Excited oxygen kinetics at electronvolt temperatures via 5-MHz RF-diplexed laser absorption spectroscopy.

A multi-MHz laser absorption sensor at 777.2 nm (12,863c m -1) is developed for simultaneous sensing of (1) O(5 S 0) number density, (2) electron number density, and (3) translational temperature at conditions relevant to high-speed entry conditions and molecular dissociation. This sensor leverages a bias tee circuit with a distributed feedback diode laser and an optimization of the laser current modulation waveform to enable temporal resolution of sub-microsecond kinetics at electronvolt temperatures. In shock-heated O 2, the precision of the temperature measurement is tested at 5 MHz and is found to be within ±5% from 6000 to 12,000 K at pressures from 0.1 to 1 atm. The present sensor is also demonstrated in a CO:Ar mixture, in parallel with a diagnostic for CO rovibrational temperature, providing an additional validation across 7500-9700 K during molecular dissociation. A demonstration of the electron number density measurement near 11,000 K is performed and compared to a simplified model of ionization. Finally, as an illustration of the utility of this high-speed diagnostic, the measurement of the heavy particle excitation rate of O(5 S 0) is extended beyond the temperatures available in the literature and is found to be well represented by k(3 P→5 S 0)=2.7×10-14 T 0.5 exp⁡(-1.428×104/T)c m 3⋅s -1 from 5400 to 12,200 K.

Intracellular sites of AQP2 S256 phosphorylation identified using inhibitors of the AQP2 recycling itinerary.

Vasopressin (VP)-regulated aquaporin-2 (AQP2) trafficking between cytoplasmic vesicles and the plasma membrane of kidney principal cells is essential for water homeostasis. VP affects AQP2 phosphorylation at several serine residues in the COOH-terminus; among them, serine 256 (S256) appears to be a major regulator of AQP2 trafficking. Mutation of this serine to aspartic acid, which mimics phosphorylation, induces constitutive membrane expression of AQP2. However, the intracellular location(s) at which S256 phosphorylation occurs remains elusive. Here, we used strategies to block AQP2 trafficking at different cellular locations in LLC-PK1 cells and monitored VP-stimulated phosphorylation of S256 at these sites by immunofluorescence and Western blot analysis with phospho-specific antibodies. Using methyl-ß-cyclodextrin, cold block or bafilomycin, and taxol, we blocked AQP2 at the plasma membrane, in the perinuclear trans-Golgi network, and in scattered cytoplasmic vesicles, respectively. Regardless of its cellular location, VP induced a significant increase in S256 phosphorylation, and this effect was not dependent on a functional microtubule cytoskeleton. To further investigate whether protein kinase A (PKA) was responsible for S256 phosphorylation in these cellular compartments, we created PKA-null cells and blocked AQP2 trafficking using the same procedures. We found that S256 phosphorylation was no longer increased compared with baseline, regardless of AQP2 localization. Taken together, our data indicate that AQP2 S256 phosphorylation can occur at the plasma membrane, in the trans-Golgi network, or in cytoplasmic vesicles and that this event is dependent on the expression of PKA in these cells.NEW & NOTEWORTHY Phosphorylation of aquaporin-2 by PKA at serine 256 (S256) occurs in various subcellular locations during its recycling itinerary, suggesting that the protein complex necessary for AQP2 S256 phosphorylation is present in these different recycling stations. Furthermore, we showed, using PKA-null cells, that PKA activity is required for vasopressin-induced AQP2 phosphorylation. Our data reveal a complex spatial pattern of intracellular AQP2 phosphorylation at S256, shedding new light on the role of phosphorylation in AQP2 membrane accumulation.

Industry-specific prevalence of elevated blood lead levels among Pennsylvania workers, 2007-2018.

OBJECTIVES: To use industry-specific denominators to more accurately examine trends in prevalence rates for occupational cases of elevated blood lead levels (eBLLs) in Pennsylvania. METHODS: We used adult (aged ≥16 years) blood lead level data from Pennsylvania (2007-2018) and industry-specific denominator data from the US Census Bureau's County Business Patterns to calculate prevalence rates for eBLLs, defined as ≥25 µg/dL. RESULTS: Of the 19 904 cases with eBLLs, 92% were due to occupational lead exposure, with 83% from workers in the battery manufacturing industry. In 2018, the prevalence rate of eBLLs for battery manufacturing (8036.4 cases per 100 000 employed battery manufacturing workers) was 543 times the overall Pennsylvania prevalence rate. The prevalence rate for battery manufacturing steeply declined 71% from 2007 to 2018. CONCLUSIONS: The battery manufacturing industry had the highest burden of occupational lead exposure in Pennsylvania, illustrating the importance of using industry-specific denominators to accurately identify sources of lead exposure. Although the prevalence rate of eBLLs declined over time, lead exposure remains a major concern among battery manufacturing workers.

Uptake, functionality, and re-release of extracellular vesicle-encapsulated cargo.

Extracellular vesicles (EVs) are membrane-encapsulated particles that carry genetically active and protein/lipid cargo that can affect the function of the recipient cell. A number of studies have described the effect of these vesicles on recipient cells and demonstrated their promise as therapeutic delivery vectors. Here we demonstrate functional delivery of EV-encapsulated RNA and protein cargo through use of luminescence and fluorescence reporters by combining organelle-targeted nanoluciferase with fluorescent proteins. We highlight a mechanism by which cells retain internalized cargo in the endosomal compartment for days, usually leading to content degradation. We also identify a mode through which recipient cells re-release internalized EVs intact after uptake. Highlighting these different fates of EVs in recipient cells sheds light on critical factors in steering functional cargo delivery and will ultimately allow more efficient use of EVs for therapeutic purposes.

Actin-related protein 2/3 complex plays a critical role in the aquaporin-2 exocytotic pathway.

The trafficking of proteins such as aquaporin-2 (AQP2) in the exocytotic pathway requires an active actin cytoskeleton network, but the mechanism is incompletely understood. Here, we show that the actin-related protein (Arp)2/3 complex, a key factor in actin filament branching and polymerization, is involved in the shuttling of AQP2 between the trans-Golgi network (TGN) and the plasma membrane. Arp2/3 inhibition (using CK-666) or siRNA knockdown blocks vasopressin-induced AQP2 membrane accumulation and induces the formation of distinct AQP2 perinuclear patches positive for markers of TGN-derived clathrin-coated vesicles. After a 20°C cold block, AQP2 formed perinuclear patches due to continuous endocytosis coupled with inhibition of exit from TGN-associated vesicles. Upon rewarming, AQP2 normally leaves the TGN and redistributes into the cytoplasm, entering the exocytotic pathway. Inhibition of Arp2/3 blocked this process and trapped AQP2 in clathrin-positive vesicles. Taken together, these results suggest that Arp2/3 is essential for AQP2 trafficking, specifically for its delivery into the post-TGN exocytotic pathway to the plasma membrane.NEW & NOTEWORTHY Aquaporin-2 (AQP2) undergoes constitutive recycling between the cytoplasm and plasma membrane, with an intricate balance between endocytosis and exocytosis. By inhibiting the actin-related protein (Arp)2/3 complex, we prevented AQP2 from entering the exocytotic pathway at the post-trans-Golgi network level and blocked AQP2 membrane accumulation. Arp2/3 inhibition, therefore, enables us to separate and target the exocytotic process, while not affecting endocytosis, thus allowing us to envisage strategies to modulate AQP2 trafficking and treat water balance disorders.

Demographic and exposure characteristics as predictors of serum per- and polyfluoroalkyl substances (PFASs) levels - A community-level biomonitoring project in Pennsylvania.

Per- and polyfluoroalkyl substances (PFASs) are widely used in industrial and consumer products and have been linked to various adverse health effects. Communities near two former military bases in Pennsylvania were exposed to PFAS through contaminated drinking water for several decades. The Pennsylvania Department of Health (DOH) conducted biomonitoring of 235 randomly selected community members living in four public water system (PWS) service areas to evaluate a toolkit developed by the Centers for Disease Control and Prevention (CDC) and the Agency for Toxic Substances and Disease Registry (ATSDR). DOH also collected data on participants' demographics, exposure history and self-reported health conditions. Serum PFAS levels were compared with the national averages for 2013-2014 and their relationships with demographic and exposure characteristics were analyzed. Of the 11 PFASs analyzed for, only perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorohexanesulfonic acid (PFHxS) and perfluorononanoic acid (PFNA) were consistently detected in the serum samples. The average levels of PFOA, PFOS, PFHxS and PFNA among the study participants were 3.13, 10.24, 6.64 and 0.74 µg per liter (µg/L), respectively. Overall, 75, 81, 94 and 59 percent of the study participants had levels exceeding the national average for PFOA (1.94 µg/L), PFOS (4.99 µg/L), PFHxS (1.35 µg/L) and PFNA (0.66 µg/L), respectively. Results indicated associations between serum levels of some PFAS compounds and sex, age, employment in the study area, PWS area, quantity of daily tap water consumption, and length of residence in the study area.

Development of CancerLinQ, a Health Information Learning Platform From Multiple Electronic Health Record Systems to Support Improved Quality of Care.

PURPOSE: ASCO, through its wholly owned subsidiary, CancerLinQ LLC, developed CancerLinQ, a learning health system for oncology. A learning health system is important for oncology patients because less than 5% of patients with cancer enroll in clinical trials, leaving evidence gaps for patient populations not enrolled in trials. In addition, clinical trial populations often differ from the overall cancer population with respect to age, race, performance status, and other clinical parameters. MATERIALS AND METHODS: Working with subscribing practices, CancerLinQ accepts data from electronic health records and transforms the local representation of a patient's care into a standardized representation on the basis of the Quality Data Model from the National Quality Forum. CancerLinQ provides this information back to the subscribing practice through a series of tools that support quality improvement. CancerLinQ also creates de-identified data sets for secondary research use. RESULTS: As of March 2020, CancerLinQ includes data from 63 organizations across the United States that use nine different electronic health records. The database includes 1,426,015 patients with a primary cancer diagnosis, of which 238,680 have had additional information abstracted from unstructured content. CONCLUSION: As CancerLinQ continues to onboard subscribing practices, the breadth of potential applications for a learning health care system widen. Future practice-facing tools could include real-world data visualization, recommendations for treatment of patients with actionable genetic variations, and identification of patients who may be eligible for clinical trials. Feeding these insights back into oncology practice ensures that we learn how to treat patients with cancer not just on the basis of the selective experience of the 5% that enroll in clinical trials, but from the real-world experience of the entire spectrum of patients with cancer in the United States.

Niveles de estrés de endodoncistas de la India durante la pandemia COVID-19 / Stress Levels of Indian Endodontists during COVID-19 Pandemic

RESUMEN Introducción: La COVID-19 se propaga por vías respiratorias y aerosoles. La pandemia originada por esta enfermedad causa pánico, miedo y estrés en todos los estratos de la sociedad. Al igual que todas las demás profesiones médicas, los dentistas, particularmente los endodoncistas, que están muy expuestos a los aerosoles, pueden mostrar estrés. Objetivo: Encuestar a los endodoncistas indios para comprender mejor sus niveles de estrés psicológico durante el confinamiento de la India durante la pandemia de la COVID-19. Métodos: Del 8 de abril al 16 de abril de 2020 se realizó una encuesta cerrada en las redes sociales de endodoncia. Se utilizó la técnica de muestreo de bola de nieve. Asimismo, se recolectaron datos demográficos básicos, entorno de práctica y otras informaciones relevantes. El estrés psicológico y la angustia percibida se calcularon a través del índice de angustia peritraumática COVID-19 y la escala de estrés percibido. El análisis de regresión multinomial se realizó para estimar la tasa de riesgo relativo y p ≤ 0,05 se consideró significativo. Resultados: Este estudio tuvo 586 endodoncistas indios que completaron esta encuesta. De estos, 311 (53,07 por ciento) eran hombres, 325 (55 por ciento) en el grupo de edad de 25-35 años, 64 por ciento en áreas urbanas, 13,14 por ciento en prácticas individuales y un cuarto de ellos eran residentes. Las mujeres endodoncistas tenían un alto estrés percibido (RRR = 2,46, p = 0,01) en comparación con los hombres, medido por PSS. Los endodoncistas más jóvenes < 25 años (RRR = 9,75; p = 0,002) y 25-35 años (RRR = 4.60; p = 0,004) en comparación con el grupo de edad > 45 años tenían más angustia. Los consultores exclusivos tuvieron RRR = 2,90, p = 0,02, para la angustia leve a moderada en comparación con la normal. Se consideran los factores que impulsan este fenómeno. Conclusiones: Durante el cierre debido a la COVID-19, los endodoncistas indios 1-en-2 tuvieron angustia, según lo medido por CPDI y 4 de cada 5 percibieron estrés, según lo indicado por PSS. Nuestro modelo identificó ciertos factores que impulsan el (des)estrés, lo que ayudaría a los formuladores de políticas a iniciar una respuesta adecuada(AU)

ABSTRACT Background: The novel 2019 COVID-19 spreads by respiratory and aerosols. COVID-19 driven pandemic causes panic, fear and stress among all strata of society. Like all other medical professions, dentists, particularly endodontists, who are highly exposed to aerosols would be exposed to stress. Objective: To survey the Indian endodontists to better understand their levels of psychological stress during the Indian lockdown COVID-19 Pandemic. Methods: From 8th April to 16th April 2020, we conducted an online survey in closed endodontic social media using snowball sampling technique, collecting basic demographic data, practice setting and relevant data. Psychological stress and perceived distress were collected through COVID-19 Peri-traumatic Distress Index and Perceived stress scale. Multinomial regression analysis was performed to estimate relative risk rate and p ≤ 0.05 was considered significant. Results: This study had 586 Indian endodontists completing this survey across India. Of these, 311(53.07 percent) were males, 325(55 percent) in the age group of 25-35 years, 64 percent in urban areas, 13.14 percent in solo-practice and a fourth of them were residents. Female endodontists had high perceived stress (RRR = 2.46, p = 0.01) as compared to males, as measured by PSS. Younger endodontists < 25 years (RRR = 9.75; p = 0.002) and 25-35years (RRR = 4.60; p = 0.004) as compared with > 45 years age-group had more distress. Exclusive consultants had RRR = 2.90, p = 0.02, for mild-to-moderate distress as compared to normal. Factors driving this phenomenon are considered. Conclusions: During the lock down due to COVID-19, 1-in-2 Indian endodontists had distress, as measured by CPDI and 4-in-5 of them had perceived stress, as indicated by PSS. Our model identified certain factors driving the (dis)stress, which would help policy framers to initiate appropriate response(AU)

Investigating the pharmacodynamic durability of GalNAc-siRNA conjugates.

One hallmark of trivalent N-acetylgalactosamine (GalNAc)-conjugated siRNAs is the remarkable durability of silencing that can persist for months in preclinical species and humans. Here, we investigated the underlying biology supporting this extended duration of pharmacological activity. We found that siRNA accumulation and stability in acidic intracellular compartments is critical for long-term activity. We show that functional siRNA can be liberated from these compartments and loaded into newly generated Argonaute 2 protein complexes weeks after dosing, enabling continuous RNAi activity over time. Identical siRNAs delivered in lipid nanoparticles or as GalNAc conjugates were dose-adjusted to achieve similar knockdown, but only GalNAc-siRNAs supported an extended duration of activity, illustrating the importance of receptor-mediated siRNA trafficking in the process. Taken together, we provide several lines of evidence that acidic intracellular compartments serve as a long-term depot for GalNAc-siRNA conjugates and are the major contributor to the extended duration of activity observed in vivo.

Author Correction: Adaptive evolution of virulence and persistence in carbapenem-resistant Klebsiella pneumoniae.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Adaptive evolution of virulence and persistence in carbapenem-resistant Klebsiella pneumoniae.

Among the most urgent public health threats is the worldwide emergence of carbapenem-resistant Enterobacteriaceae1-4, which are resistant to the antibiotic class of 'last resort'. In the United States and Europe, carbapenem-resistant strains of the Klebsiella pneumoniae ST258 (ref. 5) sequence type are dominant, endemic6-8 and associated with high mortality6,9,10. We report the global evolution of pathogenicity in carbapenem-resistant K. pneumoniae, resulting in the repeated convergence of virulence and carbapenem resistance in the United States and Europe, dating back to as early as 2009. We demonstrate that K. pneumoniae can enhance its pathogenicity by adopting two opposing infection programs through easily acquired gain- and loss-of-function mutations. Single-nucleotide polymorphisms in the capsule biosynthesis gene wzc lead to hypercapsule production, which confers phagocytosis resistance, enhanced dissemination and increased mortality in animal models. In contrast, mutations disrupting capsule biosynthesis genes impair capsule production, which enhances epithelial cell invasion, in vitro biofilm formation and persistence in urinary tract infections. These two types of capsule mutants have emerged repeatedly and independently in Europe and the United States, with hypercapsule mutants associated with bloodstream infections and capsule-deficient mutants associated with urinary tract infections. In the latter case, drug-tolerant K. pneumoniae can persist to yield potentially untreatable, persistent infection.

CRANAD-28: A Robust Fluorescent Compound for Visualization of Amyloid Beta Plaques.

CRANAD-28, a difluoroboron curcumin analogue, has been demonstrated in earlier reports to successfully label amyloid beta (Aß) plaques for imaging both ex vivo and in vivo. CRANAD-28's imaging brightness, ability to penetrate the blood brain barrier, and low toxicity make the compound a potentially potent imaging tool in Alzheimer's research. In this study, the Aß-labeling ability of CRANAD-28 was investigated in further detail using histological staining to assess different criteria, including stained Aß plaque brightness, Aß plaque size, and Aß plaque number count. The results of this study demonstrated CRANAD-28 to be superior across all criteria assessed. Furthermore, CRANAD-28 and IBA-1 antibody were used to label Aß-plaques and microglia respectively. Statistical analysis with Spearman regression revealed a statistically significant negative correlation between the size of labeled Aß plaques and surrounding microglia density. This finding provides interesting insight into Aß plaque and microglia dynamism in AD pathology and corroborates the findings of previous studies. In addition, we found that CRANAD-28 provided distinct spectral signatures for Aßs in the core and periphery of the plaques. Based on the study's results, CRANAD-28 could be considered as an alternative standard for imaging Aß-plaques in future research studies.

A Case of Isolated Unilateral Glossopharyngeal Nerve Palsy.

Isolated palsy of the glossopharyngeal nerve is rare. We report the case of an elderly patient with unilateral right glossopharyngeal nerve palsy secondary to extra cranial ischemia. On examination there was no other deficit other than an absent right gag reflex. She was diagnosed clinically with ischemic stroke of the ninth nerve, and her daily dose of aspirin was increased from 81 mg to 325 mg. Magnetic resonance imaging of the brain showed a normal brainstem and cerebellum with patent intracranial circulation. Total resolution of the paralysis was seen 2 months later. The possible mechanisms suspected were diabetic or hypertensive stenosis of the vasa nervorum or compression of the ninth nerve by an internal carotid artery dissection or aneurysm. This article discusses the various etiologies and mechanisms of this rare condition. It is unique because of the nerve's location and relationship to other structures.

Region-specific transcriptomic and functional signatures of mononuclear phagocytes in the epididymis.

In the epididymis, prevention of autoimmune responses against spermatozoa and simultaneous protection against pathogens is important for male fertility. We have previously shown that mononuclear phagocytes (MPs) are located either in the epididymal interstitium or in close proximity to the epithelium. In the initial segments (IS), these 'intraepithelial' MPs extend slender luminal-reaching projections between epithelial cells. In this study, we performed an in-depth characterisation of MPs isolated from IS, caput-corpus and cauda epididymis of CX3CR1EGFP+/- mice that express EGFP in these cells. Flow cytometry analysis revealed region-specific subsets of MPs that express combinations of markers traditionally described in 'dendritic cells' or 'macrophages'. RNA sequencing identified distinct transcriptomic signatures in MPs from each region and revealed specific genes involved in inflammatory and anti-inflammatory responses, phagosomal activity and antigen processing and presentation. Functional fluorescent in vivo labelling assays showed that higher percentages of CX3CR1+ MPs that captured and processed antigens were detected in the IS compared to other regions. Confocal microscopy showed that in the IS, caput and corpus, circulatory antigens were internalised and processed by interstitial and intraepithelial MPs. However, in the cauda only interstitial MPs internalised and processed antigens, while intraepithelial MPs did not take up antigens, indicating that all antigens have been captured before they reached the epithelial lining. Cauda MPs may thus confer a stronger protection against blood-borne pathogens compared to proximal regions. By identifying immunoregulatory mechanisms in the epididymis, our study may lead to new therapies for male infertility and epididymitis and identify potential targets for immunocontraception.

Tissue-Specific Macrophage Responses to Remote Injury Impact the Outcome of Subsequent Local Immune Challenge.

Myocardial infarction, stroke, and sepsis trigger systemic inflammation and organism-wide complications that are difficult to manage. Here, we examined the contribution of macrophages residing in vital organs to the systemic response after these injuries. We generated a comprehensive catalog of changes in macrophage number, origin, and gene expression in the heart, brain, liver, kidney, and lung of mice with myocardial infarction, stroke, or sepsis. Predominantly fueled by heightened local proliferation, tissue macrophage numbers increased systemically. Macrophages in the same organ responded similarly to different injuries by altering expression of tissue-specific gene sets. Preceding myocardial infarction improved survival of subsequent pneumonia due to enhanced bacterial clearance, which was caused by IFNÉ£ priming of alveolar macrophages. Conversely, EGF receptor signaling in macrophages exacerbated inflammatory lung injury. Our data suggest that local injury activates macrophages in remote organs and that targeting macrophages could improve resilience against systemic complications following myocardial infarction, stroke, and sepsis.

Novel role of proton-secreting epithelial cells in sperm maturation and mucosal immunity.

Epithelial cells are immune sensors and mediators that constitute the first line of defense against infections. Using the epididymis, a model for studying tubular organs, we uncovered a novel and unexpected role for professional proton-secreting 'clear cells' in sperm maturation and immune defense. The epididymal epithelium participates in the maturation of spermatozoa via the establishment of an acidic milieu and transfer of proteins to sperm cells, a poorly characterized process. We show that proton-secreting clear cells express mRNA transcripts and proteins that are acquired by maturing sperm, and that they establish close interactions with luminal spermatozoa via newly described 'nanotubes'. Mechanistic studies show that injection of bacterial antigens in vivo induces chemokine expression in clear cells, followed by macrophage recruitment into the organ. Injection of an inflammatory intermediate mediator (IFN-γ) increased Cxcl10 expression in clear cells, revealing their participation as sensors and mediators of inflammation. The functional diversity adopted by clear cells might represent a generalized phenomenon by which similar epithelial cells decode signals, communicate with neighbors and mediate mucosal immunity, depending on their precise location within an organ.

Sex-dependent differences in water homeostasis in wild-type and V-ATPase B1-subunit deficient mice.

Men tend to dehydrate more than women after prolonged exercise, possibly due to lower water intake and higher perspiration rate. Women are prone to exercise-associated hyponatremia, primarily attributed to the higher water consumption causing hypervolemia. Since aquaporin-2 (AQP2) water channels in the kidney collecting duct (CD) principal cells (PCs) are involved in maintaining water balance, we investigated their role in sex-dependent water homeostasis in wild-type (WT) C57BL/6 mice. Because CD intercalated cells (ICs) may also be involved in water balance, we also assessed the urine concentrating ability of V-ATPase B1 subunit-deficient (Atp6v1b1-/-) mice. Upon 12-hour water deprivation, urine osmolality increased by 59% in WT female mice and by only 28% in males. This difference was abolished in Atp6v1b1-/- mice, in which dehydration induced a ~30% increase in urine osmolarity in both sexes. AQP2 levels were highest in WT females; female Atp6v1b1-/- mice had substantially lower AQP2 expression than WT females, comparable to the low AQP2 levels seen in both Atp6v1b1-/- and WT males. After dehydration, AQP2 relocates towards the PC apical pole, especially in the inner stripe and inner medulla, and to a greater extent in WT females than in WT males. This apparent sex-dependent concentrating advantage was absent in Atp6v1b1-/- females, whose reduced AQP2 apical relocation was similar to WT males. Accordingly, female mice concentrate urine better than males upon dehydration due to increased AQP2 expression and mobilization. Moreover, our data support the involvement of ICs in water homeostasis, at least partly mediated by V-ATPase, in a sex-dependent manner.

Identifying an Optimal Cutoff of the Montreal Cognitive Assessment to Predict Amyloid-PET Positivity in a Referral Memory Clinic.

BACKGROUND: Brain amyloid- positron emission tomography (PET) imaging is highly sensitive for identifying Alzheimer disease. Currently, there is a lack of insight on the association between amyloid-PET status and the widely used Montreal cognitive assessment (MoCA). Studying this relationship may optimize the clinical use of amyloid-PET imaging. OBJECTIVES: To evaluate the relationship between amyloid-PET status and MoCA scores and to identify a MoCA score cutoff that translates to amyloid-PET positivity. METHODS: Using retrospective chart review, patients from 2010 to 2017 with amyloid-PET scans (positive or negative) and MoCA test scores were included. We studied the relationship between amyloid-PET status and MoCA scores and the influence of age, sex, education, and race. A MoCA score cutoff for amyloid-PET positivity was estimated. RESULTS: Among the 684 clinic patients with dementia, 99 fulfilled inclusion criteria. Amyloid-PET positivity was associated significantly with lower MoCA scores (median=19, U=847, P=0.01). The MoCA score cutoff (25) used for minimal cognitive impairment (MCI) predicted amyloid-PET positivity suboptimally (sensitivity=94.6%, specificity=13.9%). A MoCA score cutoff of 20 patients had optimal sensitivity (64.2%) and specificity (67.4%). CONCLUSIONS: Amyloid-PET positivity is associated with lower MoCA scores. Clinical utility of amyloid-PET scan is likely to be suboptimal at the MoCA score cutoff for minimal cognitive impairment.

A Systematic Review of the Epidemiologic Literature Assessing Health Outcomes in Populations Living near Oil and Natural Gas Operations: Study Quality and Future Recommendations.

A systematic method was used to review the existing epidemiologic literature and determine the state of the scientific evidence for potential adverse health outcomes in populations living near oil and natural gas (ONG) operations in the United States. The review utilized adapted systematic review frameworks from the medical and environmental health fields, such as Grading of Recommendations, Assessment, Development and Evaluations (GRADE), the Navigation Guide, and guidance from the National Toxicology Program's Office of Health Assessment and Translation (OHAT). The review included 20 epidemiologic studies, with 32 different health outcomes. Studies of populations living near ONG operations provide limited evidence (modest scientific findings that support the outcome, but with significant limitations) of harmful health effects including asthma exacerbations and various self-reported symptoms. Study quality has improved over time and the highest rated studies within this assessment have primarily focused on birth outcomes. Additional high-quality studies are needed to confirm or dispute these correlations.

Ablation of Hepatocyte Smad1, Smad5, and Smad8 Causes Severe Tissue Iron Loading and Liver Fibrosis in Mice.

A failure of iron to appropriately regulate liver hepcidin production is central to the pathogenesis of hereditary hemochromatosis. SMAD1/5 transcription factors, activated by bone morphogenetic protein (BMP) signaling, are major regulators of hepcidin production in response to iron; however, the role of SMAD8 and the contribution of SMADs to hepcidin production by other systemic cues remain uncertain. Here, we generated hepatocyte Smad8 single (Smad8fl/fl ;Alb-Cre+ ), Smad1/5/8 triple (Smad158;Alb-Cre+ ), and littermate Smad1/5 double (Smad15;Alb-Cre+ ) knockout mice to investigate the role of SMAD8 in hepcidin and iron homeostasis regulation and liver injury. We found that Smad8;Alb-Cre+ mice exhibited no iron phenotype, whereas Smad158;Alb-Cre+ mice had greater iron overload than Smad15;Alb-Cre+ mice. In contrast to the sexual dimorphism reported for wild-type mice and other hemochromatosis models, hepcidin deficiency and extrahepatic iron loading were similarly severe in Smad15;Alb-Cre+ and Smad158;Alb-Cre+ female compared with male mice. Moreover, epidermal growth factor (EGF) failed to suppress hepcidin in Smad15;Alb-Cre+ hepatocytes. Conversely, hepcidin was still increased by lipopolysaccharide in Smad158;Alb-Cre+ mice, although lower basal hepcidin resulted in lower maximal hepcidin. Finally, unlike most mouse hemochromatosis models, Smad158;Alb-Cre+ developed liver injury and fibrosis at 8 weeks. Liver injury and fibrosis were prevented in Smad158;Alb-Cre+ mice by a low-iron diet and were minimal in iron-loaded Cre- mice. Conclusion: Hepatocyte Smad1/5/8 knockout mice are a model of hemochromatosis that encompasses liver injury and fibrosis seen in human disease. These mice reveal the redundant but critical role of SMAD8 in hepcidin and iron homeostasis regulation, establish a requirement for SMAD1/5/8 in hepcidin regulation by testosterone and EGF but not inflammation, and suggest a pathogenic role for both iron loading and SMAD1/5/8 deficiency in liver injury and fibrosis.