Disseminated AIDS-associated Kaposi sarcoma without cutaneous involvement: a case report and review of literature.

Disseminated AIDS-associated Kaposi sarcoma (KS) without cutaneous lesions is rare and can present in varying ways. Diagnosis is even more challenging now when incidence of KS is on the decline. A high index of suspicion is required for early diagnosis and treatment. Therefore, the medical literature should be made aware of any manifestations of KS that can occur without the typical cutaneous lesions. A 23-year-old presented with worsening cervical lymphadenopathy, recurrent cough and bilateral leg swelling of a month duration. Examination revealed features of pericardial effusion, pulmonary fibrosis, necrotizing cervical lymphadenopathy and the presence of pityriasis rotunda at the periumbilical region. Patient was diagnosed human immunodeficiency virus (HIV) positive 6 months before she presented and was placed on antiretroviral therapy. Histology confirmed AIDS-associated KS. However, patient died before commencement of chemotherapy. The clinical course of disseminated AIDS-associated KS without cutaneous lesions can be atypical and aggressive. It is important to include KS in the differential diagnosis of cases with atypical or persistence/recurrence of clinical symptoms in spite of treatment especially in HIV patients.

Direct neuronal reprogramming of NDUFS4 patient cells identifies the unfolded protein response as a novel general reprogramming hurdle.

Mitochondria account for essential cellular pathways, from ATP production to nucleotide metabolism, and their deficits lead to neurological disorders and contribute to the onset of age-related diseases. Direct neuronal reprogramming aims at replacing neurons lost in such conditions, but very little is known about the impact of mitochondrial dysfunction on the direct reprogramming of human cells. Here, we explore the effects of mitochondrial dysfunction on the neuronal reprogramming of induced pluripotent stem cell (iPSC)-derived astrocytes carrying mutations in the NDUFS4 gene, important for Complex I and associated with Leigh syndrome. This led to the identification of the unfolded protein response as a major hurdle in the direct neuronal conversion of not only astrocytes and fibroblasts from patients but also control human astrocytes and fibroblasts. Its transient inhibition potently improves reprogramming by influencing the mitochondria-endoplasmic-reticulum-stress-mediated pathways. Taken together, disease modeling using patient cells unraveled novel general hurdles and ways to overcome these in human astrocyte-to-neuron reprogramming.

Thermal Degradation of Organophosphorus Flame Retardants.

The development of new organophosphorus flame retardants for polymeric materials is spurred by relatively low toxicity, effectiveness, and demand for replacement of more traditional materials. To function, these compounds must decompose in a degrading polymer matrix to form species which promote modification of the solid phase or generate active radical moieties that escape to the gas phase and interrupt combustion propagating reactions. An understanding of the decomposition process for these compounds may provide insight into the nature of flame retardant action which they may offer and suggest parameters for the synthesis of effective new organophosphorus flame retardants. The thermal degradation of a series of organophosphorus esters varying in the level of oxygenation at phosphorus-alkyl phosphate, aryl phosphate, phosphonate, phosphinate-has been examined. Initial degradation in all cases corresponds to elimination of a phosphorus acid. However, the facility with which this occurs is strongly dependent on the level of oxygenation at phosphorus. For alkyl phosphates elimination occurs rapidly at relatively low temperature. The same process occurs at somewhat higher temperature for aryl phosphates. Elimination of a phosphorus acid from phosphonate or phosphinate occurs more slowly and at much higher temperature. Further, the acids formed from elimination rapidly degrade further to evolve volatile species.

Hypopigmented penile fixed drug eruption.

Fixed drug eruptions (FDE) are typically associated with residual hyperpigmentation or non-pigmenting lesions. There is no distinctive histopathological feature; though, drug provocation tests (DPT) can be confirmatory within 7 days. We describe a patient with penile FDE associated with residual hypopigmentation, a prolonged refractory period to DPT and recurrent meatal stenosis.

Modeling mucus physiology and pathophysiology in human organs-on-chips.

The surfaces of human internal organs are lined by a mucus layer that ensures symbiotic relationships with commensal microbiome while protecting against potentially injurious environmental chemicals, toxins, and pathogens, and disruption of this layer can contribute to disease development. Studying mucus biology has been challenging due to the lack of physiologically relevant human in vitro models. Here we review recent progress that has been made in the development of human organ-on-a-chip microfluidic culture models that reconstitute epithelial tissue barriers and physiologically relevant mucus layers with a focus on lung, colon, small intestine, cervix and vagina. These organ-on-a-chip models that incorporate dynamic fluid flow, air-liquid interfaces, and physiologically relevant mechanical cues can be used to study mucus composition, mechanics, and structure, as well as investigate its contributions to human health and disease with a level of biomimicry not possible in the past.

Probing cell identity hierarchies by fate titration and collision during direct reprogramming.

Despite the therapeutic promise of direct reprogramming, basic principles concerning fate erasure and the mechanisms to resolve cell identity conflicts remain unclear. To tackle these fundamental questions, we established a single-cell protocol for the simultaneous analysis of multiple cell fate conversion events based on combinatorial and traceable reprogramming factor expression: Collide-seq. Collide-seq revealed the lack of a common mechanism through which fibroblast-specific gene expression loss is initiated. Moreover, we found that the transcriptome of converting cells abruptly changes when a critical level of each reprogramming factor is attained, with higher or lower levels not contributing to major changes. By simultaneously inducing multiple competing reprogramming factors, we also found a deterministic system, in which titration of fates against each other yields dominant or colliding fates. By investigating one collision in detail, we show that reprogramming factors can disturb cell identity programs independent of their ability to bind their target genes. Taken together, Collide-seq has shed light on several fundamental principles of fate conversion that may aid in improving current reprogramming paradigms.

Isolation and Direct Neuronal Reprogramming of Mouse Astrocytes.

Direct neuronal reprogramming is a powerful approach to generate functional neurons from different starter cell populations without passing through multipotent intermediates. This technique not only holds great promises in the field of disease modeling, as it allows to convert, for example, fibroblasts for patients suffering neurodegenerative diseases into neurons, but also represents a promising alternative for cell-based replacement therapies. In this context, a major scientific breakthrough was the demonstration that differentiated non-neural cells within the central nervous system, such as astrocytes, could be converted into functional neurons in vitro. Since then, in vitro direct reprogramming of astrocytes into neurons has provided substantial insights into the molecular mechanisms underlying forced identity conversion and the hurdles that prevent efficient reprogramming. However, results from in vitro experiments performed in different labs are difficult to compare due to differences in the methods used to isolate, culture, and reprogram astrocytes. Here, we describe a detailed protocol to reliably isolate and culture astrocytes with high purity from different regions of the central nervous system of mice at postnatal ages via magnetic cell sorting. Furthermore, we provide protocols to reprogram cultured astrocytes into neurons via viral transduction or DNA transfection. This streamlined and standardized protocol can be used to investigate the molecular mechanisms underlying cell identity maintenance, the establishment of a new neuronal identity, as well as the generation of specific neuronal subtypes and their functional properties.

What the snake leaves in its wake: Functional limitations and disabilities among snakebite victims in Ghanaian communities.

BACKGROUND: The estimated five million snakebites per year are an important health problem that mainly affect rural poor populations. The global goal is to halve both mortality and morbidity from this neglected tropical disease by 2030. Data on snakebite morbidity are sparse and mainly obtained from hospital records. METHODS: This community-based study was conducted among 379 rural residents with or without a history of snakebite in the Ashanti and Upper West regions of Ghana. All participants in the snakebite group were bitten at least six months before the day of survey. The World Health Organisation Disability Assessment Schedule 2.0 (WHODAS 2.0) and the Buruli Ulcer Functional Limitation Score were used to obtain patient-reported measure of functioning and disability. Long-term consequences were evaluated based on the severity of the symptoms at the time of the snakebite. FINDINGS: The median (IQR) time since the snakebite was 8.0 (3.5-16.5) years. The relative risk of disability was 1.54 (95% CI, 1.17-2.03) in the snakebite group compared to the community controls. Among patients with clinical symptoms suggesting envenoming at the time of bite, 35% had mild/moderate disabilities compared to 20% in the control group. The disability domains mainly affected by snakebite envenoming were cognition level, mobility, life activities and participation in society. A combination of the severity of symptoms at the time of the bite, age, gender and region of residence most accurately predicted the odds of having functional limitations and disabilities. CONCLUSION: The burden of snakebite in the community includes long-term disabilities of mild to moderate severity, which need to be considered when designing appropriate public health interventions. Estimating the total burden of snakebite is complicated by geographic differences in types of snakes and their clinical manifestations.

Chronic E-Cigarette Exposure Alters Human Alveolar Macrophage Morphology and Gene Expression.

INTRODUCTION: Alveolar macrophages (AMs) are lung-resident immune cells that phagocytose inhaled particles and pathogens, and help coordinate the lung's immune response to infection. Little is known about the impact of chronic e-cigarette use (ie, vaping) on this important pulmonary cell type. Thus, we determined the effect of vaping on AM phenotype and gene expression. AIMS AND METHODS: We recruited never-smokers, smokers, and e-cigarette users (vapers) and performed research bronchoscopies to isolate AMs from bronchoalveolar lavage fluid samples and epithelial cells from bronchial brushings. We then performed morphological analyses and used the Nanostring platform to look for changes in gene expression. RESULTS: AMs obtained from smokers and vapers were phenotypically distinct from those obtained from nonsmokers, and from each other. Immunocytochemistry revealed that vapers AMs had significantly elevated inducible nitric oxide synthase (M1) expression and significantly reduced CD301a (M2) expression compared with nonsmokers or smokers. Vapers' AMs and bronchial epithelia exhibited unique changes in gene expression compared with nonsmokers or smokers. Moreover, vapers' AMs were the most affected of all groups and had 124 genes uniquely downregulated. Gene ontology analysis revealed that vapers and smokers had opposing changes in biological processes. CONCLUSIONS: These data indicate that vaping causes unique changes to AMs and bronchial epithelia compared with nonsmokers and smokers which may impact pulmonary host defense. IMPLICATIONS: These data indicate that normal "healthy" vapers have altered AMs and may be at risk of developing abnormal immune responses to inflammatory stimuli.

Distinct subcellular autophagy impairments in induced neurons from patients with Huntington's disease.

Huntington's disease is a neurodegenerative disorder caused by CAG expansions in the huntingtin (HTT) gene. Modelling Huntington's disease is challenging, as rodent and cellular models poorly recapitulate the disease as seen in ageing humans. To address this, we generated induced neurons through direct reprogramming of human skin fibroblasts, which retain age-dependent epigenetic characteristics. Huntington's disease induced neurons (HD-iNs) displayed profound deficits in autophagy, characterized by reduced transport of late autophagic structures from the neurites to the soma. These neurite-specific alterations in autophagy resulted in shorter, thinner and fewer neurites specifically in HD-iNs. CRISPRi-mediated silencing of HTT did not rescue this phenotype but rather resulted in additional autophagy alterations in control induced neurons, highlighting the importance of wild-type HTT in normal neuronal autophagy. In summary, our work identifies a distinct subcellular autophagy impairment in adult patient derived Huntington's disease neurons and provides a new rationale for future development of autophagy activation therapies.

Research design considerations for chronic pain prevention clinical trials: IMMPACT recommendations.

Although certain risk factors can identify individuals who are most likely to develop chronic pain, few interventions to prevent chronic pain have been identified. To facilitate the identification of preventive interventions, an IMMPACT meeting was convened to discuss research design considerations for clinical trials investigating the prevention of chronic pain. We present general design considerations for prevention trials in populations that are at relatively high risk for developing chronic pain. Specific design considerations included subject identification, timing and duration of treatment, outcomes, timing of assessment, and adjusting for risk factors in the analyses. We provide a detailed examination of 4 models of chronic pain prevention (ie, chronic postsurgical pain, postherpetic neuralgia, chronic low back pain, and painful chemotherapy-induced peripheral neuropathy). The issues discussed can, in many instances, be extrapolated to other chronic pain conditions. These examples were selected because they are representative models of primary and secondary prevention, reflect persistent pain resulting from multiple insults (ie, surgery, viral infection, injury, and toxic or noxious element exposure), and are chronically painful conditions that are treated with a range of interventions. Improvements in the design of chronic pain prevention trials could improve assay sensitivity and thus accelerate the identification of efficacious interventions. Such interventions would have the potential to reduce the prevalence of chronic pain in the population. Additionally, standardization of outcomes in prevention clinical trials will facilitate meta-analyses and systematic reviews and improve detection of preventive strategies emerging from clinical trials.

Modeling the relative risk of SARS-CoV-2 infection to inform risk-cost-benefit analyses of activities during the SARS-CoV-2 pandemic.

Risk-cost-benefit analysis requires the enumeration of decision alternatives, their associated outcomes, and the quantification of uncertainty. Public and private decision-making surrounding the COVID-19 pandemic must contend with uncertainty about the probability of infection during activities involving groups of people, in order to decide whether that activity is worth undertaking. We propose a model of SARS-CoV-2 infection probability that can produce estimates of relative risk of infection for diverse activities, so long as those activities meet a list of assumptions, including that they do not last longer than one day (e.g., sporting events, flights, concerts), and that the probability of infection among possible routes of infection (i.e., droplet, aerosol, fomite, and direct contact) are independent. We show how the model can be used to inform decisions facing governments and industry, such as opening stadiums or flying on airplanes; in particular, it allows for estimating the ranking of the constituent components of activities (e.g., going through a turnstile, sitting in one's seat) by their relative risk of infection, even when the probability of infection is unknown or uncertain. We prove that the model is a good approximation of a more refined model in which we assume infections come from a series of independent risks. A linearity assumption governing several potentially modifiable risks factors-such as duration of the activity, density of participants, and infectiousness of the attendees-makes interpreting and using the model straightforward, and we argue that it does so without significantly diminishing the reliability of the model.

Impact of differential and time-dependent autophagy activation on therapeutic efficacy in a model of Huntington disease.

Activation of macroautophagy/autophagy, a key mechanism involved in the degradation and removal of aggregated proteins, can successfully reverse Huntington disease phenotypes in various model systems. How neuronal autophagy impairments need to be considered in Huntington disease progression to achieve a therapeutic effect is currently not known. In this study, we used a mouse model of HTT (huntingtin) protein aggregation to investigate how different methods and timing of autophagy activation influence the efficacy of autophagy-activating treatment in vivo. We found that overexpression of human TFEB, a master regulator of autophagy, did not decrease mutant HTT aggregation. On the other hand, Becn1 overexpression, an autophagic regulator that plays a key role in autophagosome formation, partially cleared mutant HTT aggregates and restored neuronal pathology, but only when administered early in the disease progression. When Becn1 was administered at a later stage, when prominent mutant HTT accumulation and autophagy impairments have occurred, Becn1 overexpression did not rescue the mutant HTT-associated phenotypes. Together, these results demonstrate that the targets used to activate autophagy, as well as the timing of autophagy activation, are crucial for achieving efficient therapeutic effects.Abbreviations: AAV: adeno-associated viral vectors; ACTB: actin beta; BECN1: beclin 1, autophagy related; DAPI: 4',6-diamidino-2-phenylindole; GO: gene ontology; HD: Huntington disease; HTT: huntingtin; ICQ: Li's intensity correlation quotient; IHC: immunohistochemistry; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; mHTT: mutant huntingtin; PCA: principal component analysis; PPP1R1B/DARPP-32: protein phosphatase 1 regulatory inhibitor subunit 1B; SQSTM1: sequestosome 1; TFEB: transcription factor EB; WB: western blot; WT: wild-type.

Scabies education in secondary schools: A multicenter study.

Background: The aim of this study was to educate secondary school students on etiology, risk factors, clinical features, treatment, and prevention of scabies; to evaluate their knowledge base on scabies before and after an educational intervention; and to reassess this knowledge base and behavioral change, 6 months after, on a second visit. Methods: Questionnaires with standard questions on scabies, graded to a maximum score of 10, were administered to students in junior secondary Classes 1 and 2 across 4 states in Nigeria. Information obtained included subjects' demographics, scabies symptomatology, risks, and preventive behaviors. Students with active scabies were diagnosed and treated. Data were analyzed with STATA. Results: The mean test scores for the pretest and posttest at first visit were 2.82 ± 1.38 and 6.30 ± 1.09, respectively. This difference was statistically significant at t = 3.95, P = 0.004. Six months later, when the same schools were re-visited, the mean test scores for the pretest and posttest were 4.63 ± 0.54 and 5.87 ± 0.25, respectively. This difference was also significant at t = 4.13, P = 0.003. The prevalence of scabies was 3.5% at first visit and 4.34% at second visit; t = 0.24, P = 0.41. Conclusions: Secondary school students lack basic education on scabies and exhibit high-risk behaviors for scabies transmission. Knowledge on scabies needs constant reinforcement.

RésuméContexte: Le but de cette étude était d'éduquer les élèves du secondaire sur l'étiologie, les facteurs de risque, les caractéristiques cliniques, le traitement et la prévention de la gale; évaluer leur base de connaissances sur la gale avant et après une intervention éducative; et de réévaluer cette base de connaissances et ce changement de comportement, six mois après, lors d'une deuxième visite. Méthodes: Des questionnaires contenant des questions standard sur la gale, notés à un score maximum de 10, ont été administrés aux élèves des classes 1 et 2 du premier cycle du secondaire dans 4 États du Nigéria. Les informations obtenues comprenaient la démographie des sujets, la symptomatologie de la gale, les risques et les comportements préventifs. Les étudiants atteints de gale active ont été diagnostiqués et traités. Les données ont été analysées avec STATA. Résultats: Les scores moyens aux tests avant et après le test lors de la première visite étaient respectivement de 2,82 ± 1,38 et 6,30 ± 1,09. Cette différence était statistiquement significative à t = 3,95, p = 0,004. Six mois plus tard, lorsque les mêmes écoles ont été revues, les scores moyens aux tests avant et après test étaient respectivement de 4,63 ± 0,54 et 5,87 ± 0,25. Cette différence était également significative à t = 4,13, p = 0,003. La prévalence de la gale était de 3,5% lors de la première visite et de 4,34% lors de la deuxième visite; t = 0,24, p = 0,41. Conclusions: Les élèves du secondaire manquent d'éducation de base sur la gale et présentent des comportements à haut risque de transmission de la gale. Les connaissances sur la gale nécessitent un renforcement constant.

A deterministic linear infection model to inform Risk-Cost-Benefit Analysis of activities during the SARS-CoV-2 pandemic.

Risk-cost-benefit analysis requires the enumeration of decision alternatives, their associated outcomes, and the quantification of uncertainty. Public and private decision-making surrounding the COVID-19 pandemic must contend with uncertainty about the probability of infection during activities involving groups of people, in order to decide whether that activity is worth undertaking. We propose a deterministic linear model of SARS-CoV-2 infection probability that can produce estimates of relative risk for diverse activities, so long as those activities meet a list of assumptions, including that they do not last longer than one day. We show how the model can be used to inform decisions facing governments and industry, such as opening stadiums or flying on airplanes. We prove that the model is a good approximation of a more refined model in which we assume infections come from a series of independent risks. The linearity assumption makes interpreting and using the model straightforward, and we argue that it does so without significantly diminishing the reliability of the model.

Policy Implications of an Approximate Linear Infection Model for SARS-CoV-2.

We propose a linear model of infection probability, and prove that this is a good approximation to a more refined model in which we assume infections come from a series of independent risks. We argue that the linearity assumption makes interpreting and using the model much easier, without significantly diminishing the reliability of the model.

Effective Biobased Phosphorus Flame Retardants from Starch-Derived bis-2,5-(Hydroxymethyl)Furan.

A series of biobased phosphorus flame retardants has been prepared by converting starch-derived bis-2,5-(hydroxymethyl)furan to the corresponding diacrylate followed by Michael addition of phosphite to generate derivatives with phosphorus moieties attached via P-C bonds. All compounds behave as effective flame retardants in DGEBA epoxy resin. The most effective is the DOPO derivative, 2,5-di[(3-dopyl-propanoyl)methyl]furan. When incorporated into a DGEBA blend at a level to provide 2% phosphorus, a material displaying a LOI of 30, an UL 94 rating of V0 and a 40% reduction in combustion peak heat release rate compared to that for resin containing no additive is obtained. The analogous compounds generated from bisphenol A and tetrabromobisphenol A exhibit similar flame-retarding properties.

Flt3 ligand augments immune responses to anti-DEC-205-NY-ESO-1 vaccine through expansion of dendritic cell subsets.

Generating responses to tumor antigens poses a challenge for immunotherapy. This phase II trial (NCT02129075) tested fms-like tyrosine kinase 3 (Flt3) ligand pre-treatment enhancement of responses to dendritic cell (DC)-targeting vaccines. We evaluated a regimen of Flt3L (CDX-301) to increase DCs and other antigen-presenting cells, poly-ICLC (TLR3 agonist that activates DCs) and a vaccine comprising anti-DEC-205-NY-ESO-1, a fusion antibody targeting CD205, linked to NY-ESO-1. High-risk melanoma patients were randomized to vaccine, with and without CDX-301. The end point was immune response to NY-ESO-1. Flt3L increased peripheral monocytes and conventional DCs (cDCs), including cross-presenting cDC1 and cDC2 and plasmacytoid DCs. Significant increases in humoral and T-cell responses and activation of DCs, natural killer cells and T cells were elicited. Transcriptional analyses revealed gene signatures associated with CDX-301 induction of an early, durable immune response. This study reveals in vivo effects of Flt3L on innate immune cells in the setting of vaccination, leading to an immunogenic vaccine regimen.

Incorporation of Comonomer exo-5-(Diphenylphosphato)Isosorbide-2-endo-Acrylate to Generate Flame Retardant Poly(Styrene).

A phosphorus containing acrylate monomer has been constructed from isosorbide, a renewable biomaterial. Treatment of isosorbide with diphenylchlorophosphate generates a mixture of phosphorus esters from which exo-5-(diphenylphosphato)isosorbide-2-endo-ol may be isolated using column chromatography. Conversion of the alcohol to the corresponding acrylate by treatment with acroyl chloride provides a reactive acryloyl monomer containing a diphenylphosphato unit. Copolymerization of this monomer, at levels to provide 1% or 2% phosphorus incorporation, with styrene generates a polymer with substantially diminished flammability compared to that for styrene homopolymer.

ADRENAL INSUFFICIENCY FROM UNILATERAL ADRENAL HEMORRHAGE IN A PATIENT ON RIVAROXABAN THROMBOPROPHYLAXIS.

OBJECTIVE: We report a case of unilateral adrenal hemorrhage resulting in adrenal insufficiency in a patient on rivaroxaban for thromboprophylaxis after total knee arthroplasty. METHODS: The clinical presentation, laboratory findings, and outcome of the case are described. An overview of the etiology, diagnosis, and treatment of adrenal hemorrhage is reviewed. RESULTS: A 61-year-old male underwent bilateral total knee replacements and postoperatively was started on rivaroxaban at 10 mg daily for thromboprophylaxis. About 2 weeks after the procedure, the patient presented with abdominal pain, nausea, vomiting, and generalized weakness. Abdominal computed tomography scan identified an ill-defined heterogeneous density in the left supra-renal fossa, and an abdominal magnetic resonance imaging scan identified diffuse thickening of the left adrenal gland with periadrenal fat stranding suggestive of adrenal hemorrhage. Adrenal insufficiency was suspected and confirmed with a cosyntropin stimulation test. Pre-stimulus cortisol level was 2.7 µg/dL and 60 minutes after cosyntropin administration it was 2.5 µg/dL. The patient was started on intravenous hydrocortisone at 100 mg every 6 hours with improvement of symptoms and discharged on oral hydrocortisone at 20 mg twice daily. Follow up abdominal magnetic resonance imaging 6 weeks after discharge demonstrated resolution of the left adrenal hemorrhage. CONCLUSION: A high clinical suspicion and early detection of adrenal hemorrhage in a patient on anticoagulation can allow for earlier intervention and improved outcomes.