Clinical utility of archived HIV-1 DNA sequencing: Optimizing antiretroviral therapy in patients with a suppressed HIV viral load

Introduction: Viral resistance testing is a cornerstone for selecting antiretroviral therapy (ART) in patients with HIV. Recommendations regarding regimen switching in the setting of virologic suppression are not standardized, but genotypic assays are frequently utilized in this scenario to help determine an efficacious medication regimen. Currently, only one genotypic assay (GA) is available for patients whose HIV RNA is less than 500 copies/mL. Little data exists for its clinical significance or utility in practice.Research Question or Hypothesis: This study aims to assess the utility of the GA by comparing ART regimens and HIV RNA pre- and post-GA.Study Design: This study is a retrospective chart review based on GA reports obtained historically through the Oklahoma State University Internal Medicine Specialty Clinic electronic medical record.Methods: The information gathered consisted of clinical indications for a GA, mutations on GA results, ART at the time of the archive draw, and ART post-GA results. Demographic and disease related information will also be collected. Other information gathered included reported compliance to therapy, and regimen tolerability.Results: Data were gathered from 67 patients, primarily male (87%), with an average age of 45. The most common indications for obtaining a GA were baseline testing (29.8%), re-establishing care (25.4%), and history of non-adherence (20.9%). Approximately half (49%) of patients had an undetectable viral load 3 months after switching their ART regimen based on GA results

Antibiotic prescriptions upon hospital discharge: A blind spot of antimicrobial stewardship

Background: Transitions of care are a known source of patient vulnerability. The incidence of medication errors during transitions of care is well-documented.1 Discharge from the hospital has proven to be one area where antimicrobial stewardship is absent or lacking and can result in: poor clinical outcomes, adverse drug events, and emergence of multidrug resistant organisms. In one study, 53% of cases reviewed found antibiotics prescribed at discharge were inappropriate.1 Large discrepancies exist between guideline recommendations and antimicrobials prescribed upon hospital discharge.2 At this time, no prior study at OSU Medical Center has analyzed the impact of antimicrobial stewardship at hospital discharge.Methods: This study will be a retrospective chart review based on a report of patients age 18 years and older discharged from OSUMC from 7/1/2018 to 6/30/2019 with CAP or uncomplicated UTI. This data will be used to determine whether optimal antibiotic therapy was prescribed upon hospital discharge. Optimal therapy is defined as: prescription in accordance with nationally-approved guidelines for the management of CAP and UTI; effective and narrowest spectrum of activity; correct dose for indication, organ dysfunction, and medication allergies; and correct duration of therapy. This study will also the assess antibiotic classes most frequently involved in errors, as well as the most commonly occurring types of errors (incorrect drug, dose, or duration). Patients with multiple types of infection will be excluded from the study. Data collected will be organized and evaluated using REDCapTM. The following data will be obtained: date of discharge, days of optimal inpatient antibiotic therapy, discharge antibiotics regimen, infection type (CAP vs. uncomplicated UTI), pertinent laboratory and microbiology data, and bacteria cultured with source and date results finalized.Results: Data collection is still ongoing. At this time, 1402 patient charts have been reviewed, and 168 patient charts met inclusion criteria. Of those included, patients were primarily female (63%) with an average age of 62 (range 21-95), and 43% were discharged on a suboptimal antibiotic regimen. The most common reason for a suboptimal regimen was an inappropriate duration of therapy (92%) followed by an incorrect medication dose (26%).Conclusions: At the time of this writing, duration of therapy far outweighs any other cause for a suboptimal discharge antibiotic regimen. By completing this study, we hope to gain more insight into how we can better serve our institution by educating physicians, reducing errors, and optimizing transitions of care

Fluorescence correlation spectroscopy, combined with bimolecular fluorescence complementation, reveals the effects of β-arrestin complexes and endocytic targeting on the membrane mobility of neuropeptide Y receptors

Fluorescence correlation spectroscopy (FCS) and photon counting histogram (PCH) analysis are powerful ways to study mobility and stoichiometry of G protein coupled receptor complexes, within microdomains of single living cells. However, relating these properties to molecular mechanisms can be challenging. We investigated the influence of β-arrestin adaptors and endocytosis mechanisms on plasma membrane diffusion and particle brightness of GFP-tagged neuropeptide Y (NPY) receptors. A novel GFP-based bimolecular fluorescence complementation (BiFC) system also identified Y1 receptor-β-arrestin complexes. Diffusion co-efficients (D) for Y1 and Y2-GFP receptors in HEK293 cell plasma membranes were 2.22 and 2.15×10−9 cm2 s−1 respectively. At a concentrationwhich promoted only Y1 receptor endocytosis, NPY treatment reduced Y1-GFPmotility (D 1.48×10−9 cm2 s−1), but did not alter diffusion characteristics of the Y2-GFP receptor. Agonist induced changes in Y1 receptor motility were inhibited by mutations (6A) which prevented β-arrestin recruitment and internalisation; conversely they became apparent in a Y2 receptor mutant with increased β-arrestin affinity. NPY treatment also increased Y1 receptor-GFP particle brightness, changes which indicated receptor clustering, and which were abolished by the 6A mutation. The importance of β-arrestin recruitment for these effects was illustrated by reduced lateral mobility (D 1.20–1.33×10−9 cm2 s−1) of Y1 receptor-β-arrestin BiFC complexes. Thus NPY-induced changes in Y receptormotility and brightness reflect early events surrounding arrestin dependent endocytosis at the plasma membrane, results supported by a novel combined BiFC/FCS approach to detect the underlying receptor-β-arrestin signalling complex

Fluorescence correlation spectroscopy, combined with bimolecular fluorescence complementation, reveals the effects of β-arrestin complexes and endocytic targeting on the membrane mobility of neuropeptide Y receptors

Fluorescence correlation spectroscopy (FCS) and photon counting histogram (PCH) analysis are powerful ways to study mobility and stoichiometry of G protein coupled receptor complexes, within microdomains of single living cells. However, relating these properties to molecular mechanisms can be challenging. We investigated the influence of β-arrestin adaptors and endocytosis mechanisms on plasma membrane diffusion and particle brightness of GFP-tagged neuropeptide Y (NPY) receptors. A novel GFP-based bimolecular fluorescence complementation (BiFC) system also identified Y1 receptor-β-arrestin complexes. Diffusion co-efficients (D) for Y1 and Y2-GFP receptors in HEK293 cell plasma membranes were 2.22 and 2.15×10−9 cm2 s−1 respectively. At a concentrationwhich promoted only Y1 receptor endocytosis, NPY treatment reduced Y1-GFPmotility (D 1.48×10−9 cm2 s−1), but did not alter diffusion characteristics of the Y2-GFP receptor. Agonist induced changes in Y1 receptor motility were inhibited by mutations (6A) which prevented β-arrestin recruitment and internalisation; conversely they became apparent in a Y2 receptor mutant with increased β-arrestin affinity. NPY treatment also increased Y1 receptor-GFP particle brightness, changes which indicated receptor clustering, and which were abolished by the 6A mutation. The importance of β-arrestin recruitment for these effects was illustrated by reduced lateral mobility (D 1.20–1.33×10−9 cm2 s−1) of Y1 receptor-β-arrestin BiFC complexes. Thus NPY-induced changes in Y receptormotility and brightness reflect early events surrounding arrestin dependent endocytosis at the plasma membrane, results supported by a novel combined BiFC/FCS approach to detect the underlying receptor-β-arrestin signalling complex

A G protein-coupled receptor dimer imaging assay reveals selectively modified pharmacology of neuropeptide Y Y1/Y5 receptor heterodimers

The ability of G protein-coupled receptors (GPCRs) to form dimers, and particularly heterodimers, offers potential for targeted therapeutics with improved selectivity. However, studying dimer pharmacology is challenging, because of signaling cross-talk or because dimerization may often be transient in nature. Here we develop a system to isolate the pharmacology of precisely defined GPCR dimers, trapped by bimolecular fluorescence complementation (BiFC). Specific effects of agonist activation on such dimers are quantified using automated imaging and analysis of their internalization, controlled for by simultaneous assessment of endocytosis of one coexpressed protomer population. We applied this BiFC system to study example neuropeptide Y (NPY) Y1 receptor dimers. Incorporation of binding-site or phosphorylation-site mutations into just one protomer of a Y1/Y1 BiFC homodimer had no impact on efficient NPY-stimulated endocytosis, demonstrating that single-site agonist occupancy, and one phosphorylated monomer within this dimer, was sufficient. For two Y1 receptor heterodimer combinations (with the Y4 receptor or β2-adrenoceptor), agonist and antagonist pharmacology was explained by independent actions on the respective orthosteric binding sites. However, Y1/Y5 receptor BiFC dimers, compared with the constituent subtypes, were characterized by reduced potency and efficacy of Y5-selective peptide agonists, the inactivity of Y1-selective antagonists, and a change from surmountable to nonsurmountable antagonism for three unrelated Y5 antagonists. Thus, allosteric interactions between Y1 and Y5 receptors modify the pharmacology of the heterodimer, with implications for potential antiobesity agents that target centrally coexpressed Y1 and Y5 receptors to suppress appetite

Development of Fetal Movement Between 26 and 36 Weeks’ Gestation in Response to Vibroacoustic Stimulation

BACKGROUND: Ultrasound observation of fetal movement has documented general trends in motor development and fetal age when motor response to stimulation is observed. Evaluation of fetal movement quality, in addition to specific motor activity, may improve documentation of motor development and highlight specific motor responses to stimulation. AIM: The aim of this investigation was to assess fetal movement at 26 and 36-weeks gestation during three conditions (baseline, immediate response to vibro-acoustic stimulation (VAS), and post-response). DESIGN: A prospective, longitudinal design was utilized. SUBJECTS: Twelve normally developing fetuses, eight females and four males, were examined with continuous ultrasound imaging. OUTCOME MEASURES: The fetal neurobehavioral coding system (FENS) was used to evaluate the quality of motor activity during 10-s epochs over the three conditions. RESULTS: Seventy-five percent of the fetuses at the 26-week assessment and 100% of the fetuses at the 36-week assessment responded with movement immediately following stimulation. Significant differences in head, fetal breathing, general, limb, and mouthing movements were detected between the 26 and 36-week assessments. Movement differences between conditions were detected in head, fetal breathing, limb, and mouthing movements. CONCLUSION: Smoother and more complex movement was observed with fetal maturation. Following VAS stimulation, an immediate increase of large, jerky movements suggests instability in fetal capabilities. Fetal movement quality changes over gestation may reflect sensorimotor synaptogenesis in the central nervous system, while observation of immature movement patterns following VAS stimulation may reflect movement pattern instability

Co-creation of a complex, multicomponent rehabilitation intervention and feasibility trial protocol for the PostUraL tachycardia Syndrome Exercise (PULSE) study

Background: There is a dearth of research to support the treatment of people with postural tachycardia syndrome (PoTS). Despite expert consensus suggesting exercise is recommended for this patient group, there are no randomised control trials examining this rigorously. The aim was to co-create a feasibility trial protocol and a rehabilitation intervention for people living with PoTS. // Methods: The intervention and feasibility trial design were co-created as part of the PostUraL tachycardia Syndrome Exercise (PULSE) study. We used the ‘three co’s framework’ of co-define, co-design and co-refine. Recruitment included key national charities and National Health Service Trusts treating people living with PoTS in the UK. Eighteen patient and public involvement members attended the co-define session, and 16 co-creators with a mix of expertise attended the subsequent co-design and co-refine sessions. Seven intervention practitioners were trained in the rehabilitation intervention, providing feedback for further co-refinement. // Results: The final co-created intervention comprises online physical activity, and lifestyle and behaviour change support sessions. It is based on functional movement activities using a patient-centred approach tailored to individual needs. Physical activity intensity is guided by individuals’ perception of effort rather than by objective measures. Recumbent bikes are provided for home use. Patients deemed randomisation to be acceptable because research in this area was considered important. // Conclusions: An innovative approach was used to co-create the PULSE intervention and feasibility trial protocol to meet the evidence-based and logistical needs of people living with PoTS, clinicians, service deliverers, third-sector organisations, academics and funders. This can be used as a successful example and template for future research internationally. People living with PoTS were recognised as experts and involved in every aspect of conceptualisation, design and refinement. This complex rehabilitation intervention is currently being tested in a randomised feasibility trial comparing the PULSE intervention with best-practice usual care for people living with PoTS. // Trial registration: ISRCTN45323485 was registered on April 7, 2020

Model-observation and reanalyses comparison at key locations for heat transport to the Arctic: Assessment of key lower latitude influences on the Arctic and their simulation

Blue-Action Work Package 2 (WP2) focuses on lower latitude drivers of Arctic change, with a focus on the influence of the Atlantic Ocean and atmosphere on the Arctic. In particular, warm water travels from the Atlantic, across the Greenland-Scotland ridge, through the Norwegian Sea towards the Arctic. A large proportion of the heat transported northwards by the ocean is released to the atmosphere and carried eastward towards Europe by the prevailing westerly winds. This is an important contribution to northwestern Europe's mild climate. The remaining heat travels north into the Arctic. Variations in the amount of heat transported into the Arctic will influence the long term climate of the Northern Hemisphere. Here we assess how well the state of the art coupled climate models estimate this northwards transport of heat in the ocean, and how the atmospheric heat transport varies with changes in the ocean heat transport. We seek to improve the ocean monitoring systems that are in place by introducing measurements from ocean gliders, Argo floats and satellites. These state of the art computer simulations are evaluated by comparison with key trans-Atlantic observations. In addition to the coupled models ‘ocean-only’ evaluations are made. In general the coupled model simulations have too much heat going into the Arctic region and the transports have too much variability. The models generally reproduce the variability of the Atlantic Meridional Ocean Circulation (AMOC) well. All models in this study have a too strong southwards transport of freshwater at 26°N in the North Atlantic, but the divergence between 26°N and Bering Straits is generally reproduced really well in all the models. Altimetry from satellites have been used to reconstruct the ocean circulation 26°N in the Atlantic, over the Greenland Scotland Ridge and alongside ship based observations along the GO-SHIP OVIDE Section. Although it is still a challenge to estimate the ocean circulation at 26°N without using the RAPID 26°N array, satellites can be used to reconstruct the longer term ocean signal. The OSNAP project measures the oceanic transport of heat across a section which stretches from Canada to the UK, via Greenland. The project has used ocean gliders to great success to measure the transport on the eastern side of the array. Every 10 days up to 4000 Argo floats measure temperature and salinity in the top 2000m of the ocean, away from ocean boundaries, and report back the measurements via satellite. These data are employed at 26°N in the Atlantic to enable the calculation of the heat and freshwater transports. As explained above, both ocean and atmosphere carry vast amounts of heat poleward in the Atlantic. In the long term average the Atlantic ocean releases large amounts of heat to the atmosphere between the subtropical and subpolar regions, heat which is then carried by the atmosphere to western Europe and the Arctic. On shorter timescales, interannual to decadal, the amounts of heat carried by ocean and atmosphere vary considerably. An important question is whether the total amount of heat transported, atmosphere plus ocean, remains roughly constant, whether significant amounts of heat are gained or lost from space and how the relative amount transported by the atmosphere and ocean change with time. This is an important distinction because the same amount of anomalous heat transport will have very different effects depending on whether it is transported by ocean or the atmosphere. For example the effects on Arctic sea ice will depend very much on whether the surface of the ice experiences anomalous warming by the atmosphere versus the base of the ice experiencing anomalous warming from the ocean. In Blue-Action we investigated the relationship between atmospheric and oceanic heat transports at key locations corresponding to the positions of observational arrays (RAPID at 26°N, OSNAP at ~55N, and the Denmark Strait, Iceland-Scotland Ridge and Davis Strait at ~67N) in a number of cutting edge high resolution coupled ocean-atmosphere simulations. We split the analysis into two different timescales, interannual to decadal (1-10 years) and multidecadal (greater than 10 years). In the 1-10 year case, the relationship between ocean and atmosphere transports is complex, but a robust result is that although there is little local correlation between oceanic and atmospheric heat transports, Correlations do occur at different latitudes. Thus increased oceanic heat transport at 26°N is accompanied by reduced heat transport at ~50N and a longitudinal shift in the location of atmospheric flow of heat into the Arctic. Conversely, on longer timescales, there appears to be a much stronger local compensation between oceanic and atmospheric heat transport i.e. Bjerknes compensation

COVID-19 in the Community: Changes to Women's Mental Health, Financial Security, and Physical Activity

Introduction This study describes changes in the mental health, financial security, and physical activity levels of women in North Carolina during the COVID-19 pandemic. Methods Data were collected from women aged 20–40 years receiving primary care at 2 health centers in North Carolina during 2020–2022. Surveys (N=127) evaluated changes in mental health, financial security, and physical activity during the COVID-19 pandemic. These outcomes were analyzed both descriptively and for association with sociodemographic factors using logistic regression. A subset of participants (n=46) participated in semistructured interviews. Interview transcripts were reviewed and evaluated for recurring themes by primary and secondary coders using a rapid-coding technique. Analysis was conducted in 2022. Results Women surveyed were 28.4% non-Hispanic White, 38.6% non-Hispanic Black, and 33.1% Hispanic/Latina. Compared with reports before the pandemic, participants reported increased frustration or boredom (69.1%), loneliness (51.6%), anxiety (64.3%), depression (52.4%), and changed sleep patterns (68.3%). Increased alcohol and other recreational substance use were associated with race and ethnicity (p<0.05) after adjustment for other sociodemographic factors. Participants reported difficulty in paying for basic expenses (44.0%). Financial difficulties during COVID-19 were associated with non-Hispanic Black race and ethnicity, less education, and lower prepandemic household income. Data showed pandemic-associated reductions in mild (32.8%), moderate (39.5%), and strenuous (43.3%) exercise, with a correlation between increased depression and reduced mild exercise. Interviews identified themes including reduced activity while working remotely, lack of gym access, and reduced motivation for exercise. Conclusions This mixed-methods study is one of the first to evaluate the mental health, financial security, and physical activity challenges women aged between 20 and 40 years in the southern U.S. faced during the COVID-19 pandemic

Freshwater exports from Arctic to the Labrador and Greenland shelf andslope.

Publisher's version (útgefin grein)We investigate whether one can detect changes in the freshwater contributions to the North Atlantic subpolar gyre(SPG), in light of the observed recent decrease of salinity in the region. We focus on two important conduits offreshwater from the Arctic to the interior North Atlantic subpolar gyre: the Coastal Labrador Current and thesouthern Greenland shelf, and use a dataset of different freshwater tracers from a set of cruises over the period2010-2014.Icelandic research institute (RANNÍS no. 152229)Peer reviewe