Features of recently transmitted HIV-1 clade C viruses that impact antibody recognition : implications for active and passive immunization.

CAPRISA, 2016.Abstract available in PDF file

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Integrating Personalized Technology in Toxicology: Sensors, Smart Glass, and Social Media Applications in Toxicology Research

Rapid proliferation of mobile technologies in social and healthcare spaces create an opportunity for advancement in research and clinical practice. The application of mobile, personalized technology in healthcare, referred to as mHealth, has not yet become routine in toxicology. However, key features of our practice environment, such as frequent need for remote evaluation, unreliable historical data from patients, and sensitive subject matter, make mHealth tools appealing solutions in comparison to traditional methods that collect retrospective or indirect data. This manuscript describes the features, uses, and costs associated with several of common sectors of mHealth research including wearable biosensors, ingestible biosensors, head-mounted devices, and social media applications. The benefits and novel challenges associated with the study and use of these applications are then discussed. Finally, opportunities for further research and integration are explored with a particular focus on toxicology-based applications

Concerted Protein and Nucleic Acid Conformational Changes Observed Prior to Nucleotide Incorporation in a Bacterial RNA Polymerase: Raman Crystallographic Evidence

Transcription elongation requires the continuous incorporation of ribonucleotide triphosphates into a growing transcript. RNA polymerases (RNAPs) are able to processively synthesize a growing RNA chain via translocation of the RNAP enzyme along its nucleic acid template strand after each nucleotide addition cycle. In this work, a time-resolved Raman spectroscopic analysis of nucleotide addition in single crystals of the <i>Thermus thermophilus</i> elongation complex (TthEC) is reported. When [¹³C,¹⁵N]­GTP (*GTP) is soaked into crystals of the TthEC, large reversible changes in the Raman spectrum that are assigned to protein and nucleic acid conformational events during a single-nucleotide incorporation are observed. The *GTP population in the TthEC crystal reaches a stable population at 37 min, while substantial and reversible protein conformational changes (mainly ascribed to changes in α-helical Raman features) maximize at approximately 50 min. At the same time, changes in nucleic acid bases and phosphodiester backbone Raman marker bands occur. Catalysis begins at approximately 65–70 min, soon after the maximal protein and DNA changes, and is monitored via the decline in a triphosphate vibrational Raman mode from *GTP. The Raman data indicate that approximately 40% of the total triphosphate population, present as *GTP, reacts in the crystal. This may suggest that a second population of noncovalently bound *GTP resides in a site distinct from the catalytic site. The data reported here are an extension of our recent work on the elongation complex (EC) of a bacterial RNAP, <i>Thermus thermophilus</i> (Tth), where Raman spectroscopy and polyacrylamide gel electrophoresis were employed to monitor incorporation and misincorporation in single TthEC crystals [Antonopoulos, I. H., et al. (2015) <i>Biochemistry 54</i>, 652–665]. Therefore, the initial study establishes the groundwork for this study. In contrast to our previous study, in which incorporation takes place very rapidly inside the crystals, the data on this single crystal exhibit a slower time regime, which allows the dissection of the structural dynamics associated with GMP incorporation within the TthEC crystal

Faculty member writing groups support productivity

In this toolbox, the authors use the example of their own faculty member writing group to offer suggestions for setting up peer mentorship. They describe the potential pitfalls and recommend that participants share similar backgrounds, interests and aims. Regular meetings are important for goal setting and motivation. Group members review each other\u27s work in a safe environment, and share in each other\u27s successes

Replication Data for: Who Wants to Hire a More Diverse Faculty? A Conjoint Analysis of Faculty and Student Preferences for Gender and Racial/Ethnic Diversity

What explains the scarcity of women and under-represented minorities among university faculty relative to their share of Ph.D. recipients? Among many potential explanations, we focus on the “demand” side of faculty diversity. Using fully randomized conjoint analysis, we explore patterns of support for, and resistance to, the hiring of faculty candidates from different social groups at two large public universities in the U.S. We find that faculty are strongly supportive of diversity: holding other attributes of (hypothetical) candidates constant, for example, faculty at both universities are between 11 to 21 percentage points more likely to prefer a Hispanic, black, or Native American candidate to a white one. Furthermore, preferences for diversity in faculty hiring are stronger among faculty than among students. These results suggest that the primary reason for the lack of diversity among faculty is not a lack of desire to hire them, but the accumulation of implicit and institutionalized biases, and their related consequences, at later stages in the pipeline

Time-Resolved Raman and Polyacrylamide Gel Electrophoresis Observations of Nucleotide Incorporation and Misincorporation in RNA within a Bacterial RNA Polymerase Crystal

The bacterial RNA polymerase (RNAP) elongation complex (EC) is highly stable and is able to extend an RNA chain for thousands of nucleotides. Understanding the processive mechanism of nucleotide addition requires detailed structural and temporal data for the EC reaction. Here, a time-resolved Raman spectroscopic analysis is combined with polyacrylamide gel electrophoresis (PAGE) to monitor nucleotide addition in single crystals of the <i>Thermus thermophilus</i> EC (TthEC) RNAP. When the cognate base GTP, labeled with ¹³C and ¹⁵N (*GTP), is soaked into crystals of the TthEC, changes in the Raman spectra show evidence of nucleotide incorporation and product formation. The major change is the reduction of *GTP’s triphosphate intensity. Nucleotide incorporation is confirmed by PAGE assays. Both Raman and PAGE methods have a time resolution of minutes. There is also Raman spectroscopic evidence of a second population of *GTP in the crystal that does not become covalently linked to the nascent RNA chain. When this population is removed by “soaking out” (placing the crystal in a solution that contains no NTP), there are no perturbations to the Raman difference spectra, indicating that conformational changes are not detected in the EC. In contrast, the misincorporation of the noncognate base, ¹³C- and ¹⁵N-labeled UTP (*UTP), gives rise to large spectroscopic changes. As in the GTP experiment, reduction of the triphosphate relative intensity in the Raman soak-in data shows that the incorporation reaction occurs during the first few minutes of our instrumental dead time. This is also confirmed by PAGE analysis. Whereas PAGE data show *GTP converts 100% of the nascent RNA 14mer to 15mer, the noncognate *UTP converts only ∼50%. During *UTP soak-in, there is a slow, reversible formation of an α-helical amide I band in the Raman difference spectra peaking at 40 min. Similar to *GTP soak-in, *UTP soak-in shows Raman spectoscopic evidence of a second noncovalently bound *UTP population in the crystal. Moreover, the second population has a marked effect on the complex’s conformational states because removing it by “soaking-out” unreacted *UTP causes large changes in protein and nucleic acid Raman marker bands in the time range of 10–100 min. The conformational changes observed for noncognate *UTP may indicate that the enzyme is preparing for proofreading to excise the misincorporated base. This idea is supported by the PAGE results for *UTP soak-out that show endonuclease activity is occurring

Sex Differences in Pediatric Poisonings by Age Group: a Toxicology Investigators\u27 Consortium (ToxIC) Analysis (2010-2016).

OBJECTIVE: To review pediatric poisonings evaluated at the bedside by medical toxicologists and reported in the ToxIC registry, by sex and age group. METHODS: Pediatric poisoning cases age ≤18 years, reported between January 2010 and December 2016, were reviewed. Descriptive statistics were used to describe study variables by age group and sex. RESULTS: A total of 12,699 cases were analyzed. There were 7517 females and 5182 males. Those \u3c 2 years old represented 12.5% of the study group (n = 1584), 17.2% were 2-6 years old (n = 2178), 8.6% were 7-12 years old (n = 1097), and 61.7% were 13-18 years old (n = 7840). The most common primary reasons for encounter were intentional pharmaceutical with 4900 females and 1836 males; intentional non-pharmaceutical with 952 females and 1213 males; unintentional pharmaceutical with 539 females and 644 males; and unintentional non-pharmaceutical with 435 females and 593 males. Overall, pharmaceuticals were the most commonly involved agents, including analgesics (20.9% of cases) and antidepressants (11% of cases): 27.8% of females and 10.7% of males were reportedly exposed to an analgesic.13.7% of females and 7.0% of males were reportedly exposed to an antidepressant. Among 1584 cases under 2 years, there were 747 females and 837 males; among 2178 cases aged 2-6 years, there were 954 females and 1224 males; among 1097 cases aged 7-12 years, there were 555 females and 542 males; and among 7840 cases aged 13-18 years, there were 5261 females and 2579 males. Death was reported in 0.7% of the cases: 20 females and 18 males. 6.1% of cases were managed with intubation: 421 females and 351 males. CONCLUSIONS: Sex-based characteristics of poisonings varied by age group among pediatric poisoning presentations reported to the ToxIC registry and further research is needed to determine implications for education and prevention efforts