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Exposure to heavy metals, such as cadmium, nickel, mercury, arsenic, lead, and hexavalent chromium has been linked to dysregulated developmental processes, such as impaired stem cell differentiation. Heavy metals are well-known modifiers of the epigenome. Stem and progenitor cells are particularly vulnerable to exposure to potentially toxic metals since these cells rely on epigenetic reprogramming for their proper functioning. Therefore, exposure to metals can impair stem and progenitor cell proliferation, pluripotency, stemness, and differentiation. In this review, we provide a comprehensive summary of current evidence on the epigenetic effects of heavy metals on stem cells, focusing particularly on DNA methylation and histone modifications. Moreover, we explore the underlying mechanisms responsible for these epigenetic changes. By providing an overview of heavy metal exposure-induced alterations to the epigenome, the underlying mechanisms, and the consequences of those alterations on stem cell function, this review provides a foundation for further research in this critical area of overlap between toxicology and developmental biology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Exposure to repetitive head impacts in contact sports is associated with neurodegenerative disorders including chronic traumatic encephalopathy (CTE), which currently can be diagnosed only at post-mortem. American football players are at higher risk of developing CTE given their exposure to repetitive head impacts. One promising approach for diagnosing CTE in vivo is to explore known neuropathological abnormalities at post-mortem in living individuals using structural MRI. MRI brain morphometry was evaluated in 170 male former American football players ages 45-74 years (n = 114 professional; n = 56 college) and 54 same-age unexposed asymptomatic male controls (n = 54, age range 45-74). Cortical thickness and volume of regions of interest were selected based on established CTE pathology findings and were assessed using FreeSurfer. Group differences and interactions with age and exposure factors were evaluated using a generalized least squares model. A separate logistic regression and independent multinomial model were performed to predict each traumatic encephalopathy syndrome (TES) diagnosis, core clinical features and provisional level of certainty for CTE pathology using brain regions of interest. Former college and professional American football players (combined) showed significant cortical thickness and/or volume reductions compared to unexposed asymptomatic controls in the hippocampus, amygdala, entorhinal cortex, parahippocampal gyrus, insula, temporal pole and superior frontal gyrus. Post hoc analyses identified group-level differences between former professional players and unexposed asymptomatic controls in the hippocampus, amygdala, entorhinal cortex, parahippocampal gyrus, insula and superior frontal gyrus. Former college players showed significant volume reductions in the hippocampus, amygdala and superior frontal gyrus compared to the unexposed asymptomatic controls. We did not observe Age × Group interactions for brain morphometric measures. Interactions between morphometry and exposure measures were limited to a single significant positive association between the age of first exposure to organized tackle football and right insular volume. We found no significant relationship between brain morphometric measures and the TES diagnosis core clinical features and provisional level of certainty for CTE pathology outcomes. These findings suggested that MRI morphometrics detect abnormalities in individuals with a history of repetitive head impact exposure that resemble the anatomic distribution of pathological findings from post-mortem CTE studies. The lack of findings associating MRI measures with exposure metrics (except for one significant relationship) or TES diagnosis and core clinical features suggested that brain morphometry must be complemented by other types of measures to characterize individuals with repetitive head impacts., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Objectives: Exposure to repetitive head impacts (RHI) is linked to the development of chronic traumatic encephalopathy (CTE), which can only be diagnosed at post-mortem. The presence of a cavum septum pellucidum (CSP) is a common finding in post-mortem studies of confirmed CTE and in neuroimaging studies of individuals exposed to RHI. This study examines CSP in living former American football players, investigating its association with RHI exposure, traumatic encephalopathy syndrome (TES) diagnosis, and provisional levels of certainty for CTE pathology., Methods: Data from the DIAGNOSE CTE Research Project were used to compare the presence and ratio of CSP in former American football players (n = 175), consisting of former college (n = 58) and former professional players (n = 117), and asymptomatic unexposed controls without RHI exposure (n = 55). We further evaluated potential associations between CSP measures and cumulative head impact index (CHII) measures (frequency, linear acceleration, and rotational force), a TES diagnosis (yes/no), and a provisional level of certainty for CTE pathology (suggestive, possible, and probable)., Results: Former American football players exhibited a higher CSP presence and ratio than unexposed asymptomatic controls. Among player subgroups, professional players showed a greater CSP ratio than former college players and unexposed asymptomatic controls. Among all football players, CHII rotational forces correlated with an increased CSP ratio. No significant associations were found between CSP measures and diagnosis of TES or provisional levels of certainty for CTE pathology., Discussion: This study confirms previous findings, highlighting a greater prevalence of CSP and a greater CSP ratio in former American football players compared with unexposed asymptomatic controls. In addition, former professional players showed a greater CSP ratio than college players. Moreover, the relationship between estimates of CHII rotational forces and CSP measures suggests that cumulative frequency and strength of rotational forces experienced in football are associated with CSP. However, CSP does not directly correlate with TES diagnosis or provisional levels of certainty for CTE, indicating that it may be a consequence of RHI associated with rotational forces. Further research, especially longitudinal studies, is needed for confirmation and to explore changes over time., Competing Interests: C.H. Adler consulted for Avion, CND Life Sciences, Jazz, and PreCon Health; LJB is Editor-in-Chief of the Journal of Neuro-Ophthalmology and is a paid consultant to Biogen (Cambridge, MA, USA); C. Bernick receives research support from the Ultimate Fighting Championship, Top Rank promotions, Haymon Boxing, Las Vegas Raiders, and Professional Bull Riders. He is a paid consultant for Aurora Concussion Therapy Systems, Inc. (St. Paul, MN); A.P. Lin consulted for Agios, BioMarin, and Moncton MRI. He is a co-founder of BrainSpec, Inc; J.L. Cummings has provided consultation to Acadia, Alkahest, AlphaCognition, AriBio, Avanir, Axsome, Behren Therapeutics, Biogen, Biohaven, Cassava, Cortexyme, Diadem, EIP Pharma, Eisai, GemVax, Genentech, Green Valley, Grifols, Janssen, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Ono, Otsuka, PRODEO, Prothena, ReMYND, Renew, Resverlogix, Roche, Signant Health, Suven, United Neuroscience, and Unlearn AI pharmaceutical, assessment, and investment companies; E.M. Reiman is a compensated scientific advisor for Alkahest, Alzheon, Aural Analytics, Denali, Green Valley, Retromer Therapeutics, and Vaxxinity and is a cofounder of ALZPath; R.A. Stern is a paid consultant to Biogen (Cambridge, MA, USA) and Lundbeck (Copenhagen, Denmark). He is a member of the Board of Directors of King-Devick Technologies, Inc. (Chicago, IL, USA), and he receives royalties for published neuropsychological tests from Psychological Assessment Resources, Inc. (Lutz, FL, USA). He has been a member of the Medical Science Committee for the National Collegiate Athletic Association Student-Athlete Concussion Injury Litigation; I.K. Koerte receives funding for a collaborative project from Abbott Inc. She receives royalties for book chapters. Her spouse is an employee at Siemens AG and a stockholder of Siemens AG and Siemens Healthineers. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: The time following a recent onset of psychosis is a critical period during which intervention may be maximally effective. Studying individuals in this period also offers an opportunity to investigate putative brain biomarkers of illness prior to the long-term effects of chronicity and medication. The Human Connectome Project for Early Psychosis (HCP-EP) was funded by the National Institutes of Mental Health (NIMH) as an extension of the original Human Connectome Project's approach to understanding the human brain and its structural and functional connections., Design: The HCP-EP data were collected at 3 sites in Massachusetts (Beth Israel Deaconess Medical Center, McLean Hospital, and Massachusetts General Hospital), and one site in Indiana (Indiana University). Brigham and Women's Hospital served as the data coordination center and as an imaging site., Results: The HCP-EP dataset includes high-quality clinical, cognitive, functional, neuroimaging, and blood specimen data acquired from 303 individuals between the ages of 16-35 years old with affective psychosis (n = 75), non-affective psychosis (n = 148), and healthy controls (n = 80). Participants with early psychosis were within 5 years of illness onset (mean duration = 1.9 years, standard deviation = 1.4 years). All data and novel or modified analytic tools developed as part of the study are publicly available to the research community through the NIMH Data Archive (NDA) or GitHub (https://github.com/pnlbwh)., Conclusions: This paper provides an overview of the specific HCP-EP procedures, assessments, and protocols, as well as a brief characterization of the study participants to make it easier for researchers to use this rich dataset. Although we focus here on discussing and comparing affective and non-affective psychosis groups, the HCP-EP dataset also provides sufficient information for investigators to group participants differently., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The food additive E171 (titanium dioxide, TiO 2 ), is widely used in foods, pharmaceuticals and cosmetics. It is a fine white powder, with at least one third of its particles sized in the nanoparticulate (˂100 nm range, TiO 2 NPs). The use of E171 is controversial as its relevant risk assessment has never been satisfactorily accomplished. In vitro and in vivo studies have shown dose-dependent toxicity in various organs including the liver. TiO 2 NPs have been shown to induce inflammation, cell death and structural and functional changes within the liver. The toxicity of TiO 2 NPs in experimental models varies between organs and according to their physiochemical characteristics and parameters such as dosage and route of administration. Among these factors, ingestion is the most significant exposure route, and the liver is a key target organ. The aim of this review is to highlight the reported adverse effects of orally administered TiO 2 NPs on the liver and to discuss the controversial state of its toxicity., (© 2024 The Authors. Journal of Applied Toxicology published by John Wiley & Sons Ltd.)

This article describes the rationale, aims, and methodology of the Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ). This is the largest international collaboration to date that will develop algorithms to predict trajectories and outcomes of individuals at clinical high risk (CHR) for psychosis and to advance the development and use of novel pharmacological interventions for CHR individuals. We present a description of the participating research networks and the data processing analysis and coordination center, their processes for data harmonization across 43 sites from 13 participating countries (recruitment across North America, Australia, Europe, Asia, and South America), data flow and quality assessment processes, data analyses, and the transfer of data to the National Institute of Mental Health (NIMH) Data Archive (NDA) for use by the research community. In an expected sample of approximately 2000 CHR individuals and 640 matched healthy controls, AMP SCZ will collect clinical, environmental, and cognitive data along with multimodal biomarkers, including neuroimaging, electrophysiology, fluid biospecimens, speech and facial expression samples, novel measures derived from digital health technologies including smartphone-based daily surveys, and passive sensing as well as actigraphy. The study will investigate a range of clinical outcomes over a 2-year period, including transition to psychosis, remission or persistence of CHR status, attenuated positive symptoms, persistent negative symptoms, mood and anxiety symptoms, and psychosocial functioning. The global reach of AMP SCZ and its harmonized innovative methods promise to catalyze the development of new treatments to address critical unmet clinical and public health needs in CHR individuals., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Resting state functional magnetic resonance imaging (rsfMRI) provides researchers and clinicians with a powerful tool to examine functional connectivity across large-scale brain networks, with ever-increasing applications to the study of neurological disorders, such as traumatic brain injury (TBI). While rsfMRI holds unparalleled promise in systems neurosciences, its acquisition and analytical methodology across research groups is variable, resulting in a literature that is challenging to integrate and interpret. The focus of this narrative review is to address the primary methodological issues including investigator decision points in the application of rsfMRI to study the consequences of TBI. As part of the ENIGMA Brain Injury working group, we have collaborated to identify a minimum set of recommendations that are designed to produce results that are reliable, harmonizable, and reproducible for the TBI imaging research community. Part one of this review provides the results of a literature search of current rsfMRI studies of TBI, highlighting key design considerations and data processing pipelines. Part two outlines seven data acquisition, processing, and analysis recommendations with the goal of maximizing study reliability and between-site comparability, while preserving investigator autonomy. Part three summarizes new directions and opportunities for future rsfMRI studies in TBI patients. The goal is to galvanize the TBI community to gain consensus for a set of rigorous and reproducible methods, and to increase analytical transparency and data sharing to address the reproducibility crisis in the field., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Exposure to nickel, an environmental respiratory toxicant, is associated with lung diseases including asthma, pulmonary fibrosis, bronchitis and cancers. Our previous studies have shown that a majority of the nickel-induced transcriptional changes are persistent and do not reverse even after the termination of exposure. This suggested transcriptional memory, wherein the cell 'remembers' past nickel exposure. Transcriptional memory, due to which the cells respond more robustly to a previously encountered stimulus has been identified in a number of organisms. Therefore, transcriptional memory has been described as an adaptive mechanism. However, transcriptional memory caused by environmental toxicant exposures has not been well investigated. Moreover, how the transcriptional memory caused by an environmental toxicant might influence the outcome of exposure to a second toxicant has not been explored. In this study, we investigated whether nickel-induced transcriptional memory influences the outcome of the cell's response to a second respiratory toxicant, nicotine. Nicotine, an addictive compound in tobacco, is associated with the development of chronic lung diseases including chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis. Our results show that nicotine exposure upregulated a subset of genes only in the cells previously exposed to nickel. Furthermore, our analyses indicate robust activation of interferon (IFN) signaling in these cells. IFN signaling is a driver of inflammation, which is associated with many chronic lung diseases. Therefore, our results suggest that nicotine exposure of lung cells that retain the transcriptional memory of previous nickel exposure could result in increased susceptibility to developing chronic inflammatory lung diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Prostaglandin E2 imparts diverse physiological effects on multiple airway cells through its actions on four distinct E-type prostanoid (EP) receptor subtypes (EP1-EP4). Gs-coupled EP2 and EP4 receptors are expressed on airway smooth muscle (ASM), yet their capacity to regulate the ASM contractile state remains subject to debate. We used EP2 and EP4 subtype-specific agonists (ONO-259 and ONO-329, respectively) in cell- and tissue-based models of human ASM contraction-magnetic twisting cytometry (MTC), and precision-cut lung slices (PCLSs), respectively-to study the EP2 and EP4 regulation of ASM contraction and signaling under conditions of histamine or methacholine (MCh) stimulation. ONO-329 was superior (<0.05) to ONO-259 in relaxing MCh-contracted PCLSs (log half maximal effective concentration [logEC 50 ]: 4.9 × 10 -7 vs. 2.2 × 10 -6 ; maximal bronchodilation ± SE, 35 ± 2% vs. 15 ± 2%). However, ONO-259 and ONO-329 were similarly efficacious in relaxing histamine-contracted PCLSs. Similar differential effects were observed in MTC studies. Signaling analyses revealed only modest differences in ONO-329- and ONO-259-induced phosphorylation of the protein kinase A substrates VASP and HSP20, with concomitant stimulation with MCh or histamine. Conversely, ONO-259 failed to inhibit MCh-induced phosphorylation of the regulatory myosin light chain (pMLC20) and the F-actin/G-actin ratio (F/G-actin ratio) while effectively inhibiting their induction by histamine. ONO-329 was effective in reversing induced pMLC20 and the F/G-actin ratio with both MCh and histamine. Thus, the contractile-agonist-dependent differential effects are not explained by changes in the global levels of phosphorylated protein kinase A substrates but are reflected in the regulation of pMLC20 (cross-bridge cycling) and F/G-actin ratio (actin cytoskeleton integrity, force transmission), implicating a role for compartmentalized signaling involving muscarinic, histamine, and EP receptor subtypes.

Although metastasis is the leading cause of cancer deaths, it is quite rare at the cellular level. Only a rare subset of cancer cells (~ 1 in 1.5 billion) can complete the entire metastatic cascade: invasion, intravasation, survival in the circulation, extravasation, and colonization (i.e. are metastasis competent). We propose that cells engaging a Polyaneuploid Cancer Cell (PACC) phenotype are metastasis competent. Cells in the PACC state are enlarged, endocycling (i.e. non-dividing) cells with increased genomic content that form in response to stress. Single-cell tracking using time lapse microscopy reveals that PACC state cells have increased motility. Additionally, cells in the PACC state exhibit increased capacity for environment-sensing and directional migration in chemotactic environments, predicting successful invasion. Magnetic Twisting Cytometry and Atomic Force Microscopy reveal that cells in the PACC state display hyper-elastic properties like increased peripheral deformability and maintained peri-nuclear cortical integrity that predict successful intravasation and extravasation. Furthermore, four orthogonal methods reveal that cells in the PACC state have increased expression of vimentin, a hyper-elastic biomolecule known to modulate biomechanical properties and induce mesenchymal-like motility. Taken together, these data indicate that cells in the PACC state have increased metastatic potential and are worthy of further in vivo analysis., (© 2023. The Author(s).)

Rhinoviruses (RVs) evoke as many as 85% of acute asthma exacerbations in children and 50% in adults and can induce airway hyperresponsiveness and decrease efficacy of current therapeutics to provide symptom relief. Using human precision-cut lung slices (hPCLSs), primary human air-liquid interface-differentiated airway epithelial cells (HAECs), and human airway smooth muscle (HASM) as preclinical experimental models, we demonstrated that RV-C15 attenuates agonist-induced bronchodilation. Specifically, airway relaxation to formoterol and cholera toxin, but not forskolin (Fsk), was attenuated following hPCLS exposure to RV-C15. In isolated HASM cells, exposure to conditioned media from RV-exposed HAECs decreased cellular relaxation in response to isoproterenol and prostaglandin E 2 , but not Fsk. Additionally, cAMP generation elicited by formoterol and isoproterenol, but not Fsk, was attenuated following HASM exposure to RV-C15-conditioned HAEC media. HASM exposure to RV-C15-conditioned HAEC media modulated expression of components of relaxation pathways, specifically GNAI1 and GRK2 . Strikingly, similar to exposure to intact RV-C15, hPCLS exposed to UV-inactivated RV-C15 showed markedly attenuated airway relaxation in response to formoterol, suggesting that the mechanism(s) of RV-C15-mediated loss of bronchodilation is independent of virus replication pathways. Further studies are warranted to identify soluble factor(s) regulating the epithelial-driven smooth muscle loss of β 2 -adrenergic receptor function.

Abstract: Mucormycosis is a devastating fungal infection known for its angioinvasive spread and hematogenous dissemination, quickly resulting in multiorgan involvement and potentially fatal complications. Timely diagnosis is essential to facilitate early, aggressive debridement, yet the diagnosis remains difficult to obtain because of the need for culture and microscopy diagnosis. We provide case examples, which highlight diagnostic pearls and the multidisciplinary approach that are critical for improving local outcomes, preventing systemic spread, and reducing mortality., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Purpose: β-Adrenoceptor agonists relieve airflow obstruction by activating β 2 -adrenoceptors, which are G protein-coupled receptors (GPCRs) expressed on human airway smooth muscle (HASM) cells. The currently available β-adrenoceptor agonists are balanced agonists, however, and signal through both the stimulatory G protein (G s )- and β-arrestin-mediated pathways. While G s signalling is beneficial and promotes HASM relaxation, β-arrestin activation is associated with reduced G s efficacy. In this context, biased ligands that selectively promote β 2 -adrenoceptor coupling to G s signalling represent a promising strategy to treat asthma. Here, we examined several β-adrenoceptor agonists to identify G s -biased ligands devoid of β-arrestin-mediated effects., Experimental Approach: G s -biased ligands for the β 2 -adrenoceptor were identified by high-throughput screening and then evaluated for G s interaction, G i interaction, cAMP production, β-arrestin interaction, GPCR kinase (GRK) phosphorylation of the receptor, receptor trafficking, ERK activation, and functional desensitization of the β 2 -adrenoceptor., Key Results: We identified ractopamine, dobutamine, and higenamine as G s -biased agonists that activate the G s /cAMP pathway upon β 2 -adrenoceptor stimulation while showing minimal G i or β-arrestin interaction. Furthermore, these compounds did not induce any receptor trafficking and had reduced GRK5-mediated phosphorylation of the β 2 -adrenoceptor. Finally, we observed minimal physiological desensitization of the β 2 -adrenoceptor in primary HASM cells upon treatment with biased agonists., Conclusion and Implications: Our work demonstrates that G s -biased signalling through the β 2 -adrenoceptor may prove to be an effective strategy to promote HASM relaxation in the treatment of asthma. Such biased compounds may also be useful in identifying the molecular mechanisms that determine biased signalling and in design of safer drugs., (© 2022 British Pharmacological Society.)

Aim: To provide an up-to-date review of thunderstorm asthma (TA), identifying causative factors, and to discuss implications for management of TA in New Zealand., Methods: A literature search was carried out to identify articles that investigate the characteristics and causative factors of TA. Nine electronic databases were searched, yielding 372 articles, reduced to 30 articles after screening for duplication and relevance., Results: TA is globally rare, with 29 reported events since 1983, but is expected to increase in frequency as Earth warms. Triggers include both pollen (particularly ryegrass pollen) and fungal spores. Individual risk factors include outdoor exposure, sensitivity to triggering allergens and history of seasonal allergic rhinitis. History of asthma is not a strong risk factor but is associated with severity of outcome. Limited data on demographic characteristics suggests that individuals aged between 20 and 60 and (in Australasia) of Asian/Indian ethnicity are at higher risk. A single TA event has been reported in New Zealand to date, but much of New Zealand may be at risk of future events given that ryegrass pastures are widely distributed, and summer thunderstorms can occur anywhere., Conclusions: We recommend developing rapidly deployable public messaging to support the health emergency management response to future TA events, together with the instigation of routine aeroallergen monitoring., Competing Interests: Nil.

Dyslipidemia and autophagy have been implicated in the pathogenesis of blinding neovascular age-related macular degeneration (NV-AMD). VLDL receptor (VLDLR), expressed in photoreceptors with a high metabolic rate, facilitates the uptake of triglyceride-derived fatty acids. Since fatty acid uptake is reduced in Vldlr-/- tissues, more remain in circulation, and the retina is fuel deficient, driving the formation in mice of neovascular lesions reminiscent of retinal angiomatous proliferation (RAP), a subtype of NV-AMD. Nutrient scarcity and energy failure are classically mitigated by increasing autophagy. We found that excess circulating lipids restrained retinal autophagy, which contributed to pathological angiogenesis in the Vldlr-/- RAP model. Triglyceride-derived fatty acid sensed by free fatty acid receptor 1 (FFAR1) restricted autophagy and oxidative metabolism in photoreceptors. FFAR1 suppressed transcription factor EB (TFEB), a master regulator of autophagy and lipid metabolism. Reduced TFEB, in turn, decreased sirtuin-3 expression and mitochondrial respiration. Metabolomic signatures of mouse RAP-like retinas were consistent with a role in promoting angiogenesis. This signature was also found in human NV-AMD vitreous. Restoring photoreceptor autophagy in Vldlr-/- retinas, either pharmacologically or by deleting Ffar1, enhanced metabolic efficiency and suppressed pathological angiogenesis. Dysregulated autophagy by circulating lipids might therefore contribute to the energy failure of photoreceptors driving neovascular eye diseases, and FFAR1 may be a target for intervention.

Computed tomographic coronary artery calcium scanning enables cardiovascular risk stratification; however, exposing patients to high radiation levels is an ongoing concern. New-generation computed tomographic systems use lower radiation doses than older systems do. To quantify comparative doses of radiation exposure, we prospectively acquired images from 220 patients with use of a 64-slice GE LightSpeed VCT scanner (control group, n=110) and a 256-slice GE Revolution scanner (study group, n=110). The groups were matched for age, sex, and body mass index; statistical analysis included t tests and linear regression. The mean dose-length product was 21% lower in the study group than in the control group (60.2 ± 27 vs 75.9 ± 22.6 mGy·cm; P <0.001) and also in each body mass index subgroup. Similarly, the mean effective radiation dose was 21% lower in the study group (0.84 ± 0.38 vs 1.06 ± 0.32 mSv) and lower in each weight subgroup. After adjustment for sex, women in the study group had a lower dose-length product (50.4 ± 23.4 vs 64.7 ± 27.6 mGy·cm) than men did and received a lower effective dose (0.7 ± 0.32 vs 0.9 ± 0.38 mSv) (P=0.009). As body mass index and waist circumference increased, so did doses for both scanners. Our study group was exposed to radiation doses lower than the previously determined standard of 1 mSv, even after adjustment for body mass index and waist circumference. In 256-slice scanning for coronary artery calcium, radiation doses are now similar to those in lung cancer screening and mammography., (© 2022 by the Texas Heart® Institute, Houston.)

G protein-coupled receptors display multifunctional signaling, offering the potential for agonist structures to promote conformational selectivity for biased outputs. For β 2 -adrenergic receptors (β 2 AR), unbiased agonists stabilize conformation(s) that evoke coupling to Gαs (cyclic adenosine monophosphate [cAMP] production/human airway smooth muscle [HASM] cell relaxation) and β-arrestin engagement, the latter acting to quench Gαs signaling, contributing to receptor desensitization/tachyphylaxis. We screened a 40-million-compound scaffold ranking library, revealing unanticipated agonists with dihydroimidazolyl-butyl-cyclic urea scaffolds. The S -stereoisomer of compound C1 shows no detectable β-arrestin engagement/signaling by four methods. However, C1- S retained Gαs signaling-a divergence of the outputs favorable for treating asthma. Functional studies with two models confirmed the biasing: β 2 AR-mediated cAMP signaling underwent desensitization to the unbiased agonist albuterol but not to C1- S , and desensitization of HASM cell relaxation was observed with albuterol but not with C1- S These HASM results indicate biologically pertinent biasing of C1- S , in the context of the relevant physiologic response, in the human cell type of interest. Thus, C1- S was apparently strongly biased away from β - arrestin, in contrast to albuterol and C5- S C1- S structural modeling and simulations revealed binding differences compared with unbiased epinephrine at transmembrane (TM) segments 3,5,6,7 and ECL2. C1- S (R2 = cyclohexane) was repositioned in the pocket such that it lost a TM6 interaction and gained a TM7 interaction compared with the analogous unbiased C5- S (R2 = benzene group), which appears to contribute to C1- S biasing away from β-arrestin. Thus, an agnostic large chemical-space library identified agonists with receptor interactions that resulted in relevant signal splitting of β 2 AR actions favorable for treating obstructive lung disease., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Penile inversion vaginoplasty is the most common technique used for gender affirming genital surgery in the treatment of gender dysphoria among transwomen. As vaginoplasty becomes more widely available, the management of associated complications has become its own field. There is a relative dearth of literature on surgery for complications following vaginoplasty. This review illustrates surgical technique and management options for patient reported complaints and complications following vaginoplasty. The goal of this manuscript is 2-fold (1) to introduce community surgeons to common postoperative issues they may encounter and (2) provide a systematic operative approach to complications for reconstructive surgeons who see transgender patients regularly., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Activation of free fatty acid receptors (FFAR1 and FFAR4) which are G protein-coupled receptors (GPCRs) with established (patho)physiological roles in a variety of obesity-related disorders, induce human airway smooth muscle (HASM) cell proliferation and shortening. We reported amplified agonist-induced cell shortening in HASM cells obtained from obese lung donors. We hypothesized that FFAR1 modulate excitation-contraction (EC) coupling in HASM cells and play a role in obesity-associated airway hyperresponsiveness., Methods: In HASM cells pre-treated (30 min) with FFAR1 agonists TAK875 and GW9508, we measured histamine-induced Ca 2+ mobilization, myosin light chain (MLC) phosphorylation, and cortical tension development with magnetic twisting cytometry (MTC). Phosphorylation of MLC phosphatase and Akt also were determined in the presence of the FFAR1 agonists or vehicle. In addition, the effects of TAK875 on MLC phosphorylation were measured in HASM cells desensitized to β 2 AR agonists by overnight salmeterol treatment. The inhibitory effect of TAK875 on MLC phosphorylation was compared between HASM cells from age and sex-matched non-obese and obese human lung donors. The mean measurements were compared using One-Way ANOVA with Dunnett's test for multiple group comparisons or Student's t-test two-group comparison. For cortical tension measurements by magnetic twisted cytometry, mixed effect model using SAS V.9.2 was applied. Means were considered significant when p ≤ 0.05., Results: Unexpectedly, we found that TAK875, a synthetic FFAR1 agonist, attenuated histamine-induced MLC phosphorylation and cortical tension development in HASM cells. These physiological outcomes were unassociated with changes in histamine-evoked Ca 2+ flux, protein kinase B (AKT) activation, or MLC phosphatase inhibition. Of note, TAK875-mediated inhibition of MLC phosphorylation was maintained in β 2 AR-desensitized HASM cells and across obese and non-obese donor-derived HASM cells., Conclusions: Taken together, our findings identified the FFAR1 agonist TAK875 as a novel bronchoprotective agent that warrants further investigation to treat difficult-to-control asthma and/or airway hyperreactivity in obesity.

The recent discovery of sensory (tastant and odorant) G protein-coupled receptors on the smooth muscle of human bronchi suggests unappreciated therapeutic targets in the management of obstructive lung diseases. Here we have characterized the effects of a wide range of volatile odorants on the contractile state of airway smooth muscle (ASM) and uncovered a complex mechanism of odorant-evoked signaling properties that regulate excitation-contraction (E-C) coupling in human ASM cells. Initial studies established multiple odorous molecules capable of increasing intracellular calcium ([Ca 2+ ] i ) in ASM cells, some of which were (paradoxically) associated with ASM relaxation. Subsequent studies showed a terpenoid molecule (nerol)-stimulated OR2W3 caused increases in [Ca 2+ ] i and relaxation of ASM cells. Of note, OR2W3-evoked [Ca 2+ ] i mobilization and ASM relaxation required Ca 2+ flux through the store-operated calcium entry (SOCE) pathway and accompanied plasma membrane depolarization. This chemosensory odorant receptor response was not mediated by adenylyl cyclase (AC)/cyclic nucleotide-gated (CNG) channels or by protein kinase A (PKA) activity. Instead, ASM olfactory responses to the monoterpene nerol were predominated by the activity of Ca 2+ -activated chloride channels (TMEM16A), including the cystic fibrosis transmembrane conductance regulator (CFTR) expressed on endo(sarco)plasmic reticulum. These findings demonstrate compartmentalization of Ca 2+ signals dictates the odorant receptor OR2W3-induced ASM relaxation and identify a previously unrecognized E-C coupling mechanism that could be exploited in the development of therapeutics to treat obstructive lung diseases., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

Background: Thyroid dysfunction is associated with cognitive impairment, mood disturbance, and postnatal depression. Sufficient thyroid hormone synthesis requires adequate intake of iodine, selenium, and iron. Iodine deficiency was historically a problem for New Zealand, and initiatives were introduced to overcome the problem: (1) mandatory fortification of all bread (except organic) with iodized salt (2009) and (2) provision of subsidized iodine supplements for pregnant and breastfeeding women (2010). Subsequent to these initiatives, most adults and children have adequate iodine status; however, status among breastfeeding women and their infants remains unclear. This paper outlines the methodology of the Mother and Infant Nutrition Investigation (MINI) study: an observational longitudinal cohort study of breastfeeding women and their infants., Objective: This study will determine (1) women's iodine intake and status among supplement users and nonusers; (2) women's intake and status of iodine, selenium, and iron relating to thyroid function; (3) associations between women's selenium status, thyroid function, and postnatal depression; (4) infants' iodine and selenium status relating to first year neurodevelopment., Methods: Breastfeeding women aged over 16 years with a healthy term singleton infant were recruited from Manawatu, New Zealand. Participants attended study visits 3, 6, and 12 months postpartum. Maternal questionnaires investigated supplement use before and after birth, iodine knowledge, and demographic information. Dietary assessment and urine, blood, and breast milk samples were taken to measure iodine, selenium, and iron intake/status. The Edinburgh Postnatal Depression Scale was used repeatedly to screen for postnatal depression. Thyroid hormones (free triiodothyronine, free thyroxine, thyroid stimulating hormone, thyroglobulin, antithyroglobulin antibodies, and antithyroid peroxidase) were measured in blood samples, and thyroid gland volume was measured by ultrasound at 6 months postpartum. Infant iodine and selenium concentrations were determined in urine. The Ages and Stages Questionnaire was used to assess infant development at 4, 8, and 12 months., Results: Data collection was completed. Biological samples analysis, excluding nail clippings, is complete. Data analysis and presentation of the results will be available after 2020., Conclusions: This study will provide data on the current iodine status of breastfeeding women. It will also provide a greater understanding of the three essential minerals required for optimal thyroid function among breastfeeding women. The prospective longitudinal design allows opportunities to examine women's mental health and infant neurodevelopment throughout the first year, a crucial time for both mothers and their infants., Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12615001028594; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=369324., International Registered Report Identifier (irrid): DERR1-10.2196/18560., (©Ying Jin, Jane Coad, Shao J Zhou, Sheila Skeaff, Cheryl Benn, Nicholas Kim, Rachael L Pond, Louise Brough. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 27.08.2020.)

As a promising next-generation solar cell, the power conversion efficiency of a silicon quantum dot (Si-QD) solar cell is still low. In this work, the band-gap structure of a Si-QD layer was modified to improve the power conversion efficiency of a Si-QD solar cell. A stepwise band-gap Si-QD (SB Si-QD) layer with a high bandgap top layer (about 2.22 eV) and a low band-gap bottom layer (about 1.98 eV) was grown on a Si (100) substrate. The open circuit voltage and short circuit current were improved by band-gap engineering of the Si-QD absorption layer. As a result, the power conversion efficiency of the SB Si-QD solar cell increased from 16.50% to 17.50%, compared to that of a Si-QD solar cell with a uniform band gap. This results will provide a guide to design advanced Si-QD solar cells by considering the band-gap structure in the Si-QD absorption layer.

Coronary artery disease is the leading cause of morbidity and mortality. Tools have been developed to accurately diagnose and evaluate coronary artery disease. Coronary CT angiography (CCTA) provides detailed imaging to deliver precise analysis and prognostic information. We sought to compare the radiation dose from a 256-detector-row CT scanner with that from a 64-detector-row CT scanner across a similar profile of patients. Methods: Consecutive patients were screened for the Converge Registry study and, after consenting to be included, were enrolled in accordance with an Institutional Review Board-approved protocol. A control group who underwent 64-row CCTA were matched by age, sex, and body mass index (BMI) with a group who underwent 256-row CCTA. Results: We compared 110 patients in each group. We found that mean dose-length product (DLP) was significantly lower in the 256-row group than in the 64-row group ( P < 0.05). The radiation dose was reduced by 32% with use of the 256-row scanner for BMIs of 18.5-24.9 (DLP, 111.2 vs. 76.1 mGy-cm [1.56 vs. 1.07 mSv]; P < 0.05). For each BMI subgroup, there was a significant decrease in dose. Regression analysis found that with increasing BMIs, DLP significantly increased for both scanners. Conclusion: The 256-row scanner provided CCTA scans at significantly lower radiation doses than the 64-row scanner in different BMI groups, with all other variables accounted for. Lower radiation exposure along with lower contrast requirements can provide images with high diagnostic accuracy and less risk to the patient., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Introduction: Patient perspectives on chaperone use during examinations, especially in surgical subspecialties, are understudied. We aimed to identify specific patient cohorts that desire the presence of chaperones and compare patient and surgeon perspectives, all in an effort to improve quality of care., Methods and Materials: We prospectively administered a 15-question survey to all patients visiting 2 plastic surgery outpatient clinics between January 2015 and April 2016. Data on demographics, types of procedures (cosmetic or reconstructive), area of examination (sensitive or nonsensitive), views on chaperone use, type of chaperone, and instances of inappropriate behavior by surgeons were collected. Univariate analysis was performed after stratifying patients on their individual desire to have a chaperone. Subsequently, multivariate regression models were constructed to identify individual patient cohorts independently more likely to require a chaperone., Results: A total of 398 participants were surveyed. There were 58.3% female and 41.7% male respondents; of whom 41.8% were 55 years or older and 8.1% were younger than 24 years. Ninety percent of all patients were receiving care for a reconstructive procedure. Most (77%) were being examined over a nonsensitive area. Overall, 82.1% preferred not to have a chaperone present during examinations. Most (72.6%) felt the sex of the examining physician was inconsequential to their need for a chaperone. Most (54.8%) preferred either a family member or a friend to be the chaperone. Only 1.8% (n = 7) experienced inappropriate behavior, of whom 77% (n = 5) noted the absence of a chaperone while being examined. On multivariate analysis, younger patients and examination over a sensitive area were independently associated with a higher odd of requiring a chaperone (odds ratios, 3.4 [95% confidence interval, 1.3-8.9; P = 0.016] and 3.9 [95% confidence interval, 1.9-6.7; P < 0.001], respectively)., Conclusions: Most patients did not want a chaperone during examinations. Younger patients and those having a sensitive area examined were independently more likely to desire a chaperone. Patients preferred having their family member or friend as their chaperone. Given the major differences in perceptions, plastic surgeons should consider selectively using chaperones rather than the carte blanche use of chaperones with every patient.

Intro: Coronary artery disease is the leading cause for morbidity and mortality. Tools have been developed to accurately diagnose and evaluate coronary artery disease. Coronary computed tomographic angiography (CCTA) scans provide detailed imaging along with analysis to in order to deliver precise analysis and prognostic information. We sought to evaluate the radiation doses of the 256 detector CT scanner to a 64 slice scanner across a similar profile of patients. Methods: Consecutive patients were screened, enrolled, and consented for the Converge Registry study, in accordance with the Institutional Review Board (IRB) approved protocol. 110 patients underwent CCTA using the GE Revolution 256 detector CT scanner. We matched patients by age, gender and body mass index (BMI) who underwent 64 slice CT scanning. Results: We compared 110 patients in each group. We found that mean dose length product (DLP, presented also in the tables below in millisieverts (mSv)) was significantly lower in the Revolution 256 detector group compared to the 64 slice control group (p<0.05). The radiation dose was reduced 32% with use of Revolution 256 detector scanner for BMI between 18.5 and 24.9 (DL P = 111.2 vs 76.1; 1.56 vs 1.07 mSv; p<0.05). For each BMI subgroup, there was a significant decrease in dose. Regression analysis found that with the increase in BMI both scanners experienced a significant increase in DLP. Conclusion: We are able to demonstrate that the 256 slice CT scanner is able to provide CCTA scans at significantly lower radiation doses compared to the 64 row scanner at different BMI groups, with all other variables accounted for. Lower radiation exposures along with lower contrast requirements can provide quality imaging with high diagnostic accuracy and less risk to the patient., (Copyright © 2019 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Background: Cubital tunnel syndrome is a common compressive neuropathy of the upper extremity. The anconeus epitrochlearis muscle is an unusual but occasional contributor. We review our experience with this anomalous muscle in elbows with cubital tunnel syndrome. Methods: We retrospectively reviewed charts of 13 patients noted to have an anconeus epitrochlearis muscle associated with cubital tunnel syndrome. Results: Ten patients had unilateral ulnar neuropathy supported by nerve conduction studies. Three had bilateral cubital tunnel syndrome symptoms with 1 of those having normal nerve conduction studies for both elbows. Eight elbows were treated with myotomy of the anconeus epitrochlearis muscle and submuscular transposition of the ulnar nerve. The other 8 elbows were treated with myotomy of the anconeus epitrochlearis muscle and in situ decompression of the ulnar nerve only. All but 1 patient had either clinical resolution or improvement of symptoms at follow-up ranging from 2 weeks to 1 year after surgery. The 1 patient who had persistent symptoms had received myotomy and in situ decompression of the ulnar nerve only. Conclusions: An anomalous anconeus epitrochlearis occasionally results in compression of the ulnar nerve but is usually an incidental finding. Its contribution to compression neuropathy can be tested intraoperatively by passively ranging the elbow while observing the change in vector and tension of its muscle fibers over the ulnar nerve. Regardless of findings, we recommend myotomy of the muscle and in situ decompression of the ulnar nerve. Submuscular transposition of the ulnar nerve may be necessary if there is subluxation.

Gender affirmation surgery is paramount in the treatment of gender dysphoria for transgender individuals. For transgender women, vaginoplasty offers the opportunity for removal of masculine-appearing genitalia and replacement with a gender-congruent appearance. While numerous techniques have been described in the past, approaches have standardized considerably. Herein, we describe a technique to penile inversion vaginoplasty and focus on some of the critical steps of the procedure to try to optimize patient outcomes. We also review relevant literature regarding perioperative outcomes., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background: Increased arterial stiffness is reportedly associated with cardiac remodelling, including the left atrium and left ventricle, in middle-aged and older adults. However, little is known about this association in young adults., Methods: In total, 73 patients (44 (60%) men) aged 25 to 45 years with suspected coronary artery disease were included in the analysis. The left atrial volume index (LAVI), left ventricular volume index (LVVI), and left ventricular mass index (LVMI) were measured using coronary computed tomography angiography (CCTA). Arterial stiffness was assessed with the cardio-ankle vascular index (CAVI). An abnormally high CAVI was defined as that above the age- and sex-specific cut-off points of the CAVI., Results: Compared with patients with a normal CAVI, those with an abnormally high CAVI were older and had a greater prevalence of diabetes mellitus, higher diastolic blood pressure, greater coronary artery calcification score, and a greater LAVI (33.5±10.3 vs. 43.0±10.3mL/m 2 , p <0.01). In contrast, there were no significant differences in the LVVI or LVMI between the subgroups with a normal CAVI and an abnormally high CAVI. Multivariate linear regression analysis showed that the LAVI was significantly associated with an abnormally high CAVI (standardised regression coefficient=0.283, p=0.03)., Conclusions: The present study demonstrated that increased arterial stiffness is associated with the LAVI, which reflects the early stages of cardiac remodelling, independent of various comorbidity factors in young adults with suspected coronary artery disease., (Copyright © 2018 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

The underlying values and priorities that drive policy responses depend largely on the constructs that researchers and decision makers select to measure and the metrics used. Despite much recent attention being given to sustainable diets and food systems and to the importance of clearly measuring sustainability to meet targets, to achieve goals, and to appraise dietary and environmental policies, it is not commonly agreed how the different indicators of sustainable diets are assessed. The evidence base for assessment of these indicators are frequently weak, fragmented, and arbitrary. The aim of this paper was to compare a range of published methods and indicators for assessing sustainable diets and food systems in order to harmonise them. Keyword and reference searches were performed in PubMed, Scopus, CAB Abstracts, and Web of Knowledge. Fifty-two studies (21 proposed methods and 31 used methods) that combined environment, nutrition and health, and socioeconomic aspects of sustainable diets were reviewed. The majority (over 90%) of the studies focused on high-income countries. Twenty-eight studies assessed the environmental effects of different dietary practices, eight of the studies examined the nutrition and health indicators used for assessing sustainable food systems, and seven studies assessed the social and economic costs of diets. A classification of the elements was developed, and common elements are proposed for standardizing. These elements were categorized into nutrition and health indicators, environment indicators, and socioeconomic indicators. Standardized or harmonized indicators can be used for consistency and applicability purposes and to support, implement, and monitor relevant policies.

Human vascular connexins (Cx37, Cx40, Cx43, and Cx45) can form various types of gap junction channels to synchronize vasodilation/constriction to control local circulation. Most of our knowledge on heterotypic gap junctions of these vascular connexins was from studies on rodent connexins. In human vasculature, the same four homolog connexins exist, but whether these human connexins can form heterotypic GJs as those of rodents have not been fully studied. Here we used in vitro expression system to study the coupling status and GJ channel properties of human heterotypic Cx37/Cx40, Cx37/Cx43, and Cx37/Cx45 GJs. Our results showed that Cx37/Cx43 and Cx37/Cx45 GJs, but not Cx37/Cx40 GJs, were functional and each with unique rectifying channel properties. The failure of docking between Cx37 and Cx40 could be rescued by designed Cx40 variants. Characterization of the heterotypic Cx37/Cx43 and Cx37/Cx45 GJs may help us in understanding the intercellular communication at the myoendothelial junction., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background and Objectives: Malnutrition is a public health problem especially among the Pacific Small Island developing nations. This study assessed malnutrition with dietary intakes in households of South Tarawa, Kiribati, a West Pacific Island Nation State., Methods and Study Design: A cross-sectional community-based study design was used. One hundred and sixty-one households were selected from Betio, Bikenibeu and Teaorereke towns using a systematic random sampling method. About 35% each of the households was selected from Bikenebue and Besio while 30.4% was selected from Teaoraeke. Family (including children) dietary surveys including 24- hour dietary recall were administered to assess adequacy of nutrient intakes and dietary diversity using Household Diet Diversity Scores. A 3-day weighed food record was collected on a sub-sample. Data were analysed using FoodWorks Pro 8 for nutrient intake and Statistical Product for Service Solution (SPSS) version 21 for descriptive statistics., Results: Sixty-one percent of the subjects had the lowest dietary diversity, 36.3% had a medium dietary diversity and only 2.7% had the highest dietary diversity. Based on the weighed food record results (n=29), male subjects of all age groups had adequate intakes of riboflavin, niacin, vitamin C, magnesium, iron and zinc, but had high intakes of protein and sodium; and low intakes of potassium and calcium. Female subjects had adequate intakes of vitamin C, iron, magnesium and zinc, but had high intakes of protein and sodium; and low intakes of potassium and calcium., Conclusions: Across all groups, 61% of the adult Kiribati population studied showed low dietary diversity, and a high prevalence of multiple micronutrient deficiencies.

Gap junction (GJ) channels are oligomers of connexins forming channels linking neighboring cells. GJs formed by different connexins show distinct unitary channel conductance (γ j ), transjunctional voltage-dependent gating ( V j -gating) properties, and modulation by intracellular magnesium ([Mg 2+ ] i ). The underlying molecular determinants are not fully clear. Previous experimental evidence indicates that residues in the amino terminal (NT) and initial segment of the first extracellular (E1) domain influence the γ j , V j -gating, and/or [Mg 2+ ] i modulation in several GJs. Increasing negatively charged residues in Cx50 (connexin50) E1 (G46D or G46E) increased γ j , while increasing positively charged residue (G46K) reduced the γ j Sequence alignment of Cx50 and Cx37 in the NT and E1 domains revealed that in Cx50 G8 and V53, positions are negatively charged residues in Cx37 (E8 and E53, respectively). To evaluate these residues together, we generated a triple variant in Cx50, G8E, G46E, and V53E simultaneously to study its γ j , V j -gating properties, and modulation by [Mg 2+ ] i Our data indicate that the triple variant and individual variants G8E, G46E, and V53E significantly increased Cx50 GJ γ j without a significant change in the V j gating. In addition, elevated [Mg 2+ ] i reduced γ j in Cx50 and all the variant GJs. These results and our homology structural models suggest that these NT/E1 residues are likely to be pore-lining and the variants increased the negative electrostatic potentials along the GJ pore to facilitate the γ j of this cation-preferring GJ channel. Our results indicate that electrostatic properties of the Cx50 GJ pore are important for the γ j and the [Mg 2+ ] i modulation., (© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

This case report describes eradication of carbapenem-resistant Klebsiella pneumoniae from an ischial pressure injury in a patient who underwent a 3-week course of nontoxic three-part combination local wound therapy. With this therapy, providers prevented systemic spread of this multidrug-resistant pathogen and avoided the nephrotoxicity associated with conventional triple antibiotic therapy.

Background and Aim: The association of HIV with coronary atherosclerosis has been established; however, the progression of coronary atherosclerosis over time among participants with HIV is not well known. The Multicenter AIDS Cohort Study Quantitative Coronary Plaque Progression Study is a large prospective multicenter study quantifying progression of coronary plaque assessed by serial coronary computed tomography angiography (CTA)., Patients and Methods: HIV-infected and uninfected men who were enrolled in the Multicenter AIDS Cohort Study Cardiovascular Substudy were eligible to complete a follow-up contrast coronary CTA 3-6 years after baseline. We measured coronary plaque volume and characteristics (calcified and noncalcified plaque including fibrous, fibrous-fatty, and low attenuation) and vulnerable plaque among HIV-infected and uninfected men using semiautomated plaque software to investigate the progression of coronary atherosclerosis over time., Conclusion: We describe a novel, large prospective multicenter study investigating incidence, transition of characteristics, and progression in coronary atherosclerosis quantitatively assessed by serial coronary CTAs among HIV-infected and uninfected men.

Gap junction (GJ) channels form low resistance passages between cardiomyocytes and play a role in the rapid propagation of action potentials in the heart. A GJ channel is formed by two properly docked hemichannels and each hemichannel is a hexamer of connexins. Connexin40 (Cx40) and Cx43 are the dominant connexins in atrial myocytes, while Cx45 is mostly expressed in the sinoatrial (SA) and atrioventricular (AV) nodes which directly connect nodal cells with atrial myocytes, possibly via heterotypic Cx40/Cx45 and/or Cx43/Cx45 GJs. However, the functional status and channel properties of human heterotypic Cx40/Cx45 or Cx43/Cx45 GJs have not been studied. Here we investigated human Cx40/Cx45 and Cx43/Cx45 heterotypic GJs by recombinant expression in GJ deficient cells. Unlike the finding on rodent connexins, cell pairs expressing human Cx40 in one and Cx45 in the other failed to form morphological and functional GJs. Modifications in human Cx40 with designed variants (D55N or P193Q, but not P193K) are sufficient to establish morphological and functional heterotypic GJs with Cx45. In contrast, heterotypic human Cx43/Cx45 GJs are functional similar to that described for rodent Cx43/Cx45 GJs. Detailed kinetic characterizations of human heterotypic Cx43/Cx45 GJs revealed a rapid asymmetric V j -gating and a much slower recovery, which could reduce the GJ conductance in a junctional delay, action potential frequency, and direction dependent manner. Dynamic uncoupling in Cx45-containing GJs might contribute to a slower action potential propagation in the AV node., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The synthesis and crystal structure of the title compound, C 14 H 8 Br 2 , is described. The mol-ecule is positioned on a twofold rotation axis and the asymmetric unit consists of half a mol-ecule with the other half being generated by symmetry. The presence of two large bromine atoms in the bay region significantly distorts the mol-ecule from planarity and the mean planes of the two terminal rings of the phenanthrene system are twisted away from each other by 28.51 (14)°. The torsion angle between the two C-Br bonds is 74.70 (14)° and the distance between the two Br atoms is 3.2777 (13) Å. The mol-ecules pack in layers in the crystal, with the centroids of the central rings of the phenanthrene units in adjacent layers separated by a distance of 4.0287 (10) Å. These centroids are shifted by 2.266 (6) Å relative to each other, indicating slippage in the stacking arrangement. Furthermore, the distance between the centroids of the terminal and central rings of the phenanthrene units in adjacent layers is slightly shorter at 3.7533 (19) Å. While all of the mol-ecules within each layer are oriented in the same direction, those in adjacent layers are oriented in the opposite direction, leading to anti-parallel stacks.

Mounting evidence implicates antiretroviral (ARV) drugs as potential contributors to the persistence and evolution of clinical and pathological presentation of HIV-associated neurocognitive disorders in the post-ARV era. Based on their ability to induce endoplasmic reticulum (ER) stress in various cell types, we hypothesized that ARV-mediated ER stress in the central nervous system resulted in chronic dysregulation of the unfolded protein response and altered amyloid precursor protein (APP) processing. We used in vitro and in vivo models to show that HIV protease inhibitor (PI) class ARVs induced neuronal damage and ER stress, leading to PKR-like ER kinase-dependent phosphorylation of the eukaryotic translation initiation factor 2α and enhanced translation of β-site APP cleaving enzyme-1 (BACE1). In addition, PIs induced β-amyloid production, indicative of increased BACE1-mediated APP processing, in rodent neuroglial cultures and human APP-expressing Chinese hamster ovary cells. Inhibition of BACE1 activity protected against neuronal damage. Finally, ARVs administered to mice and SIV-infected macaques resulted in neuronal damage and BACE1 up-regulation in the central nervous system. These findings implicate a subset of PIs as potential mediators of neurodegeneration in HIV-associated neurocognitive disorders., (Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Colorectal cancer has a high worldwide incidence. Japan, a country that is geographically and culturally similar to the Republic of Korea (here after Korea), has recently reported a decreasing trend in the incidence of colorectal cancer. However, Korea had the highest incidence of colorectal cancer among Asian countries in 2012. Our aim was to observe the changing trends in incidence and mortality of colorectal cancer in Korea and to compare them to those in Japan. Incidence data were collected from the Korean Central Cancer Registry and mortality data were collected from Korean Statistical Information Service. Incidence and mortality data on colorectal cancer in Japan were acquired from the National Cancer Center in Japan. Age-standardized incidence and mortality rates were determined based on Segi's world population. Screening data from both countries were collected from the national cancer center in each country. In Korea, the age-standardized incidence rate of colorectal cancer in both sexes was 20.9 to 38.0 per 100,000 from 1999 to 2012 and the rate in males increased more dramatically than in females. In addition, the increase between 2002 and 2012 was first observed in the age group over 40. In Japan, the incidence of colorectal cancer has been more constant over recent years than in Korea. The age-standardized mortality rate of colorectal cancer in both sexes in Korea was 8.5 to 9.3 per 100,000 from 2000 to 2013, and the trend in mortality was constant during this period. In Japan, the mortality rate decreased slightly during the same period. Crude screening rates were increased overall in both Korea and Japan during the period studied. Since the incidence of colorectal cancer has increased in Korea, the control of this cancer is an important public health issue. As Japan has achieved a reduction in colorectal cancer, adjustment of Korea's current systems for screening and treatment of colorectal cancer according to those of Japan may contribute to improved colorectal cancer control in Korea.

Pyoderma fistulans sinifica, also known as fox den disease, is a rare and poorly understood inflammatory disorder of the skin and subcutaneous tissues. This disorder is often mistaken for other inflammatory skin disorders and treated inappropriately. The authors describe the case of a 53-year-old male who presented to the colorectal surgery service with a longstanding diagnosis of perirectal Crohn's disease. Despite aggressive immunosuppression and numerous surgical procedures, the patient continued to have unrelenting purulent drainage from the skin of his buttocks. Following wide excision of the affected skin and subcutaneous tissues by the colorectal surgeon, the plastic surgery team reconstructed the 30 cm x 55 cm wound using a combination of local flaps and skin grafts. The initial pathology report of the excised specimen confirmed the presence of nonspecific abscesses and inflammation. Upon special request by the plastic surgery team, the sample was resectioned with the specific intent of establishing a diagnosis of fox den disease. The additional slides met the criteria for an unequivocal diagnosis of fox den disease. Immunosuppression was discontinued and the patient healed his wounds without complication. Fox den disease is often overlooked because of the obscurity of the disease and the special histological sectioning needed to establish a diagnosis. In this case, the patient was unnecessarily treated with immunosuppressive drugs for more than 3 decades because of a misdiagnosis. With increased awareness of fox den disease, perhaps its pathophysiology can be better elucidated as more patients are appropriately diagnosed and treated.

It has been previously shown that relatively simple computational fluid dynamics (CFD) models can be used to calculate the transfer impedances, including the associated end corrections, of microperforated panels. The impedance is estimated by first calculating the pressure difference across a single hole when a transient input velocity is imposed, and then Fourier transforming the result to obtain the impedance as a function of frequency. Since the size of the hole and the dimensions of the inlet and outlet channels are very small compared to a wavelength, the flow through the hole can be modeled as incompressible. By using those procedures, Bolton and Kim extended Maa's classical theory to include a resistive end correction for sharp-edged cylindrical holes which differs from those previously proposed by the inclusion of a static component. Here it is shown that CFD models can also be used to compute end corrections for tapered holes. Since practical experimental characterization of perforated materials often involves measurement of the static flow resistance, a closed form empirical equation for that quantity has been developed. Finally, it is shown that configurations having equivalent static flow resistances can yield different acoustic absorptions.

Purpose: There is a paucity of literature regarding the use of chaperones by surgeons when examining patients. Use of a chaperone not only makes the patient comfortable but also potentially protects the surgeon from perceived misconduct. This is especially true for plastic surgeons who examine sensitive areas commonly. The purpose of this study was to determine the current trends in chaperone use by plastic surgeons when examining patients., Materials and Methods: A 23-question online survey was sent to all members of the American Society of Plastic Surgeons. Data collected online were analyzed using Student t test and Pearson χ test. A P < 0.05 was considered significant., Results: Of the 4990 surgeons polled, 830 (16.6%) responded to some or all of the questions (707 [85%] male; 117 [14%] female). The overall chaperone use by plastic surgeons during all examinations of patients was 30%. This rate increased up to 60% while examining sensitive areas. Male surgeons reported a higher frequency of chaperone use than female surgeons (P < 0.001). Cosmetic surgeons had a higher rate of chaperone use compared to reconstructive surgeons (P = 0.001). Similarly, surgeons who had been in practice for more than 20 years reported a higher rate of chaperone use compared to surgeons in practice for less than 20 years (P = 0.032). Sixty-one (7.6%; 56 male and 5 female) surgeons reported being accused of inappropriate behavior by patients, of whom 49 (80%) did not have a chaperone present. There was no significant difference among male and female surgeons in rates of being accused of inappropriate behavior (7.9% vs 4.2%, P = 0.19)., Conclusions: There was a higher rate of chaperone use by male plastic surgeons, surgeons with more than 20 years experience, and cosmetic surgeons. Despite the difference in chaperone use between the sexes, both had similar rates of being accused of inappropriate behavior during examinations by patients, and although these incidents were quite low, most had no chaperone present during those examinations.

The "environmental dependency syndrome" refers to a loss of personal autonomy such that a person's environment almost entirely controls their actions. The goal of this study is to learn if patients with frontotemporal degeneration (FTD) exhibit prolonged TV watching, a behavior which may be a symptom of environmental dependency. We recruited 40 patients with FTD and 48 patients with Alzheimer's disease (AD), and asked these participants' caregivers about TV watching behaviors including total viewing time and channel/show preference, along with other behaviors indicative of environmental dependency. Compared to AD patients, FTD patients watched TV for a longer time. In addition, the patients who watched more TV showed more signs of environmental dependency. Increased TV watching may be a sign of environmental dependency, however further research is needed to explore other hypotheses.

Background: The purpose of this study was to determine the current preferences of plastic surgeons regarding preoperative assessment and their effect on clinical outcome in primary breast augmentation., Methods: An eight-question online survey was sent to members of the American Society of Plastic Surgeons. Data collected online were analyzed using Student's t test or Pearson's chi-square test. A value of p < 0.05 was considered statistically significant., Results: The response rate was 20.1 percent (604 respondents). Breast base diameter [n = 286 (47.4 percent)] was ranked the most important consideration vital in choosing implants. Most surgeons chose to reeducate their patients to resolve a conflict between their patient's implant size request and the surgeon's clinical judgment [n = 385 (63.7 percent)], whereas 151 (25 percent) would proceed anyway. Those surgeons who chose reeducation ranked breast base diameter as a vital consideration significantly higher than those who would accommodate their patients (2.03 ± 1.41 versus 2.31 ± 1.41; p = 0.041). Similarly, surgeons who reeducated their patients ranked implant volume as the vital consideration significantly lower than those who accommodated their patients (2.90 ± 1.67 versus 2.44 ± 1.47; p = 0.002). Regarding size change, 332 surgeons (55 percent) reported their rate was 5 percent or less, whereas 272 (45 percent) reported it was greater than 5 percent. Surgeons who reported a 5 percent or less rate ranked implant volume significantly lower than those with reoperation rates greater than 5 percent (2.93 ± 1.71 versus 2.55 ± 1.53; p = 0.004)., Conclusions: Breast base diameter and implant volume were the two most important considerations in choosing an implant for breast augmentation. Reported reoperation rates for size change were significantly lower for surgeons who regarded breast base diameter as more vital than those who valued implant volume more.

Alzheimer disease (AD) is a complex disorder that involves numerous cellular and subcellular alterations including impairments in mitochondrial homeostasis. To better understand the role of mitochondrial dysfunction in the pathogenesis of AD, we analyzed brains from clinically well-characterized human subjects and from the 3xTg-AD mouse model of AD. We find Aβ and critical components of the γ-secretase complex, presenilin-1, -2, and nicastrin, accumulate in the mitochondria. We used a proteomics approach to identify binding partners and show that heat shock protein 60 (HSP60), a molecular chaperone localized to mitochondria and the plasma membrane, specifically associates with APP. We next generated stable neural cell lines expressing human wild-type or Swedish APP, and provide corroborating in vitro evidence that HSP60 mediates translocation of APP to the mitochondria. Viral-mediated shRNA knockdown of HSP60 attenuates APP and Aβ mislocalization to the mitochondria. Our findings identify a novel interaction between APP and HSP60, which accounts for its translocation to the mitochondria.

We compared the outcomes of intramedullary nailing with plate-screw fixation in the treatment for ipsilateral fracture of the hip and femoral shaft. A retrospective study. Level 1 Trauma. Forty-one patients (32 males and 9 females; mean age, 34 years; age range, 21-53) with ipsilateral hip and femoral shaft fractures were treated between 1995 and 2005. Eighteen patients were injured in motor vehicle accidents, and 23 fell from a height. All patients were treated by one of the two methods of internal fixation: a screw-plate fixation (n = 24, Group I) or intramedullary nailing (n = 17, Group II). The fracture union time, nonunion, delayed union, implant failure, need of further surgeries, and functional outcomes were investigated and compared. Fisher's exact test showed that Group I had a significantly higher frequency of nonunion than that of Group II (P = 0.029). Although Group I had more nonunions, delayed unions, and revision operations than Group II, the total union time was similar for both groups. Intramedullary nailing was found to be superior to screw-plate fixation due to improved functional bearing, increased rate of union, stability, and mechanical solidity. The reconstruction nail method is an acceptable alternative treatment for ipsilateral hip and femoral shaft fractures.

Atherosclerosis is a major cardiovascular disease involving accumulations of lipids, white blood cells, and other materials on the inside of artery walls. Since the calcification found in the advanced stage of atherosclerosis dramatically enhances the mechanical properties of the plaque, restoring the original lumen of the artery remains a challenge. High-speed rotational atherectomy, when performed with an ablating grinder to remove the plaque, produces much better results in the treatment of calcified plaque compared to other methods. However, the high-speed rotation of the Rotablator commercial rotational atherectomy device produces microcavitation, which should be avoided because of the serious complications it can cause. This research involves the development of a high-speed rotational ablation tool that does not generate microcavitation. It relies on surface modification to achieve the required surface roughness. The surface roughness of the tool for differential cutting was designed based on lubrication theory, and the surface of the tool was modified using Nd:YAG laser beam engraving. Electron microscope images and profiles indicated that the engraved surface of the tool had approximately 1 μm of root mean square surface roughness. The ablation experiment was performed on hydroxyapatite/polylactide composite with an elastic modulus similar to that of calcified plaque. In addition, differential cutting was verified on silicone rubber with an elastic modulus similar to that of a normal artery. The tool performance and reliability were evaluated by measuring the ablation force exerted, the size of the debris generated during ablation, and through visual inspection of the silicone rubber surface.

Purpose: We determined whether stone attenuation can predict stone fragmentation after shock wave lithotripsy in the pediatric population. Previous studies show that preoperative attenuation in HU on noncontrast computerized tomography predicts shock wave lithotripsy success. To our knowledge study of this parameter in the pediatric population has been lacking to date., Materials and Methods: We performed a multi-institutional review of the records of 53 pediatric patients 1 to 18 years old who underwent shock wave lithotripsy for 3.8 to 36.0 mm renal calculi. Stone size, average skin-to-stone distance and attenuation value were determined by bone windows on preoperative noncontrast computerized tomography. Success was defined as radiographically stone-free status at 2 to 12-week followup after a single lithotripsy session without the need for further sessions or ancillary procedures., Results: After lithotripsy 33 patients (62%) were stone-free and 20 had incomplete fragmentation or required additional procedures. Mean ± SD stone attenuation in successfully treated patients vs those with incomplete fragmentation was 710 ± 294 vs 994 ± 379 HU (p = 0.007). Logistical regression analysis revealed that only attenuation in HU was a significant predictor of success. When patients were stratified into 2 groups (less than 1,000 and 1,000 HU or greater), the shock wave lithotripsy success rate was 77% and 33%, respectively (p <0.003)., Conclusions: Stone attenuation less than 1,000 HU is a significant predictor of shock wave lithotripsy success in the pediatric population. This finding suggests that attenuation values have a similar predictive value in the pediatric population as that previously reported in the adult population., (Copyright © 2010 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)