Protease inhibitor associated mutations compromise the efficacy of therapy in human immunodeficiency virus – 1 (HIV-1) infected pediatric patients: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Although the introduction of combined therapy with reverse transcriptase and protease inhibitors has resulted in considerable decrease in HIV related mortality; it has also induced the development of multiple drug-resistant HIV-1 variants.</p> <p>The few studies on HIV-1 mutagenesis in HIV infected children have not evaluated the impact of HIV-1 mutations on the clinical, virological and immunological presentation of HIV disease that is fundamental to optimizing the treatment regimens for these patients.</p> <p>Results</p> <p>A cross sectional study was conducted to evaluate the impact of treatment regimens and resistance mutation patterns on the clinical, virological, and immunological presentation of HIV disease in 41 children (25 male and 16 female) at the Robert Wood Johnson Pediatric AIDS Program in New Brunswick, New Jersey. The study participants were symptomatic and had preceding treatment history with combined ARV regimens including protease inhibitors (PIs), nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Fifteen (36.6%) children were treated with NRTI+NNRTI+ PI, 6 (14.6%) with NRTI+NNRTIs, 13 (31.7%) with NRTI+PIs, and the remaining 7 (17.1%) received NRTIs only.</p> <p>Combined ARV regimens did not significantly influence the incidence of NRTI and NNRTI associated mutations. The duration of ARV therapy and the child's age had no significant impact on the ARV related mutations. The clinico-immunological presentation of the HIV disease was not associated with ARV treatment regimens or number of resistance mutations. However, primary mutations in the protease (PR) gene increased the likelihood of plasma viral load (PVL) ≥ 10,000 copies/mL irrespective of the child's age, duration of ARV therapy, presence of NRTI and NNRTI mutation. Viremia ≥ 10,000 copies/mL was recorded in almost all the children with primary mutations in the PR region (n = 12/13, 92.3%) as compared with only 50.0% (n = 14/28) of HIV infected children without (PR-), P < 0.008. However, CD-4 T cells were not affected by the mutations in the PR gene of the HIV-1 isolates.</p> <p>Conclusion</p> <p>Primary PR resistance mutations significantly increase the likelihood for high viral replication in pediatric patients with moderate/severe HIV-1 infection, which may affect the long-term clinical prognosis of the HIV infected children.</p

Intracerebral Hemorrhage with Intraventricular Extension—Getting the Prognosis Right Early

BackgroundEarly accurate outcome prognostication for patients with intracerebral hemorrhage (ICH) and accompanying intraventricular hemorrhage (IVH) is often challenging (1). Acute hydrocephalus often contributes to a poor clinical exam (2) and can portend significant morbidity and mortality (3). Accordingly, the inpatient neurologist may feel inclined to recommend limitations of care for an ICH patient admitted with a large IVH burden and poor exam.Case presentationWe present a patient with significant IVH and minimal ICH who deteriorated rapidly to coma after presentation. Despite this exam, an initially non-functioning diversion of cerebrospinal fluid (CSF) and temporary halt of further attempts of CSF diversion in the setting of an early “do not resuscitate order,” our patient gradually improved and, with supportive ICU care and rehabilitation, was able to communicate and ambulate with assistance at 12 weeks.ConclusionPatients with ICH with IVH do have the capacity to improve dramatically even with relatively conservative management. Unless previous limitations of care exist, we recommend that early judgments of prognosis for patients with ICH and/or IVH should be delayed for at least 72 h until the patient’s clinical trajectory over time is better understood

A Neurology Clerkship Curriculum Using Video-Based Lectures and Just-in-Time Teaching (JiTT)

Just-in-time teaching is an educational strategy that involves tailoring in-session learning activities based on student performance in presession assessments. We implemented this strategy in a third-year neurology clerkship. Linked to core neurology clerkship lectures, eight brief video-based lectures and knowledge assessments were developed. Students watched videos and completed multiple-choice questions, and results were provided to faculty, who were given the opportunity to adjust the in-person lecture accordingly. Feedback was obtained by surveys of students and faculty lecturers and from student focus groups and faculty. Student performance on the end-of-clerkship examination was analyzed. Between October 2016 and April 2017, 135 students participated in the curriculum, and 56 students (41.5%) responded to the surveys. Most students agreed or strongly agreed that the new curriculum enhanced their learning and promoted their sense of responsibility in learning the content. Faculty agreed that this pedagogy helped prepare students for class. Most students watched the entire video-based lecture, although there was a trend toward decreased audience retention with longer lectures. There were no significant changes in performance on the end-of-clerkship examination after implementation of just-in-time teaching. In focus groups, students emphasized the importance of tying just-in-time teaching activities to the lecture and providing video-based lectures well in advance of the lectures. Just-in-time teaching using video-based lectures is an acceptable and feasible method to augment learning during a neurology clinical clerkship. We believe this method could be used in other neurology clerkships with similar success

Cerebral Blood Flow Response During Bolus Normal Saline Infusion After Ischemic Stroke

We quantified cerebral blood flow response to a 500 cc bolus of 0.9%% normal saline (NS) within 96 hours of acute ischemic stroke (AIS) using diffuse correlation spectroscopy (DCS). Materials and Methods: Subjects with AIS in the anterior, middle, or posterior cerebral artery territory were enrolled within 96 hours of symptom onset. DCS measured relative cerebral blood flow (rCBF) in the bilateral frontal lobes for 15 minutes at rest (baseline), during a 30-minute infusion of 500 cc NS (bolus), and for 15 minutes after completion (post-bolus). Mean rCBF for each time period was calculated for individual subjects and median rCBF for the population was compared between time periods. Linear regression was used to evaluate for associations between rCBF and clinical features. Results: Among 57 subjects, median rCBF (IQR) increased relative to baseline in the ipsilesional hemisphere by 17% (-2.0%, 43.1%), P< 0.001, and in the contralesional hemisphere by 13.3% (-4.3%, 36.0%), P < .004. No significant associations were found between ipsilesional changes in rCBF and age, race, infarct size, infarct location, presence of large vessel stenosis, NIH stroke scale, or symptom duration. Conclusion: A 500 cc bolus of .9% NS produced a measurable increase in rCBF in both the affected and nonaffected hemispheres. Clinical features did not predict rCBF response2811NINDSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) [R01 NS060653]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [P41-EB015893, R25 NS065745

Coronal Heating as Determined by the Solar Flare Frequency Distribution Obtained by Aggregating Case Studies

Flare frequency distributions represent a key approach to addressing one of the largest problems in solar and stellar physics: determining the mechanism that counter-intuitively heats coronae to temperatures that are orders of magnitude hotter than the corresponding photospheres. It is widely accepted that the magnetic field is responsible for the heating, but there are two competing mechanisms that could explain it: nanoflares or Alfv\'en waves. To date, neither can be directly observed. Nanoflares are, by definition, extremely small, but their aggregate energy release could represent a substantial heating mechanism, presuming they are sufficiently abundant. One way to test this presumption is via the flare frequency distribution, which describes how often flares of various energies occur. If the slope of the power law fitting the flare frequency distribution is above a critical threshold, $\alpha=2$ as established in prior literature, then there should be a sufficient abundance of nanoflares to explain coronal heating. We performed $>$600 case studies of solar flares, made possible by an unprecedented number of data analysts via three semesters of an undergraduate physics laboratory course. This allowed us to include two crucial, but nontrivial, analysis methods: pre-flare baseline subtraction and computation of the flare energy, which requires determining flare start and stop times. We aggregated the results of these analyses into a statistical study to determine that $\alpha = 1.63 \pm 0.03$. This is below the critical threshold, suggesting that Alfv\'en waves are an important driver of coronal heating.Comment: 1,002 authors, 14 pages, 4 figures, 3 tables, published by The Astrophysical Journal on 2023-05-09, volume 948, page 7