Polyglutamine tracts as autophagy regulators

By Yoskaly Lazo-Fernandez, PhD

Polyglutamine tracts (polyQ tracts) are long chains of glutamine amino acidspresent in the sequence of many proteins. The length of polyQ tracts within proteins varies significantly as normal alleles of specific genes usually contain different number of the cytosine-adenine-guanine (CAG) nucleotide repeats¹.

It has long been known that polyQ tracts play a role in the etiology of several inheritable neurodegenerative disorders, including spinocerebellar ataxia, and Huntington's disease². These 'polyglutamine diseases' result from the excessive elongation of a polyQ tract in a particular gene which causes the resultant protein to become toxic. The toxicity of mutated polyQ tracts has been extensively studied and several explanatory hypotheses have been proposed: aggregation of polyQ tract proteins, transcriptional dysregulation, mitochondrial dysfunction, and impairment of both the ubiquitin-proteasome and autophagy-lysosome protein degradation systems.

Western blot analysis of Htt in four different lymphoblast HD cell lines extracts each expressing ~65 (mutant) and ~20 (normal) CAG repeats. Lanes 1-4  (A), HTT mAb clone 1A771 recognizes only the expanded or long form of Htt. (B), A different Htt antibody recognizing both normal and mutant Htt.

Interestingly, the physiological function of polyQ tracts in normal proteins remained unclear until very recently.  This breakthrough has been published in a Nature paper³ that depicted very detailed and exhaustive studies performed by David Rubinsztein's group at the University of Cambridge in the UK. This group uncovered an interesting regulatory function of normal polyQ tract-containing protein ataxin 3 on autophagy.

In their experiments, Ashkenazi et al.³ explored whether the knockdown or overexpression of genes involved in polyQ diseases like ataxin 3 (related to spinocerebellar ataxia) and huntingtin (Huntington's disease) affected autophagosome formation, an essential step for proper autophagy function⁴. The knockdown of wild type ataxin 3 impaired autophagosome formation in different biological models including cultured mouse neurons and liver cells, as well as in immortalized human cultured cells. Conversely, the overexpression of ataxin 3 in the same models stimulated autophagosome formation. Most importantly, the authors identified the key component of autophagosome biogenesis that is affected by the modulation of ataxin 3 expression, beclin 1, which is a particularly important protein for the induction of autophagy after nutrient depletion^4,5. Ataxin 3 was shown to be essential for the protection of beclin 1 from polyubiquitination and degradation, which made much sense since ataxin 3 is a deubiquitinating enzyme involved in the regulation of protein homeostasis. In fact, the polyQ tracts in ataxin 3 are necessary for its binding to and deubiquitination of beclin 1. Interestingly, longer polyQ tracts diminished the deubiquitinating activity of ataxin 3 and created a much stronger binding affinity of the mutated ataxin 3 to beclin 1. Longer polyQ tracts in huntingtin and other polyQ proteins also bonded strongly to beclin 1, leading to a competitive blockade of the functional interaction between wild type ataxin 3 and beclin 1, and thus resulting in excessive beclin 1 degradation and autophagy impairment.

Overall, this new study provides insight into the physiological function of normal polyQ tracts as binding domains to beclin 1, and therefore as regulators of autophagy. Also, this insight reveals a new integrative model by which mutated polyQ tract-containing proteins may cause disease. According to this new model, mutated polyQ tracts create a stronger than normal binding to beclin 1, which then blocks ataxin 3's binding and deubiquitination of beclin 1, causing beclin 1's excessive degradation. This sequence of events results in impaired basal levels of autophagy in polyQ disease patients which could explain the progressive toxic protein accumulation and aggregation observed in their neurons. Moreover, since impaired autophagy has been implicated in many chronic diseases like cancer and diabetes, perhaps the use of modulators targeting this new mechanism of autophagy regulation may provide alternative pharmacological treatments.

Learn more about autophagy regulation

References

1. Rinaldi & Fischbeck. Pathological Mechanisms of Polyglutamine Diseases. Nature Education 8, (2015).
   
2. Fan et al. Polyglutamine (PolyQ) Diseases: Genetics to Treatments. Cell Transplantation 23, 441–458(18)
3. Ashkenazi et al. Polyglutamine tracts regulate beclin 1-dependent autophagy. Nature 545, 108–111 (2017).
4. Cohen-Kaplan, Livneh, Avni, Cohen-Rosenzweig & Ciechanover. The ubiquitin-proteasome system and autophagy: Coordinated and independent activities. The International Journal of Biochemistry & Cell Biology 79, 403–418 (2016).
5. Kang, Zeh, Lotze & Tang. The Beclin 1 network regulates autophagy and apoptosis. Cell Death & Differentiation 18, 571–580 (2011).

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Comparative Transcriptomics of Seasonal Phenotypic Flexibility in Two North American Songbirds

Abstract

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Descriptive Error in the Text

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Nonhealing Leg Ulcer in a Middle-aged Indian Man

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Thyroid Function in Children With Alopecia Areata

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The Epidemic of Guns

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Anesthesia Duration and Head and Neck Microvascular Reconstruction Complications

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Combining Rhinoplasty With Upper Lip–Lift Using a Single Incision Line

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Outcomes of Buccinator Treatment With Botulinum Toxin in Facial Synkinesis

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Botulinum Neuromodulators in Facial Synkinesis Management

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THE NON-NEURONAL AND NON-MUSCULAR EFFECTS OF BOTULINUM TOXIN: A Graceful Opportunity for a Deadly Molecule to Treat a Human Disease in the Skin and Beyond

Abstract

There is growing evidence that botulinum neurotoxins (BoNTs) exhibit biological effects on various human cell types with a host of associated clinical implications. The BoNT receptors and intracellular targets are not unique for neurotransmission. They have been found in both neuronal and non-neuronal cells, but there are differences in the way BoNT binds to, and acts on neuronal vs. non-neuronal cells. The non-neuronal cells expressing one or more BoNT/A-binding proteins and/or cleavage target SNAP-25 include epidermal keratinocytes, mesenchymal stem cells from subcutaneous adipose, nasal mucosal cells, urothelial cells, intestinal epithelial cells, neutrophils, macrophages, and prostate, breast and alveolar epithelial cells, BoNT/A can also elicit specific biological effects in dermal fibroblasts, sebocytes and vascular endothelial cells. The reported non-traditional applications of BoNT in dermatologic conditions include hyperhidrosis, Hailey-Hailey disease, Darier disease, inversed psoriasis, aquagenic palmoplantar keratoderma, pachyonychia congenita, multiple eccrine hydrocystomas, eccrine angiomatous hamartoma, eccrine sweat gland nevi, congenital eccrine nevus, Raynaud phenomenon and cutaneous leiomyomas. Experimental studies demonstrated BoNT/A ability to protect skin flaps, facilitate wound healing, decrease thicknesses of hypertrophic scars, produce an anti-aging effect, and improve a mouse model of psoriasiform dermatitis. Furthermore, experimental studies also have revealed extracutaneous effects of BoNT arising from its anti-inflammatory and anti-cancer properties. Therefore, it is clear that BoNTs have a much wider zone of influence than originally understood, and that these ubiquitous events are based on individual cellular responses to the cholinergic impacts of BoNTs, which represents fertile grounds for future studies that are highly likely to result in impactful discoveries.

This article is protected by copyright. All rights reserved.

Incentivized goodness

Abstract

It will be argued that humans have a rational self-interest in voluntarily opting to subject themselves to moral bioenhancement. This interest is based on the fact that goodness appears to be conducive to happiness. Those who understand that will be more inclined to opt for safe and effective moral bioenhancement technologies that have the potential to augment our motivation to become better. The more people decide to follow this path, the likelier it is that states will adopt suitable policies that incentivize moral bioenhancement. Hence, goodness, happiness and state incentivized moral bioenhancement can operate in a circularly supportive fashion.

Epstein-Barr Virus-Positive Diffuse Large B-Cell Lymphoma Presenting with Vaginal Sloughing and Ulcerated Skin Nodule

Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma (NHL) with subtypes that can be distinguished on the basis of clinical, immunophenotypic, morphologic, and molecular characteristics. The genital tract as a primary site for NHL is very rare (1).

High calcium enhances the expression of double-stranded RNA sensors and antiviral activity in epidermal keratinocytes

Abstract

Double-stranded RNA (dsRNA) sensors including TLR3, MDA5, and RIG-I are expressed in epidermal keratinocytes, and play an important immunological role by enhancing various innate and adaptive immune responses. Although the role of elevated extracellular calcium concentration in keratinocyte differentiation is well understood, the effect of high calcium on dsRNA sensors is not well studied.

We investigated alterations in dsRNA sensor expression and antiviral activity induced by a high extracellular concentration of calcium in epidermal keratinocytes. Normal human epidermal keratinocytes (NHEKs) were stimulated with high calcium and/or synthetic dsRNA, poly (I:C). TLR3, IFIH1 (MDA5), and DDX58 (RIG-I) expression were measured via qPCR, and IFN-β and human beta defensin 2 (HBD2) levels were measured using ELISA. TLR3 localization was evaluated with immunocytofluorescence. Antiviral activity was quantified with virus plaque assays using herpes simplex virus type-1 (HSV-1). High calcium significantly upregulated mRNA expression of TLR3, IFIH1, and DDX58 in NHEKs. In addition, high calcium significantly enhanced poly (I:C)-induced anti-HSV-1 activity in NHEKs. The anti-viral molecule, HBD2 but not IFN-β induction by poly (I:C) was enhanced by high calcium.

Our findings indicate that high levels of extracellular calcium enhance the expression of dsRNA sensors and augment antiviral activity in epidermal keratinocytes.

This article is protected by copyright. All rights reserved.

Development of an asporogenic Bacillus cereus strain to improve keratinase production in exponential phase by switching sigmaH on and sigmaF off

Abstract

Many bacteria, including the genus Bacillus are able to produce proteases (keratinase). In Bacillus, proteases are produced in the stationary phase and initial stages of sporulation. Protease production is coordinated with sporulation in which expression of various genes by different sigma factors manages the transition from exponential to the stationary phase. In the present study the sigma-F gene of an indigenous Bacillus cereus strain, which is involved in transcription of maintaining sporulation genes was deleted. Meanwhil the sigma-H, which its product activates the genes that function in the zero phase of sporulation and inhibits suppression of protease production, and spo0B genes were expressed in the exponential phase under the control of a sucrose inducible promoter from Bacillus sacPA operon. For the first time, an asporogenic strain of B. cereus was generated that produced higher keratinase (390 U in compare to the 198 U of wild strain) and protease (450 U in compare to the 290 U of wild strain) activities in the exponential growth phase by induction with sucrose. The new strain is promising for production of keratinase for degradation of feather waste to produce feather meal for poultry feed and decrease environmental pollution of poultry industry.

Hormonal contraceptives and risk of ischemic stroke in women with migraine: a consensus statement from the European Headache Federation (EHF) and the European Society of Contraception and Reproductive Health (ESC)

Several data indicate that migraine, especially migraine with aura, is associated with an increased risk of ischemic stroke and other vascular events. Of concern is whether the risk of ischemic stroke in migra...

Immunohistochemical markers informing the diagnosis of sebaceous carcinoma and its distinction from its mimics: Adipophilin and Factor XIIIa to the rescue?

In this issue of the Journal of Cutaneous Pathology, Tjarks et al. present a study that advances our understanding of the diagnosis of sebaceous neoplasms (in particular, sebaceous carcinoma) and the lesions that mimic them (1).

Calciphylaxis with Pseudoxanthoma Elasticum-like Changes: A Case Series

BACKGROUND

Calciphylaxis and pseudoxanthoma elasticum (PXE) are rare, clinically distinct, disorders that share a common feature of cutaneous calcification that vary widely in their cutaneous presentation.

METHODS

We conducted a descriptive, retrospective review of biopsy specimens collected over a two-year period. Only specimens with a histologic and clinical diagnosis of calciphylaxis were included in the review. Specimens were then histologically examined for features of pseudoxanthoma elasticum in the dermis and/or subcutaneous fat, utilizing hematoxylin and eosin staining. Von Kossa and Verhoeff-Van Gieson special stains were also performed to examine calcification and elastic fibers, respectively.

RESULTS

We reviewed 13 biopsy specimens from 9 patients with known clinical and histologic evidence of calciphylaxis, both uremic and non-uremic types. Upon reexamination, we found that 46.2% (n=6/13) of the specimens demonstrated concomitant PXE-like changes uniquely localized to the subcutaneous fat.

CONCLUSION

The presence of PXE-like changes in the subcutis may heighten suspicion for a diagnosis of calciphylaxis in the appropriate clinical setting and be helpful when classic histologic features are subtle or absent.

Folliculotropic mycosis fungoides presenting with a solitary lesion: clinicopathological features and long-term follow-up data in a series of nine cases

Folliculotropic mycosis fungoides (FMF) is a rare but distinct variant of mycosis fungoides (MF), histologically characterized by the presence of folliculotropic infiltrates, often with sparing of the epidermis, and clinically by the preferential involvement of the head and neck region.¹

Me and I Are Not Friends, Just Aquaintances: on Thought Insertion and Self-Awareness

Abstract

A group of philosophers suggests that a sense of mineness intrinsically contained in the phenomenal structure of all conscious experiences is a necessary condition for a subject to become aware of himself as the subject of his experiences i.e. self-awareness. On this view, consciousness necessarily entails phenomenal self-awareness. This paper argues that cases of delusions of thought insertion undermine this claim and that such a phenomenal feature plays little role in accounting for the most minimal type of self-awareness entailed by phenomenal consciousness. First, I clarify the main view endorsing this claim i.e. the Self-Presentational View of Consciousness and formulate the challenge from thought insertion. After, I offer a systematic evaluation of all the strategies used by the advocates of this view to deal with this challenge. Finally, I conclude that most of these strategies are unsatisfactory for they rest in unwarranted premises, imprecisions about the agentive nature of cognitive experiences, and especially, lack of distinction between the different ways in which subjects can become aware of their own thoughts.

Acknowledgment of Reviewers

Testicular torsion and reperfusion: evidences for biochemical and molecular alterations

Abstract

This study was done in order to determine the molecular and biochemical alterations following testicular torsion (TT) and torsion-reperfusion (TR). For this purpose, 54 male Wistar rats were divided into five groups as control group (n = 6) and experimental group subjected to 1, 2, 4, and 8 h unilateral left torsion induction (n = 12 in each group). After induction of TT, testicular samples were collected from each group (n = 6), and the other six rats of each group underwent the same period of reperfusion after TT and then were sampled. Histological changes, the mRNA and protein expression of heat shock protein-70 (Hsp70), and caspase-3 were examined using reverse transcriptase-PCR (RT-PCR) and immunohistochemistry, respectively. Testicular total antioxidant capacity (TAC), glutathione peroxidase (GSH-px), and malondialdehyde (MDA) levels were evaluated. The mRNA damage and DNA fragmentation were assessed. The TT and TR significantly reduced differentiation and spermiogenesis indices (p < 0.05). The TT- and TR-induced groups exhibited a severe reduction in Hsp70 expression as well as remarkable enhancement in caspase-3 expression. The TAC and GSH-px levels were decreased and the MDA content was increased in TT- and TR-induced groups. Finally, the TT and TR enhanced mRNA damage and DNA fragmentation. The TT- and TR-induced damaging oxidative stress, diminished Hsp70 expression, and enhanced caspase-3 mRNA and protein levels result in apoptosis following 1, 2, and 4 h. Whereas, following 8 h, TT and TR initiate the necrosis by inducing energy depletion as well as severe mRNA damage.

Taking Multiple Exposure Into Account Can Improve Assessment of Chemical Risks

Abstract

During work, operators may be exposed to several chemicals simultaneously. Most exposure assessment approaches only determine exposure levels for each substance individually. However, such individual-substance approaches may not correctly estimate the toxicity of 'cocktails' of chemicals, as the toxicity of a cocktail may differ from the toxicity of substances on their own. This study presents an approach that can better take into account multiple exposure when assessing chemical risks. Almost 30000 work situations, monitored between 2005 and 2014 and recorded in two French databases, were analysed using MiXie software. The algorithms employed in MiXie can identify toxicological classes associated with several substances, based on the additivity of the selected effects of each substance. The results of our retrospective analysis show that MiXie was able to identify almost 20% more potentially hazardous situations than identified using a single-substance approach. It therefore appears essential to review the ways in which multiple exposure is taken into account during risk assessment.

Seven years of clinical experience with the Yeast Traffic Light PNA FISH: assay performance and possible implications on antifungal therapy

Abstract

We evaluated the performance of Yeast Traffic Light PNA FISH (YTL PNA FISH) in identification of Candida spp. from blood cultures. A total of 200 new episodes of candidemia were analysed prospectively. The YTL PNA FISH results were reported to the clinicians and data on antifungal therapy was documented. In total, there were 164/200 (82%) positive blood culture bottles with monomicrobial growth. Coverage of monomicrobial yeasts was 150/164 (91.5%). YTL PNA FISH could identify 23/24 (95.8%) Candida spp. in bottles with concomitant growth of bacteria and one yeast. Growth of two or more different yeasts was observed in 12/200 (6%) blood culture bottles and the method could identify all yeasts in 8/12 (66.7%). Data on antifungal treatment was available for 181/200 patients (90.5%). In 132/137 (96.4%) samples from patients without antifungal treatment, YTL PNA FISH could identify the Candida spp. or gave a negative result for yeasts not included in panel, and based on the result guide appropriate antifungal therapy the same day when the blood culture bottle signaled positive. The present study shows that YTL PNA FISH is a rapid, reliable diagnostic method which significantly reduces time delay for choice of appropriate antifungal therapy for critically ill patients.

This article is protected by copyright. All rights reserved.

Undiagnosed Diabetes Mellitus in Community-Acquired Pneumonia: A Prospective Cohort Study

Abstract

Background

Diabetes mellitus is an important risk factor for community-acquired pneumonia, whereas the prevalence of undiagnosed diabetes mellitus and prediabetes in patients with community-acquired pneumonia is largely unknown. We aimed to determine the prevalence of prediabetes, undiagnosed diabetes mellitus, and risk factors associated with undiagnosed diabetes mellitus in a large European community-acquired pneumonia cohort.

Methods

This was a multicenter prospective cohort study of hospitals and private practices in Germany and Austria encompassing 1961 adults with community-acquired pneumonia included in the German Community-Acquired Pneumonia Competence Network (CAPNETZ) study between 2007 and 2014. The prevalence of undiagnosed diabetes mellitus and prediabetes was estimated based on hemoglobin A1c measurements. Logistic regression was used to assess risk factors for undiagnosed diabetes mellitus.

Results

Fifteen percent of patients had known diabetes mellitus. Among patients without known diabetes mellitus, 5.0% had undiagnosed diabetes mellitus and 37.5% had prediabetes. Male sex (odds ratio [OR], 2.45 [95% confidence interval {CI}, 1.35–4.45]), body mass index ≥25 kg/m² (OR, 2.64 [95% CI, 1.48–4.72]), and hyperglycemia at admission (6–11 mM: OR, 2.93 [95% CI, 1.54–5.60] and ≥11 mM: OR, 44.76 [95% CI, 17.58–113.98]) were associated with undiagnosed diabetes mellitus. Patients with undiagnosed diabetes mellitus had a higher 180-day mortality rate compared to patients without diabetes mellitus (12.1% vs 3.8%, respectively; P = .001).

Conclusions

Undiagnosed diabetes mellitus was prevalent among community-acquired pneumonia. Male sex, overweight, and hyperglycemia at admission were associated with undiagnosed diabetes mellitus. The long-term mortality among patients with undiagnosed diabetes mellitus was high compared to patients without diabetes mellitus.

Dermatological and environmental toxicological impact of the sunscreen ingredient oxybenzone/benzophenone-3

Summary

Oxybenzone (Benzophenone-3) is an emerging human and environmental contaminant used in sunscreens and personal care products to help minimize the damaging effects of ultraviolet radiation. The Center for Disease Control fourth national report on human exposure to environmental chemicals demonstrated that approximately 97% of the people tested have oxybenzone present in their urine, and independent scientists have reported various concentrations in waterways and fish worldwide. Oxybenzone can also react with chlorine, producing hazardous by-products that can concentrate in swimming pools and wastewater treatment plants. Moreover, adverse reactions could very well be increased by the closed loop of ingesting fish contaminated with oxybenzone and/or washing the ingredient off our bodies and having it return in drinking water as treatment plants do not effectively remove the chemical as part of their processing protocols. In humans, oxybenzone has been reported to produce contact and photocontact allergy reactions, implemented as a possible endocrine disruptor and has been linked to Hirschsprung's disease. Environmentally, oxybenzone has been shown to produce a variety of toxic reactions in coral and fish ranging from reef bleaching to mortality. Lastly, with the rise in skin cancer rates and the availability of more effective sunscreen actives such as micronized zinc oxide and titanium dioxide, serious doubts about the relative prevention benefit of personal care products containing oxybenzone must be raised and compared with the potential negative health and environmental effects caused by the accumulation of this and other chemicals in the ecosystem.

The pathogenesis of cutaneous squamous cell carcinoma in organ transplant recipients

Summary

The pathogenesis of keratinocyte carcinoma following organ transplantation is multifactorial, and recent evidence suggests a complex and often synergistic interplay between the carcinogenic effects of ultraviolet radiation, compromised immune surveillance, direct pro- and anticarcinogenic effects of drugs, oncogenic viruses (in particular, beta-genus human papillomaviruses) and host genetic susceptibility factors. We present an overview of those factors for which there is currently the most convincing evidence and highlight important gaps in our knowledge. In particular, a clear understanding of the interdependence and relative contributions of these co-factors is currently lacking, yet has important implications for rational development of clinically relevant biomarkers and targeted strategies for treatment and prevention of post-transplant keratinocyte cancers.

Research gaps in the management and prevention of cutaneous squamous cell carcinoma in organ transplant recipients

Summary

Although tremendous progress has been made in recent years in skin cancer care for organ transplant recipients, significant gaps remain in data-driven clinical guidelines, particularly for the treatment and prevention of cutaneous squamous cell carcinoma (cSCC), the most common malignancy among this population. In this review, we aim to summarize current knowledge around the management of cSCC and highlight the most significant gaps in knowledge that continue to pose challenges in the delivery of skin cancer care for organ transplant recipients. We suggest future directions for research that will bridge existing gaps and establish evidence-driven guidelines for primary prevention, screening and treatment of cSCC in this high-risk patient population.

TRPA1 channel participates in tacrolimus-induced pruritus in a chronic contact hypersensitivity murine model

Tacrolimus ointment (FK506), a calcineurin inhibitor, is a widely used topical medication in atopic dermatitis (AD) [1]. Although it is effective, pruritus and stinging sensation are common, particularly in AD patients [1]. Mediators of mast cells such as histamine have been suggested to be involved in the pathogenesis of tacrolimus-related pruritus by binding to the corresponding receptors on sensory nerve fibers [2]. Histamine acts on histamine receptors (HR) and activates the downstream transduction channel transient receptor potential V1 (TRPV1), which induces histamine-dependent pruritus [3].

Objective assessment of colonoscope manipulation skills in colonoscopy training

Abstract

Objective

Manipulation of the colonoscope is a technical challenge for novice clinicians which is best learned in a simulated environment. It involves the coordination of scope tip steering with scope insertion, using a rotated image as reference. The purpose of this work is to develop and validate a system which objectively assesses colonoscopy technical skills proficiency in an arbitrary training environment, allowing novices to assess their technical proficiency prior to real patient encounters.

Methods

We implemented a motion tracking setup to objectively analyze and assess the way operators perform colonoscopies, including an analysis of wrist and elbow joint motions. Subsequently, we conducted a validation study to verify whether our motion analysis could discriminate novice colonoscopists from experts. Participants navigated a wooden bench-top model using a standard colonoscope while their motions were tracked.

Results

The developed motion tracking setup allowed colonoscopists of varying levels of proficiency to have their colonoscope manipulation assessed, and was able to be operated by a trained non-technical operator. Novice operators had significantly greater median times (101.5 vs. 31.5 s) and number of hand movements (62.0 vs. 21.5) than experts. Experts, however, spent a significantly greater proportion of time in extreme ranges of wrist and elbow joint motion than novices.

Conclusion

We have developed and implemented a hand and joint motion analysis system that is able to discriminate novices from experts based on objective measures of motion. These metrics could, thus, serve as proxies for technical proficiency during training.

Releasing the “GENI”: integrating authentic microbial genomics research into the classroom through GENI-ACT

Abstract

The integration of genomics research into the undergraduate biology curriculum provides students with the opportunity to become familiar with bioinformatics tools and answer original research questions. Our purpose with this research project was to upscale the research experience through integration with classroom experience giving students access to authentic research projects. Students annotated 60 predicted ABC genes of Methanothermobacter thermautotrophicus and Methanobacterium sp. SWAN-1, and they were required to present a research poster to demonstrate their understanding of the project. During this research project a number of tests, assessments and surveys were conducted to assess familiarity with technical and conceptual understanding of genome annotation, satisfaction with annotation instruction, gain in bioinformatics research skills, scientific communications skills and increased student interest in research. We found that students gained significant skills in bioinformatics, specifically genome annotation skills and also gained confidence in their abilities to carry out scientific research. As a result of this authentic undergraduate research experience under-represented students were motivated to pursue future careers in STEM fields.

Plasmids can transfer to Clostridium difficile CD37 and 630Δ erm both by a DNase resistant conjugation-like mechanism and a DNase sensitive mechanism

Abstract

Broad host range conjugative plasmids that replicate in Escherichia coli have been widely used to mobilise smaller replicons, bearing their cognate origin of transfer (oriT) into a variety of organisms that are less tractable genetically, such as Clostridium (Clostridioides) difficile. In this work we demonstrated that the oriT region of pMTL9301 (derived from RK2) is not required for transfer between E. coli and C. difficile strains 630Δerm and CD37 and that this oriT-independent transfer is abolished in the presence of DNase when CD37 is the recipient. Transfer to the 630Δerm strain is DNase resistant even without an obvious oriT, when E. coli CA434 is used as a donor and is sensitive to DNase when E. coli HB101 is the donor.

Keeping education fresh—not just in microbiology

Abstract

Innovative practice from around the globe, addressing a range of recent educational themes and trends, was published in the FEMS Microbiology Letters virtual Thematic Issue 'Keeping Education Fresh' in October 2017. Its thought-provoking content is reviewed here to more directly facilitate reflections and discussions in the professional community. The focus is on best practice approaches when enhancing student engagement, how to adjust those to the diversity of learners, learning situations and infrastructures, and to a broad range of subjects. The need for authentic learning and to move away from didactic teaching is emphasized. The 'students as researchers' theme is featured e.g. in context of service learning. Creative approaches are presented such as using performing arts, popular culture and gamification. The development of interdisciplinary and intercultural competences, and the exploration of socioscientific themes and philosophical issues are considered. Revisions of curricula and programmes, reflective of educational advancements and sector drivers, are discussed from undergraduate to postgraduate and professional specialist level also in light of problem-based learning, interactive distance and on-campus learning, and even the legacy of Massive Open Online Courses. Such changes always require resources and skills, and carry risks. Yet, innovation is a risk worth taking to keep education fresh.

Microbial organic acid production as carbon dioxide sink

Abstract

Mixed-substrate conversions are an under-regarded option to fix carbon dioxide in significant amounts. In such a conversion, carbon dioxide together with one other carbon source such as glucose is converted to a single carbon product. With mixed-substrate conversions, it is possible to incorporate carbon dioxide into products with higher oxidation states than the co-substrate. Using abundant co-substrates such as glucose, glycerol or methanol, it is possible to produce organic acids anaerobically, using CO₂ both as an electron acceptor and as an additional carbon source. Here, we outline the thermodynamic feasibility to produce industrially important organic acids with this approach to provide guidance for future metabolic engineering endeavours.

Degradation of the recalcitrant oil spill components anthracene and pyrene by a microbially driven Fenton reaction

Abstract

Oil spill components include a range of toxic saturated, aromatic and polar hydrocarbons, including pyrene and anthracene. Such contaminants harm natural ecosystems, adversely affect human health and negatively impact tourism and the fishing industries. Current physical, chemical and biological remediation technologies are often unable to completely remove recalcitrant oil spill components, which accumulate at levels greater than regulatory limits set by the Environmental Protection Agency. In the present study, a microbially driven Fenton reaction, previously shown to produce hydroxyl (HO^•) radicals that degrade chlorinated solvents and associated solvent stabilizers, was also found to degrade source zone concentrations of the oil spill components, pyrene (10 μM) and anthracene (1 μM), at initial rates of 0.82 and 0.20 μM h⁻¹, respectively. The pyrene- and anthracene-degrading Fenton reaction was driven by the metal-reducing facultative anaerobe Shewanella oneidensis exposed to alternating aerobic and anaerobic conditions in the presence of Fe(III). Similar to the chlorinated solvent degradation system, the pyrene and anthracene degradation systems required neither the continual supply of exogenous H₂O₂ nor UV-induced Fe(III) reduction to regenerate Fe(II). The microbially driven Fenton reaction provides the foundation for the development of alternate ex situ and in situ oil and gas spill remediation technologies.

Bioactive and biocontrol potential of endophytic fungi associated with Brugmansia aurea Lagerh

Abstract

This study describes 32 fungal endophytes isolated from different tissues of Brugmansia aurea Lagerh. Each fungal strain was authenticated based on internal transcribed spacer rDNA sequence. Phylogenetic analysis showed that these fungi are distributed in three classes, seven orders and 12 genera. The dichloromethane extracts of endophytic strains were screened for anticancer and antimicrobial activity. Anticancer activity of extracts against human cancer cell lines revealed that 50% strains are active with IC₅₀ < 10 μg/mL. While analysing antimicrobial potential against both Gram-positive and Gram-negative bacteria, 56.25% endophytic strains displayed activity at least against one of the tested human pathogenic bacteria with minimum inhibitory concentration of 12.5–100 μg/mL. In vitro antagonistic activity of endophytes was analysed against Sclerotinia sp., Aspergillus fumigatus, Fusarium solani, A. flavus and F. oxysporum pathogen. The broad-spectrum anti-phytopathogenic activity was shown by R2BA. The presence of ketoacyl synthase domain of polyketide synthase gene and high degree of bioactivity shown by endophytic fungi suggested that they have potential to produce therapeutic compounds and to serve as biocontrol agent.

The Rural Plastic Surgery Residency Rotation: Rising to Meet a National Crisis

No abstract available

Plastic Surgery 2017: The Abstract Supplement

No abstract available

Disseminierte rotbräunliche Papeln bei einem jungen Mann

Extracellular small heat shock proteins: exosomal biogenesis and function

Abstract

Small heat shock proteins (sHsps) belong to the family of heat shock proteins (Hsps): some are induced in response to multiple stressful events to protect the cells while others are constitutively expressed. Until now, it was believed that Hsps, including sHsps, are present inside the cells and perform intracellular functions. Interestingly, several groups recently reported the extracellular presence of Hsps, and sHsps have also been detected in sera/cerebrospinal fluids in various pathological conditions. Secretion into the extracellular milieu during many pathological conditions suggests additional or novel functions of sHsps in addition to their intracellular properties. Extracellular sHsps are implicated in cell-cell communication, activation of immune cells, and promoting anti-inflammatory and anti-platelet responses. Interestingly, exogenous administration of sHsps showed therapeutic effects in multiple disease models implying that extracellular sHsps are beneficial in pathological conditions. sHsps do not possess signal sequence and, hence, are not exported through the classical Endoplasmic reticulum-Golgi complex (ER-Golgi) secretory pathway. Further, export of sHsps is not inhibited by ER-Golgi secretory pathway inhibitors implying the involvement of a nonclassical secretory pathway in sHsp export. In lieu, lysoendosomal and exosomal pathways have been proposed for the export of sHsps. Heat shock protein 27 (Hsp27), αB-crystallin (αBC), and Hsp20 are shown to be exported by exosomes. Exosomes packaged with sHsps have beneficial effects in in vivo disease models. However, secretion mechanisms and therapeutic use of sHsps have not been elucidated in detail. Therefore, this review aimed at highlighting the current understanding of sHsps (Hsp27, αBC, and Hsp20) in the extracellular medium.

Views of Dermatopathologists about Clonality Assays in the Diagnosis of Cutaneous T cell and B cell Lymphoproliferative Disorders

Background

Appropriate use criteria have been developed for many tests using expert judgment, evidence-based practice, and clinical experience. In this context, the opinions of practitioners about clonality assays in various clinical scenarios where cutaneous lymphoma is suspected are reported.

Methods

An Appropriate Use Criteria Task Force sponsored by the American Society of Dermatopathology (ASDP) synthesized clinical scenarios for cutaneous lymphoproliferative disorders (LPD). We conducted, summarized, and presented a relevant literature search to an audience of 144 dermatopathologists with a variety of practice experiences at the 53^rd Annual Meeting of the ASDP in Chicago, IL.

Results

27 clinical scenarios for lymphoproliferative disorders (13 T cell and 14 B cell) were defined. 40 relevant studies for T-cell receptor gene clonality assays and 20 relevant studies for IgH/IgK clonality assays were identified. Audience response data from participating dermatopathologists reflected a wide variety of approaches to the application of clonality assays in the evaluation of LPDs, based on practice setting, personal experience and test availability.

Conclusions

Our clinical scenario analysis and literature review revealed well supported clinical scenarios and identified opportunities for additional research to further define the utility of clonality assays in some clinical scenarios.

Soforttypreaktionen auf Protonenpumpeninhibitoren am Beispiel von Pantoprazol und Omeprazol

Zusammenfassung

Protonenpumpeninhibitoren (PPIs) gehören zu den am häufigsten eingenommenen Medikamenten weltweit. Allergien auf diese Substanzgruppe sind selten, können aber zu schweren Soforttypreaktionen führen. Insbesondere treten auch Kreuzreaktionen zwischen den verschiedenen PPIs auf. In dieser Fallserie werden 4 Patienten mit Soforttypreaktionen auf die Protonenpumpenhemmer Pantoprazol und/oder Omeprazol beschrieben.

In the Literature

News

Cover

Recurrent High Fever Due to Intestinal Bacteria-Associated Bacteremia

(See pages 1764–5 for the Answer to the Photo Quiz.)

2017 HIV Medicine Association of Infectious Diseases Society of America Clinical Practice Guideline for the Management of Chronic Pain in Patients Living With Human Immunodeficiency Virus

Abstract

Pain has always been an important part of human immunodeficiency virus (HIV) disease and its experience for patients. In this guideline, we review the types of chronic pain commonly seen among persons living with HIV (PLWH) and review the limited evidence base for treatment of chronic noncancer pain in this population. We also review the management of chronic pain in special populations of PLWH, including persons with substance use and mental health disorders. Finally, a general review of possible pharmacokinetic interactions is included to assist the HIV clinician in the treatment of chronic pain in this population.It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. The Infectious Diseases Society of American considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.

Recurrent High Fever due to Intestinal Bacteria-Associated Bacteremia

(See page 1763 for the Photo Quiz.)

Evolving Understanding of the Causes of Pneumonia in Adults, With Special Attention to the Role of Pneumococcus

Abstract

Before 1945, Streptococcus pneumoniae caused more than 90% of cases of pneumonia in adults. After 1950, the proportion of pneumonia caused by pneumococcus began to decline. Pneumococcus has continued to decline; at present, this organism is identified in fewer than fewer10%–15% of cases. This proportion is higher in Europe, a finding likely related to differences in vaccination practices and smoking. Gram-negative bacilli, Staphylococcus aureus, Chlamydia, Mycoplasma, and Legionella are each identified in 2%–5% of patients with pneumonia who require hospitalization. Viruses are found in 25% of patients, up to one-third of these have bacterial coinfection. Recent studies fail to identify a causative organism in more than 50% of cases, which remains the most important challenge to understanding lower respiratory infection. Our findings have important implications for antibiotic stewardship and should be considered as new policies for empiric pneumonia management are developed.

Pneumonia Mortality in Children Aged <5 Years in 56 Countries: A Retrospective Analysis of Trends from 1960 to 2012

Abstract

Background

Pneumonia is now the second leading cause of death for children aged <5 years worldwide. However, analyses of the long-term evolution of under-5 mortality from pneumonia are still scarce in the literature. We aimed to explore long-term trends of under-5 mortality from pneumonia in 56 countries from 1960 to 2012.

Methods

Data on under-5 mortality from pneumonia were extracted from the World Health Organization mortality database. Long-term trends were assessed for 56 countries and for 4 national income transition groups. We also used joinpoint regression analysis to detect distinct period segments of long-term trends and estimate the annual percent of changes of each period segment.

Results

The average mortality rate from pneumonia for children aged 0–4 years in 56 countries declined from 163.0 per 100000 children (95% confidence interval [CI], 119.4 to 212.8) in 1960 to 9.9 per 100000 children (95% CI, 6.4 to 13.4) in 2012, with an average annual percent of change of −5.6% (95% CI, −7.2% to −3.9%). The temporal trends of childhood mortality were different between national income transition groups.

Conclusions

Our findings suggest a striking overall downward trend in under-5 mortality from pneumonia between 1960 and 2012. However, the rate and absolute terms of decline differ by national income transition group. These variable patterns between national income transition groups may inform further intervention setting and priority setting.

2017 HIVMA of IDSA Clinical Practice Guideline for the Management of Chronic Pain in Patients Living With HIV

Abstract

Pain has always been an important part of human immunodeficiency virus (HIV) disease and its experience for patients. In this guideline, we review the types of chronic pain commonly seen among persons living with HIV (PLWH) and review the limited evidence base for treatment of chronic noncancer pain in this population. We also review the management of chronic pain in special populations of PLWH, including persons with substance use and mental health disorders. Finally, a general review of possible pharmacokinetic interactions is included to assist the HIV clinician in the treatment of chronic pain in this population.It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. The Infectious Diseases Society of American considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.

Assessment of Efficacy and Safety of Arterolane Maleate–Piperaquine Phosphate Dispersible Tablets in Comparison With Artemether-Lumefantrine Dispersible Tablets in Pediatric Patients With Acute Uncomplicated Plasmodium falciparum Malaria: A Phase 3, Randomized, Multicenter Trial in India and Africa

Abstract

Background

Administration of artemisinin-based combination therapy (ACT) to infant and young children can be challenging. A formulation with accurate dose and ease of administration will improve adherence and compliance in children. The fixed-dose combination dispersible tablet of arterolane maleate (AM) 37.5 mg and piperaquine phosphate (PQP) 187.5 mg can make dosing convenient in children.

Methods

This multicenter (India and Africa), comparative, parallel-group trial enrolled 859 patients aged 6 months to 12 years with Plasmodium falciparum malaria. Patients were randomized in a ratio of 2:1 to AM-PQP (571 patients) once daily and artemether-lumefantrine (AL) (288 patients) twice daily for 3 days and followed for 42 days.

Results

The cure rate (ie, polymerase chain reaction–corrected adequate clinical and parasitological response) in the per-protocol population at day 28 was 100.0% and 98.5% (difference, 1.48% [95% confidence interval {CI}, .04%–2.91%]) in the AM-PQP and AL arms, respectively, and 96.0% and 95.8% (difference, 0.14% [95% CI, –2.68% to 2.95%]) in the intention-to-treat (ITT) population. The cure rate was comparable at day 42 in the ITT population (AM-PQP, 94.4% vs AL, 93.1%). The median parasite clearance time was 24 hours in both the arms. The median fever clearance time was 6 hours in AM-PQP and 12 hours in the AL arm. Both the treatments were found to be safe and well tolerated. Overall, safety profile of both the treatments was similar.

Conclusions

The efficacy and safety of fixed-dose combination of AM and PQP was comparable to AL for the treatment of uncomplicated P. falciparum malaria in pediatric patients.

Clinical Trials Registration

CTRI/2014/07/004764.

Empiric Therapy With Carbapenem-Sparing Regimens for Bloodstream Infections due to Extended-Spectrum β-Lactamase–Producing Enterobacteriaceae: Results From the INCREMENT Cohort

Abstract

Background

There is little information about the efficacy of active alternative drugs to carbapenems except β-lactam/β-lactamase inhibitors for the treatment of bloodstream infections (BSIs) due to extended-spectrum β-lactamase–producing Enterobacteriaceae (ESBL-E). The objective of this study was to assess the outcomes of patients with BSI due to ESBL-E who received empiric therapy with such drugs (other active drugs [OADs]) or carbapenems.

Methods

A multinational retrospective cohort study of patients with BSI due to ESBL-E who received empiric treatment with OADs or carbapenems was performed. Cox regression including a propensity score for receiving OADs was performed to analyze 30-day all-cause mortality as main outcome. Clinical failure and length of stay were also analyzed.

Results

Overall, 335 patients were included; 249 received empiric carbapenems and 86 OADs. The most frequent OADs were aminoglycosides (43 patients) and fluoroquinolones (20 patients). Empiric therapy with OADs was not associated with mortality (hazard ratio [HR], 0.75; 95% confidence interval [CI], .38–1.48) in the Cox regression analysis. Propensity score–matched pairs, subgroups, and sensitivity analyses did not show different trends; specifically, the adjusted HR for aminoglycosides was 1.05 (95% CI, .51–2.16). OADs were neither associated with 14-day clinical failure (adjusted odds ratio, 0.62; 95% CI, .29–1.36) nor length of hospital stay.

Conclusions

We were unable to show that empiric treatment with OAD was associated with a worse outcome compared with carbapenems. This information allows more options to be considered for empiric therapy, at least for some patients, depending on local susceptibility patterns of ESBL-E.

Short-term Peripheral Venous Catheter–Related Bloodstream Infections: A Systematic Review

Abstract

Short-term peripheral venous catheters (PVCs) are commonly used in healthcare settings. To determine the magnitude of bloodstream infections (BSIs) related to their use, PubMed, article bibliographies, and the authors' library were searched for pertinent articles. The incidence of PVC-related BSIs was 0.18% among 85063 PVCs. Short-term PVCs accounted for a mean of 6.3% and 23% of nosocomial BSIs and nosocomial catheter-related BSIs, respectively. Prolonged dwell time and catheter insertion under emergent conditions increased risk of PVC-related bloodstream infection (PVCR-BSI). If approximately 200 million PVCs are successfully inserted into adult patients each year in the United States, there may be many PVCR-BSIs occurring yearly. Clinicians should obtain blood cultures in patients with evidence of PVC infection and systemic symptomatology such as fever, carefully inspect the PVC insertion site in bacteremic or fungemic patients, and remove PVCs associated with localized infection with or without associated BSI.

Treatment of Early Syphilis

To the Editor—Andrade and colleagues addressed an important clinical issue in their randomized study of 1 vs 3 penicillin injections for human immunodeficiency virus (HIV)–infected patients with early syphilis [1]. However, there remain several questions. First, the estimated difference in treatment success between the 2 arms was substantial (95% vs 75%), resulting in the calculation of a moderate sample size of 108 patients for the study. However, the literature does not give any evidence that 20% of differences in the outcome have to be expected between the enhanced vs standard group [2]. Nevertheless, the authors were not able to fully enroll the study and finally closed on only 64 patients. The allocation of patients to the 2 study arms was not sufficiently balanced. Fifty-five percent were treated with 1 penicillin injection and 45% with 3 penicillin injections. Furthermore, the geometric means of the rapid plasma reagin (RPR) titers at baseline were not well balanced (116 vs 78, respectively). Both the sample size calculations and the imbalances in study patients severely impact the clinical significance of the study. Moreover, the response rates after 12 months differed substantially between groups (80% vs 93%). As the conception for the trial was not a noninferiority study, the results do not allow the conclusion that 1 injection of penicillin is not inferior to 3 injections. Taken together, we cannot agree with the authors' conclusion that a larger study would only detect a small but clinically insignificant difference in treatment outcome.

Redefining Human Immunodeficiency Virus (HIV) Preexposure Prophylaxis Failures

To the Editor—Failures of daily oral human immunodeficiency virus (HIV) preexposure prophylaxis (PrEP) with tenofovir disoproxil fumarate/emtricitabine are rare, with only 3 HIV seroconversions documented among patients adherent to PrEP at the time of infection [1–3]. However, PrEP failures could be defined more broadly as HIV infections that occur at any point along the PrEP continuum of care [4]. Here, we describe HIV infections among individuals who sought or were referred for PrEP within the Kaiser Permanente Northern California (KPNC) healthcare system.

Uptake of Antibiotic Stewardship Programs in US Acute Care Hospitals: Findings From the 2015 National Healthcare Safety Network Annual Hospital Survey

Abstract

To assess uptake of the Centers for Disease Control and Prevention's Core Elements of Hospital Antibiotic Stewardship Programs, we analyzed stewardship practices as reported in the 2015 National Healthcare Safety Network's Annual Hospital Survey. Hospital uptake of all 7 core elements increased from 40.9% in 2014 to 48.1% in 2015.

Successful Therapy of a Multidrug-Resistant Extended-Spectrum β-Lactamase–Producing and Fluoroquinolone-Resistant Salmonella enterica Subspecies enterica Serovar Typhi Infection Using Combination Therapy of Meropenem and Fosfomycin

Abstract

We report a traveler who acquired a Salmonella enterica subspecies enterica serovar Typhi strain with resistance against β-lactams, cephalosporins (extended-spectrum β-lactamase–producing type SHV-12), and quinolones (plasmid-mediated quinolone resistance gene qnrB7). After clinical deterioration using meropenem monotherapy, treatment success was achieved after commencement of fosfomycin in conjunction with high-dose meropenem. The case illustrates clinical challenges of multidrug-resistant S. Typhi.

Performance of Rapid Diagnostic Testing in Patients with Suspected Malaria in Cambodia, a Low-Endemicity Country Aiming for Malaria Elimination

To the Editor—We read with interest the article by Ranadive et al [1] assessing the performance of malaria rapid diagnostic testing (RDT) vs polymerase chain reaction (PCR) in Swaziland, a low-transmission country aiming at elimination. Through a large regional data set collected from 37 health facilities over 2 years, they demonstrated the poor sensitivity of RDT (First Response Malaria Ag P. falciparum HRP-2 Detection Rapid Card Test, Premier Medical) for Plasmodium falciparum (Pf) diagnosis (51.7%), due to a high proportion of low-density infections among symptomatic subjects (54/162 [33.3%]), along with a low positive predictive value (PPV) (67.3% for all samples and 62.3% for ≥100 parasites/µL samples), due to the high proportion of false positivity (32.4%). To overcome some of the limitations of the study (eg, the decision to include only 10% of negative RDTs samples), the authors called for more inclusive analyses.

Reproductive Aging and Hepatic Fibrosis Progression in Human Immunodeficiency Virus/Hepatitis C Virus–Coinfected Women

Abstract

Background

Severity of hepatic fibrosis is greater in postmenopausal than in premenopausal women, perhaps owing to protective effects of estrogens. However, prior studies of estrogen and liver fibrosis lack serial fibrosis measures, adjustment for age, or longitudinal observations in coinfected populations.

Methods

In a longitudinal cohort of women coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV), we assessed fibrosis progression across reproductive age, using validated serum fibrosis markers, aminotransferase platelet ratio index (APRI) and fibrosis 4 (FIB-4). Fibrosis rate was evaluated within each woman as she transitioned from pre- to postmenopause, defined by a biomarker of ovarian function.

Results

The median follow-up (n = 405) was 9.1 years (interquartile range, 5.0–15.2 years), with a median menopausal age of 49 years (47–52 years). When fully controlled for chronologic aging, the fibrosis progression rate was accelerated during perimenopause, as shown using FIB-4 (0.12 units per year faster than during premenopause; 95% confidence interval [CI], .02–.21; P = .01) and APRI (0.05 units per year faster; −.002 to .09; P = .06). Accelerated fibrosis was also observed during postmenopause compared with premenopause, for FIB-4 (0.14 units per year faster; 95% CI, −.01 to .29; P = .07) and APRI (0.07 units per year faster; −.003 to .15; P = .06). Accelerated fibrosis in perimenopause persisted after adjustment for Hispanic ethnicity, antiretroviral use, and alcohol (0.10 FIB-4 units per year faster than during premenopause; 95% CI, .008–.20; P = .03).

Conclusions

In HIV/HCV-coinfected women, hepatic fibrosis accelerates with reproductive aging. Accelerated fibrosis begins in perimenopause, highlighting a previously unrecognized group of women at increased risk for advanced fibrosis and associated complications. Longitudinal analyses of fibrosis rates across reproductive age should be conducted in non–HCV-related liver diseases, given potential implications in a broader spectrum of women.

Anti-infective Acquisition Costs for a Stewardship Program: Getting to the Bottom Line

Abstract

Background

Though antimicrobial stewardship programs (ASPs) are in place for patient safety, financial justification is often required. In 2016, the Infectious Diseases Society of America (IDSA) recommended that anti-infective costs be measured by patient-level administration data normalized for patient census. Few publications use this methodology. Here, we aim to compare 3 methods of drug cost analysis during 3 phases of an ASP as an example of this recommendation's implementation.

Methods

At a freestanding pediatric hospital, we retrospectively assessed anti-infective cost using pharmacy purchasing data, patient-level administration data from the electronic medical record (EMR), and patient-level administration data from the Pediatric Hospital Information Systems (PHIS) database, all normalized to patient census. Costs pre-ASP, while planning the ASP, and post-ASP were then compared for each method.

Results

Significant differences in costs between the methods were observed. Pharmacy purchasing endorsed minimal financial benefit (decrease planning to post-ASP of $590 dollars per 1000 patient-days), while the EMR and PHIS data endorsed a decrease of $12785 and $21380 per 1000 patient-days, respectively, for a total yearly cost savings of $54656 for pharmacy purchasing data, $1184336 for EMR data, and $2117522 for PHIS data.

Conclusions

Pharmacy purchasing data underestimated cost savings compared with EMR and PHIS data, while EMR and PHIS data were comparable in magnitude of savings. At Children's Hospital Colorado, savings justified the full cost of the ASP. EMR patient-level administration data, normalized to patient census, offers a readily available and standardized measure of anti-infective costs over time.

Public trust and ‘ethics review’ as a commodity: the case of Genomics England Limited and the UK’s 100,000 genomes project

Abstract

The UK Chief Medical Officer's 2016 Annual Report, Generation Genome, focused on a vision to fully integrate genomics into all aspects of the UK's National Health Service (NHS). This process of integration, which has now already begun, raises a wide range of social and ethical concerns, many of which were discussed in the final Chapter of the report. This paper explores how the UK's 100,000 Genomes Project (100 kGP)—the catalyst for Generation Genome, and for bringing genomics into the NHS—is negotiating these ethical concerns. The UK's 100 kGP, promoted and delivered by Genomics England Limited (GEL), is an innovative venture aiming to sequence 100,000 genomes from NHS patients who have a rare disease, cancer, or an infectious disease. GEL has emphasised the importance of ethical governance and decision-making. However, some sociological critique argues that biomedical/technological organisations presenting themselves as 'ethical' entities do not necessarily reflect a space within which moral thinking occurs. Rather, the 'ethical work' conducted (and displayed) by organisations is more strategic, relating to the politics of the organisation and the need to build public confidence. We set out to explore whether GEL's ethical framework was reflective of this critique, and what this tells us more broadly about how genomics is being integrated into the NHS in response to the ethical and social concerns raised in Generation Genome. We do this by drawing on a series of 20 interviews with individuals associated with or working at GEL.

A novel technique for clinical examination of buried head and neck free flaps

Abstract

Monitoring buried flaps within the head and neck presents a unique challenge to the microsurgeon. We conducted an independent review of the literature using Medline, PubMed and Q Read performed up to February 2017. This showed that head and neck free flaps have contemporary success rates of between 92 and 98%, which is similar to rates reported for all types of flaps (90–98%). Studies looking specifically at buried free flaps were scarce, with success rates (90–98%) precisely mirroring those of studies looking at all flaps. In studies in which both buried and non-buried flaps were stratified, buried flaps did have lower rates of success (93.5 vs. 98.2% and 93 vs. 98%). While overall success rates may have been similar, lower rates of salvage were clearly shown for buried flaps. Salvage rates ranged from 0 to 75%. The highest rate was achieved using implantable Doppler, which has been shown to increase salvage rates by up to 21%. However, this technique is associated with significant rates of false positives, which have been shown to be between 8 and 40.4% Another monitoring technique in use for buried flaps was externalised monitoring segments, which has been associated with higher rates of pharyngeal fistula in head and neck reconstruction. In this article, we present a variation of the Acland's empty-and-refill test which may be used to monitor buried flaps that have a venous anastomosis in an end-to-end fashion to the external jugular vein.

Level of Evidence: Level IV, diagnostic study.

42 Annual Congress of AOMSI Nagpur 16–18 Nov 2017

Panorama Dermatologische Praxis

Antibiotic stewardship: a European perspective

Abstract

Antibiotic stewardship programmes, which are a set of interventions aiming at prescribing antibiotics appropriately and responsibly, are one of the key strategies to tackle the current worldwide bacterial resistance crisis. We will present here some examples of international and national initiatives, with a focus on Europe, discuss the role of clinical microbiologists, and present some perspectives and future developments.Antibiotic stewardship (ABS) is one of the key strategies to tackle the current worldwide bacterial resistance crisis (http://ift.tt/2u2bzuV). It refers to a set of interventions aiming at prescribing antibiotics appropriately and responsibly, even though its precise definition is still a topic of debate (Dyar 2017a, Mendelson 2017).This Commentary will focus on antibiotic stewardship in human medicine, but we acknowledge the importance of a One Health approach, including veterinary medicine, agriculture and the environment.

Synechococcus plasticity under environmental changes

Abstract

Cyanobacteria are among the oldest photoautotrophic organisms on Earth, and have contributed to shaping the planet's biogeochemistry with their significant biomass and key metabolic activities. Synechococcus, the focus of this review, is one of the prevalent genera in the order Chroococcales, common in oceans and lakes and characterized by a coccoid unicellular or microcolony morphology. The evolution of its phycobilisomes is the key of the adaptation of this tiny photosynthetic cell to different light regimes and environmental conditions. Furthermore, Synechococcus strains are widely distributed from the equator to the poles, showing an extreme adaptability to high and low temperatures. Because of their structural plasticity and ecological adaptability, these cyanobacteria are particularly interesting in the current condition of fast climate change. Moreover, picocyanobacteria of the Synechococcus genus have a potentially vast impact on global cycles thanks to their significant role in the biogeochemical cycles of aquatic ecosystems. As increasing abundances are predicted for this genus worldwide, and in light of the connection between cyanobacteria and global change events, a better characterization of these organisms promises important and timely ecological insights. Here, I will summarize the morphological and genetic characteristics of Synechococcus strains and their distribution in freshwater lakes, also considering its marine counterpart.

Book Review

Enfermedad de Darier lineal en 5 pacientes

Publication date: November 2017
Source:Piel, Volume 32, Issue 9
Author(s): Mónica García-Arpa, Miguel A. Flores-Terry, Natalia Villasanti-Rivas, Evelina J. de la Cruz Gómez, Monserrat Franco-Muñoz, Claudia Ramos-Rodríguez

Linfedema en ambos pies secundario a migración de silicona líquida

Publication date: November 2017
Source:Piel, Volume 32, Issue 9
Author(s): Daniel Morgado-Carrasco, Andrea Combalia, Erika Rodríguez-Lobato, Xavier Fustà-Novell, Llúcia Alós-Hernandez

Utilidad de los métodos de imagen en el diagnóstico de las dermatosis

Publication date: November 2017
Source:Piel, Volume 32, Issue 9
Author(s): Francisca Reculé, Stefanía Toso, Rodrigo Loubies

Reacciones cutáneas a fármacos en el paciente con leucemia/linfoma

Publication date: November 2017
Source:Piel, Volume 32, Issue 9
Author(s): Mar Llamas-Velasco, Pedro Rodríguez-Jiménez, Pablo Chicharro, Javier Sánchez-Pérez

Tratamiento del dolor en úlceras venosas crónicas

Publication date: November 2017
Source:Piel, Volume 32, Issue 9
Author(s): Adrián Imbernón-Moya, Francisco Javier Ortiz-de Frutos, Mónica Sanjuán-Álvarez, Isabel Portero-Sánchez, Antonio Aguilar-Martínez, Miguel Ángel Gallego-Valdés

Rash familiar

Publication date: November 2017
Source:Piel, Volume 32, Issue 9
Author(s): Carlos González-Cruz, Gloria Aparicio Español, Carla Ferrándiz-Pulido

Dermatología en la sala de urgencia. Diagnóstico y comentario

Publication date: November 2017
Source:Piel, Volume 32, Issue 9
Author(s): Carolina Sepúlveda, Marta Sousa, Jorge Nepomuceno

Rash familiar. Diagnóstico y comentario

Publication date: November 2017
Source:Piel, Volume 32, Issue 9
Author(s): Carlos González-Cruz, Gloria Aparicio Español, Carla Ferrándiz-Pulido

Lesión nodular frontal de rápido crecimiento. Diagnóstico y comentario

Publication date: November 2017
Source:Piel, Volume 32, Issue 9
Author(s): Andrea Estébanez, José M. Martín, Liria Térradez

Láser excimer 308nm en dermatología

Publication date: November 2017
Source:Piel, Volume 32, Issue 9
Author(s): Gabriela Tapia, Cristina Martínez, Hilda Rojas

Infraethics–on the Conditions of Possibility of Morality

Adult-onset Still's disease in a patient with psoriasis vulgaris showing inverse correlation of disease activity

Eruptive multiple seborrheic keratoses with a palm tree-like pattern without underlying malignancy

Two cases of skin infection during psoriasis treatment with brodalumab

Non-lesional skin biopsy for a diagnosis of neuronal intranuclear inclusion disease

Complete excision of proliferating core in auricular keloids significantly reduces local recurrence: A prospective study

Abstract

Keloids are mysterious soft-tissue tumors that are characterized by excessive reparative processes composed of collagen-forming fibroblasts and inflammatory cells. Generally, complete tumor excision regardless of sufficient margin is considered as a first-line treatment because they are considered reactive rather than a neoplastic condition. Recently, a specific part of the keloids is being highlighted as an important microstructure for local recurrence, but there has been very little evidence. We conducted a prospective study to evaluate the relationship of recurrence and several clinicopathological parameters with specific focus on surgical resection margin. A total 87 cases of auricular keloids from 71 patients were included. The resection margins were carefully evaluated by an exhaustive grossing method and thorough microstructural assessment. During up to 48.8 months of the follow-up period, local recurrence has been monitored and documented. The clinicopathological data including symptoms, bilaterality, size, location, prior treatment and operation history, gross type and etiology were collected and analyzed. Positive margin status was significantly related to tumor recurrence (P < 0.0001). Complete excision warrants a lower recurrence of auricular keloids in an Asian population. The most reasonable explanation for this seems to be remnant "proliferating core", which may serve a key role in local recurrence.

Incremental Improvement in Osteosarcoma Chemotherapy?

LAG-3: another brake to release in breast cancer?

Abstract: 3D Domestic Printer Use in Rhinoplasty

No abstract available

Could the determination of Aspergillus fumigatus mating type have prognostic value in invasive aspergillosis?

Summary

A clear link between mating type and virulence has been demonstrated for some fungal pathogens, but not for Aspergillus fumigatus as of yet. An association between mating type and invasiveness has recently been established. The mating type proportion (MAT1-1:MAT1-2) of 213 A. fumigatus strains was determined (48.5%:51.5%) and results were in agreement with previous studies. However, these percentages changed when the strain collection was divided into azole susceptible and resistant strains. The 163 susceptible strains kept these proportions, but among the 50 azole resistant strains 60.0% MAT1-1 and 40% MAT1-2 were found. Moreover, looking at the clinical outcome associated to 27 azole resistant strains, we found that MAT1-1 was linked to a high mortality rate (64%) while the rate associated to MAT1-2 genotype was markedly lower (15%). The pathogenicity linked to the Mat type was tested in a Galleria mellonella model of infection, showing that MAT1-1 strains were consistently more pathogenic than MAT1-2, independently of their susceptibility phenotype. This data would suggest that A. fumigatus mating type determination at the time of diagnosis could have a prognostic value in invasive aspergillosis.

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Deep facial mycosis due to Trichophyton verrucosum – molecular genetic identification of the dermatophyte in paraffin-embedded tissue – case report and review of the literature

Abstract

Deep trichophytosis is relatively uncommon. The infection of the bearded area is also known as sycosis barbae or tinea barbae and can be caused by various fungal species, most often zoophilic fungi.

We report on an 80-year-old male patient with severe sycosis barbae who had no animal contact and was treated with systemic antibiosis without improvement. Microbial and mycological investigations using swabs from oozing lesions revealed Staphylococcus hemolyticus and Candida parapsilosis. Histology demonstrated fungal elements in hair follicles. Paraffin-embedded material was subjected to further mycological analysis. For molecular diagnostics DNA was prepared from paraffin sections for real-time polymerase chain reaction (RT-PCR). For sequencing, DNA was isolated from paraffin-embedded skin tissue and the ITS region of the rDNA was selected. Sequencing of the ITS2 region of rRNA revealed a 100% accordance with Trichophyton (T.) verrucosum. Treatment with oral terbinafine achieved a complete remission. Sycosis barbae is an important differential diagnosis for infections of the bearded area.

Nucleic acid amplification techniques (NAAT) are more and more used for direct examination of dermatophytes in clinical samples, e. g. T. verrucosum. NAAT are also used as culture confirmation tests for identification of rare dermatophytes like T. verrucosum. Today, singleplex and multiplex quantitative real-time PCR (qRT-PCR) assays for the detection of the most common dermatophytes including T. verrucosum in clinical specimens are available. Recently, an ITS2 PCR assay has been succefully used for direct detection of T. verrucosum in paraffin-embedded formalin fixed skin tissue. The PCR is fast and highly specific. The sensitivity of direct molecular detection of the dermatophytes both in native clinical material, and in paraffin-embedded skin tissue can been increased.

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A sporadic case of granulomatous disease negative for NOD2 mutations and mimicking Blau syndrome

Cutaneous manifestations of phosphate solution extravasation

Summary

Extravasation injuries are common in patients receiving multiple intravenous infusions. Although such injuries are closely associated with the infusion of cytotoxic chemotherapy, they have also been been associated with extravasation of noncytotoxic drugs. Extravasation injuries can lead to skin ulceration and nerve and tendon damage, and therefore to permanent disability. We report three cases of phosphate solution extravasation leading to unusual cutaneous manifestations.

Effectiveness and safety of polidocanol for the treatment of hemangiomas and vascular malformations: A meta-analysis

Abstract

A meta-analysis was conducted to investigate the efficacy and safety of polidocanol versus other conventional therapies in treating hemangiomas (HMs) and vascular malformations (VMs). Literature search was conducted in the Cochrane, Embase, PubMed, Web of Science, CNKI, CBM, VIP, and WanFang databases until March 5, 2017. A meta-analysis was conducted using Revman 5.3 software. A total of 19 randomized controlled trials (RCTs) involving 1,514 participants met the inclusion criteria. Regarding the effectiveness, statistically significant differences were observed between polidocanol and all the independent treatments (p = .006), but not between polidocanol and pingyangmycin (p = .16). Combination therapy of polidocanol with any other conventional treatments (p = .0001), pingyangmycin (p = .005) or hemoclip (p = .008) elicited a better response compared to treatment with these treatments independently. A meta-analysis on the risk of adverse events (AEs) showed a lower risk for polidocanol versus other treatments, for example, all the conventional treatments used independently (p < .00001) and pingyangmycin (p < .00001). Combination therapy of polidocanol with pingyangmycin also yielded a significantly lower risk of AEs (p < .00001). Polidocanol is at least as effective as other conventional therapies on HMs and VMs (especially venous malformations). The former is much safer. Combining its use with other treatments may produce excellent results. Our study provides strong evidence supporting the use of polidocanol for HMs and VMs.

Comparison of clinical efficacy and safety of thermotherapy versus cryotherapy in treatment of skin warts: A randomized controlled trial

Abstract

The effect of thermotherapy in the treatment of skin warts in comparison to cryotherapy, as the standard conventional method, has remained uncertain. This study aimed to assess the clinical efficacy and safety of thermotherapy and cryotherapy in removing skin warts. This randomized controlled trial was conducted on 52 patients aged 18 years and over with ≤ 10 skin warts. The participants were randomly assigned into two groups to receive cryotherapy (every 2 to 3 weeks up to six sessions if required) or thermotherapy (one session). The patients in both groups were followed every 2 to 3 weeks for the first three months, and then three months after the last treatment session. The clearance rate was 79.2% in the thermotherapy group and 58.3% in the cryotherapy group with no significant difference (p = 0.212). The rate of scarring in the thermotherapy group was 20% (p = .018). A higher clearance rate was achieved in the thermotherapy group. However, this result was not statistically significant. There were some minimal post-treatment complications. Patients needed only one session of thermotherapy. Due to the risk of scarring, we suggest thermotherapy only as a suitable treatment method for palmoplantar warts.

Unconventional use of fractional ablative CO2 laser in facial cutaneous sarcoïdosis