Impact of micafungin on Candida auris ß-glucan masking and neutrophil interactions.

Invasive fungal pathogen Candida auris has become a public health threat causing outbreaks of high mortality infections. Drug resistance often limits treatment options. For Candida albicans, subinhibitory concentrations of echinocandins unmask immunostimulatory ß-glucan, augmenting immunity. Here we analyze the impact of echinocandin treatment of C. auris on ß-glucan exposure and human neutrophil interactions. We show subinhibitory concentrations lead to minimal glucan unmasking and only subtle influences on neutrophil functions for the isolates belonging to circulating clades. The data suggest that echinocandin treatment will not largely alter phagocytic responses. Glucan masking pathways appear to differ between C. auris and C. albicans.

Mechanisms of pathogenicity for the emerging fungus Candida auris.

Candida auris recently emerged as an urgent public health threat, causing outbreaks of invasive infections in healthcare settings throughout the world. This fungal pathogen persists on the skin of patients and on abiotic surfaces despite antiseptic and decolonization attempts. The heightened capacity for skin colonization and environmental persistence promotes rapid nosocomial spread. Following skin colonization, C. auris can gain entrance to the bloodstream and deeper tissues, often through a wound or an inserted medical device, such as a catheter. C. auris possesses a variety of virulence traits, including the capacity for biofilm formation, production of adhesins and proteases, and evasion of innate immune responses. In this review, we highlight the interactions of C. auris with the host, emphasizing the intersection of laboratory studies and clinical observations.

Collagen fingerprinting traces the introduction of caprines to island Eastern Africa.

The human colonization of eastern Africa's near- and offshore islands was accompanied by the translocation of several domestic, wild and commensal fauna, many of which had long-term impacts on local environments. To better understand the timing and nature of the introduction of domesticated caprines (sheep and goat) to these islands, this study applied collagen peptide fingerprinting (Zooarchaeology by Mass Spectrometry or ZooMS) to archaeological remains from eight Iron Age sites, dating between ca 300 and 1000 CE, in the Zanzibar, Mafia and Comoros archipelagos. Where previous zooarchaeological analyses had identified caprine remains at four of these sites, this study identified goat at seven sites and sheep at three, demonstrating that caprines were more widespread than previously known. The ZooMS results support an introduction of goats to island eastern Africa from at least the seventh century CE, while sheep in our sample arrived one-two centuries later. Goats may have been preferred because, as browsers, they were better adapted to the islands' environments. The results allow for a more accurate understanding of early caprine husbandry in the study region and provide a critical archaeological baseline for examining the potential long-term impacts of translocated fauna on island ecologies.

Candida auris Cell Wall Mannosylation Contributes to Neutrophil Evasion through Pathways Divergent from Candida albicans and Candida glabrata.

Candida auris, a recently emergent fungal pathogen, has caused invasive infections in health care settings worldwide. Mortality rates approach 60% and hospital spread poses a public health threat. Compared to other Candida spp., C. auris avoids triggering the antifungal activity of neutrophils, innate immune cells that are critical for responding to many invasive fungal infections, including candidiasis. However, the mechanism underpinning this immune evasion has been largely unknown. Here, we show that C. auris cell wall mannosylation contributes to the evasion of neutrophils ex vivo and in a zebrafish infection model. Genetic disruption of mannosylation pathways (PMR1 and VAN1) diminishes the outer cell wall mannan, unmasks immunostimulatory components, and promotes neutrophil engagement, phagocytosis, and killing. Upon examination of these pathways in other Candida spp. (Candida albicans and Candida glabrata), we did not find an impact on neutrophil interactions. These studies show how C. auris mannosylation contributes to neutrophil evasion though pathways distinct from other common Candida spp. The findings shed light on innate immune evasion for this emerging pathogen. IMPORTANCE The emerging fungal pathogen Candida auris presents a global public health threat. Therapeutic options are often limited for this frequently drug-resistant pathogen, and mortality rates for invasive disease are high. Previous study has demonstrated that neutrophils, leukocytes critical for the antifungal host defense, do not efficiently recognize and kill C. auris. Here, we show how the outer cell wall of C. auris promotes immune evasion. Disruption of this mannan polysaccharide layer renders C. auris susceptible to neutrophil killing ex vivo and in a zebrafish model of invasive candidiasis. The role of these mannosylation pathways for neutrophil evasion appears divergent from other common Candida species.

Candida auris infection and biofilm formation: going beyond the surface.

PURPOSE OF REVIEW: Emergent fungal pathogen C. auris is spreading in hospitals throughout the world and mortality rates for patients with invasive disease approach 60%. This species exhibits a heightened capacity to colonize skin, persist on hospital surfaces, rapidly disseminate in healthcare settings, and resist antifungal therapy. RECENT FINDINGS: Current investigations show that C. auris produces biofilms, surface-adherent communities that resist antifungals and withstand desiccation. These biofilms form when C. auris is growing on skin or in conditions expected in the hospital environment and on implanted medical devices. SUMMARY: Here we will highlight the topic of biofilm formation by C. auris. We illustrate how this process influences resistance to antimicrobials and promotes nosocomial transmission.

Dairy pastoralism sustained eastern Eurasian steppe populations for 5,000 years.

Dairy pastoralism is integral to contemporary and past lifeways on the eastern Eurasian steppe, facilitating survival in agriculturally challenging environments. While previous research has indicated that ruminant dairy pastoralism was practiced in the region by circa 1300 BC, the origin, extent and diversity of this custom remain poorly understood. Here, we analyse ancient proteins from human dental calculus recovered from geographically diverse locations across Mongolia and spanning 5,000 years. We present the earliest evidence for dairy consumption on the eastern Eurasian steppe by circa 3000 BC and the later emergence of horse milking at circa 1200 BC, concurrent with the first evidence for horse riding. We argue that ruminant dairying contributed to the demographic success of Bronze Age Mongolian populations and that the origins of traditional horse dairy products in eastern Eurasia are closely tied to the regional emergence of mounted herding societies during the late second millennium BC.

Automated and Computer-Assisted Detection, Classification, and Diagnosis of Diabetic Retinopathy.

Background: The introduction of artificial intelligence (AI) in medicine has raised significant ethical, economic, and scientific controversies. Introduction: Because an explicit goal of AI is to perform processes previously reserved for human clinicians and other health care personnel, there is justified concern about the impact on patient safety, efficacy, equity, and liability. Discussion: Systems for computer-assisted and fully automated detection, triage, and diagnosis of diabetic retinopathy (DR) from retinal images show great variation in design, level of autonomy, and intended use. Moreover, the degree to which these systems have been evaluated and validated is heterogeneous. We use the term DR AI system as a general term for any system that interprets retinal images with at least some degree of autonomy from a human grader. We put forth these standardized descriptors to form a means to categorize systems for computer-assisted and fully automated detection, triage, and diagnosis of DR. The components of the categorization system include level of device autonomy, intended use, level of evidence for diagnostic accuracy, and system design. Conclusion: There is currently minimal empirical basis to assert that certain combinations of autonomy, accuracy, or intended use are better or more appropriate than any other. Therefore, at the current stage of development of this document, we have been descriptive rather than prescriptive, and we treat the different categorizations as independent and organized along multiple axes.

Practice Guidelines for Ocular Telehealth-Diabetic Retinopathy, Third Edition.

Contributors The following document and appendices represent the third edition of the Practice Guidelines for Ocular Telehealth-Diabetic Retinopathy. These guidelines were developed by the Diabetic Retinopathy Telehealth Practice Guidelines Working Group. This working group consisted of a large number of subject matter experts in clinical applications for telehealth in ophthalmology. The editorial committee consisted of Mark B. Horton, OD, MD, who served as working group chair and Christopher J. Brady, MD, MHS, and Jerry Cavallerano, OD, PhD, who served as cochairs. The writing committees were separated into seven different categories. They are as follows: 1.Clinical/operational: Jerry Cavallerano, OD, PhD (Chair), Gail Barker, PhD, MBA, Christopher J. Brady, MD, MHS, Yao Liu, MD, MS, Siddarth Rathi, MD, MBA, Veeral Sheth, MD, MBA, Paolo Silva, MD, and Ingrid Zimmer-Galler, MD. 2.Equipment: Veeral Sheth, MD (Chair), Mark B. Horton, OD, MD, Siddarth Rathi, MD, MBA, Paolo Silva, MD, and Kristen Stebbins, MSPH. 3.Quality assurance: Mark B. Horton, OD, MD (Chair), Seema Garg, MD, PhD, Yao Liu, MD, MS, and Ingrid Zimmer-Galler, MD. 4.Glaucoma: Yao Liu, MD, MS (Chair) and Siddarth Rathi, MD, MBA. 5.Retinopathy of prematurity: Christopher J. Brady, MD, MHS (Chair) and Ingrid Zimmer-Galler, MD. 6.Age-related macular degeneration: Christopher J. Brady, MD, MHS (Chair) and Ingrid Zimmer-Galler, MD. 7.Autonomous and computer assisted detection, classification and diagnosis of diabetic retinopathy: Michael Abramoff, MD, PhD (Chair), Michael F. Chiang, MD, and Paolo Silva, MD.

The Indian Health Service Primary Care-Based Teleophthalmology Program for Diabetic Eye Disease Surveillance and Management.

Background: Historically, fewer than half of American Indians and Alaska Natives (AI/AN) with diabetes received the annual diabetic retinopathy (DR) examination that is considered the minimum standard of care; this rate is similar to that of the general United States (U.S.) population with diabetes. Solution: The Indian Health Service-Joslin Vision Network (IHS-JVN) Teleophthalmology Program in 2000 to increase compliance with DR standards of care among AI/AN through validated, primary care-based telemedicine. The IHS-JVN provides remote diagnosis of DR severity, with a report including management recommendations that is returned to the patient's primary care provider. The program conforms with the American Telemedicine Association (ATA) Practice Guidelines for Ocular Telehealth-Diabetic Retinopathy. Outcomes: The IHS-JVN has been expanding incrementally since the first patients were recruited in 2000; this expansion coincides with large improvements in the annual DR examination rates reported as part of local, regional, and national regulatory compliance under the Government Performance and Results Act (GPRA). Currently, with 99 clinical implementations in 23 states, IHS-JVN is the largest primary care-based ATA validation category three telemedicine program in the U.S. Summary: This article describes the program's workflow, imaging and reading technologies, diagnostic protocols, reports to providers, training, quality assurance processes, and geographical distribution. In addition to its clinical use, the program has been utilized in research on utilization of diabetic eye care, cost-effectiveness, technology development, and DR epidemiology of the AI/AN population. Potential next steps for this program are discussed.

Candida auris Forms High-Burden Biofilms in Skin Niche Conditions and on Porcine Skin.

Emerging pathogen Candida auris causes nosocomial outbreaks of life-threatening invasive candidiasis. It is unclear how this species colonizes skin and spreads in health care facilities. Here, we analyzed C. auris growth in synthetic sweat medium designed to mimic axillary skin conditions. We show that C. auris demonstrates a high capacity for biofilm formation in this milieu, well beyond that observed for the most commonly isolated Candida sp., Candida albicans The C. auris biofilms persist in environmental conditions expected in the hospital setting. To model C. auris skin colonization, we designed an ex vivo porcine skin model. We show that C. auris proliferates on porcine skin in multilayer biofilms. This capacity to thrive in skin niche conditions helps explain the propensity of C. auris to colonize skin, persist on medical devices, and rapidly spread in hospitals. These studies provide clinically relevant tools to further characterize this important growth modality.IMPORTANCE The emerging fungal pathogen Candida auris causes invasive infections and is spreading in hospitals worldwide. Why this species exhibits the capacity to transfer efficiently among patients is unknown. Our findings reveal that C. auris forms high-burden biofilms in conditions mimicking sweat on the skin surface. These adherent biofilm communities persist in environmental conditions expected in the hospital setting. Using a pig skin model, we show that C. auris also forms high-burden biofilm structures on the skin surface. Identification of this mode of growth sheds light on how this recently described pathogen persists in hospital settings and spreads among patients.

Use of graded Semmes Weinstein monofilament testing for ascertaining peripheral neuropathy in people with and without diabetes.

AIMS: To assess peripheral neuropathy (PN) using graded Semmes Weinstein monofilaments (SWMs) and determine factors associated with PN among adult volunteers with and without diabetes. METHODS: Adult volunteers were assessed for distal sensory PN using three graded SWMs. Four PN levels were defined: 0 (no PN; felt all three filaments), 1 (subclinical PN; insensate to 1-g filament), 2 (insensate to 10-g), or 3 (insensate to 75-g). Levels 2-3 were considered clinical PN. Associations with PN were determined using ordinal logistic regression. RESULTS: In 1564 subjects (median age 41.9 years, 50.1% women), PN was subclinical or worse in 68.9% and clinical in 11.2%. Age-sex-race-adjusted prevalence of clinical PN was greater in people with diabetes (15.3%) than without (6.1%; P < 0.001). Associated factors included older age, male sex, greater BMI, greater heart rate, lower mean arterial pressure, and family history of diabetes or cardiovascular diseases. Higher PN levels associated with worse albuminuria and retinopathy. Only older age and male sex associated with PN both in people with and without diabetes. CONCLUSIONS: PN is common in our sample, notably in those without diabetes, although diabetes greatly increases its risk. Using graded SWMs may have a prognostic value as it permits the identification of subclinical PN.

A Rheological Investigation of Carbon Nanotube Grease.

The use of carbon nanotubes (CNTs) as a thickening agent in polyalphaolefin oils to create CNT-grease has significant merit. Given the abnormally high thermal conductivities of CNTs, it is conceivable that a CNT-grease would exhibit excellent thermal conductivity. The rheological response of CNT-greases is important for two reasons: to determine if the grease will have sufficient lubricating properties and to provide critical information on the structure and particle-particle interactions of CNT suspensions. The viscoelastic response and evidence of creep recovery support the theory of the stable 3 Dimensional network (3D) formation in the CNT-grease. The elastic response indicates that significant energy is needed to dismember the network structure and initiate viscous flow. The macroscopic rheological investigation provides additional information regarding the structure of CNT-grease and particle-particle interactions at high SWNT concentrations, ~10.0 wt. The knowledge gained concerning the structure of CNT suspensions will allow its manipulation to achieve better thermal properties.

Prevalence of diabetic retinopathy and diabetic macular edema in a primary care-based teleophthalmology program for American Indians and Alaskan Natives.

BACKGROUND: Diabetes and its complications are more common in American Indians and Alaska Natives (AI/AN) than other US racial/ethnic populations. Prior reports of diabetic retinopathy (DR) prevalence in AI/AN are dated, and research on diabetic macular edema (DME) is limited. This study characterizes the recent prevalence of DR and DME in AI/AN using primary care-based teleophthalmology surveillance. METHODS: This is a multi-site, clinic-based, cross-sectional study of DR and DME. The sample is composed of AI /AN patients with diabetes (n = 53,998), served by the nationally distributed Indian Health Service-Joslin Vision Network Teleophthalmology Program (IHS-JVN) in primary care clinics of US Indian Health Service (IHS), Tribal, and Urban Indian health care facilities (I/T/U) from 1 November 2011 to 31 October 2016. Patients were recruited opportunistically for a retinal examination using the IHS-JVN during their regular diabetes care. The IHS-JVN used clinically validated, non-mydriatic, retinal imaging and retinopathy assessment protocols to identify the severity levels of non-proliferative diabetic retinopathy (NPDR), proliferative diabetic retinopathy (PDR), DME, and sight threatening retinopathy (STR; a composite measure). Key social-demographic (age, gender, IHS area), diabetes-related health (diabetes therapy, duration of diabetes, A1c), and imaging technology variables were examined. The analysis calculated frequencies and percentages of severity levels of disease. RESULTS: Prevalence of any NPDR, PDR, DME, and STR among AI/AN patients undergoing DR teleophthalmology surveillance by IHS-JVN was 17.7%, 2.3%, 2.3%, and 4.2%, respectively. Prevalence was lowest in Alaska and highest among patients with A1c >/ = 8%, duration of diabetes > 10 years, or using insulin. CONCLUSIONS: Prevalence of DR in this cohort was approximately half that in previous reports for AI/AN, and prevalence of DME was less than that reported in non-AI/AN populations. A similar reduction in diabetes related end-stage renal disease in the same population and time period has been reported by other researchers. Since these two diabetic complications share a common microvasculopathic mechanism, this coincident change in prevalence may also share a common basis, possibly related to improved diabetes management.

Access to Digital Communication Technology and Perceptions of Telemedicine for Patient Education among American Indian Patients with Diabetes.

INTRODUCTION: Health care access for medically underserved patients managing chronic conditions is challenging. While telemedicine can support patient education and engagement, the "digital divide" may be particularly problematic among the medically underserved. This study evaluated physical access to digital devices, use of e-mail and social media tools, and perceptions of telemedicine among American Indian (AI) patients with diabetes mellitus (DM). METHODS: Survey data were collected from AI patients with DM during teleophthalmology exams. RESULTS: Eighty-eight percent of patients had access to digital device(s), 70% used e-mail, and 56% used social media. Younger age and greater education were positively associated with e-mail and social media use (p < .05). Most (60%) considered telemedicine an excellent medium for health-related patient education. DISCUSSION: American Indian patients with DM had access enabling patient education via telemedicine. Future work should examine patient technology preferences and effectiveness of technology-based education in improving outcomes among medically underserved populations.

Reconstructing Prehistoric African Population Structure.

We assembled genome-wide data from 16 prehistoric Africans. We show that the anciently divergent lineage that comprises the primary ancestry of the southern African San had a wider distribution in the past, contributing approximately two-thirds of the ancestry of Malawi hunter-gatherers ∼8,100-2,500 years ago and approximately one-third of the ancestry of Tanzanian hunter-gatherers ∼1,400 years ago. We document how the spread of farmers from western Africa involved complete replacement of local hunter-gatherers in some regions, and we track the spread of herders by showing that the population of a ∼3,100-year-old pastoralist from Tanzania contributed ancestry to people from northeastern to southern Africa, including a ∼1,200-year-old southern African pastoralist. The deepest diversifications of African lineages were complex, involving either repeated gene flow among geographically disparate groups or a lineage more deeply diverging than that of the San contributing more to some western African populations than to others. We finally leverage ancient genomes to document episodes of natural selection in southern African populations. PAPERCLIP.

Reconstructing Asian faunal introductions to eastern Africa from multi-proxy biomolecular and archaeological datasets.

Human-mediated biological exchange has had global social and ecological impacts. In sub-Saharan Africa, several domestic and commensal animals were introduced from Asia in the pre-modern period; however, the timing and nature of these introductions remain contentious. One model supports introduction to the eastern African coast after the mid-first millennium CE, while another posits introduction dating back to 3000 BCE. These distinct scenarios have implications for understanding the emergence of long-distance maritime connectivity, and the ecological and economic impacts of introduced species. Resolution of this longstanding debate requires new efforts, given the lack of well-dated fauna from high-precision excavations, and ambiguous osteomorphological identifications. We analysed faunal remains from 22 eastern African sites spanning a wide geographic and chronological range, and applied biomolecular techniques to confirm identifications of two Asian taxa: domestic chicken (Gallus gallus) and black rat (Rattus rattus). Our approach included ancient DNA (aDNA) analysis aided by BLAST-based bioinformatics, Zooarchaeology by Mass Spectrometry (ZooMS) collagen fingerprinting, and direct AMS (accelerator mass spectrometry) radiocarbon dating. Our results support a late, mid-first millennium CE introduction of these species. We discuss the implications of our findings for models of biological exchange, and emphasize the applicability of our approach to tropical areas with poor bone preservation.

Operational Components of Telemedicine Programs for Diabetic Retinopathy.

Diabetic retinopathy is a leading cause of new-onset vision loss worldwide. Treatments supported by large clinical trials are effective in preserving vision, but many persons do not receive timely diagnosis and treatment of diabetic retinopathy, which is typically asymptomatic when most treatable. Telemedicine evaluation to identify diabetic retinopathy has the potential to improve access to care and improve outcomes, but incomplete implementation of published standards creates a risk to program utility and sustainability. In a prior article, we reviewed the literature regarding the impact of imaging device, number and size of retinal images, pupil dilation, type of image grader, and diagnostic accuracy on telemedicine assessment for diabetic retinopathy. This article reviews the literature regarding the impact of automated image grading, cost effectiveness, program standards, and quality assurance (QA) on telemedicine assessment of diabetic retinopathy. Telemedicine assessment of diabetic retinopathy has the potential to preserve vision, but greater attention to development and implementation of standards is needed to better realize its potential.

Clinical Components of Telemedicine Programs for Diabetic Retinopathy.

Diabetic retinopathy is a leading cause of new-onset vision loss worldwide. Treatments supported by large clinical trials are effective in preserving vision, but many persons do not receive timely diagnosis and treatment of diabetic retinopathy, which is typically asymptomatic when most treatable. Telemedicine evaluation to identify diabetic retinopathy has the potential to improve access to care, but there are no universal standards regarding camera choice or protocol for ocular telemedicine. We review the literature regarding the impact of imaging device, number and size of retinal images, pupil dilation, type of image grader, and diagnostic accuracy on telemedicine assessment for diabetic retinopathy. Telemedicine assessment of diabetic retinopathy has the potential to preserve vision, but further development of telemedicine specific technology and standardization of operations are needed to better realize its potential.

Ancient crops provide first archaeological signature of the westward Austronesian expansion.

The Austronesian settlement of the remote island of Madagascar remains one of the great puzzles of Indo-Pacific prehistory. Although linguistic, ethnographic, and genetic evidence points clearly to a colonization of Madagascar by Austronesian language-speaking people from Island Southeast Asia, decades of archaeological research have failed to locate evidence for a Southeast Asian signature in the island's early material record. Here, we present new archaeobotanical data that show that Southeast Asian settlers brought Asian crops with them when they settled in Africa. These crops provide the first, to our knowledge, reliable archaeological window into the Southeast Asian colonization of Madagascar. They additionally suggest that initial Southeast Asian settlement in Africa was not limited to Madagascar, but also extended to the Comoros. Archaeobotanical data may support a model of indirect Austronesian colonization of Madagascar from the Comoros and/or elsewhere in eastern Africa.

Identification of Diabetic Retinopathy and Ungradable Image Rate with Ultrawide Field Imaging in a National Teleophthalmology Program.

PURPOSE: To compare diabetic retinopathy (DR) identification and ungradable image rates between nonmydriatic ultrawide field (UWF) imaging and nonmydriatic multifield fundus photography (NMFP) in a large multistate population-based DR teleophthalmology program. DESIGN: Multiple-site, nonrandomized, consecutive, cross-sectional, retrospective, uncontrolled imaging device evaluation. PARTICIPANTS: Thirty-five thousand fifty-two eyes (17 526 patients) imaged using NMFP and 16 218 eyes (8109 patients) imaged using UWF imaging. METHODS: All patients undergoing Joslin Vision Network (JVN) imaging with either NMFP or UWF imaging from May 1, 2014, through August 30, 2015, within the Indian Health Service-JVN program, which serves American Indian and Alaska Native communities at 97 sites across 25 states, were evaluated. All retinal images were graded using a standardized validated protocol in a centralized reading center. MAIN OUTCOME MEASURES: Ungradable rate for DR and diabetic macular edema (DME). RESULTS: The ungradable rate per patient for DR and DME was significantly lower with UWF imaging compared with NMFP (DR, 2.8% vs. 26.9% [P < 0.0001]; DME, 3.8% vs. 26.2% [P < 0.0001]). Identification of eyes with either DR or referable DR (moderate nonproliferative DR or DME or worse) was increased using UWF imaging from 11.7% to 24.2% (P < 0.0001) and from 6.2% to 13.6% (P < 0.0001), respectively. In eyes with DR imaged with UWF imaging (n = 3926 eyes of 2402 patients), the presence of predominantly peripheral lesions suggested a more severe level of DR in 7.2% of eyes (9.6% of patients). CONCLUSIONS: In a large, widely distributed DR ocular telehealth program, as compared with NMFP, nonmydriatic UWF imaging reduced the number of ungradable eyes by 81%, increased the identification of DR nearly 2-fold, and identified peripheral lesions suggesting more severe DR in almost 10% of patients, thus demonstrating significant benefits of this imaging method for large DR teleophthalmology programs.