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Variants in seven genes (LRRK2, GBA1, PRKN, SNCA, PINK1, PARK7 and VPS35) have been formally adjudicated as causal contributors to Parkinson's disease; however, individuals with Parkinson's disease are often unaware of their genetic status since clinical testing is infrequently offered. As a result, genetic information is not incorporated into clinical care, and variant-targeted precision medicine trials struggle to enrol people with Parkinson's disease. Understanding the yield of genetic testing using an established gene panel in a large, geographically diverse North American population would help patients, clinicians, clinical researchers, laboratories and insurers better understand the importance of genetics in approaching Parkinson's disease. PD GENEration is an ongoing multi-centre, observational study (NCT04057794, NCT04994015) offering genetic testing with results disclosure and genetic counselling to those in the US (including Puerto Rico), Canada and the Dominican Republic, through local clinical sites or remotely through self-enrolment. DNA samples are analysed by next-generation sequencing including deletion/duplication analysis (Fulgent Genetics) with targeted testing of seven major Parkinson's disease-related genes. Variants classified as pathogenic/likely pathogenic/risk variants are disclosed to all tested participants by either neurologists or genetic counsellors. Demographic and clinical features are collected at baseline visits. Between September 2019 and June 2023, the study enrolled 10 510 participants across >85 centres, with 8301 having received results. Participants were: 59% male; 86% White, 2% Asian, 4% Black/African American, 9% Hispanic/Latino; mean age 67.4 ± 10.8 years. Reportable genetic variants were observed in 13% of all participants, including 18% of participants with one or more 'high risk factors' for a genetic aetiology: early onset (<50 years), high-risk ancestry (Ashkenazi Jewish/Basque/North African Berber), an affected first-degree relative; and, importantly, in 9.1% of people with none of these risk factors. Reportable variants in GBA1 were identified in 7.7% of all participants; 2.4% in LRRK2; 2.1% in PRKN; 0.1% in SNCA; and 0.2% in PINK1, PARK7 or VPS35 combined. Variants in more than one of the seven genes were identified in 0.4% of participants. Approximately 13% of study participants had a reportable genetic variant, with a 9% yield in people with no high-risk factors. This supports the promotion of universal access to genetic testing for Parkinson's disease, as well as therapeutic trials for GBA1 and LRRK2-related Parkinson's disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: The purpose of this study was to quantify the accuracy of partial volume-corrected three-dimensional volume flow (3DVF) measurements as a function of spatial sampling beam density using carefully-designed parametric analyses in order to inform the target applications of 3DVF., Methods: Experimental investigations employed a mechanically-swept curvilinear ultrasound array to acquire 3D color flow (6.3 MHz) images in flow phantoms consisting of four lumen diameters (6.35, 4.88, 3.18 and 1.65 mm) with volume flow rates of 440, 260, 110 and 30 mL/min, respectively. Partial volume-corrected three-dimensional volume flow (3DVF) measurements, based on the Gaussian surface integration principle, were computed at five regions of interest positioned between depths of 2 and 6 cm in 1 cm increments. At each depth, the color flow beam point spread function (PSF) was also determined, using in-phase/quadrature data, such that 3DVF bias could then be related to spatial sampling beam density. Corresponding simulations were performed for a laminar parabolic flow profile that was sampled using the experimentally-measured PSFs. Volume flow was computed for all combinations of lumen diameters and the PSFs at each depth., Results: Accurate 3DVF measurements, i.e., bias less than ±20%, were achieved for spatial sampling beam densities where at least 6 elevational color flow beams could be positioned across the lumen. In these cases, greater than 8 lateral color flow beams were present. PSF measurements showed an average lateral-to-elevational beam width asymmetry of 1:2. Volume flow measurement bias increased as the color flow beam spatial sampling density within the lumen decreased., Conclusion: Applications of 3DVF, particularly those in the clinical domain, should focus on areas where a spatial sampling density of 6 × 6 (lateral x elevational) beams can be realized in order to minimize measurement bias. Matrix-based ultrasound arrays that possess symmetric PSFs may be advantageous to achieve adequate beam densities in smaller vessels., Competing Interests: Conflict of interest Pinter, SZ: Equipment support, General Electric Healthcare Company. Rubin, JM: Research and equipment support, General Electric Healthcare Company. Hall, AL: At time of data acquisition, Employee, General Electric Healthcare Company. Fowlkes, JB: Research and equipment support, General Electric Healthcare Company. Kripfgans, OD: Research and equipment support, General Electric Healthcare Company., (Copyright © 2024 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the feasibility and impact of offering genetic testing and counseling to patients with Parkinson's disease (PD), with the potential to enroll in gene-targeted clinical trials and improve clinical care., Methods: A multicenter, exploratory pilot study at 7 academic hospital sites in the United States tracked enrollment and randomized participants to receive results and genetic counseling at local sites or by genetic counselors, remotely. Follow-up surveys measured participant/provider satisfaction, knowledge, and psychological impact., Results: From September 5, 2019 to January 4, 2021, 620 participants were enrolled and 387 completed outcome surveys. There were no significant differences in outcomes between local and remote sites, with both arms reporting high knowledge and satisfaction scores (>80%). Notably, 16% of those tested had reportable PD gene variants (pathogenic/likely pathogenic/risk allele)., Conclusion: Local clinicians, as well as genetic counselors, with educational support as needed, can effectively return genetic results for PD as we observed favorable outcome measures in both groups. Increasing access to PD genetic testing and counseling is urgent; this can inform future efforts to integrate genetic testing and counseling into clinical care for all those with PD., Competing Interests: Conflict of Interest Lola Cook received partial funding of salaries from the Michael J. Fox Foundation (MJFF) and Parkinson’s Foundation; Jennifer Verbrugge received partial funding of salaries from the Michael J. Fox Foundation (MJFF) and Parkinson’s Foundation and received travel funding for Movement Disorders Society International Congress, Madrid, Spain September 2022, abstract and poster presentation PD GENEration Clinical Phase: Genetic Diagnostic Yield and Clinical Characteristics by the Parkinson’s Foundation and paid to Indiana University School of Medicine; Tae-Hwi Schwantes-An, no disclosures; Jeanine Schulze received partial funding of salaries from the MJFF and Parkinson’s Foundation; James C. Beck is employed by the Parkinson’s Foundation, and receives funding for grants through their institution from NIH; Anna Naito is employed by the Parkinson’s Foundation; Anne Hall is a research advocate and received funding of grants from Parkinson’s Foundation for acting as a Steering Committee Member; Amanda K. Chan, no disclosures; Cynthia J. Casaceli, no disclosures; Karen Marder received funding of grants from Parkinson’s Foundation for acting as a Steering Committee Member, receives funding of grants from NIH, MJ FOX, CHDI, HSG, HDSA, Prilenia, Novartis, Roche, Springer, receives consulting fees from Novartis, and receives funding for leadership on Enroll HD Oversight Committee (CHDI) and HSG steering committee; Martha Nance received funding of grants from Parkinson’s Foundation for acting as a Steering Committee Member, received payment for presentation at Parkinson’s Foundation and Parkinson Study Group conferences, received support for attending Parkinson Study Group conference, and is the Chair of Genetics and Environment Working Group for Parkinson Study Group; Michael A. Schwarzschild received funding of grants from Parkinson’s Foundation for acting as a Steering Committee Member, receives funding of grants or conference support from NIH, MJFF, Farmer Family Foundation, Sergey Brin Family Foundation, American Parkinson’s Disease Association, Cure Parkinson’s, Parkinson’s Foundation, Harvard School of Public Health (NIH, DoD), GSK, GE Healthcare, receives consulting fees through Parkinson Study Group for PSG advisory services (including to Bial, Biogen [LUMA/LIGHTHOUSE trials global SC], UCB [ORHCESTRA trial PSG SC]) and through Sutter Health (NIA), Northwestern Univ (NINDS), Cure Parkinson’s for Steering Committee services (for TOPAZ and SPARX3), International Linked Clinical Trial Committee (CP), participates on an Alzheimer’s drug trial Data Monitoring Committee services for Eli Lilly & Co., and is Chair, Exec. Committee for Parkinson Study Group; Tanya Simuni received funding of grants from Parkinson’s Foundation for acting as a Steering Committee Member, receives funding of manuscript by MJFF for Parkinson’s Research, receives funding of grants by Amneal, Biogen, Roche, Neuroderm, Sanofi, Prevail and UCB, is an investigator for NINDS, MJFF, Parkinson’s Foundation studies, receives consulting fees from 4D Pharma, Acadia, AcureX, AskBio, Amneal, Blue Rock Therapeutics, Caraway Therapeutics, Critical Path for Parkinson's Consortium (CPP), Denali, MJFF, Neuroderm, Sanofi, Sinopia, Sunovion, Roche, Takeda, UCB, Vanqua Bio and Voyager, and is on the advisory board for Acadia, AcureX, AskBio, Amneal, Denali, Sunovion, Roche, and on the Scientific Advisory Board for 4D Pharma, Neuroderm, Sanofi and UCB; Anne-Marie Wills received funding of grants from Parkinson’s Foundation for acting as a Steering Committee Member, and receives funding of grants by NIA/NIH, Roche/Genentech, Biogen, and their institution participates on Data Safety Monitoring Board or Advisory Board for Ono Pharmaceuticals and Amylyx Pharmaceuticals; Roy N. Alcalay received funding of grants from Parkinson’s Foundation for acting as a Steering Committee Member, receives funding from NIH, Department of Defense, MJFF, the Silverstein Foundation for GBA/PD and received consulting fees from Sanofi, Ono Therapeutics, Avrobio, Takeda, Gain Therapeutics, Merck, GSK, Caraway., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Genetic testing for persons with Parkinson's disease is becoming increasingly common. Significant gains have been made regarding genetic testing methods, and testing is becoming more readily available in clinical, research, and direct-to-consumer settings. Although the potential utility of clinical testing is expanding, there are currently no proven gene-targeted therapies, but clinical trials are underway. Furthermore, genetic testing practices vary widely, as do knowledge and attitudes of relevant stakeholders. The specter of testing mandates financial, ethical, and physician engagement, and there is a need for guidelines to help navigate the myriad of challenges. However, to develop guidelines, gaps and controversies need to be clearly identified and analyzed. To this end, we first reviewed recent literature and subsequently identified gaps and controversies, some of which were partially addressed in the literature, but many of which are not well delineated or researched. Key gaps and controversies include: (1) Is genetic testing appropriate in symptomatic and asymptomatic individuals without medical actionability? (2) How, if at all, should testing vary based on ethnicity? (3) What are the long-term outcomes of consumer- and research-based genetic testing in presymptomatic PD? (4) What resources are needed for clinical genetic testing, and how is this impacted by models of care and cost-benefit considerations? Addressing these issues will help facilitate the development of consensus and guidelines regarding the approach and access to genetic testing and counseling. This is also needed to guide a multidisciplinary approach that accounts for cultural, geographic, and socioeconomic factors in developing testing guidelines. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: There is growing clinical and research utilization of genetic testing in Parkinson's disease (PD), including direct-to-consumer testing., Objectives: The aim is to determine the international landscape of genetic testing in PD to inform future worldwide recommendations., Methods: A web-based survey assessing current practices, concerns, and barriers to genetic testing and counseling was administered to the International Parkinson and Movement Disorders Society membership., Results: Common hurdles across sites included cost and access to genetic testing, and counseling, as well as education on genetic counseling. Region-dependent differences in access to and availability of testing and counseling were most notable in Africa. High-income countries also demonstrated heterogeneity, with European nations more likely to have genetic testing covered through insurance than Pan-American and Asian countries., Conclusions: This survey highlights not only diversity of barriers in different regions but also the shared and highly actionable needs for improved education and access to genetic counseling and testing for PD worldwide. © 2023 International Parkinson and Movement Disorder Society., (© 2023 International Parkinson and Movement Disorder Society.)

Objective: To explore the relationships between social and environmental factors and parenting self-efficacy (PSE) among mothers of preterm infants hospitalized in neonatal intensive care units (NICUs) using a social determinants of health (SDoH) framework., Method: We analyzed data from a prospective cohort study that included 187 mother-infant dyads admitted to four NICUs in the Mountain West region between June 2017 and December 2019. We used multivariable linear regression models to assess the independent associations between maternal and infant characteristics and PSE., Results: Our final multiple linear regression model predicting the efficacy score including maternal race/ethnicity, age, insurance, employment status before giving birth, gestational age, depression, and having other children was significant (F(12,160) = 3.17, p = .0004, adjusted R¬2 = .131). Significant predictors of PSE were race/ethnicity (β= 3.3, p = .022), having another child/children (β= 4.2, p = .005), and depression (β= -4.2, p = .004)., Conclusions: Findings suggest that social workers and medical practitioners should consider SDoH, such as insurance type, household income, and employment, along with traditional clinical indicators when assessing families' infant care needs. Social workers, medical practitioners, and researchers should be mindful of how implicit bias may influence the allocation of care and parental supports., Competing Interests: Conflict of Interest None declared.

We investigate alternative methods for constructing quality-adjusted medical price indexes both theoretically and empirically using medical claims data. The methodology and assumptions applied in the formation of the index have substantive effects on the magnitude of the quality-adjusted price changes. A method based on utility theory produces the most robust and accurate results, while alternative methods used in recent work overstate inflation. Based on Medicare claims data for three medical conditions, we find declining prices across each condition when properly adjusted for quality., (Copyright © 2022. Published by Elsevier B.V.)

Objectives: Evaluate the association between maternal social factors and maternal time spent in the NICU for very preterm infants admitted to 4 level III and IV NICUs., Methods: In this prospective observational cohort study, we enrolled mother-infant dyads whose infants were born <32 weeks' gestation. Enrollment occurred after 2 weeks of NICU exposure, when maternal social factors and demographic information was collected. Maternal time spent in the NICU was abstracted from the electronic medical record and was dichotomized into 0 to 6 days and ≥6 days per week. Demographic differences between the 2 groups were compared by using χ 2 tests. Logistic regression was used to assess the independent association between maternal social factors and the average number of days per week spent in the NICU., Results: A total of 169 mother-infant dyads were analyzed. Maternal social factors associated with more time spent in the NICU included an annual household income of >$100 000, compared with those with an annual household income of <$50 000 (adjusted odds ratio [aOR]: 5.68; 95% confidence interval [CI] 1.77-18.19), a travel time <30 minutes to the NICU (compared with those who traveled >60 minutes [aOR: 7.85; 95% CI 2.81-21.96]), and the lack of other children in the household, compared with women with other children (aOR: 3.15; 95% CI 1.39-7.11)., Conclusions: Maternal time spent in the NICU during a prolonged birth hospitalization of a very preterm infant differed by socioeconomic status, travel time, and presence of other dependents. Strategies to better identify and reduce these disparities to optimize engagement and, subsequently, improve infant health outcomes is needed., Competing Interests: POTENTIAL CONFLICTS OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Background: Bifidobacteria are commensal microbes of the mammalian gastrointestinal tract. In this study, we aimed to identify the intestinal colonization mechanisms and key metabolic pathways implemented by Bifidobacterium dentium., Results: B. dentium displayed acid resistance, with high viability over a pH range from 4 to 7; findings that correlated to the expression of Na+/H+ antiporters within the B. dentium genome. B. dentium was found to adhere to human MUC2+ mucus and harbor mucin-binding proteins. Using microbial phenotyping microarrays and fully-defined media, we demonstrated that in the absence of glucose, B. dentium could metabolize a variety of nutrient sources. Many of these nutrient sources were plant-based, suggesting that B. dentium can consume dietary substances. In contrast to other bifidobacteria, B. dentium was largely unable to grow on compounds found in human mucus; a finding that was supported by its glycosyl hydrolase (GH) profile. Of the proteins identified in B. dentium by proteomic analysis, a large cohort of proteins were associated with diverse metabolic pathways, indicating metabolic plasticity which supports colonization of the dynamic gastrointestinal environment., Conclusions: Taken together, we conclude that B. dentium is well adapted for commensalism in the gastrointestinal tract.

Background & Aims: The human gut microbiota can regulate production of serotonin (5-hydroxytryptamine [5-HT]) from enterochromaffin cells. However, the mechanisms underlying microbial-induced serotonin signaling are not well understood., Methods: Adult germ-free mice were treated with sterile media, live Bifidobacterium dentium, heat-killed B dentium, or live Bacteroides ovatus. Mouse and human enteroids were used to assess the effects of B dentium metabolites on 5-HT release from enterochromaffin cells. In vitro and in vivo short-chain fatty acids and 5-HT levels were assessed by mass spectrometry. Expression of tryptophan hydroxylase, short-chain fatty acid receptor free fatty acid receptor 2, 5-HT receptors, and the 5-HT re-uptake transporter (serotonin transporter) were assessed by quantitative polymerase chain reaction and immunostaining. RNA in situ hybridization assessed 5-HT-receptor expression in the brain, and 5-HT-receptor-dependent behavior was evaluated using the marble burying test., Results: B dentium mono-associated mice showed increased fecal acetate. This finding corresponded with increased intestinal 5-HT concentrations and increased expression of 5-HT receptors 2a, 4, and serotonin transporter. These effects were absent in B ovatus-treated mice. Application of acetate and B dentium-secreted products stimulated 5-HT release in mouse and human enteroids. In situ hybridization of brain tissue also showed significantly increased hippocampal expression of 5-HT-receptor 2a in B dentium-treated mice relative to germ-free controls. Functionally, B dentium colonization normalized species-typical repetitive and anxiety-like behaviors previously shown to be linked to 5-HT-receptor 2a., Conclusions: These data suggest that B dentium, and the bacterial metabolite acetate, are capable of regulating key components of the serotonergic system in multiple host tissues, and are associated with a functional change in adult behavior., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To decrease the average length of stay (LOS) of opioid-exposed newborns (OENs) by 20% from baseline from April 2017 to December 2019., Methods: The Colorado Hospitals Substance Exposed Newborn Quality Improvement Collaborative is a consortium of neonatal providers, public health experts, and legislative experts that provides infrastructure and resources for Colorado birthing hospitals to undertake initiatives focused on improving the care of OENs. The Colorado Hospitals Substance Exposed Newborn Quality Improvement Collaborative was started in September 2017 and includes 19 birthing hospitals in Colorado, with 12 contributing data to the centralized database. The interventions were focused on (1) hospital engagement and (2) increasing nonpharmacologic care (by using the Eat, Sleep, Console assessment tool; developing guidelines for breastfeeding eligibility; employing comfort measures before pharmacologic therapy; and administering opiate therapy on an as-needed basis)., Results: From April 2017 to December 2019, 787 OENs were identified. Among infants ≥35 weeks' gestational age without other medical diagnoses ( n = 647), statistical process control charts revealed significant reduction in the primary outcome of interest, average hospital LOS, from 14.8 to 5.9 days. For all OENs, receipt of pharmacologic therapy declined from 61% to 23%. Among OENs who received pharmacologic therapy (and were ≥35 weeks' gestational age without other medical diagnoses), average LOS also declined from 21.9 to 8.0 days., Conclusions: Through standardization of OEN care focused on family engagement and nonpharmacologic care, this statewide collaborative reduced average LOS, the percentage of OENs requiring opiate therapy, and average LOS for OENs requiring opiate therapy., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

New interventions are needed in advanced chronic graft-versus-host disease (GVHD). In a phase II, single-arm, multicenter trial, we examined the efficacy of ixazomib in patients with chronic GVHD who had progressed after at least 1 previous line of systemic immunosuppressive (IS) therapy. Ixazomib was given as a 4 mg oral dose weekly on days 1, 8, and 15 of a 28-day cycle for up to 6 total cycles. The primary endpoint was 6-month treatment failure, a composite endpoint including death, relapse, and requirement for an additional line of systemic IS therapy. A total of 50 subjects were enrolled at 6 institutions. The median time from the onset of chronic GVHD to enrollment was 2.8 years (interquartile range, 1.5 to 4.3 years). The degree of chronic GVHD at enrollment was National Institutes of Health (NIH)-defined moderate (16%) or severe (84%), predominantly classic (80% versus 20% overlap), with 52% of patients having involvement of 4 or more organs. The patients were heavily pretreated, with 39 (78%) receiving 3 or more previous lines of systemic therapy for chronic GVHD. Of the 50 patients treated, 26 completed 6 months of planned therapy. The 6-month treatment failure rate was significantly lower than the historical benchmark (28% versus 44%; P = .01) previously established in second-line therapy for chronic GVHD. No patient, transplantation, or chronic GVHD variables were significantly associated with 6-month treatment failure. NIH-defined overall response rate was 40% at 6 months. Overall survival was 92% at 6 months and 90% at 12 months. Ixazomib met the primary endpoint of low treatment failure at 6 months in the setting of advanced chronic GVHD. At 6 months, the NIH-defined rate of complete/partial response was 40%, and 52% of patients remained on ixazomib therapy, suggesting that the low treatment failure rate was due in part due to prevention of progressive disease that would have required additional treatment., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Key Points: Enteroids are a physiologically relevant model to examine the human intestine and its functions. Previously, the measurable cytokine response of human intestinal enteroids has been limited following exposure to host or microbial pro-inflammatory stimuli. Modifications to enteroid culture conditions facilitated robust human cytokine responses to pro-inflammatory stimuli. This new human enteroid culture methodology refines the ability to study microbiome:human intestinal epithelium interactions in the laboratory., Abstract: The intestinal epithelium is the primary interface between the host, the gut microbiome and its external environment. Since the intestinal epithelium contributes to innate immunity as a first line of defence, understanding how the epithelium responds to microbial and host stimuli is an important consideration in promoting homeostasis. Human intestinal enteroids (HIEs) are primary epithelial cell cultures that can provide insights into the biology of the intestinal epithelium and innate immune responses. One potential limitation of using HIEs for innate immune studies is the relative lack of responsiveness to factors that stimulate epithelial cytokine production. We report technical refinements, including removal of extracellular antioxidants, to facilitate enhanced cytokine responses in HIEs. Using this new method, we demonstrate that HIEs have distinct cytokine profiles in response to pro-inflammatory stimuli derived from host and microbial sources. Overall, we found that host-derived cytokines tumour necrosis factor and interleukin-1α stimulated reactive oxygen species and a large repertoire of cytokines. In contrast, microbial lipopolysaccharide, lipoteichoic acid and flagellin stimulated a limited number of cytokines and histamine did not stimulate the release of any cytokines. Importantly, HIE-secreted cytokines were functionally active, as denoted by the ability of human blood-derived neutrophil to migrate towards HIE supernatant containing interleukin-8. These findings establish that the immune responsiveness of HIEs depends on medium composition and stimuli. By refining the experimental culture medium and creating an environment conducive to epithelial cytokine responses by human enteroids, HIEs can facilitate exploration of many experimental questions pertaining to the role of the intestinal epithelium in innate immunity., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

Purpose: Genetic testing for Parkinson disease (PD) has not been widely used in clinical practice. In preparation for upcoming precision medicine-designed clinical trials for GBA and LRRK2, we evaluated movement disorders specialists' current practice, knowledge, attitudes, and barriers to genetic testing in PD., Methods: An anonymous questionnaire was sent to movement disorders specialists at 146 Parkinson Study Group (PSG) sites in the United States (n = 131) and Canada (n = 15) to assess their knowledge and attitudes about genetic testing for PD., Results: One hundred seventy-eight (47.6%) PSG clinicians completed the questionnaire. Forty-one percent of respondents had not referred any PD patients for genetic testing in the last year and >80% reported referring fewer than 11 patients over the same period. Most common reasons for not referring for genetic testing included lack of insurance coverage/cost to the patient and lack of perceived utility. On a scale of 0-100, the mean level of comfort in respondents' own ability to genetically counsel PD patients on GBA and LRRK2 was 52 (SD = 28). Sixty percent of clinicians correctly answered all questions about the inheritance and penetrance of GBA and LRRK2 variants., Conclusions: There is an urgent need to increase knowledge and reduce practical barriers to genetic counseling and testing in PD.

Background: Living with Parkinson disease (PD) is complicated by an unpredictable disease course which can delay planning for future needs. This study explores patient and care partner needs related to future planning using a palliative care framework with physical, psychological, social, cultural, end-of-life, and ethical aspects of care in PD to guide analysis., Methods: Secondary analysis of patient and care partner interviews from a randomized clinical trial comparing interdisciplinary outpatient palliative care versus standard care for individuals with PD and care partners in an academic setting. Sixty participants were interviewed (30 patients and 30 care partners) about needs related to future planning. Team-based thematic analysis was used to identify key themes., Results: Many care partners and patients living with PD described a desire for information about what to expect and how to plan for the future. Participants posed multiple questions about PD progression and devised the metaphor of a "roadmap" as a guide for decision making and planning. When exploring the concept of a PD roadmap, five themes emerged: (I) desire for a comprehensive tool for future planning, such as a roadmap, (II) care partner preferences for specific future planning, (III) PD-related life changes as opportunity for future planning and decision-making, (IV) cues from family, peers, and medical professionals about "location" on the roadmap, and (V) opportunities and challenges to integrating a PD roadmap into patient-centered care., Conclusions: Patients and care partners described key needs related to future planning that can inform a comprehensive roadmap to assist with education, communication, and decision making. A roadmap tool can promote individualized anticipatory guidance and multidimensional shared decision-making discussions between patients, care partners, and the healthcare team related to PD progression.

Background: Histamine is a key mediator of the anti-inflammatory activity conferred by the probiotic organism Lactobacillus reuteri ATCC PTA 6475 in animal models of colitis and colorectal cancer. In L. reuteri, histamine synthesis and secretion requires L-histidine decarboxylase and a L-histidine/histamine exchanger. Chloride channel (ClC)-family proton/chloride antiporters have been proposed to act as electrochemical shunts in conjunction with amino acid decarboxylase systems, correcting ion imbalances generated by decarboxylation through fixed ratio exchange of two chloride ions for one proton. This family is unique among transporters by facilitating ion flux in either direction. Here we examine the histidine decarboxylase system in relation to ClC antiporters in the probiotic organism Lactobacillus reuteri., Results: In silico analyses reveal that L. reuteri possesses two ClC transporters, EriC and EriC2, as well as a complete histidine decarboxylase gene cluster (HDC) for the synthesis and export of histamine. When the transport activity of either proton/chloride antiporter is disrupted by genetic manipulation, bacterial histamine output is reduced. Using fluorescent reporter assays, we further show that ClC transporters affect histamine output by altering intracellular pH and membrane potential. ClC transport also alters the expression and activity of two key HDC genes: the histidine decarboxylase (hdcA) and the histidine/histamine exchanger (hdcP)., Conclusions: Histamine production is a potentially beneficial feature for intestinal microbes by promoting long-term colonization and suppression of inflammation and host immune responses. ClC transporters may serve as tunable modulators for histamine production by L. reuteri and other gut microbes.

The fitness effect of a mutation can depend on both its genetic background, known as epistasis, and the prevailing external environment. Many examples of these dependencies are known, but few studies consider both aspects in combination, especially as they affect mutations that have been selected together. We examine interactions between five coevolved mutations in eight diverse environments. We find that mutations are, on average, beneficial across environments, but that there is high variation in their fitness effects, including many examples of mutations conferring a cost in some, but not other, genetic background-environment combinations. Indeed, even when global interaction trends are accounted for, specific local mutation interactions are common and differed across environments. One consequence of this dependence is that the range of trade-offs in genotype fitness across selected and alternative environments are contingent on the particular evolutionary path followed over the mutation landscape. Finally, although specific interactions were common, there was a consistent pattern of diminishing returns epistasis whereby mutation effects were less beneficial when added to genotypes of higher fitness. Our results underline that specific mutation effects are highly dependent on the combination of genetic and external environments, and support a general relationship between a genotype's current fitness and its potential to increase in fitness., (© 2019 The Author(s). Evolution © 2019 The Society for the Study of Evolution.)

The histamine H2 receptor (H2R) is a G protein-coupled receptor that mediates cyclic AMP production, protein kinase A activation, and MAP kinase signaling. In order to explore the multifaceted effects of histamine signaling on immune cells, phagocytosis was evaluated using primary mouse-derived macrophages. Phagocytosis is initiated by signaling via surface-bound scavenger receptors and can be regulated by autophagy. Absence of H2R signaling resulted in diminished phagocytosis of live bacteria and synthetic microspheres by primary macrophages from histamine H2 receptor gene (Hrh2)-deficient mice. Flow cytometry and immunofluorescence microscopy were used to quantify phagocytosis of phylogenetically diverse bacteria as well as microspheres of defined chemical composition. Autophagy and scavenger receptor gene expression were quantified in macrophages after exposure to Escherichia coli. Expression of the autophagy genes, Becn1 and Atg12, was increased in Hrh2 -/- macrophages, indicating upregulation of autophagy pathways. Expression of the Macrophage Scavenger Receptor 1 gene (Msr1) was diminished in Hrh2-deficient macrophages, supporting the possible importance of histamine signaling in scavenger receptor abundance and macrophage function. Flow cytometry confirmed diminished MSR1 surface abundance in Hrh2 -/- macrophages. These data suggest that H2R signaling is required for effective phagocytosis by regulating the process of autophagy and scavenger receptor MSR1 abundance in macrophages., (© 2019 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.)

Much remains unknown about how the intestinal microbiome interfaces with the protective intestinal mucus layer. Bifidobacterium species colonize the intestinal mucus layer and can modulate mucus production by goblet cells. However, select Bifidobacterium strains can also degrade protective glycans on mucin proteins. We hypothesized that the human-derived species Bifidobacterium dentium would increase intestinal mucus synthesis and expulsion, without extensive degradation of mucin glycans. In silico data revealed that B. dentium lacked the enzymes necessary to extensively degrade mucin glycans. This finding was confirmed by demonstrating that B. dentium could not use naive mucin glycans as primary carbon sources in vitro To examine B. dentium mucus modulation in vivo , Swiss Webster germfree mice were monoassociated with live or heat-killed B. dentium Live B. dentium -monoassociated mice exhibited increased colonic expression of goblet cell markers Krüppel-like factor 4 ( Klf4 ), Trefoil factor 3 ( Tff3 ), Relm -β, Muc2 , and several glycosyltransferases compared to both heat-killed B. dentium and germfree counterparts. Likewise, live B. dentium -monoassociated colon had increased acidic mucin-filled goblet cells, as denoted by Periodic Acid-Schiff-Alcian Blue (PAS-AB) staining and MUC2 immunostaining. In vitro , B. dentium -secreted products, including acetate, were able to increase MUC2 levels in T84 cells. We also identified that B. dentium -secreted products, such as γ-aminobutyric acid (GABA), stimulated autophagy-mediated calcium signaling and MUC2 release. This work illustrates that B. dentium is capable of enhancing the intestinal mucus layer and goblet cell function via upregulation of gene expression and autophagy signaling pathways, with a net increase in mucin production. IMPORTANCE Microbe-host interactions in the intestine occur along the mucus-covered epithelium. In the gastrointestinal tract, mucus is composed of glycan-covered proteins, or mucins, which are secreted by goblet cells to form a protective gel-like structure above the epithelium. Low levels of mucin or alterations in mucin glycans are associated with inflammation and colitis in mice and humans. Although current literature links microbes to the modulation of goblet cells and mucins, the molecular pathways involved are not yet fully understood. Using a combination of gnotobiotic mice and mucus-secreting cell lines, we have identified a human-derived microbe, Bifidobacterium dentium , which adheres to intestinal mucus and secretes metabolites that upregulate the major mucin MUC2 and modulate goblet cell function. Unlike other Bifidobacterium species, B. dentium does not extensively degrade mucin glycans and cannot grow on mucin alone. This work points to the potential of using B. dentium and similar mucin-friendly microbes as therapeutic agents for intestinal disorders with disruptions in the mucus barrier., (Copyright © 2019 Engevik et al.)

Objective: Advance care planning (ACP) is a core quality measure in caring for individuals with Parkinson disease (PD) and there are no best practice standards for how to incorporate ACP into PD care. This study describes patient and care partner perspectives on ACP to inform a patient- and care partner-centered framework for clinical care., Methods: This is a qualitative descriptive study of 30 patients with PD and 30 care partners within a multisite, randomized clinical trial of neuropalliative care compared to standard care. Participants were individually interviewed about perspectives on ACP, including prior and current experiences, barriers to ACP, and suggestions for integration into care. Interviews were analyzed using theme analysis to identify key themes., Results: Four themes illustrate how patients and care partners perceive ACP as part of clinical care: (1) personal definitions of ACP vary in the context of PD; (2) patient, relationship, and health care system barriers exist to engaging in ACP; (3) care partners play an active role in ACP; (4) a palliative care approach positively influences ACP. Taken together, the themes support clinician initiation of ACP discussions and interdisciplinary approaches to help patients and care partners overcome barriers to ACP., Conclusions: ACP in PD may be influenced by patient and care partner perceptions and misperceptions, symptoms of PD (e.g., apathy, cognitive dysfunction, disease severity), and models of clinical care. Optimal engagement of patients with PD and care partners in ACP should proactively address misperceptions of ACP and utilize clinic teams and workflow routines to incorporate ACP into regular care., (© 2019 American Academy of Neurology.)

Inflammatory bowel disease (IBD) is a well-known risk factor for the development of colorectal cancer. Prior studies have demonstrated that microbial histamine can ameliorate intestinal inflammation in mice. We tested the hypothesis whether microbe-derived luminal histamine suppresses inflammation-associated colon cancer in Apc min/+ mice. Mice were colonized with the human-derived Lactobacillus reuteri. Chronic inflammation was induced by repeated cycles of low-dose dextran sulfate sodium (DSS). Mice that were given histamine-producing L. reuteri via oral gavage developed fewer colonic tumors, despite the presence of a complex mouse gut microbiome. We further demonstrated that administration of a histamine H1-receptor (H1R) antagonist suppressed tumorigenesis, while administration of histamine H2-receptor (H2R) antagonist significantly increased both tumor number and size. The bimodal functions of histamine include protumorigenic effects through H1R and antitumorigenic effects via H2R, and these results were supported by gene expression profiling studies on tumor specimens of patients with colorectal cancer. Greater ratios of gene expression of H2R ( HRH2) vs. H1R ( HRH1) were correlated with improved overall survival outcomes in patients with colorectal cancer. Additionally, activation of H2R suppressed phosphorylation of mitogen-activated protein kinases (MAPKs) and inhibited chemokine gene expression induced by H1R activation in colorectal cancer cells. Moreover, the combination of a H1R antagonist and a H2R agonist yielded potent suppression of lipopolysaccharide-induced MAPK signaling in macrophages. Given the impact on intestinal epithelial and immune cells, simultaneous modulation of H1R and H2R signaling pathways may be a promising therapeutic target for the prevention and treatment of inflammation-associated colorectal cancer. NEW & NOTEWORTHY Histamine-producing Lactobacillus reuteri can suppress development of inflammation-associated colon cancer in an established mouse model. The net effects of histamine may depend on the relative activity of H1R and H2R signaling pathways in the intestinal mucosa. Our findings suggest that treatment with H1R or H2R antagonists could yield opposite effects. However, by harnessing the ability to block H1R signaling while stimulating H2R signaling, novel strategies for suppression of intestinal inflammation and colorectal neoplasia could be developed.

Adequate nutrition during the pre- and early-postnatal periods plays a critical role in programming early neurodevelopment. Disruption of neurodevelopment by nutritional deficiencies can result not only in lasting functional deficits, but increased risk of neuropsychiatric disease in adulthood. Historical periods of famine such as the Dutch Hunger Winter and the Chinese Famine have provided foundational evidence for the long-term effects of developmental malnutrition on neuropsychiatric outcomes. Because neurodevelopment is a complex process that consists of many nutrient- and brain-region-specific critical periods, subsequent clinical and pre-clinical studies have aimed to elucidate the specific roles of individual macro- and micronutrient deficiencies in neurodevelopment and neuropsychiatric pathologies. This review will discuss developmental iron deficiency (ID), the most common micronutrient deficiency worldwide, as a paradigm for understanding the role of early-life nutrition in neurodevelopment and risk of neuropsychiatric disease. We will review the epidemiologic data linking ID to neuropsychiatric dysfunction, as well as the underlying structural, cellular, and molecular mechanisms that are thought to underlie these lasting effects. Understanding the mechanisms driving lasting dysfunction and disease risk is critical for development and implementation of nutritional policies aimed at preventing nutritional deficiencies and their long-term sequelae.

Human intestinal microbes participate actively at the interface of diet, nutrition, and overall health status. These biodiverse communities of microorganisms have a broader metabolic repertoire compared with their host, and they are able to synthesize and degrade substrates that would be otherwise unavailable. In recent years, we have recognized that healthy microbial communities are important for energy harvest and the regulation of body systems outside the digestive tract. Microbial dysbiosis, however, has been implicated in a number of human disorders, including obesity and inflammation. This dichotomy highlights the need to understand the factors that determine the composition and metabolic output of our resident and transient microbes. Throughout the human lifespan, we know that diet plays a major role in shaping gut microbial communities, as well as directing the types and amounts of metabolites produced. Understanding the factors that affect microbial metabolic output within the host may help identify the roles of microbes in health, as well as new targets for treatment in disease. In this article, we review facets of the assembly and activities of the healthy human intestinal microbiome, as well as ways that the microbiota has been shown to influence the host via metabolism of two dietary macronutrients: carbohydrates and amino acids.

The Bureau of Economic Analysis recently created new price indexes for health care in its health care satellite account and now faces the problem of how to adjust them for quality. I review the literature on this topic and divide the articles that created quality-adjusted price indexes for individual medical conditions into those that use primarily outcomes-based adjustments and those that use only process-based adjustments. Outcomes-based adjustments adjust the indexes based on observed aggregate health outcomes, usually mortality. Process-based adjustments adjust the indexes based on the treatments provided and medical knowledge of their effectiveness. Outcomes-based adjustments are easier to implement, while process-based adjustments are more demanding in terms of data and medical knowledge. In general, the research literature shows adjusting for quality in the measurement of output in the medical sector to be quantitatively important.

Intrauterine growth restricted (IUGR) infants are at increased risk for neurodevelopmental deficits that suggest the hippocampus and cerebral cortex may be particularly vulnerable. Evaluate regional neurochemical profiles in IUGR and normally grown (NG) 7-day old rat pups using in vivo 1 H magnetic resonance (MR) spectroscopy at 9.4 T. IUGR was induced via bilateral uterine artery ligation at gestational day 19 in pregnant Sprague-Dawley dams. MR spectra were obtained from the cerebral cortex, hippocampus and striatum at P7 in IUGR (N = 12) and NG (N = 13) rats. In the cortex, IUGR resulted in lower concentrations of phosphocreatine, glutathione, taurine, total choline, total creatine (P < 0.01) and [glutamate]/[glutamine] ratio (P < 0.05). Lower taurine concentrations were observed in the hippocampus (P < 0.01) and striatum (P < 0.05). IUGR differentially affects the neurochemical profile of the P7 rat brain regions. Persistent neurochemical changes may lead to cortex-based long-term neurodevelopmental deficits in human IUGR infants.

I construct a disease-based medical expenditure index for Medicare Advantage (private plan) enrollees using data from the Medicare Current Beneficiary Survey from 2001 to 2009. I create the indexes by modeling total health-care expenditure as a function of each respondent's diagnoses. Total medical inflation for this population is found to be 5.7 percent annually. By comparison, medical inflation in the Medicare fee-for-service (FFS) population is 4.5 percent annually. The difference is partly due to differential reporting of drug and nondrug spending in the MCBS for FFS beneficiaries; once this is corrected for, inflation among FFS beneficiaries is 5.0 percent. The remaining difference results from drug spending increasingly more rapidly among Medicare Advantage enrollees. I show that the introduction of Part D accounts for much of, and possibly all the remaining gap in inflation.

Background: Candida auris is a globally emerging multidrug resistant fungal pathogen causing nosocomial transmission. We report an ongoing outbreak of C. auris in a London cardio-thoracic center between April 2015 and July 2016. This is the first report of C. auris in Europe and the largest outbreak so far. We describe the identification, investigation and implementation of control measures., Methods: Data on C. auris case demographics, environmental screening, implementation of infection prevention/control measures, and antifungal susceptibility of patient isolates were prospectively recorded then analysed retrospectively. Speciation of C. aur is was performed by MALDI-TOF and typing of outbreak isolates performed by amplified fragment length polymorphism (AFLP)., Results: This report describes an ongoing outbreak of 50 C. auris cases over the first 16 month (April 2015 to July 2016) within a single Hospital Trust in London. A total of 44 % ( n  = 22/50) patients developed possible or proven C. auris infection with a candidaemia rate of 18 % ( n  = 9/50). Environmental sampling showed persistent presence of the yeast around bed space areas. Implementation of strict infection and prevention control measures included: isolation of cases and their contacts, wearing of personal protective clothing by health care workers, screening of patients on affected wards, skin decontamination with chlorhexidine, environmental cleaning with chorine based reagents and hydrogen peroxide vapour. Genotyping with AFLP demonstrated that C. auris isolates from the same geographic region clustered., Conclusion: This ongoing outbreak with genotypically closely related C. auris highlights the importance of appropriate species identification and rapid detection of cases in order to contain hospital acquired transmission.

Background: Adult cochlear implant (CI) candidacy is assessed in part by the use of speech perception measures. In the United Kingdom the current cut-off point to fall within the CI candidacy range is a score of less than 50% on the BKB sentences presented in quiet (presented at 70 dBSPL)., Goal: The specific goal of this article was to review the benefit of adding the AB word test to the assessment test battery for candidacy., Results: The AB word test scores showed good sensitivity and specificity when calculated based on both word and phoneme scores. The word score equivalent for 50% correct on the BKB sentences was 18.5% and it was 34.5% when the phoneme score was calculated; these scores are in line with those used in centres in Wales (15% AB word score)., Conclusion: The goal of the British Cochlear Implant Group (BCIG) service evaluation was to determine if the pre-implant assessment measures are appropriate and set at the correct level for determining candidacy, the future analyses will determine whether the speech perception cut-off point for candidacy should be adjusted and whether other more challenging measures should be used in the candidacy evaluation.

Background: Hypoglycemia (HG) is common in intrauterine growth restricted (IUGR) neonates. In normally grown (NG) neonatal rats, acute HG causes neuronal injury in the brain; the cerebral cortex is more vulnerable than the hippocampus (HPC). We hypothesized that the IUGR brain is less vulnerable to HG-induced injury while preserving regional variation in vulnerability., Methods: We induced IUGR via bilateral uterine artery ligation on gestational day 19 (term 22 d) rats. On postnatal day 14, insulin-induced HG of equivalent severity and duration (blood glucose < 40 mg/dl for 240 min) was produced in IUGR and NG (IUGR/HG and NG/HG). Neuronal injury in the cortex and HPC was quantified 6-72 h later using Fluoro-Jade B (FJB) histochemistry. The mRNA expression of monocarboxylate transporters, MCT1 and MCT2, and glucose transporters, GLUT1 and GLUT3, was determined using quantitative PCR., Results: There were fewer FJB-positive (FJB+) cells in the cortex of IUGR/HG; no difference was observed in FJB+ cells in HPC. Core body temperature was lower in IUGR/HG compared with NG/HG. MCT2 expression was increased in the IUGR cortex., Conclusion: HG-induced neuronal injury is decreased in the cortex of the developing IUGR brain. Adaptations including systemic hypothermia and enhanced delivery of alternative substrates via MCT2 might protect against HG-induced neuronal injury in IUGR.

In 2005, the National Institutes of Health (NIH) Chronic Graft-versus-Host Disease (GVHD) Consensus Response Criteria Working Group recommended several measures to document serial evaluations of chronic GVHD organ involvement. Provisional definitions of complete response, partial response, and progression were proposed for each organ and for overall outcome. Based on publications over the last 9 years, the 2014 Working Group has updated its recommendations for measures and interpretation of organ and overall responses. Major changes include elimination of several clinical parameters from the determination of response, updates to or addition of new organ scales to assess response, and the recognition that progression excludes minimal, clinically insignificant worsening that does not usually warrant a change in therapy. The response definitions have been revised to reflect these changes and are expected to enhance reliability and practical utility of these measures in clinical trials. Clarification is provided about response assessment after the addition of topical or organ-targeted treatment. Ancillary measures are strongly encouraged in clinical trials. Areas suggested for additional research include criteria to identify irreversible organ damage and validation of the modified response criteria, including in the pediatric population., (Published by Elsevier Inc.)

Objectives: Three-dimensional (3D)/4-dimensional (4D) sonographic measurement of blood volume flow in transjugular intrahepatic porto systemic shunt revision with the intention of objective assessment of shunt patency., Methods: A total of 17 patients were recruited (12 male and 5 female; mean age, 55 years; range, 30-69 years). An ultrasound system equipped with a 2.0-5.0-MHz probe was used to acquire multivolume 3D/4D color Doppler data sets to assess prerevision and postrevision shunt volume flow. Volume flow was computed offline based on the principle of surface integration of Doppler-measured velocity vectors in a lateral-elevational c-surface positioned at the color flow focal depth (range, 8.0-11.5 cm). Volume flow was compared to routine measurements of the prerevision and postrevision portosystemic pressure gradient. Prerevision volume flow was compared with the outcome to determine whether a flow threshold for revision could be defined., Results: Linear regression of data from revised transjugular intrahepatic portosystemic shunt cases showed an inverse correlation between the mean-normalized change in prerevision and postrevision shunt volume flow and the mean-normalized change in the prerevision and postrevision portosystemic pressure gradient (r(2) = 0.51; P = .020). Increased shunt blood flow corresponded to a decreased pressure gradient. Comparison of prerevision flows showed preliminary threshold development at 1534 mL/min, below which a shunt revision may be recommended (P = .21; area under the receiver operating characteristic curve = 0.78)., Conclusions: Shunt volume flow measurement with 3D/4D Doppler sonography provides a potential alternative to standard pulsed wave Doppler metrics as an indicator of shunt function and predictor of revision., (© 2015 by the American Institute of Ultrasound in Medicine.)

Objectives: Three-dimensional (3D) umbilical cord blood volume flow measurement with the intention of providing a straightforward, consistent, and accurate method that overcomes the limitations associated with traditional pulsed wave Doppler flow measurement and provides a means by which to recognize and manage at-risk pregnancies., Methods: The first study involved 3D sonographic volume flow measurements in 7 healthy ewes whose pregnancies ranged from 18 to 19 weeks' gestation (7 singletons). Sonographic umbilical arterial and venous flow measurements from each fetus were compared to the corresponding average measured arterial/venous flow to assess the feasibility of measurement in a static vessel. A second complementary study involved 3D sonographic volume flow measurements in 7 healthy women whose pregnancies ranged from 17.9 to 36.3 weeks' gestation (6 singletons and 1 twin). Umbilical venous flow measurements were compared to similar flow measurements reported in the literature. Pregnancy outcomes were abstracted from the medical records of the recruited patients., Results: In the fetal sheep model, arterial/venous flow comparisons yielded errors of 10% or less for 8 of the 9 measurements. In the clinical study, venous flow measurements showed agreement with the literature over a range of gestational ages. Two of the 7 patients in the clinical study had lower flow than anticipated for gestational age; one had a subsequent diagnosis of intrauterine growth restriction, and the other had preeclampsia., Conclusions: Accurate measurement of umbilical blood volume flow can be performed with relative ease in both the sheep model and in humans using the proposed 3D sonographic flow measurement technique. Results encourage further development of the method as a means for diagnosis and identification of at-risk pregnancies.

Transplant recipients require immunosuppression to prevent allograft rejection, placing them at risk of opportunistic infections including fungal infection. Difficulties in managing fungal infections include: establishing diagnosis, poor treatment response, drug interactions and toxicity. We report our single centre experience of treating fungal infections using systemic non-Amphotericin current generation antifungals. Patients receiving inpatient antifungal therapy from September 2005 to December 2010 were identified from pharmacy records. Fungal infections were retrospectively classified according to European Organization for Research and Treatment of Cancer (EORTC) criteria. Treatment outcomes were classified in a manner similar to those used in clinical trials. Two hundred and forty-nine recipients received antifungal treatment, 204 lungs and 45 hearts. One hundred and one patients received Voriconazole, 82 Caspofungin and 65 received both agents. One patient was unsuccessfully treated with additional Amphotericin. Treatment duration varied from 1.5 to 12 weeks. One hundred and sixty-five patients had a complete response, 24 had a partial response and in 60 patients treatment was unsuccessful. The response to systemic non-Amphotericin based antifungal therapy was high. We propose that diagnostic criteria without positive identification of a fungus allow treatment to be started early with few clinically relevant side effects., (© 2012 The Authors. Transplant International © 2012 European Society for Organ Transplantation.)

Objective: The study objective was to evaluate whether a novel global position system (GPS)-like position-sensing technology will enable accurate co-registration of images between imaging modalities. Co-registration of images obtained by different imaging modalities will allow for comparison and fusion between imaging modalities, and therefore has significant clinical and research implications. We compared ultrasound (US) and magnetic resonance imaging (MRI) scans of carotid endarterectomy (CEA) specimens using a novel position-sensing technology that uses an electromagnetic (EM) transmitter and sensors mounted on a US transducer. We then evaluated in vivo US-US and US-MRI co-registration., Methods: Thirteen CEA specimens underwent 3.0 Tesla MRI, after which images were uploaded to a LOGIQ E9 3D (GE Healthcare, Wauwatosa, WI) US system and registered by identifying two to three common points. A similar method was used to evaluate US-MRI co-registration in patients with carotid atherosclerosis. For carotid intima-media thickness (C-IMT) measurements, 10 volunteers underwent bilateral carotid US scans co-registered to three-dimensional US maps created on the initial visit, with a repeat scan 2 days later., Results: For the CEA specimens, there was a mean of 20 (standard error [SE] 2.0) frames per MRI slice. The mean frame difference, over 33 registration markers, between MRI and US scans for readers 1 and 2 was -2.82 ± 19.32 and 2.09 ± 14.68 (mean ± 95% CI) frames, respectively. The US-MRI intraclass correlation coefficients (ICCs) for the first and second readers were 0.995 and 0.997, respectively. For patients with carotid atherosclerosis, the mean US frames per MRI slice (9 [SE 2.3]) was within range of that observed with CEA specimens. Inter-visit, intra-reader, and inter-reader reproducibility of C-IMT measurements were consistently high (side-averaged ICC >0.9)., Conclusion: Accurate co-registration between US and other modalities is feasible with a GPS-like technology, which has significant clinical and research applicability., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Our group has proposed the concept of subharmonic aided pressure estimation (SHAPE) utilizing microbubble-based ultrasound contrast agent signals for the noninvasive estimation of hydrostatic blood pressures. An experimental system for in vitro SHAPE was constructed based on two single-element transducers assembled confocally at a 60 degree angle to each other. Changes in the first, second and subharmonic amplitudes of five different ultrasound contrast agents were measured in vitro at static hydrostatic pressures from 0-186 mmHg, acoustic pressures from 0.35-0.60 MPa peak-to-peak and frequencies of 2.5-6.6 MHz. The most sensitive agent and optimal parameters for SHAPE were determined using linear regression analysis and implemented on a Logiq 9 scanner (GE Healthcare, Milwaukee, WI). This implementation of SHAPE was then tested under dynamic-flow conditions and compared to pressure-catheter measurements. Over the pressure range studied, the first and second harmonic amplitudes reduced approximately 2 dB for all contrast agents. Over the same pressure range, the subharmonic amplitudes decreased by 9-14 dB and excellent linear regressions were achieved with the hydrostatic pressure variations (r = 0.98, p < 0.001). Optimal sensitivity was achieved at a transmit frequency of 2.5 MHz and acoustic pressure of 0.35 MPa using Sonazoid (GE Healthcare, Oslo, Norway). A Logiq 9 scanner was modified to implement SHAPE on a convex transducer with a frequency range from 1.5-4.5 MHz and acoustic pressures from 0-3.34 MPa. Results matched the pressure catheter (r2 = 0.87). In conclusion, subharmonic contrast signals are a good indicator of hydrostatic pressure. Out of the five ultrasound contrast agents tested, Sonazoid was the most sensitive for subharmonic pressure estimation. Real-time SHAPE has been implemented on a commercial scanner and offers the possibility of allowing pressures in the heart and elsewhere to be obtained noninvasively.

Parametric maps showing perfusion of contrast media can be useful tools for characterizing lesions in breast tissue. In this study we show the feasibility of parametric subharmonic imaging (SHI), which allows imaging of a vascular marker (the ultrasound contrast agent) while providing near complete tissue suppression. Digital SHI clips of 16 breast lesions from 14 women were acquired. Patients were scanned using a modified LOGIQ 9 scanner (GE Healthcare, Waukesha, WI) transmitting/receiving at 4.4/2.2 MHz. Using motion-compensated cumulative maximum intensity (CMI) sequences, parametric maps were generated for each lesion showing the time to peak (TTP), estimated perfusion (EP), and area under the time-intensity curve (AUC). Findings were grouped and compared according to biopsy results as benign lesions (n = 12, including 5 fibroadenomas and 3 cysts) and carcinomas (n = 4). For each lesion CMI, TTP, EP, and AUC parametric images were generated. No significant variations were detected with CMI (P = .80), TTP (P = .35), or AUC (P = .65). A statistically significant variation was detected for the average pixel EP (P = .002). Especially, differences were seen between carcinoma and benign lesions (mean ± SD, 0.10 ± 0.03 versus 0.05 ± 0.02 intensity units [IU]/s; P = .0014) and between carcinoma and fibroadenoma (0.10 ± 0.03 versus 0.04 ± 0.01 IU/s; P = .0044), whereas differences between carcinomas and cysts were found to be nonsignificant. In conclusion, a parametric imaging method for characterization of breast lesions using the high contrast to tissue signal provided by SHI has been developed. While the preliminary sample size was limited, results show potential for breast lesion characterization based on perfusion flow parameters.

Aim: To evaluate the agreement between contrast-enhanced ultrasound imaging and histopathology in an animal model of atherosclerosis., Methods and Results: Atherosclerosis was studied in both femoral arteries of four Rapacz familial hypercholesterolaemia (RFH) swine. Contrast-enhanced ultrasound imaging of the eight femoral arteries was performed at baseline and at 5, 12, 26, and 43 weeks follow-up after percutaneous transluminal stimulation of atherosclerosis to assess the progression of intima-media thickness (IMT) and the density and extent of the vasa vasorum network. Contrast-enhanced ultrasound imaging allowed an early detection of atherosclerosis and showed a significant gradual progression of atherosclerosis over time. IMT increased from 0.22 +/- 0.05 mm at baseline to 0.45 +/- 0.06 mm (P < 0.001) at follow-up. The density of the vasa vasorum network increased during follow-up and was significantly higher in advanced than in early atherosclerosis. The findings with contrast-enhanced ultrasound were confirmed by histopathological specimens of the arterial wall., Conclusion: Contrast-enhanced ultrasound is effective for in vivo detection of vasa vasorum in atherosclerotic plaques in the RFH swine model. After stimulation of atherosclerosis, contrast-enhanced ultrasound demonstrated a significantly increased IMT and significantly increased density of the vasa vasorum network in the developing atherosclerotic plaque, which was validated by histology.

Objective: The purpose of this study was to test the efficacy of static and dynamic cumulative maximum intensity (CMI) subharmonic imaging (SHI) in breast ultrasound studies., Methods: Contrast-enhanced SHI was performed in 14 women using a modified LOGIQ 9 scanner (GE Healthcare, Milwaukee, WI) transmitting/receiving at 4.4/2.2 MHz. Following mammography, baseline scans of gray scale ultrasound and power Doppler imaging (PDI) were performed. Contrast-enhanced PDI and gray scale SHI were performed after contrast agent administration. Static CMI-SHI is a composite image summarizing blood flow over multiple frames using the maximum intensity projection technique. The dynamic CMI-SHI mode depicts the gradual inflow pattern of the contrast agent in blood vessels. Both CMI-SHI modes were set up using a new automated sum-absolute-difference-based block-matching algorithm to reduce noise and blurring and compensate for motion artifacts. Evaluation of the imaging modes for detecting breast cancer was done by an experienced radiologist, blinded to histopathologic findings. Sensitivity, specificity, and receiver operating characteristic (ROC) analyses were computed and compared for all ultrasound imaging modes and mammography. Results Of the 16 lesions, 4 were malignant. The area under the ROC curve (A(z)) for the diagnosis of breast cancer was 0.64 for gray scale and PDI, 0.67 for contrast-enhanced PDI, 0.76 for mammography, 0.78 for SHI, and 0.75 for static CMI-SHI. For the dynamic CMI-SHI mode, the A(z) increased to 0.90, and this was significantly better than mammography (P = .03)., Conclusions: The new dynamic CMI-SHI mode produced the highest A(z) for the diagnosis of breast cancer compared to conventional techniques and thus appears to improve diagnosis of breast cancer relative to conventional techniques, albeit based on a limited patient population.

To verify a previously reported three-dimensional (3D) ultrasound method for the measurement of time-average volumetric blood flow, experiments were performed under pulsatile flow conditions, including in vivo investigations, and results were compared with accepted, but invasive, "gold standard" techniques. Results showed that volume averaging results in the correct time-average volume flow without the need for cardiac gating. Unlike other currently employed methods, this method is independent of Doppler angle, flow profile and vessel geometry. A GE Logiq 9 ultrasound system (GE Medical Systems, Milwaukee, WI, USA) and a four-dimensional (4D) 10L and 4D 16L probe were used to acquire 3D Doppler measurements in the femoral and carotid arteries of four canines. Two invasive blood flow meters were used (electromagnetic for one canine and ultrasonic for three canines) as the gold standard techniques. Transcutaneous color flow measurements were taken to obtain 3D volume data sets encompassing the vessel. Constant depth planes were used to integrate color flow pixels encompassing the entire vessel cross-section. Power Doppler data were used to correct for partial volume effects. An artificial stenosis was induced to vary the ambient volume flow. Unrestricted, bidirectional flow was measured as high as 400 mL min(-1). Several flow restrictions were imposed that decreased the measured volumetric flow rate to as low as 30 mL min(-1). All flow rate estimates (n=38) were plotted against results obtained via the gold standards. A general line fit resulted in y = 0.926 x - 0.87 (r(2) = 0.95), which corresponds to a 0.6% flow offset relative to the average flow rate of 142 mL min(-1), as well as a 7.4% error in the linearity of our estimate. A secondary curve fit was performed that required the slope to be 1 and the intercept to be 0, which yielded an r(2)-value of 0.93. The percent-error distribution was computed and fitted to a Gaussian function, which yielded mu=-7.04% and sigma=9.52%. Theoretical studies were conducted to estimate the expected error in our volume flow measurements as a function of number of samples (N) used for averaging pulsatile waveforms. Experiments showed the same 1/N dependence as theory. Direct comparisons of volume flow rate estimates using volumetric color Doppler and independent standards showed that our method has good accuracy under in vivo pulsatile blood flow conditions.

We present 2 cases of Aspergillus endocarditis occurring in lung transplant recipients, both of whom were treated with early surgical intervention and triazole anti-fungal agents. Neither had evidence of airway colonization/infection with Aspergillus post-transplant, suggesting hematogenous spread of fungi at the time of surgery as a possible mechanism of infection. One case was successfully treated and discharged from the hospital, but, despite initial recovery, death occurred 10 months later due to a recurrence of Aspergillus endocarditis. Aspergillus endocarditis should be considered a relapsing disease and survivors of the condition should receive ongoing anti-fungal therapy.

Although simple cysts are easily identified using sonography, description and management of nonsimple cysts remains uncertain. This study evaluated whether the correlation coefficient differences between breast tissue and lesions, obtained from 2D breast elastography, could potentially distinguish nonsimple cysts from cancers and fibroadenomas. We hypothesized that correlation coefficients in cysts would be dramatically lower than surrounding tissue because noise, imaging artifacts, and particulate matter move randomly and decorrelate quickly under compression, compared with solid tissue. For this preliminary study, 18 breast lesions (7 nonsimple cysts, 4 cancers, and 7 fibroadenomas) underwent imaging with 2D elastography at 7.5 MHz through a TPX (a polymethyl pentene copolymer) 2.5 mm mammographic paddle. Breasts were compressed similar to mammographic positioning and then further compressed for elastography by 1 to 7%. Images were correlated using 2D phase-sensitive speckle tracking algorithms and displacement estimates were accumulated. Correlation coefficient means and standard deviations were measured in the lesion and adjacent tissue, and the differential correlation coefficient (DCC) was introduced as the difference between these values normalized to the correlation coefficient of adjacent tissue. Mean DCC values in nonsimple cysts were 24.2 +/- 11.6%, 5.7 +/- 6.3% for fibroadenomas, and 3.8 +/- 2.9 % for cancers (p < 0.05). Some of the cysts appeared smaller in DCC images than gray-scale images. These encouraging results demonstrate that characterization of nonsimple breast cysts may be improved by using DCC values from 2D elastography, which could potentially change management options of these cysts from intervention to imaging follow-up. A dedicated clinical trial to fully assess the efficacy of this technique is recommended.

Purpose: To prospectively compare accuracy of gray-scale subharmonic imaging (SHI) with that of standard gray-scale ultrasonography (US), power Doppler US (with and without contrast material), and mammography for the diagnosis of breast cancer, with histopathologic or clinical follow-up results as the reference standard., Materials and Methods: This HIPAA-compliant pilot study had institutional review board approval; all subjects gave written informed consent. Fourteen women (age range, 37-66 years) had 16 biopsy-proved breast lesions. In SHI, pulses are transmitted at one frequency, but only echoes at half that frequency (the subharmonic) are received. A US scanner was modified to perform gray-scale SHI (transmitting at 4.4 and receiving at 2.2 MHz). Precontrast imaging (gray-scale US and power Doppler) was followed by contrast material-enhanced power Doppler and gray-scale SHI. A reader blinded to mammographic and pathologic findings assessed diagnosis on a six-point scale. Sensitivity, specificity, accuracy, and receiver operating characteristic (ROC) curves were computed for mammography, gray-scale and power Doppler imaging (pre- and postcontrast), and SHI., Results: Of the 16 lesions, four (25%) were malignant. Mammography had 100% sensitivity and 20% specificity. Sensitivity and specificity, respectively, were 50% and 92% for precontrast imaging and 75% and 75% for contrast-enhanced power Doppler. SHI had 75% sensitivity and 83% specificity. Specificity was higher for all US modes than for mammography (P<.04). There were no significant differences in specificity among US modes or in sensitivity (P>or=.50). Area under the ROC curve for the diagnosis of breast cancer was 0.64 for standard gray-scale US and power Doppler US, 0.67 for contrast-enhanced power Doppler US, 0.76 for mammography, and 0.78 for SHI (P>.20). Contrast enhancement was better with SHI than with power Doppler (100% vs 44% of lesions with good or excellent enhancement; P=.004)., Conclusion: SHI appears to improve the diagnosis of breast cancer relative to conventional US and mammography, albeit on the basis of results in a very limited number of subjects., (Copyright (c) RSNA, 2007.)

Disseminated varicella-zoster virus infection after organ transplantation in adults is a rare but serious event causing significant morbidity and mortality. We describe our 10-year experience of 13 cases in a single center, including risk factors for infection, lack of protection from pre-existing anti-varicella-zoster virus antibodies, and unusual modes of presentation, including disseminated intravascular coagulation. We also report our preliminary observation of resolution of infection without sequelae in 4 patients with severe disseminated varicella-zoster virus infection who were treated with the combination of intravenous acyclovir and polyspecific intravenous immunoglobulin.

Objective: The purpose of this study was to evaluate a 3-dimensional (3D) sonographic method for the measurement of volumetric flow under conditions of known flow rates and Doppler angles., Methods: A GE/Kretz Voluson 730 system (GE Healthcare, Milwaukee, WI) and RAB2-5 probe were used to acquire 3D Doppler measurements in a custom flow phantom. Blood-mimicking fluid circulated by a computer-controlled pump provided a range of flow velocities (2-15 mL/s). A 6-axis positioning system maneuvered the ultrasound probe through a range of angles (40 degrees-70 degrees and 110 degrees -140 degrees) with respect to the tube (orthogonal to the tube being 90 degrees). Volume data sets were obtained spanning 29 degrees lateral and 20 degrees elevational angles encompassing the flow tube in a scanning time of less than 10 seconds. Power Doppler data were used to correct for partial volume effects., Results: Using a single angle (110 degrees) with respect to the flow tube, measured and actual volume flow rates were within the 95% confidence interval over the full range of flow rates. At flow rates of 5 and 10 mL/s, the measured volume flow rates were all within +/-15% of actual values for the range of angles tested and also stayed within the 95% confidence interval., Conclusions: Direct comparisons of volume flow rates estimated with 3D sonography and known flow rates showed that the method has good accuracy. Subsequent comparisons under pulsatile and in vivo conditions will be needed to verify this performance for clinical applications.

We report a 56-year-old who underwent orthotopic heart transplantation following left ventricular assist device bridge to transplantation. His postoperative course was complicated by severe sternal wound infection with Acinetobacter species requiring extensive debridement and reconstruction with a pectoralis major flap. This was followed by a total sternectomy, pectoralis flap debridement, and vacuum-assisted dressing.

Vector Doppler methods are used to obtain angle independent in-plane velocity information. Velocity magnitude as well as direction are reconstructed from regular steered colour flow and from split-aperture Doppler acquisitions. Spatially resolved in-plane velocity was obtained through Doppler colour flow mode and subsequent data triangulation. A depth-invariant constant Doppler angle was achieved by using a depth expanding transmit-receive Doppler aperture. Velocities of up to 50 cm s(-1) and 360 degrees vector velocity directions were measured. This was achieved by creating a spinning solid disc phantom. Such a phantom was built to allow underwater mounting and spinning of a solid disc-shaped ultrasound phantom (maximum velocity of 50 cm s-1). Doppler triangulation was realised by steered Doppler and by a split-aperture approach. Results of both imaging methods are shown. Split-aperture results showed errors of less then 10% for velocity magnitude estimation and less then 2.5 degrees for directional information.