed morphometric characterization, findings are often equivocal. In this meta-analysis, we employed the harmonized ENIGMA shape analysis protocols to collaboratively investigate subcortical brain structure shape differences between individuals with schizophrenia and healthy control participants. The study analyzed data from 2,833 individuals with schizophrenia and 3,929 healthy control participants contributed by 21 worldwide research groups participating in the ENIGMA Schizophrenia Working Group. Harmonized shape analysis protocols were applied to each site's data independently for bilateral hippocampus, amygdala, caudate, accumbens, putamen, pallidum, and thalamus obtained from T1-weighted structural MRI scans. Mass univariate meta-analyses revealed more-concave-than-convex shape differences in the hippocampus, amygdala, accumbens, and thalamus in individuals with schizophrenia compared with control participants, more-convex-than-concave shape differences in the putamen and pallidum, and both concave and convex shape differences in the caudate. Patterns of exaggerated asymmetry were observed across the hippocampus, amygdala, and thalamus in individuals with schizophrenia compared to control participants, while diminished asymmetry encompassed ventral striatum and ventral and dorsal thalamus. Our analyses also revealed that higher chlorpromazine dose equivalents and increased positive symptom levels were associated with patterns of contiguous convex shape differences across multiple subcortical structures. Findings from our shape meta-analysis suggest that common neurobiological mechanisms may contribute to gray matter reduction across multiple subcortical regions, thus enhancing our understanding of the nature of network disorganization in schizophrenia., Center for Integrated Healthcare, U.S. Department of Veterans Affairs, Grant/Award Number: I01 CX000497; Commonwealth Health Research Board, Grant/Award Number: HRA_POR/2011/100; Conselho Nacional de Desenvolvimento Científico e Tecnológico, Grant/Award Numbers: 478466/2009, 480370/2009; Department of Energy, Labor and Economic Growth, Grant/Award Number: DE-FG02-99ER62764; Forskningsrådet om Hälsa, Arbetsliv och Välfärd, Grant/Award Numbers: K2009-62X-15077-06-3, K2012-61X-15077-09-3, 523-2014-3467, 2009-7053, 2013-2838; Fundação Amazônia Paraense de Amparo à Pesquisa, Grant/Award Numbers: 2009/14891-9, 2010/18672-7, 2012/23796-2, 2013/039; Instituto de Salud Carlos III, Grant/Award Numbers: FIS 00/3095, 01/3129, PI020499, PI060507, PI10/001; National Health and Medical Research Council, Grant/Award Numbers: 1009064, 496682; National Institutes of Health, Grant/Award Numbers: 1RC1MH089257, MH 60722, MH019112, MH064045, MH085096, MH098130, MO1 RR025758, P41RR14075, P50 MH071616, R01 DA053028, R01 EB020062, R01 HD050735, R01 MH056584, R01 MH084803, R01 MH116147, R01 MH117601, R01EB005846, R01EB015611, R01MH074797, R21 MH097196, R21MH097196, R37MH43375, S10 OD023696, T32 AG058507, T32 MH073526, TR000153, U01 MH097435, U24 RR021382A, U24 RR021992, U24 RR025736, U24 RR21992, U24RR021992, U54 EB020403, U54EB020403, UL1 TR000153; National Science Foundation, Grant/Award Numbers: 1636893, 1734853; Norges Forskningsråd, Grant/Award Numbers: 213837, 217776, 223273; Science Foundation Ireland, Grant/Award Numbers: 08/IN.1/B1916, 12/IP/1359; Wellcome Trust, Grant/Award Number: 072894/2/03/Z.

In order to determine, document, and communicate the value of respiratory therapists performing respiratory care procedures, the respiratory care profession needs to position itself to capture and report both time and value standards that can be applied in allocating respiratory care resources. To do this, we propose a new metric called value-efficiency. If we wish to use value-efficiency as a metric to justify respiratory care activities and support labor budgets, there are three key considerations: (1) What value does respiratory care add to the health care organization? (2) Are the interventions provided necessary and of clinical value? (3) What is the value of the respiratory therapist in the delivery of these services? Significant challenges are facing the respiratory care profession and a focus on value-efficiency is a direction the profession must pursue. This approach is a practical response to the increasing demands of payers, administrators, consultants, and patients.

Background In search of innovative approaches to the challenge of uncontrolled hypertension, we assessed the association between preference for immediate gratification (i.e., high discounting rate), low medication adherence, and uncontrolled blood pressure (BP) in adults with hypertension. Methods Using a probability discounting model and the Collier–Williams hypothetical discount rate framework, participants in this cross-sectional study reported their preference for a smaller amount of money available immediately (high discount rate; immediate gratification preference) vs. a larger amount available 1 year later (low discount rate; delayed gratification preference). Multivariable Poisson regression was used to test the association of high discounting rates with low antihypertensive medication adherence using the validated 4-item Krousel-Wood Medication Adherence Scale (K-Wood-MAS-4 score ≥1). Mediation of the association between high discounting rate and uncontrolled BP (systolic/diastolic BP ≥ 130/80 mm Hg) by low adherence was tested using the counterfactual approach. Results Among 235 participants (mean age 63.7 ± 6.7 years; 51.1% women; 41.9% Black), 50.6% had a high 1-year discount rate, 51.9% had low K-Wood-MAS-4 adherence, and 59.6% had uncontrolled BP. High discounting rates were associated with low adherence (adjusted prevalence ratio 1.58, 95% confidence interval (CI) 1.18, 2.12). Forty-three percent (95% CI 40.9%, 45.8%) of the total effect of high discount rate on uncontrolled BP was mediated by low adherence. Conclusions Adults with preference for immediate gratification had worse adherence; low adherence partially mediated the association of high discount rate with uncontrolled BP. These results support preference for immediate gratification as an innovative factor underlying low medication adherence and uncontrolled BP.

Background: Talazoparib, a PARP1 inhibitor, is active in germline BRCA1/2 mutant advanced HER2-negative breast cancer, but its activity beyond BRCA1/2 less well understood. The Talazoparib Beyond BRCA clinical trial treated 20 patients with germline (g) or somatic (s) mutations in HR pathways genes other than BRCA1/2, which included PALB2, CHEK2, ATM, BRIP1, RAD50, ATR, PTEN, and FANCA. Talazoparib treatment was associated with a 31% overall response rate in patients with breast cancer, including tumor regression from baseline as best response in 6 out of 6 patients treated gPALB2 mutations. We now present the results of additional genomic studies to further characterize treatment responses and resistance mechanisms. Methods: Primary and metastatic tumor biopsies were assessed using the commercially-available next-generation sequencing HRD assay (Myriad). Panel gene sequencing of tumors was performed for 108 genes associated with genomic instability. Loss-of-heterozygosity (LOH) was assessed in tumors. Tumor/normal exome sequencing identified pre-treatment somatic variants. Circulating-tumor DNA at baseline and disease progression was assessed by targeted panel sequencing and plasma whole exome sequencing. Results: Of the 18 HRD assays performed, 3 failed and were thus excluded. Seven patients had HRD analysis performed on both primary and metastatic tumors. For these patients the HRD score was significantly higher in the metastasis versus the primary (means 46.2 versus 36.5, p = 0.018 by paired t-test). By panel sequencing of tumors (n=18) the most common alterations detected included mutations in PIK3CA (n=8), PALB2 (n=6), ATM (n=5), KRAS (n=4), PTEN (n=5) and TP53 (n=4). In all cases except one, the HR-associated mutation used as entry criteria were detected. LOH analysis showed that of tumors with gPALB2 mutations, 3 of the 6 had LOH for PALB2, and an additional two tumors had 2 independent PALB2 mutations suggesting bi-allelic inactivation. The one remaining tumor had an uncertain LOH result due to test failure. Thus, it is likely that most, if not all, of the tumors in our cohort with gPALB2 mutations had complete inactivation of PALB2 gene function. Other detected mutations that were associated with LOH included all sTP53 mutations (n=4), all gCHEK2 mutations (n=3), gFANCA (n=1), all sRB1 mutations (n=3) and NF1 (n=1). Of the three gATM mutations one had LOH, while the others had two independent mutations, suggestive of bi-allelic inactivation. sATM mutations were associated with LOH in a breast cancer and with 2 independent (possibly bi-allelic) mutations in a non-breast cancer. Additional results from ctDNA targeted sequencing and plasma whole exome sequencing of baseline and progression samples will be presented. Conclusions: In this proof-of-concept phase II study, talazoparib demonstrated activity in HER2-negative advanced breast cancer patients with a HR pathway mutation beyond BRCA1/2, especially in patients with gPALB2 mutations and high HRD scores. These additional genomic analyses provide evidence that HRD scores may be significantly higher in metastatic samples compared to primary tumors. Also, we detected either LOH or bi-allelic inactivation for most HR-associated mutations used to determine eligibility. These findings may inform selection of patients for PARP inhibitor monotherapy beyond BRCA1/2. Citation Format: Joshua J Gruber, Anosheh Afghahi, Alyssa Hatton, Wyatt Gross, Jessica Foran, Alex McMillan, James M Ford, Melinda L Telli. Genomic analysis from the talazoparib beyond BRCA clinical trial: Homologous recombination (HR) deficiency scores, loss-of-heterozygosity and mutations in non-BRCA1/2 mutant tumors with other HR mutations [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD10-12.

Post-fundoplication dyspepsia is a common complication of gastric fundoplication surgeries. This can be attributable to the loss of fundal relaxation, decreased gastric accommodation, and/or alterations in gastric motility and sensitivity following fundoplication. The role of neuromodulators in the management of such symptoms is unknown. We retrospectively assessed the efficacy of neuromodulators such as tricyclic antidepressants, buspirone, and mirtazapine for the management of post-fundoplication dyspepsia.

BackgroundSchizophrenia is associated with aberrant gamma band power, hypothesized to reflect imbalance in the excitation-inhibition (E/I) ratio and undermine neural signal efficiency. Relationships between resting-state gamma, E/I balance, and regional hemodynamics from the fMRI BOLD signal are unknown.MethodsWe recorded simultaneous EEG-fMRI at rest, with eyes open, in people with schizophrenia (n= 57) and people without a psychiatric diagnosis (n= 46) and identified gamma and aperiodic EEG parameters associated with E/I balance. Measures from all EEG channels were entered into a whole-brain, parametric modulation analysis followed by statistical correction for multiple comparisons. Sensory gating was assessed using the Sensory Gating Inventory, and psychotic symptoms were assessed using the Positive and Negative Syndrome Scale.ResultsAcross groups, gamma power modestly predicts a steeper aperiodic slope (greater inhibition), without group differences in either gamma power or aperiodic slope. In schizophrenia, gamma-BOLD coupling was reduced in bilateral auditory regions of the superior temporal gyri and inversely correlated with sensory gating deficits and symptom severity. Analysis of the spectral features of scanner sounds revealed distinct peaks in the gamma range, reflecting a rapidly repeating scanner pulse sound present throughout the resting state recording.ConclusionRegional hemodynamic support for putative inhibitory and excitatory contributions to resting EEG are aberrant in SZ. Deficient gamma coupling to auditory BOLD may reflect impaired gating of fMRI-scanner sound.

OBJECTIVES Although pharmacy benefit carve-outs are promoted as a cost-containment tool, their impact on medical spending is not well understood. We compare the health care spending of Blue Cross and Blue Shield of Louisiana (BCBSLA) members covered by an integrated ("carved-in") pharmacy benefit with that of members covered under a pharmacy benefit carve-out. STUDY DESIGN Matched, longitudinal cohort study. METHODS We identified members with coverage through an employer contracting for administrative services only (ie, self-insured) and determined whether they received a pharmacy benefit through BCBSLA. We matched members with and without integrated benefits using a baseline year and compared their medical spending trajectories in 3 subsequent years. These comparisons were repeated in the subset of patients with chronic comorbidities. RESULTS Among patients with chronic illnesses, relative growth in per-member per-month (PMPM) medical spending was significantly lower in the integrated benefit group by the second and third follow-up years. Neither the level nor the growth of PMPM medical spending significantly differed in the full population sample, although point estimates suggest that the integrated benefit members may be on a lower cost growth trajectory over time. CONCLUSIONS Members with chronic illnesses receiving an integrated pharmacy benefit experienced slower medical cost growth compared with members covered by a pharmacy carve-out. Group leaders and brokers should consider the additional cost savings achieved by integrated pharmacy benefits when comparing the total costs of carve-in vs carve-out prescription drug programs.

In this work, we focus on explicitly nonlinear relationships in functional networks. We introduce a technique using normalized mutual information (MI), that calculates the nonlinear correlation between different brain regions. We demonstrate our proposed approach using simulated data, then apply it to a dataset previously studied in (Damaraju et al., 2014). This resting-state fMRI data included 151 schizophrenia patients and 163 age- and gender-matched healthy controls. We first decomposed these data using group independent component analysis (ICA) and yielded 47 functionally relevant intrinsic connectivity networks. Our analysis showed a modularized nonlinear relationship among brain functional networks that was particularly noticeable in the sensory and visual cortex. Interestingly, the modularity appears both meaningful and distinct from that revealed by the linear approach. Group analysis identified significant differences in nonlinear dependencies between schizophrenia patients and healthy controls particularly in visual cortex, with controls showing more nonlinearity in most cases. Certain domains, including cognitive control, and default mode, appeared much less nonlinear, whereas links between the visual and other domains showed evidence of substantial nonlinear and modular properties. Overall, these results suggest that quantifying nonlinear dependencies of functional connectivity may provide a complementary and potentially important tool for studying brain function by exposing relevant variation that is typically ignored.Further, we propose a method that captures both linear and nonlinear effects in a ‘boosted’ approach. This method increases the sensitivity to group differences in comparison to the standard linear approach, at the cost of being unable to separate linear and nonlinear effects.

Obstruction from stricturing Crohn's disease remains one of the most common reasons for intervention. Acute inflammation is often responsive to medications, but chronic fibrosis is unlikely to respond and will generally go on to require additional treatment. Newer methods, such as endoscopic balloon dilation, are gaining grounds in strictures that are amenable, but with high recurrence and strictures that may not be endoscopically accessible, surgery still plays a key role in the treatment of obstructing Crohn's disease.

Clostridium (or Clostridioides) difficile infection (CDI) is a common side effect of antimicrobial therapy and is increasingly linked with health care-associated transmissions. Antimicrobial stewardship programs (ASP) have demonstrated success in decreasing in-hospital CDI cases. We implemented an ASP targeting inappropriate or unnecessary use of all antibiotics especially empiric piperacillin-tazobactam and fluoroquinolone use. Concurrently, we monitored all health-care associated CDI. Our CDI cases were markedly decreased after initiation of our ASP.

Acute lymphoblastic leukemia (ALL) develops in the bone marrow in the vicinity of stromal cells known to promote tumor development and treatment resistance. We previously showed that the cyclooxygenase (COX) inhibitor indomethacin prevents the ability of stromal cells to diminish p53-mediated killing of cocultured ALL cells in vitro, possibly by blocking the production of prostaglandin E(2) (PGE(2)). Here, we propose that PGE(2) released by bone marrow stromal cells might be a target for improved treatment of pediatric ALL. We used a xenograft model of human primary ALL cells in nonobese diabetic-scid IL2rγ(null) mice to show that indomethacin delivered in the drinking water delayed the progression of ALL in vivo. The progression was monitored by noninvasive in vivo imaging of the engrafted leukemic cells, as well as by analyses of CD19(+)CD10(+) leukemic blasts present in spleen or bone marrow at the termination of the experiments. The indomethacin treatment increased the level of p53 in the leukemic cells, implying that COX inhibition might reduce progression of ALL by attenuating protective paracrine PGE(2) signaling from bone marrow stroma to leukemic cells.

It is well recognised that medical training globally and at all levels lacks sufficient incorporation of genetics and genomics education to keep up with the rapid advances and growing application of genomics to clinical care. However, the best strategy to implement these desired changes into postgraduate medical training and engage learners is still unclear. We developed a novel elective rotation in ‘Genomic Medicine and Undiagnosed Diseases’ for categorical Internal Medicine Residents to address this educational gap and serve as an adaptable model for training that can be applied broadly across different specialties and at other institutions. Key curriculum goals achieved include increased understanding about genetic testing modalities and tools available for diagnosis and risk analysis, the role of genetics-trained allied health professionals, and indications and limitations of genetic and genomic testing in both rare and common conditions.

Rationale: Little direction exists on how to integrate early palliative care in chronic obstructive pulmonary disease (COPD). Objectives: We sought to identify patient and family caregiver early palliative care needs across stages of COPD severity. Methods: As part of the Medical Research Council Framework developmental phase for intervention development, we conducted a formative evaluation of patients with moderate to very severe COPD (forced expiratory volume in 1 s [FEV(1)]/FVC < 70% and FEV(1) < 80%-predicted) and their family caregivers. Validated surveys on quality of life, anxiety and depressive symptoms, and social isolation quantified symptom severity. Semi-structured interviews were analyzed for major themes on early palliative care and needs in patients and family caregivers and across COPD severity stages. Results: Patients (n = 10) were a mean (±SD) age of 60.4 (±7.5) years, 50% African American, and 70% male, with 30% having moderate COPD, 30% severe COPD, and 40% very severe COPD. Family caregivers (n = 10) were a mean age of 58.3 (±8.7) years, 40% African American, and 10% male. Overall, 30% (n = 6) of participants had poor quality of life, 45% (n = 9) had moderate–severe anxiety symptoms, 25% (n = 5) had moderate–severe depressive symptoms, and 40% (n = 8) reported social isolation. Only 30% had heard of palliative care, and most participants had misconceptions that palliative care was end-of-life care. All participants responded positively to a standardized description of early palliative care and were receptive to its integration as early as moderate stage. Five broad themes of early palliative care needs emerged: 1) coping with COPD; 2) emotional symptoms; 3) respiratory symptoms; 4) illness understanding; and 5) prognostic awareness. Coping with COPD and emotional symptoms were commonly shared early palliative care needs. Patients with very severe COPD and their family caregivers prioritized illness understanding and prognostic awareness compared with those with moderate–severe COPD. Conclusions: Patients with moderate to very severe COPD and their family caregivers found early palliative care acceptable and felt it should be integrated before end-stage. Of the five broad themes of early palliative care needs, coping with COPD and emotional symptoms were the highest priority, followed by respiratory symptoms, illness understanding, and prognostic awareness.

BACKGROUND: Margin negative resection of rectal cancer with minimally invasive techniques remains technically challenging. Robotic surgery has potential advantages over traditional laparoscopy. We hypothesize that the difference in the rate of negative margin status will be < 6% between laparoscopic and robotic approach. METHODS: The National Cancer Database (2010–2014) was queried for adults with locally advanced rectal cancer who underwent neoadjuvant chemoradiation and curative resection to conduct an observational retrospective cohort study of a prospectively maintained database. Patients were grouped by either robotic (ROB) or laparoscopic (LAP) approach in an intent-to-treat analysis. Primary outcome was negative margin status, defined as a composite of circumferential resection margin and distal margin. Secondary outcomes included length of stay (LOS), readmission, 90-day mortality, and overall survival. RESULTS: 7616 patients with locally advanced rectal cancer who underwent minimally invasive resection were identified. 2472 (32%) underwent attempted robotic approach. The overall conversion rate was 13% and was increased in the laparoscopic group [LAP: 15% vs. ROB: 8%; OR 0.47; 95% CI (0.39, 0.57)]. Differences in margin negative resection rate were within the prespecified range of practical equivalence (LAP: 93% vs.: ROB 94%; 95% CI (0.69, 1.06); p(δ) = 1). For secondary outcomes, there was no difference in 30-day readmission [LAP: 9% vs.: ROB 8%; 95% CI (0.84, 1.24)] and 90-day mortality [LAP: 1% vs.: ROB 1%; 95% CI (0.38, 1.24)]. While the median LOS was 5 days in both groups, the mean LOS was 0.6 (95% CI: 0.24, 0.89) days shorter in the robotic group. CONCLUSION: This robust analysis supports either robotic or laparoscopic approach for resection of locally advanced rectal cancer from a margin perspective. Both have similar readmission and 5-year overall survival rates. Patients undergoing robotic surgery have a 0.6-day decrease in LOS and decreased conversion rate.

Evidence for gadolinium-based contrast agent- (GBCA-) induced disease continues to mount. Risk factors for gadolinium-induced systemic fibrosis are entirely unexplored. Obesity-related renal injury is characterized by activation of glomerular mesangial cells and podocyte damage with alteration of lipid metabolism/lipid accumulation in both cell types resulting in matrix accumulation and eventual progression to glomerulosclerosis. We examined the consequences of GBCA treatment in the kidneys from mice with normal kidney function and the potential interplay between obesity and gadolinium exposure. We found that administration of GBCA (4 weeks) causes significant renal fibrosis and podocyte injury that are associated with metabolic disorders as evidenced by dyslipidemia. Metabolomic analysis demonstrated that renal lipid metabolism and metabolic markers of collagen turnover are significantly altered by gadolinium. GBCA stimulates myeloid-derived fibrocytes to the kidney. Obesity was induced by feeding a group of mice a high fat diet (HFD) for 22 weeks. Groups were sub-randomized to GBCA treatment versus none for 4 weeks before sacrifice. HFD-induced fibrosis and podocyte injury were worsened by GBCA. Similarly, HFD-mediated hyperlipidemia and lipid metabolites were exacerbated by gadolinium. This is the first evidence that GBCA causes significant metabolic disorders and kidney injury in mice without renal insufficiency and that the injurious actions of GBCA are amplified by obesity. The understanding of the functional interplay between gadolinium and obesity will allow the development of therapeutic interventions or the establishment of effective preventive measures to reduce gadolinium- and obesity-mediated renal pathologies.

There is growing evidence that rather than using a single brain imaging modality to study its association with physiological or symptomatic features, the field is paying more attention to fusion of multimodal information. However, most current multimodal fusion approaches that incorporate functional magnetic resonance imaging (fMRI) are restricted to second-level 3D features, rather than the original 4D fMRI data. This trade-off is that the valuable temporal information is not utilized during the fusion step. Here we are motivated to propose a novel approach called "parallel group ICA+ICA" that incorporates temporal fMRI information from group independent component analysis (GICA) into a parallel independent component analysis (ICA) framework, aiming to enable direct fusion of first-level fMRI features with other modalities (e.g., structural MRI), which thus can detect linked functional network variability and structural covariations. Simulation results show that the proposed method yields accurate intermodality linkage detection regardless of whether it is strong or weak. When applied to real data, we identified one pair of significantly associated fMRI-sMRI components that show group difference between schizophrenia and controls in both modalities, and this linkage can be replicated in an independent cohort. Finally, multiple cognitive domain scores can be predicted by the features identified in the linked component pair by our proposed method. We also show these multimodal brain features can predict multiple cognitive scores in an independent cohort. Overall, results demonstrate the ability of parallel GICA+ICA to estimate joint information from 4D and 3D data without discarding much of the available information up front, and the potential for using this approach to identify imaging biomarkers to study brain disorders.

Land use change is often a result of negotiation between different interests. Focusing on negotiation practices helps to provide a nuanced understanding of land use change processes over time. We examine negotiations within a concession model for land development in the southern tropical peatlands of Central Kalimantan province in Indonesia. This region can be described as a ‘resource frontier’, where historical landscape transformations from large development projects and oil palm plantations intersect with state models of forest conservation and recent Reducing Emissions from Degradation and Forest Degradation (REDD+) projects. The study drew on actor-network theory (ANT) and combined an ethnographic approach with document analysis for understanding how these landscape transformations and land allocation for large concessions has left a legacy of continuing uncertainty and conflict over land. There is considerable gaming between actors to achieve their desired outcome. Increased competition for land and contested legal arrangements mean that the negotiations are virtually never-ending. ‘Winning’ at one stage of a negotiation may mean that those who feel they have lost will organise and use the system to challenge the outcomes. These findings show that attempts to implement pre-determined plans or apply global environmental goals at resource frontiers will become entangled in fluid and messy negotiations over land, rather than achieving any desired new status quo.

The utility of positron emission tomography-computed tomography (PET-CT) in distinguishing Richter's transformation versus chronic lymphocytic leukemia (CLL) progression after ibrutinib and/or idelalisib was assessed in a post hoc analysis of a phase II study of venetoclax. Patients underwent PET-CT at screening and were not enrolled/treated if Richter's transformation was confirmed pathologically. Of 167 patients screened, 57 met criteria for biopsy after PET-CT. Of 35 patients who underwent biopsy, eight had Richter's transformation, two had another malignancy, and 25 had CLL. A PET-CT maximum standardized uptake value (SUVmax) ≥10 had 71% sensitivity and 50% specificity for detecting Richter's transformation [Odds Ratio (OR): 2.5, 95%CI: 0.4-15; P=0.318]. Response rate to venetoclax was similar for screening SUVmax

Background: Emerging data suggest that some patients with TNBC could benefit from the addition of immune-based therapy. This observation is in part due to the significant association between distinct tumor-infiltrating lymphocytes (TILs) and prognosis in TNBC. Efforts to comprehensively characterize the immune microenvironment of TNBCs are critically important to gain a better understanding of the immune landscape and how it influences response to both standard chemotherapy and immunotherapy. We previously assessed both stromal TILs (sTILs) and intraepithelial TILs (iTILs) from pre-treatment tumor samples from patients enrolled on a phase II study of neoadjuvant gemcitabine, carboplatin and iniparib (PrECOG 0105; NCT00813956). We found that both iTILS and sTILS significantly associated with pathologic response. Furthermore, we assessed a novel 'in silico flow cytometry' gene expression-based method, CIBERSORT, designed to assess overall immune content and deconvolute the relative levels of distinct leukocyte subsets in tumors. Specific leukocyte subsets significantly associated with pCR included activated memory CD4+ T cells, CD8+ T cells and M1 macrophages (all p Methods: We performed SPARTA - Spatial Perception And Regional Tumor Analysis - a multiplexed immunohistochemistry-based technology with data visualization and analysis modules that is designed to capture clinically relevant information about the tumor microenvironment in 72 pre-treatment FFPE tumor sections from patients enrolled on PrECOG 0105. SPARTA was used to test and analyze the coordinated expression of PD-L1, PD-1, CD45RO, CD4, CD8 and HLA-DRA in the study cohort from whole slide scanned images. Pathologic response at the time of surgery was evaluated using the residual cancer burden index. Germline BRCA1 and BRCA2 status was known for all patients. Results: Of 72 samples, 67 were evaluable for SPARTA analysis. Within a subset of tumors separately profiled by both SPARTA (FFPE/IHC microscopy) and CIBERSORT (Frozen/RNA GEP), we found significant correlation for clinically relevant TIL subpopulations, including for CD8+ T cells (r=0.83, p Conclusions: Spatial mapping of the immune microenvironment in primary TNBC reveals distinct immune cell populations associated with response to neoadjuvant platinum-based therapy. Citation Format: Telli ML, Vinayak S, Khododoust MS, Gruber JJ, Ford JM, Sanchez P, Banayan N, Azimi S, Tumeh PC, Newman AM, Alizadeh AA. Spatial mapping of the immune microenvironment in primary triple-negative breast cancer (TNBC) and association with neoadjuvant therapy response [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD5-12.

Background Resection of T4 colon cancer remains challenging compared to lower T stages. Data on the effect of neoadjuvant radiation to improve resectability and survival are lacking. The purpose of this study is to describe the use and outcomes of neoadjuvant radiation therapy in clinical T4 colon cancer. Methods Adults with clinical evidence of T4 locally advanced colon cancer were included from the National Cancer Database (2004–2014). Bivariate and multivariable analyses were used to examine the association between neoadjuvant radiation therapy and R 0 resection rate, multivisceral resection, and overall survival. Results Fifteen thousand two hundred and seven patients with clinical T4 disease who underwent resection were identified over the study period. One hundred ninety-five (1.3%) underwent neoadjuvant radiation therapy. Factors associated with the use of neoadjuvant radiation therapy included younger age, male sex, private insurance, lower Charlson Comorbidity Index score, and treatment at an academic research program. Neoadjuvant radiation therapy was associated with superior R 0 resection rates (87.2% neoadjuvant radiation therapy vs 79.8% no neoadjuvant radiation therapy; P = .009). Five-year overall survival was increased in the neoadjuvant radiation therapy group (62.0% neoadjuvant radiation therapy vs 45.7% no neoadjuvant radiation therapy; P P = .01). In a subgroup analysis of T4b patients, there was an even greater size effect in adjusted overall survival (odds ratio 1.71; 95% confidence interval 1.07–2.72; P = .02). Conclusion Although radiation is rarely used in locally advanced colon cancer, this National Cancer Database analysis suggests that the use of neoadjuvant radiation for clinical T4 disease may be associated with superior R 0 resection rates and improved overall survival. Patients with clinical T4b disease may benefit the most from treatment. Neoadjuvant radiation therapy should be considered on a case-by-case basis in locally advanced colon cancer.

In 1999, Kwon et al. reported several electroencephalographic gamma band auditory steady-state response (ASSR) abnormalities in schizophrenia, spawning approximately 100 subsequent studies. While many studies replicated the finding of reduced 40-Hz ASSR power in schizophrenia and extended this by showing that 40-Hz phase synchrony (phase-locking factor [PLF]) was also reduced, none attempted to replicate the original phase delay finding of Kwon et al. Accordingly, we measured the 40-Hz ASSR phase-locking angle (PLA) to assess phase delay and examined its differential sensitivity to schizophrenia, relative to power and PLF measures.To obtain ASSRs, electroencephalography data were recorded from 28 patients with schizophrenia and 25 healthy control subjects listening to repeated 40-Hz 500-ms click trains. Evoked power, total power, PLF, and PLA were calculated after Morlet wavelet time-frequency decomposition of single trial data from electrode Fz.In patients with schizophrenia, 40-Hz PLA was significantly reduced (i.e., phase delayed) (p.0001) and was unrelated to reductions in their 40-Hz power or PLF. PLA discriminated patients from healthy control subjects with 85% accuracy compared with 67% for power and 65% for PLF.Consistent with the original Kwon et al. study, 40-Hz click train-driven gamma oscillations were phase delayed in schizophrenia. Importantly, this phase delay abnormality was substantially larger than the gamma power and phase synchrony abnormalities that have been the focus of prior 40-Hz ASSR studies in schizophrenia. PLA provides a unique neurobiological measure of gamma band abnormalities in schizophrenia, likely reflecting a distinct pathophysiological mechanism from those underlying PLF and power abnormalities.

Incorporating values of the public in decisions is a way to approach accountability, transparency and inclusiveness in disaster management, but may not be an easy fit with existing systems. In this study, we analysed a bushfire risk planning system in Victoria, Australia, to identify where and how values, and value conflicts, are managed in decision-making. Using a modified institutional approach, we found a diverse set of seven strategies by which values are managed in different parts and levels of the planning system. At the policy level, cycling through time and multiple objective setting established priorities and frameworks for staff at lower levels. At the strategic planning level, a bias to measurable values and institutional norms for relying on science limited consideration of some social values. In a previously undescribed strategy for managing values, ‘risk prioritisation’, technical risk analysis was used to prioritise places for protection, overshadowing difficult questions of value. Finally, in moving to decisions, both team deliberation and weighting strategies were used to balance values. Staff recognised a need for new tools and processes for managing some social values. An obvious opportunity for incorporating values of the public in this system is to include them in the sets of multiple objectives that guide planning. Staff also saw opportunities to expand community engagement and develop qualitative ways to justify decisions, but these faced some challenges within longstanding institutional norms for basing decisions on ecological and bushfire sciences.

RATIONALE: Sporadic reports of alcohol consumption being linked to menstrual cycle phase highlight the need to consider hormonally-characterized menstrual cycle phase in understanding the sex-specific effects of risk for alcohol drinking in women. OBJECTIVES: We investigated the association between menstrual cycle phase, characterized by circulating progesterone and menses, with accurate daily alcohol intakes in rhesus monkeys, and the contribution of progesterone derived neuroactive steroids to cycle-related alcohol drinking. METHODS: Menses (daily) and progesterone (2–3x/week) were obtained in female monkeys (n=8, 5 ethanol, 3 control) for 12–18 months. Ethanol monkeys were then induced to drink ethanol (4% w/v; 3 months) and given 22 hrs/day access to ethanol and water for approximately one year. In selected cycles, a panel of neuroactive steroids were assayed during follicular and luteal phases from pre-ethanol and ethanol exposure. RESULTS: There were minimal to no effects of ethanol on menstrual cycle length, progesterone levels, follicular or luteal phase length. The monkeys drank more ethanol during the luteal phase, compared to the follicular phase, and ethanol intake was highest in the late luteal phase when progesterone declines rapidly. Two neuroactive steroids were higher during the luteal phase versus the follicular phase, and several neuroactive steroids were higher in the pre- vs post-ethanol drinking menstrual cycles. CONCLUSIONS: This is the first study to show that normal menstrual cycle fluctuations in progesterone, particularly during the late luteal phase, can modulate ethanol intake. Two of 11 neuroactive steroids were selectively associated with the effect of cycle progesterone on ethanol drinking, suggesting possible links to CNS mechanisms of ethanol intake control.

Alcohol use disorder (AUD) is a chronic condition with devastating health and socioeconomic effects. Still, pharmacotherapies to treat AUD are scarce. In a prior study aimed at identifying novel AUD therapeutic targets, we investigated the DNA methylome of the nucleus accumbens core (NAcc) of rhesus macaques after chronic alcohol use. The G-protein coupled receptor 39 (GPR39) gene was hypermethylated and its expression downregulated in heavy alcohol drinking macaques. GPR39 encodes a Zn(2+)-binding metabotropic receptor known to modulate excitatory and inhibitory neurotransmission, the balance of which is altered in AUD. These prior findings suggest that a GPR39 agonist would reduce alcohol intake. Using a drinking-in-the-dark two bottle choice (DID-2BC) model, we showed that an acute 7.5 mg/kg dose of the GPR39 agonist, TC-G 1008, reduced ethanol intake in mice without affecting total fluid intake, locomotor activity or saccharin preference. Furthermore, repeated doses of the agonist prevented ethanol escalation in an intermittent access 2BC paradigm (IA-2BC). This effect was reversible, as ethanol escalation followed agonist “wash out”. As observed during the DID-2BC study, a subsequent acute agonist challenge during the IA-2BC procedure reduced ethanol intake by ~47%. Finally, Gpr39 activation was associated with changes in Gpr39 and Bdnf expression, and in glutamate release in the NAcc. Together, our findings suggest that GPR39 is a promising target for the development of prevention and treatment therapies for AUD.

Sensitivity to anticonvulsant effects of the γ-aminobutyric acid(A) receptor-active neurosteroid allopregnanolone (ALLO) during ethanol withdrawal varies across genotypes, with high sensitivity in genotypes with mild withdrawal and low sensitivity in genotypes with high withdrawal. The present studies determined whether the resistance to ALLO during withdrawal in mouse genotypes with high handling-induced convulsions (HICs) during withdrawal could be overcome with use of ganaxolone (GAN), the metabolically stable derivative of ALLO. In separate studies, male and female Withdrawal Seizure-Prone (WSP-1) and DBA/2J (D2) mice were exposed to air (controls) or 72 hour ethanol vapor and then were scored for HICs during withdrawal (hourly for the first 12 hours, then at hours 24 and 25). After the HIC scoring at hours 5 and 9, mice were injected with 10 mg/kg GAN or vehicle. Area under the HIC curve (AUC) for hours 5 – 12 was analyzed. In control WSP-1 mice, GAN significantly reduced AUC by 52% (males) and 63% (females), with effects that were absent or substantially reduced during withdrawal. In contrast, GAN significantly reduced AUC in both control and ethanol-withdrawing male and female D2 mice. AUC was decreased by 81% (males) and 70% (females) in controls and by 35% (males) and 21% (females) during withdrawal. The significant anticonvulsant effect of GAN during withdrawal in D2 but not WSP-1 mice suggests that different mechanisms may contribute to ALLO insensitivity during withdrawal in these two genotypes. Importantly, the results in D2 mice suggest that GAN may be a useful treatment for ethanol withdrawal-induced seizures.

Background Racial discrepancies in treatment and outcomes of acute diverticulitis have been observed, yet underlying factors are poorly understood. We aimed to identify racial inequalities in health literacy among patients hospitalized with acute diverticulitis and characterize factors associated with more severe presentation. Methods We performed retrospective cohort analysis of 947 Black or White patients admitted with acute diverticulitis at a quaternary referral center from January 2009 through September 2019. Health literacy was determined by the validated Brief Health Literacy Screening, and socioeconomic status was defined by area deprivation index, a composite of multiple neighborhood socioeconomic deprivation measures. The primary outcome was severity of disease presentation represented by systemic inflammatory response syndrome criteria; secondary outcomes included intensive care unit admission, length of stay, and invasive interventions. Results Among all study participants, 121 (12.8%) self-identified as Black. Overall, 140 (14.8%) patients had inadequate health literacy, and 495 (52.3%) had area deprivation index greater than the national median. There was no association between race or area deprivation index and health literacy. A total of 340 (35.9%) patients met criteria for systemic inflammatory response syndrome, and 88 (9.3%) underwent an intervention; median length of stay was 3.5 days. Race, health literacy, and area deprivation index were not significantly associated with outcomes (P > .05). Conclusion Among patients with acute diverticulitis, no difference in severity of presentation by race, health literacy, or area deprivation index was observed. These findings suggest that differences in presentation of acute diverticulitis may not be driven by these social factors. Future studies should include considerations of clinical characteristics of acute diverticulitis, such as the role of access and underuse of healthcare resources.