The 3 levels of HIV stigma in the United States military: perspectives from service members living with HIV.

BACKGROUND: Epidemiological surveillance data indicate that a majority of HIV-infected in the United States (U.S.) military are African-Americans and men who have sex with men. There is limited research about barriers to HIV prevention among military service members and the unique factors that contribute to HIV stigma. METHODS: A convenience sample of 30 U.S. service members were recruited from an infectious disease clinic. In depth interviews were conducted and data analyzed using a thematic coding process. RESULTS: Two broad categories were identified: 1) Outcomes of HIV Stigma: Fear of Rejection, Shame, and Embarrassment; and 2) Strategies for combating stigma which include increasing HIV education and prevention resources. Military policies and institutional culture regarding sexuality were found to contribute to stigma. CONCLUSIONS: Participants identified a need for HIV education and suggested individuals living with HIV serve as mentors. A peer-to-peer intervention for delivering HIV prevention education may address these needs and reduce HIV stigma.

Spatiochemically Profiling Microbial Interactions with Membrane Scaffolded Desorption Electrospray Ionization-Ion Mobility-Imaging Mass Spectrometry and Unsupervised Segmentation.

Imaging the inventory of microbial small molecule interactions provides important insights into microbial chemical ecology and human medicine. Herein we demonstrate a new method for enhanced detection and analysis of metabolites present in interspecies interactions of microorganisms on surfaces. We demonstrate that desorption electrospray ionization-imaging mass spectrometry (DESI-IMS) using microporous membrane scaffolds (MMS) enables enhanced spatiochemical analyses of interacting microbes among tested sample preparation techniques. Membrane scaffolded DESI-IMS has inherent advantages compared to matrix-assisted laser desorption ionization (MALDI) and other IMS methods through direct IMS analyses of microbial chemistry in situ. This rapid imaging method yields sensitive MS analyses with unique m/z measurements when compared to liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) via unmediated sampling by MMS DESI-IMS. Unsupervised segmentation imaging analysis of acquired DESI-IMS data reveals distinct chemical regions corresponding to intermicrobial phenomenon such as predation and communication. We validate the method by linking Myxovirescin A and DKxanthene-560 to their known biological roles of predation and phase variation, respectively. In addition to providing the first topographic locations of known natural products, we prioritize 54 unknown features using segmentation within the region of predation. Thus, DESI-IMS and unsupervised segmentation spatially annotates the known biology of myxobacteria and provides functional exploration of newly uncharacterized small molecules.

The Belmont Report at 40: Reckoning With Time.

It was the summer of 1972 when a stunned nation first learned of the infamous Tuskegee Syphilis Study, during which hundreds of poor, disease-stricken black men from Macon County Alabama, had been deliberately left untreated for 40 years. Coming on the heels of multiple, earlier examples of unethical human experimentation, the Tuskegee Syphilis Study made it plain that the moral foundation of human subject research was in desperate need of repair. Blind reliance on the Nuremberg Code and the Declaration of Helsinki was no longer going to suffice. It was against this backdrop that Congress resolved to act. Numerous hearings and multiple spirited discussions later, an agreement was struck to constitute the "Commission." The outgrowth of a retreat held at the Smithsonian Institution's Belmont Conference Center, the Belmont Report lays out a principled analytical framework to "guide the resolution of ethical problems arising from research involving human subjects." Durable and ever-present, the Belmont Report, which is the foundational document that reset the ethics of human subject research, must now reckon with all-important novel issues of the day that could not have been foreseen by its drafters.

Projecting the Supply and Demand for Certified Genetic Counselors: a Workforce Study.

As of May 2017, there were 4242 Certified Genetic Counselors (CGC) (American Board of Genetic Counseling, Inc. 2017) and 41 graduate-level genetic counseling training programs (Accreditation Council for Genetic Counseling 2017) in North America, and the demand for CGCs continues to increase. In the Fall of 2015 the Genetic Counselor Workforce Working Group, comprised of representatives from the American Board of Genetic Counseling (ABGC), the Accreditation Council for Genetic Counseling (ACGC), the Association of Genetic Counseling Program Directors (AGCPD), the American Society of Human Genetics (ASHG), and the National Society of Genetic Counselors (NSGC) commissioned a formal workforce study to project supply of and demand for CGCs through 2026. The data indicate a shortage of genetic counselors engaged in direct patient care. Assuming two scenarios for demand, supply is expected to reach equilibrium between 2024 and 2030. However, given the rate of growth in genetic counseling training programs in the six months since the study was completed, it is reasonable to expect that the number of new programs may be higher than anticipated by 2026. If true, and assuming that growth in programs is matched by equivalent growth in clinical training slots, the supply of CGCs in direct patient care would meet demand earlier than these models predict.

Human immunodeficiency virus associated thrombotic thrombocytopenic purpura, a clinical conundrum.

HIV complicates the diagnostic and therapeutic approaches to idiopathic thrombotic thrombocytopenic purpura (TTP), prompting debate in the literature regarding the benefit of plasma exchange versus simple plasma infusion. Herein we present a case of HIV-TTP, initially treated conservatively with plasma infusion but because of progressive neurologic decline, required urgent plasma exchange for resolution of hematologic derangements and neurologic sequelae. Based on the available literature, there appears to be a spectrum of HIV-associated TTP disorders. Patients with advanced HIV disease and opportunistic infections who present with thrombotic microangiopathy tend to respond to simple plasma infusion, while patients with less progressive HIV disease tend to behave like those with idiopathic TTP, requiring plasma exchange rather than simple plasma infusion. This article illustrates that in patients with HIV-TTP who do not respond to plasma infusion, early escalation to plasma exchange may help avoid life-threatening complications such as seizures and even death.

Factors Influencing the Decision-Making Process and Long-Term Interpersonal Outcomes for Parents Who Undergo Preimplantation Genetic Diagnosis for Fanconi Anemia: a Qualitative Investigation.

Fanconi anemia (FA) is characterized by congenital malformations, progressive bone marrow failure, and predisposition to malignancy. Hematopoietic stem cell transplantation is used to treat FA, and best results are attained with sibling donors who are human leukocyte antigen (HLA) identical matches. Preimplantation genetic diagnosis (PGD) offers parents of an affected child the opportunity to have an unaffected child who is an HLA match. While some research has investigated parents' experiences during the PGD process, no published studies specifically address factors influencing their decision-making process and long-term interpersonal outcomes. The aims of this study are to: (1) examine parents' expectations and the influence of media, bioethics, and religion on their decision to undergo PGD; (2) examine parents' social support and emotional experiences during their PGD process; and (3) characterize long-term effects of PGD on relationship dynamics (partner, family, friends), others' attitudes, and parental regret. Nine parents participated in semi-structured interviews. Thematic analysis revealed their decision to use PGD was variously influenced by media, bioethics, and religion, in particular, affecting parents' initial confidence levels. Moreover, the PGD process was emotionally complex, with parents desiring varying amounts and types of support from different sources at different times. Parents reported others' attitudes towards them were similar or no different than before PGD. Parental regret regarding PGD was negligible. Results of this study will promote optimization of long-term care for FA families.

Multi-mode acquisition (MMA): An MS/MS acquisition strategy for maximizing selectivity, specificity and sensitivity of DIA product ion spectra.

In proteomics studies, it is generally accepted that depth of coverage and dynamic range is limited in data-directed acquisitions. The serial nature of the method limits both sensitivity and the number of precursor ions that can be sampled. To that end, a number of data-independent acquisition (DIA) strategies have been introduced with these methods, for the most part, immune to the sampling issue; nevertheless, some do have other limitations with respect to sensitivity. The major limitation with DIA approaches is interference, i.e., MS/MS spectra are highly chimeric and often incapable of being identified using conventional database search engines. Utilizing each available dimension of separation prior to ion detection, we present a new multi-mode acquisition (MMA) strategy multiplexing both narrowband and wideband DIA acquisitions in a single analytical workflow. The iterative nature of the MMA workflow limits the adverse effects of interference with minimal loss in sensitivity. Qualitative identification can be performed by selected ion chromatograms or conventional database search strategies.

Evaluation of miR-122 as a Serum Biomarker for Hepatotoxicity in Investigative Rat Toxicology Studies.

MicroRNAs are short noncoding RNAs involved in regulation of gene expression. Certain microRNAs, including miR-122, seem to have ideal properties as biomarkers due to good stability, high tissue specificity, and ease of detection across multiple species. Recent reports have indicated that miR-122 is a highly liver-specific marker detectable in serum after liver injury. The purpose of the current study was to assess the performance of miR-122 as a serum biomarker for hepatotoxicity in short-term (5-28 days) repeat-dose rat toxicology studies when benchmarked against routine clinical chemistry and histopathology. A total of 23 studies with multiple dose levels of experimental compounds were examined, and they included animals with or without liver injury and with various hepatic histopathologic changes. Serum miR-122 levels were quantified by reverse transcription quantitative polymerase chain reaction. Increases in circulating miR-122 levels highly correlated with serum elevations of liver enzymes, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST) and glutamate dehydrogenase (GLDH). Statistical analysis showed that miR-122 outperformed ALT as a biomarker for histopathologically confirmed liver toxicity and was equivalent in performance to AST and GLDH. Additionally, an increase of 4% in predictive accuracy was obtained using a multiparameter approach incorporating miR-122 with ALT, AST, and GLDH. In conclusion, serum miR-122 levels can be utilized as a biomarker of hepatotoxicity in acute and subacute rat toxicology studies, and its performance can rival or exceed those of standard enzyme biomarkers such as the liver transaminases.

Human cytomegalovirus resistance to deoxyribosylindole nucleosides maps to a transversion mutation in the terminase subunit-encoding gene UL89.

Human cytomegalovirus (HCMV) infection can cause severe illnesses, including encephalopathy and mental retardation, in immunocompromised and immunologically immature patients. Current pharmacotherapies for treating systemic HCMV infections include ganciclovir, cidofovir, and foscarnet. However, long-term administration of these agents can result in serious adverse effects (myelosuppression and/or nephrotoxicity) and the development of viral strains with reduced susceptibility to drugs. The deoxyribosylindole (indole) nucleosides demonstrate a 20-fold greater activity in vitro (the drug concentration at which 50% of the number of plaques was reduced with the presence of drug compared to the number in the absence of drug [EC50] = 0.34 µM) than ganciclovir (EC50 = 7.4 µM) without any observed increase in cytotoxicity. Based on structural similarity to the benzimidazole nucleosides, we hypothesize that the indole nucleosides target the HCMV terminase, an enzyme responsible for packaging viral DNA into capsids and cleaving the DNA into genome-length units. To test this hypothesis, an indole nucleoside-resistant HCMV strain was isolated, the open reading frames of the genes that encode the viral terminase were sequenced, and a G766C mutation in exon 1 of UL89 was identified; this mutation resulted in an E256Q change in the amino acid sequence of the corresponding protein. An HCMV wild-type strain, engineered with this mutation to confirm resistance, demonstrated an 18-fold decrease in susceptibility to the indole nucleosides (EC50 = 3.1 ± 0.7 µM) compared to that of wild-type virus (EC50 = 0.17 ± 0.04 µM). Interestingly, this mutation did not confer resistance to the benzimidazole nucleosides (EC50 for wild-type HCMV = 0.25 ± 0.04 µM, EC50 for HCMV pUL89 E256Q = 0.23 ± 0.04 µM). We conclude, therefore, that the G766C mutation that results in the E256Q substitution is unique for indole nucleoside resistance and distinct from previously discovered substitutions that confer both indole and benzimidazole nucleoside resistance (D344E and A355T).

New insight into the photoheterotrophic growth of the isocytrate lyase-lacking purple bacterium Rhodospirillum rubrum on acetate.

Purple non-sulfur bacteria are well known for their metabolic versatility. One of these bacteria, Rhodospirillum rubrum S1H, has been selected by the European Space Agency to ensure the photoheterotrophic assimilation of volatile fatty acids in its regenerative life support system, MELiSSA. Here, we combined proteomic analysis with bacterial growth analysis and enzymatic activity assays in order to better understand acetate photoassimilation. In this isocitrate lyase-lacking organism, the assimilation of two-carbon compounds cannot occur through the glyoxylate shunt, and the citramalate cycle has been proposed to fill this role, while, in Rhodobacter sphaeroides, the ethylmalonyl-CoA pathway is used for acetate assimilation. Using proteomic analysis, we were able to identify and quantify more than 1700 unique proteins, representing almost one-half of the theoretical proteome of the strain. Our data reveal that a pyruvate : ferredoxin oxidoreductase (NifJ) could be used for the direct assimilation of acetyl-CoA through pyruvate, potentially representing a new redox-balancing reaction. We additionally propose that the ethylmalonyl-CoA pathway could also be involved in acetate assimilation by the examined strain, since specific enzymes of this pathway were all upregulated and activity of crotonyl-CoA reductase/carboxylase was increased in acetate conditions. Surprisingly, we also observed marked upregulation of glutaryl-CoA dehydrogenase, which could be a component of a new pathway for acetate photoassimilation. Finally, our data suggest that citramalate could be an intermediate of the branched-chain amino acid biosynthesis pathway, which is activated during acetate assimilation, rather than a metabolite of the so-called citramalate cycle.

The chromosome-centric human proteome project: a call to action.

The grand vision of the human proteome project (HPP) is moving closer to reality with the recent announcement by HUPO of the creation of the HPP consortium in charge of the development of a two-part HPP, one focused on the description of proteomes of biological samples or related to diseases (B/D-HPP) and the other dedicated to a systematic description of proteins as gene products encoded in the human genome (the C-HPP). This new initiative of HUPO seeks to identify and characterize at least one representative protein from every gene, create a protein distribution atlas and a protein pathway or network map. This vision for proteomics can be the roadmap of biological and clinical research for years to come if it delivers on its promises. The Industrial Advisory Board (IAB) to HUPO shares the visions of C-HPP. The IAB will support and critically accompany the overall project goals and the definitions of the critical milestones. The member companies are in a unique position to develop hardware and software, reagents and standards, procedures, and workflows to ensure a reliable source of tools available to the proteomics community worldwide. In collaboration with academia, the IAB member companies can and must develop the tools to reach the ambitious project goals. We offer to partner with and challenge the academic groups leading the C-HPP to define both ambitious and obtainable goals and milestones to make the C-HPP a real and trusted resource for future biology.

Lens subluxation with stretched ciliary processes in a girl with Goltz syndrome.

PURPOSE: To report lens subluxation with additional stretching of the ciliary processes as ocular features of Goltz syndrome. METHODS: Case report. RESULTS: A now 4-year old girl was diagnosed at birth with Goltz syndrome. Best-corrected visual acuity was 1/60 in both eyes. Slitlamp examination showed bilateral iris colobomata and inferior subluxation of the lens with abnormally stretched ciliary processes. Funduscopy revealed bilateral chorioretinal and optic disc colobomata. CONCLUSIONS: Ocular anomalies are often associated with Goltz syndrome. Although ectopia lentis is a known ocular feature, this is the first case of lens subluxation with additional, abnormally stretched ciliary processes.

Bifocal optic and facial nerve t-cell lymphoma.

PURPOSE: Optic nerve and optic nerve sheath infiltration by a systemic lymphoma is uncommon, but is exceedingly rare when caused by a T-cell lymphoma. This then generally occurs in association with central nervous system (CNS) involvement. We report on a rare case of optic and facial nerve T-cell lymphoma infiltration, without CNS involvement. METHODS: A 63-year old female with systemic T-cell lymphoma in clinical remission presented with painful loss of vision in the left eye. She was initially treated for presumed recurrent optic neuritis. A thorough clinical work-up was performed, followed by an optic nerve biopsy with histopathology. RESULTS: There was no perception of light in the left eye, with a marked relative afferent pupillary defect. Fundoscopy showed significant optic disc oedema and a large peripapillary subretinal infiltration. Subsequently, she developed a 7th cranial nerve paresis. Cranial MRI showed thickening and contrast enhancement of the left optic nerve and right facial nerve. Optic nerve biopsy showed infiltration of CD3- and CD5- positive lymphocytes. A complete systemic workup revealed no evidence of disease elsewhere. The patient was thus considered to have bifocal cranial recurrence of T-cell lymphoma, for which radiotherapy was started. CONCLUSIONS: Optic nerve infiltration from systemic lymphoma is rare and generally occurs with CNS involvement. A bifocal pattern of recurrence from systemic T-cell lymphoma involving the right facial nerve and left optic nerve was seen in this patient. A review of the literature highlights the highly atypical nature of this presentation.

Analysing family service needs of typically underserved families in the USA.

BACKGROUND: Present day service systems evolved from the traditional model of disability intervention where the child with the disability and the family were viewed as pathological entities that needed to be fixed rather than supported. Scholars have increasingly called for a greater focus on the family in service delivery, but few studies have empirically examined the practical reality of such a shift. The present paper examines the disability-related formal service supports within the family quality of life (FQOL) framework in a sample of predominantly low-income, minority families in the USA. METHODS: Cross-sectional data collected from a convenience sample of 149 families using the Family Quality of Life Survey (FQOLS-2006) was analysed at the univariate, bivariate and multivariate levels. RESULTS: Over half of the families indicated that they needed more help from the service system, and the largest barrier to accessing services was a lack of information. Almost all families viewed service support as very important to their overall FQOL; however, only half of them were satisfied with the formal support that they were receiving. Less than half of the families reported having many service support opportunities and high attainment of service support, although most took high initiative in pursuing formal supports. The path model illustrated the complex inter-relationships between the six dimensions of service support. CONCLUSIONS: Findings underscore the need for resources to empower families and the value of using the FQOLS-2006 to ascertain the service support needs and strengths of families.

[Practical application of the charter of pharmaceutical sales visit]. / Application pratique de la charte de la visite médicale.

BACKGROUND: Visits from pharmaceutical representatives are controlled in France by regulations, but also by a Charter of good practice. The goal of this study was to measure compliance to the conditions of this charter by participating pharmaceutical companies. MATERIAL AND METHODS: An assessment grid was drafted to determine compliance to interdictions and obligations concerning the information provided during visits from pharmaceutical representatives. RESULTS: We studied 20 visits from pharmaceutical representatives. All of the documents and obligatory information were only provided in 5% of cases. During 80% of these meetings, the pharmaceutical representatives made a comparison with competitor's drugs, which was associated with negative remarks in 44% of cases. The pharmaceutical representatives promoted cases of use outside those, which had received marketing approval in 35%. Gifts or samples were offered at the end of these meetings in 20% of cases. Prohibited practices were observed in a total of 85% of cases. DISCUSSION: This study shows that meetings are respected by pharmaceutical representatives in terms of regulations related to donations. In opposite, there is a very low compliance concerning the proper use of the drug, whether to provide official documentation, to give information respectful of other pharmaceutical companies or to promote the proper use. CONCLUSION: Our results suggest that, at present hospital visits by pharmaceutical representatives do not respect the commitments made by the pharmaceutical industry, and do not make it possible to ensure that honest information is provided to favor the proper use of drugs.

[Audits of good practice: implantable medical devices are also concerned]. / Audits de bon usage : les dispositifs médicaux implantables sont aussi concernés.

INTRODUCTION: Within the framework of a good practices agreement, French hospitals must perform clinical audits of costly molecules and implantable medical devices (IMD) to justify their medical costs. We present two examples of clinical audits of IMD: hip arthroplasties and cardiac stimulators. PATIENTS AND METHODS: The clinical audits were managed by the pharmacy with the support of the medical teams. Retrospective evaluation of patient files was performed by a pharmaceutical team using evaluation grids developed from official references from the French National Authority for Health and French National Health Insurance. RESULTS: The audit of hip arthroplasty procedures, including a retrospective and prospective study, showed that 95.4% and 96.9% of the surgical procedures followed guidelines. The audit of cardiac stimulators showed 100% agreement with guidelines. The audit of traceability showed that 97% of the files were complete. DISCUSSION: These audits show that the cost increases of the IMD are linked to following guidelines. It is important for these audits of pertinent use to be performed by both physicians and pharmacists. CONCLUSION: There is very little information in the literature or from authorities to help implement these audits. It would be interesting to propose common prospective and retrospective methods to evaluate the pertinent use of IMD.

Impact of cascade reporting of antimicrobial susceptibility on fluoroquinolone and meropenem consumption at a Veterans' Affairs medical center.

OBJECTIVE: To determine whether cascade reporting is associated with a change in meropenem and fluoroquinolone consumption. DESIGN: A quasi-experimental study was conducted using an interrupted time series to compare antimicrobial consumption before and after the implementation of cascade reporting. SETTING: A 399-bed, tertiary-care, Veterans' Affairs medical center. PARTICIPANTS: Antimicrobial consumption data across 8 inpatient units were extracted from the Center for Disease Control and Prevention (CDC) National Health Safety Network (NHSN) antimicrobial use (AU) module from April 2017 through March 2019, reported as antimicrobial days of therapy (DOT) per 1,000 days present (DP). INTERVENTION: Cascade reporting is a strategy of reporting antimicrobial susceptibility test results in which secondary agents are only reported if an organism is resistant to primary, narrow-spectrum agents. A multidisciplinary team developed cascade reporting algorithms for gram-negative bacteria based on local antibiogram and infectious diseases practice guidelines, aimed at restricting the use of fluoroquinolones and carbapenems. The algorithms were implemented in March 2018. RESULTS: Following the implementation of cascade reporting, mean monthly meropenem (P =.005) and piperacillin/tazobactam (P = .002) consumption decreased and cefepime consumption increased (P < .001). Ciprofloxacin consumption decreased by 2.16 DOT per 1,000 DP per month (SE, 0.25; P < .001). Clostridioides difficile rates did not significantly change. CONCLUSION: Ciprofloxacin consumption significantly decreased after the implementation of cascade reporting. Mean meropenem consumption decreased after cascade reporting was implemented, but we observed no significant change in the slope of consumption. cascade reporting may be a useful strategy to optimize antimicrobial prescribing.

Benzimidazole analogs inhibit human herpesvirus 6.

Several benzimidazole nucleoside analogs, including 1H-ß-D-ribofuranosyl-2-bromo-5,6-dichlorobenzimidazole (BDCRB) and 1H-ß-L-ribofuranosyl-2-isopropylamino-5,6-dichlorobenzimidazole (maribavir [MBV]), inhibit the replication of human cytomegalovirus. Neither analog inhibited the related betaherpesvirus human herpesvirus 6 (HHV-6). Additional analogs of these compounds were evaluated against both variants of HHV-6, and two L-analogs of BDCRB had good antiviral activity against HHV-6A, as well as more modest inhibition of HHV-6B replication.

Genome sequence of the edible cyanobacterium Arthrospira sp. PCC 8005.

We determined the genome sequence of Arthrospira sp. PCC 8005, a cyanobacterial strain of great interest to the European Space Agency for its nutritive value and oxygenic properties in the Micro-Ecological Life Support System Alternative (MELiSSA) biological life support system for long-term manned missions into space.

Inhibition of human immunodeficiency virus type 1 by triciribine involves the accessory protein nef.

Triciribine (TCN) is a tricyclic nucleoside that inhibits human immunodeficiency virus type 1 (HIV-1) replication by a unique mechanism not involving the inhibition of enzymes directly involved in viral replication. This activity requires the phosphorylation of TCN to its 5' monophosphate by intracellular adenosine kinase. New testing with a panel of HIV and simian immunodeficiency virus isolates, including low-passage-number clinical isolates and selected subgroups of HIV-1, multidrug resistant HIV-1, and HIV-2, has demonstrated that TCN has broad antiretroviral activity. It was active in cell lines chronically infected with HIV-1 in which the provirus was integrated into chromosomal DNA, thereby indicating that TCN inhibits a late process in virus replication. The selection of TCN-resistant HIV-1 isolates resulted in up to a 750-fold increase in the level of resistance to the drug. DNA sequence analysis of highly resistant isolate HIV-1(H10) found five point mutations in the HIV-1 gene nef, resulting in five different amino acid changes. DNA sequencing of the other TCN-resistant isolates identified at least one and up to three of the same mutations observed in isolate HIV-1(H10). Transfer of the mutations from TCN-resistant isolate HIV-1(H10) to wild-type virus and subsequent viral growth experiments with increasing concentrations of TCN demonstrated resistance to the drug. We conclude that TCN is a late-phase inhibitor of HIV-1 replication and that mutations in nef are necessary and sufficient for TCN resistance.