Differential susceptibility of cells infected with defective and intact HIV proviruses to killing by obatoclax and other small molecules.

OBJECTIVES: Some drugs that augment cell-intrinsic defenses or modulate cell death/survival pathways have been reported to selectively kill cells infected with HIV or SIV, but comparative studies are lacking. We hypothesized that these drugs may differ in their ability to kill cells infected with intact and defective proviruses. DESIGN: To investigate this hypothesis, drugs were tested ex vivo on Peripheral Blood Mononuclear Cells (PBMC) from nine ART-suppressed individuals. METHODS: We tested drugs currently in clinical use or human trials, including auranofin (p53 modulator), interferon alpha2A, interferon gamma, acitretin (RIG-I inducer), GS-9620/vesatolimod (TLR7 agonist), nivolumab (PD-1 blocker), obatoclax (Bcl-2 inhibitor), birinapant (IAP inhibitor), bortezomib (proteasome inhibitor), and INK128/sapanisertib (mTOR[c]1/2 inhibitor). After six days of treatment, we measured cell counts/viabilities and quantified levels of total, intact, and defective HIV DNA by droplet digital PCR (Intact Proviral DNA Assay). RESULTS: Obatoclax reduced intact HIV DNA (median = 27-30% of DMSO) but not defective or total HIV DNA. Other drugs showed no statistically significant effects. CONCLUSIONS: Obatoclax and other Bcl-2 inhibitors deserve further study in combination therapies aimed at reducing the intact HIV reservoir in order to achieve a functional cure and/or reduce HIV-associated immune activation.

Effectiveness and Safety of Endoanchors in Abdominal and Thoracic Endovascular Aneurysm Repair: A Systematic Review and Meta-analysis.

PURPOSE: This systematic review aimed to summarize the effectiveness and safety of endoanchor, a stabilizing device for the proximal endograft designed to prevent endoleak and stent migration in endovascular aneurysm repair (EVAR) and thoracic endovascular aneurysm repair (TEVAR). MATERIALS AND METHODS: A systematic review and meta-analysis was conducted per the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guideline. Literature up to May 31, 2023 was searched and independently screened from 4 databases. Data were pooled for meta-analysis. Primary outcomes included intraoperative and follow-up endoleak, stent migration, and reintervention rates; sac regression; and 30-day all-cause mortality. RESULTS: Sixteen EVAR (n=1145) and 6 TEVAR studies (n=163) using the Heli-Fx EndoAnchor system were included from 2225 retrieved records. For EVAR patients (mean follow-up=11.9 months), the endoleak, graft migration, and reintervention rates were 3.97% (95% confidence interval [CI]=0.36%-1.99%), 0.004% (95% CI=0.00%-0.76%), and 5.43% (95% CI=0.86%-12.54%), respectively. The endoleak rates for primary and revision EVAR were 0.16% (95% CI=0.00%-1.65%) and 3.60% (95% CI=0.14%-9.72%), respectively. Only 4 cases of 30-day mortality (n=4) were reported in the literature. For TEVAR patients, the endoleak, stent migration, and reintervention rates were 7.4% (95% CI=0.03%-0.13%), 0.2% (95% CI=0.00%-0.06%), and 17.1% (95% CI=0.01%-0.45%), respectively. The 30-day mortality was 0.9% (95% CI=0%-0.12%). CONCLUSIONS: Endoanchor fixation in EVAR and TEVAR is effective and safe in preventing and treating endoleak and stent migration. The mortality is minimal in EVAR but higher in TEVAR. CLINICAL IMPACT: Endoleak, graft migration, and reintervention in EVAR and TEVAR with endoanchor use were rare. Mortality in EVAR was low. The adjunctive deployment of endoanchors is an effective and safe means to prevent and treat endoleak and stent migration in EVAR and TEVAR. Yet, long-term efficacy and safety data and randomized controlled trials would be required to definitively recommend endoanchor use in routine clinical practice.

Association of change in fat and lean mass with incident cardiovascular events for women in midlife and beyond: A prospective study using dual-energy x-ray absorptiometry (DXA).

OBJECTIVE: To determine whether changes in fat and lean mass over time, quantified using dual-energy x-ray absorptiometry (DXA), are related to incident cardiovascular events. Previous studies using surrogate anthropometric methods have had inconsistent findings. STUDY DESIGN: Prospective, longitudinal observational study of women aged 40 to 80 randomly selected from the electoral roll and stratified into decades: 40-49, 50-59, 60-69 and 70-79 years. MAIN OUTCOME MEASURES: Changes in anthropometric measurements (body mass index and waist-to-hip ratio) and DXA-quantified fat mass and lean mass between the first and fifth years of the study. Incident cardiovascular events recorded from the sixth to the 12th year. RESULTS: In total 449 participants (87.9 %) were analyzed. A 10 % or greater decrease in total fat mass index was associated with a 67 % lower likelihood of any cardiovascular event (OR = 0.33, 95%CI 0.15-0.71); no association was observed for an increase. A 10 % or greater decrease in abdominal fat mass index was associated with a 62 % lower likelihood of incident stroke (OR = 0.38, 95%CI 0.16-0.91); no association was observed for an increase. A 10 % or greater decrease in appendicular lean mass index resulted in increased odds ratio of 2.91 for incident peripheral artery events (OR = 2.91, 95%CI 1.18-7.20). CONCLUSIONS: Reducing fat mass for women in midlife and beyond may decrease the risk of cardiovascular events. An increase in fat mass may not contribute to additional cardiovascular events. A reduction in limb muscle mass may provide an independent marker for cardiometabolic risk and peripheral artery disease. No independent association was found using anthropometric measurements and incident cardiovascular events.

DNA:RNA Hybrids Are Major Dinoflagellate Minicircle Molecular Types.

Peridinin-containing dinoflagellate plastomes are predominantly encoded in nuclear genomes, with less than 20 essential chloroplast proteins carried on "minicircles". Each minicircle generally carries one gene and a short non-coding region (NCR) with a median length of approximately 400-1000 bp. We report here differential nuclease sensitivity and two-dimensional southern blot patterns, suggesting that dsDNA minicircles are in fact the minor forms, with substantial DNA:RNA hybrids (DRHs). Additionally, we observed large molecular weight intermediates, cell-lysate-dependent NCR secondary structures, multiple bidirectional predicted ssDNA structures, and different southern blot patterns when probed with different NCR fragments. In silico analysis suggested the existence of substantial secondary structures with inverted repeats (IR) and palindrome structures within the initial ~650 bp of the NCR sequences, in accordance with conversion event(s) outcomes with PCR. Based on these findings, we propose a new transcription-templating-translation model, which is associated with cross-hopping shift intermediates. Since dinoflagellate chloroplasts are cytosolic and lack nuclear envelope breakdown, the dynamic DRH minicircle transport could have contributed to the spatial-temporal dynamics required for photosystem repair. This represents a paradigm shift from the previous understanding of "minicircle DNAs" to a "working plastome", which will have significant implications for its molecular functionality and evolution.

The Role of Health Policy and Systems in the Uptake of Community-Based Health Insurance Schemes in Low- and Middle-Income Countries: A Narrative Review.

This study explores how health policies and systems can affect voluntary uptake of community-based health insurance (CBHI) schemes in low- and middle-income countries (LMICs). A narrative review was conducted involving searches of 10 databases (Medline, Global Index Medicus, Cumulative Index to Nursing, and Allied Health Literature, Health Systems Evidence, Worldwide Political Science Abstracts, PsycINFO, International Bibliography of the Social Sciences, EconLit, Bibliography of Asian Studies, and Africa Wide Information) across the social sciences, economics, and medical sciences. A total of 8107 articles were identified through the database searches, 12 of which were retained for analysis and narrative synthesis after 2 stages of screening. Our findings suggest that in the absence of directly subsidizing CBHI schemes by governments in LMICs, government policies can nonetheless promote voluntary uptake of CBHIs through intentional actions in 3 key areas: (a) improving quality of care, (b) providing a regulatory framework that integrates CBHIs into the national health system and its goals, and (c) leveraging administrative and managerial capacity to facilitate enrollment. The findings of this study highlight several considerations for CBHI planners and governments in LMICs to promote voluntary enrollment in CBHIs. Governments can effectively extend their outreach toward marginalized and vulnerable populations that are excluded from social protection by formulating supportive regulatory, policy, and administrative provisions that enhance voluntary uptake of CBHI schemes.

Oleaginous Heterotrophic Dinoflagellates-Crypthecodiniaceae.

The heterotrophic Crypthecodinium cohnii is a major model for dinoflagellate cell biology, and a major industrial producer of docosahexaenoic acid, a key nutraceutical and added pharmaceutical compound. Despite these factors, the family Crypthecodiniaceae is not fully described, which is partly attributable to their degenerative thecal plates, as well as the lack of ribotype-referred morphological description in many taxons. We report here significant genetic distances and phylogenetic cladding that support inter-specific variations within the Crypthecodiniaceae. We describe Crypthecodinium croucheri sp. nov. Kwok, Law and Wong, that have different genome sizes, ribotypes, and amplification fragment length polymorphism profiles when compared to the C. cohnii. The interspecific ribotypes were supported by distinctive truncation-insertion at the ITS regions that were conserved at intraspecific level. The long genetic distances between Crypthecodiniaceae and other dinoflagellate orders support the separation of the group, which includes related taxons with high oil content and degenerative thecal plates, to be ratified to the order level. The current study provides the basis for future specific demarcation-differentiation, which is an important facet in food safety, biosecurity, sustainable agriculture feeds, and biotechnology licensing of new oleaginous models.

Dinoflagellate Amphiesmal Dynamics: Cell Wall Deposition with Ecdysis and Cellular Growth.

Dinoflagellates are a major aquatic protist group with amphiesma, multiple cortical membranous "cell wall" layers that contain large circum-cortical alveolar sacs (AVs). AVs undergo extensive remodeling during cell- and life-cycle transitions, including ecdysal cysts (ECs) and resting cysts that are important in some harmful algal bloom initiation-termination. AVs are large cortical vesicular compartments, within which are elaborate cellulosic thecal plates (CTPs), in thecate species, and the pellicular layer (PL). AV-CTPs provide cellular mechanical protection and are targets of vesicular transport that are replaced during EC-swarmer cell transition, or with increased deposition during the cellular growth cycle. AV-PL exhibits dynamical-replacement with vesicular trafficking that are orchestrated with amphiesmal chlortetracycline-labeled Ca2+ stores signaling, integrating cellular growth with different modes of cell division cycle/progression. We reviewed the dynamics of amphiesma during different cell division cycle modes and life cycle stages, and its multifaceted regulations, focusing on the regulatory and functional readouts, including the coral-zooxanthellae interactions.

Door-in-door-out times for patients with large vessel occlusion ischaemic stroke being transferred for endovascular thrombectomy: a Victorian state-wide study.

Background: Time to reperfusion is an important predictor of outcome in ischaemic stroke from large vessel occlusion (LVO). For patients requiring endovascular thrombectomy (EVT), the transfer times from peripheral hospitals in metropolitan and regional Victoria, Australia to comprehensive stroke centres (CSCs) have not been studied. Aims: To determine transfer and journey times for patients with LVO stroke being transferred for consideration of EVT. Methods: All patients transferred for consideration of EVT to three Victorian CSCs from January 2017 to December 2018 were included. Travel times were obtained from records matched to Ambulance Victoria and the referring centre via Victorian Stroke Telemedicine or hospital medical records. Metrics of interest included door-in-door-out time (DIDO), inbound journey time and outbound journey time. Results: Data for 455 transferred patients were obtained, of which 395 (86.8%) underwent EVT. The median DIDO was 107 min (IQR 84-145) for metropolitan sites and 132 min (IQR 108-167) for regional sites. At metropolitan referring hospitals, faster DIDO was associated with use of the same ambulance crew to transport between hospitals (75 (63-90) vs 124 (99-156) min, p<0.001) and the administration of thrombolysis prior to transfer (101 (79-133) vs 115 (91-155) min, p<0.001). At regional centres, DIDO was consistently longer when patients were transported by air (160 (127-195) vs 116 (100-144) min, p<0.001). The overall door-to-door time by air was shorter than by road for sites located more than 250 km away from the CSC. Conclusion: Transfer times differ significantly for regional and metropolitan patients. A state-wide database to prospectively collect data on all interhospital transfers for EVT would be helpful for future study of optimal transport mode at regional sites and benchmarking of DIDO across the state.

Using body cameras to quantify the duration of a Code Stroke and identify workflow issues: a continuous observation workflow time study.

OBJECTIVE: 'Code Stroke' (Code) is used in health services to streamline hyperacute assessment and treatment delivery for patients with ischaemic stroke. However, there are few studies that detail the time spent on individual components performed during a Code. We sought to quantify the time taken for each process during a Code and investigate associations with modifiable and non-modifiable factors. DESIGN: Continuous observation workflow time study. SETTING AND PARTICIPANTS: Recordings of 100 Codes were performed at a high-volume primary stroke centre in Melbourne, Australia, between January and June 2020 using a body camera worn by a member of the stroke team. MAIN OUTCOME MEASURES: The main measures included the overall duration of Codes and the individual processes within the Code workflow. Associations between variables of interest and process times were explored using linear regression models. RESULTS: 100 Codes were captured, representing 19.2% of all Codes over the 6 months. The median duration of a complete Code was 54.2 min (IQR 39.1-74.7). Administrative work performed after treatment is completed (median 21.0 min (IQR 9.8-31.4)); multimodal CT imaging (median 13.0 min (IQR 11.5-15.7)), and time between decision and thrombolysis administration (median 8.1 min (IQR 6.1-10.8)) were the longest components of a Code. Tenecteplase was able to be prepared faster than alteplase (median 1.8 vs 4.9 min, p=0.02). The presence of a second junior doctor was associated with shorter administrative work time (median 10.3 vs 25.1 min, p<0.01). No specific modifiable factors were found to be associated with shorter overall Code duration. CONCLUSIONS: Codes are time intensive. Time spent on decision-making was a relatively small component of the overall Code duration. Data from body cameras can provide granular data on all aspects of Code workflow to inform potential areas for improvement at individual centres.

Transcriptomic Signatures of Human Immunodeficiency Virus Post-Treatment Control.

Posttreatment controllers (PTCs) are rare HIV-infected individuals who can limit viral rebound after antiretroviral therapy interruption (ATI), but the mechanisms of this remain unclear. To investigate these mechanisms, we quantified various HIV RNA transcripts (via reverse transcription droplet digital PCR [RT-ddPCR]) and cellular transcriptomes (via RNA-seq) in blood cells from PTCs and noncontrollers (NCs) before and two time points after ATI. HIV transcription initiation did not significantly increase after ATI in PTCs or in NCs, whereas completed HIV transcripts increased at early ATI in both groups and multiply-spliced HIV transcripts increased only in NCs. Compared to NCs, PTCs showed lower levels of HIV DNA, more cell-associated HIV transcripts per total RNA at all times, no increase in multiply-spliced HIV RNA at early or late ATI, and a reduction in the ratio of completed/elongated HIV RNA after early ATI. NCs expressed higher levels of the IL-7 pathway before ATI and expressed higher levels of multiple cytokine, inflammation, HIV transcription, and cell death pathways after ATI. Compared to the baseline, the NCs upregulated interferon and cytokine (especially TNF) pathways during early and late ATI, whereas PTCs upregulated interferon and p53 pathways only at early ATI and downregulated gene translation during early and late ATI. In NCs, viral rebound after ATI is associated with increases in HIV transcriptional completion and splicing, rather than initiation. Differences in HIV and cellular transcription may contribute to posttreatment control, including an early limitation of spliced HIV RNA, a delayed reduction in completed HIV transcripts, and the differential expression of the IL-7, p53, and TNF pathways. IMPORTANCE The findings presented here provide new insights into how HIV and cellular gene expression change after stopping ART in both noncontrollers and posttreatment controllers. Posttreatment control is associated with an early ability to limit increases in multiply-spliced HIV RNA, a delayed (and presumably immune-mediated) ability to reverse an initial rise in processive/completed HIV transcripts, and multiple differences in cellular gene expression pathways. These differences may represent correlates or mechanisms of posttreatment control and may provide insight into the development and/or monitoring of therapeutic strategies that are aimed at a functional HIV cure.

New Assay Reveals Vast Excess of Defective over Intact HIV-1 Transcripts in Antiretroviral Therapy-Suppressed Individuals.

Most of the HIV DNA in infected individuals is noninfectious because of deleterious mutations. However, it is unclear how much of the transcribed HIV RNA is potentially infectious or defective. To address this question, we developed and validated a novel intact viral RNA assay (IVRA) that uses droplet digital reverse transcriptase PCR (dd-RT-PCR) for the commonly mutated packaging signal (Psi) and Rev response element (RRE) regions (from the intact proviral DNA assay [IPDA]) to quantify likely intact (Psi+ RRE+), 3' defective (Psi+ RRE-), and 5' defective (Psi- RRE+) HIV RNA. We then applied the IPDA and IVRA to quantify intact and defective HIV DNA and RNA from peripheral CD4+ T cells from 9 antiretroviral therapy (ART)-suppressed individuals. Levels of 3' defective HIV DNA were not significantly different from those of 5' defective HIV DNA, and both were higher than intact HIV DNA. In contrast, 3' defective HIV RNA (median 86 copies/106 cells; 94% of HIV RNA) was much more abundant than 5' defective (2.1 copies/106 cells; 5.6%) or intact (0.6 copies/106 cells; <1%) HIV RNA. Likewise, the frequency of CD4+ T cells with 3' defective HIV RNA was greater than the frequency with 5' defective or intact HIV RNA. Intact HIV RNA was transcribed by a median of 0.018% of all proviruses and 2.2% of intact proviruses. The vast excess of 3' defective RNA over 5' defective or intact HIV RNA, which was not observed for HIV DNA, suggests that HIV transcription is completely blocked prior to the RRE in most cells with intact proviruses and/or that cells transcribing intact HIV RNA are cleared at very high rates. IMPORTANCE We developed a new assay that can distinguish and quantify intact (potentially infectious) as well as defective HIV RNA. In ART-treated individuals, we found that the vast majority of all HIV RNA is defective at the 3' end, possibly due to incomplete transcriptional processivity. Only a very small percentage of all HIV RNA is intact, and very few total or intact proviruses transcribe intact HIV RNA. Though rare, this intact HIV RNA is tremendously important because it is necessary to serve as the genome of infectious virions that allow transmission and spread, including rebound after stopping ART. Moreover, intact viral RNA may contribute disproportionately to the immune activation, inflammation, and organ damage observed with untreated and treated HIV infection. The intact viral RNA assay can be applied to many future studies aimed at better understanding HIV pathogenesis and barriers to HIV cure.

Electrochemically induced in vitro focal hypoxia in human neurons.

Focalised hypoxia is widely prevalent in diseases such as stroke, cardiac arrest, and dementia. While in some cases hypoxia improves cellular functions, it mostly induces or exacerbates pathological changes. The lack of methodologies that can simulate focal acute hypoxia, in either animal or cell culture, impedes our understanding of the cellular consequences of hypoxia. To address this gap, an electrochemical localised oxygen scavenging system (eLOS), is reported, providing an innovative platform for spatiotemporal in vitro hypoxia modulation. The electrochemical system is modelled showing O2 flux patterns and localised O2 scavenging and hypoxia regions, as a function of distance from the electrode and surrounding flux barriers, allowing an effective focal hypoxia tool to be designed for in vitro cell culture study. O2 concentration is reduced in an electrochemically defined targeted area from normoxia to hypoxia in about 6 min depending on the O2-flux boundaries. As a result, a cell culture-well was designed, where localised O2 scavenging could be induced. The impact of localised hypoxia was demonstrated on human neural progenitor cells (hNPCs) and it was shown that miniature focal hypoxic insults can be induced, that evoke time-dependent HIF-1α transcription factor accumulation. This transcription is "patterned" across the culture according to the electrochemically induced spatiotemporal hypoxia gradient. A basic lacunar infarct model was also developed through the application of eLOS in a purpose designed microfluidic device. Miniature focal hypoxic insults were induced in cellular processes of fully oxygenated cell bodies, such as the axons of human cortical neurons. The results demonstrate experimentally that localised axonal hypoxic stress can lead to significant increase of neuronal death, despite the neurons remaining at normoxia. This suggests that focal hypoxic insult to axons alone is sufficient to impact surrounding neurons and may provide an in vitro model to study the impact of microinfarcts occurring in the deep cerebral white matter, as well as providing a promising tool for wider understanding of acute hypoxic insults with potential to uncover its pathophysiology in multiple diseases.

Leveraging learning experience design: digital media approaches to influence motivational traits that support student learning behaviors in undergraduate online courses.

Higher education may benefit from investigating alternative evidence-based methods of online learning to understand students' learning behaviors while considering students' social cognitive motivational traits. Researchers conducted an in situ design-based research (DBR) study to investigate learner experience design (LXD) methods, deploying approaches of asynchronous video, course dashboards, and enhanced user experience. This mixed-methods study (N = 181) assessed associations of students' social cognitive motivational traits (self-efficacy, task-value, self-regulation) influencing their learning behaviors (engagement, elaboration, critical thinking) resulting from LXD. Social cognitive motivational traits were positively predictive of learning behaviors. As motivational factors increased, students' course engagement, usage of elaboration, and critical thinking skills increased. Self-efficacy, task-value, and self-regulation explained 31% of the variance of engagement, 47% of the explained variance of critical thinking skills, and 57% of the explained variance in the usage of elaboration. As a predictor, task-value beliefs increased the proportion of explained variance in each model significantly, above self-efficacy and self-regulation. Qualitative content analysis corroborated these findings, explaining how LXD efforts contributed to motivations, learning behaviors, and learning experience. Results suggest that mechanisms underpinning LXD and students' learning behaviors are likely the result of dynamically catalyzing social cognitive motivational factors. The discussion concludes with the LXD affordances that explain the positive influences in students' social cognitive motivational traits and learning behaviors, while also considering constraints for future iterations.

Incidence of Severe COVID-19 Illness Following Vaccination and Booster With BNT162b2, mRNA-1273, and Ad26.COV2.S Vaccines.

Importance: Evidence describing the incidence of severe COVID-19 illness following vaccination and booster with BNT162b2, mRNA-1273, and Ad26.COV2.S vaccines is needed, particularly for high-risk populations. Objective: To describe the incidence of severe COVID-19 illness among a cohort that received vaccination plus a booster vaccine dose. Design, Setting, and Participants: Retrospective cohort study of adults receiving care at Veterans Health Administration facilities across the US who received a vaccination series plus 1 booster against SARS-CoV-2, conducted from July 1, 2021, to May 30, 2022. Patients were eligible if they had received a primary care visit in the prior 2 years and had documented receipt of all US Food and Drug Administration-authorized doses of the initial mRNA vaccine or viral vector vaccination series after December 11, 2020, and a subsequent documented booster dose between July 1, 2021, and April 29, 2022. The analytic cohort consisted of 1 610 719 participants. Exposures: Receipt of any combination of mRNA-1273 (Moderna), BNT162b2 (Pfizer-BioNTech), and Ad26.COV2.S (Janssen/Johnson & Johnson) primary vaccination series and a booster dose. Main Outcomes and Measures: Outcomes were breakthrough COVID-19 (symptomatic infection), hospitalization with COVID-19 pneumonia and/or death, and hospitalization with severe COVID-19 pneumonia and/or death. A subgroup analysis of nonoverlapping populations included those aged 65 years or older, those with high-risk comorbid conditions, and those with immunocompromising conditions. Results: Of 1 610 719 participants, 1 100 280 (68.4%) were aged 65 years or older and 132 243 (8.2%) were female; 1 133 785 (70.4%) had high-risk comorbid conditions, 155 995 (9.6%) had immunocompromising conditions, and 1 467 879 (91.1%) received the same type of mRNA vaccine (initial series and booster). Over 24 weeks, 125.0 (95% CI, 123.3-126.8) per 10 000 persons had breakthrough COVID-19, 8.9 (95% CI, 8.5-9.4) per 10 000 persons were hospitalized with COVID-19 pneumonia or died, and 3.4 (95% CI, 3.1-3.7) per 10 000 persons were hospitalized with severe pneumonia or died. For high-risk populations, incidence of hospitalization with COVID-19 pneumonia or death was as follows: aged 65 years or older, 1.9 (95% CI, 1.4-2.6) per 10 000 persons; high-risk comorbid conditions, 6.7 (95% CI, 6.2-7.2) per 10 000 persons; and immunocompromising conditions, 39.6 (95% CI, 36.6-42.9) per 10 000 persons. Subgroup analyses of patients hospitalized with COVID-19 pneumonia or death by time after booster demonstrated similar incidence estimates among those aged 65 years or older and with high-risk comorbid conditions but not among those with immunocompromising conditions. Conclusions and Relevance: In a US cohort of patients receiving care at Veterans Health Administration facilities during a period of Delta and Omicron variant predominance, there was a low incidence of hospitalization with COVID-19 pneumonia or death following vaccination and booster with any of BNT162b2, mRNA-1273, or Ad26.COV2.S vaccines.

The Role of Serious Video Games in the Treatment of Disordered Eating Behaviors: Systematic Review.

BACKGROUND: Eating disorders and other forms of disordered eating cause significant complications and comorbidities in patients. However, full remission with current standard treatment remains low. Challenges to treatment include underdiagnosis and high dropout rates, as well as difficulties in addressing underlying emotion dysregulation, poor impulse control, and personality traits. Serious video games (SVGs), which have the advantages of being highly engaging and accessible, may be potential tools for delivering various forms of treatment in addressing the underlying psychopathology of disordered eating. OBJECTIVE: This review aims to provide an overview of the possible mechanisms by which SVGs may affect the clinical course of disordered eating, while evaluating the outcomes of studies that have assessed the role of SVGs in the treatment of disordered eating. METHODS: A systematic search was performed on PubMed, PsycINFO, and Embase, using keywords related to SVGs, disordered eating, and eating disorders. A narrative synthesis was subsequently carried out. RESULTS: In total, 2151 papers were identified, of which 11 (0.51%) were included. Of these 11 studies, 10 (91%) were randomized controlled trials, and 1 (9%) was a quasi-experimental study. The types of SVG interventions varied across the studies and targeted different mechanisms of disordered eating, ranging from addressing problem-solving and emotion regulation skills to neurocognitive training for inhibitory control. Most (10/11, 91%) of the studies showed some benefit of the SVGs in improving certain physical, behavioral, or psychological outcomes related to disordered eating. Some (4/11, 36%) of the studies also showed encouraging evidence of the retention of these benefits at follow-up. CONCLUSIONS: The studies included in this review provide collective evidence to suggest the various roles SVGs can play in plugging potential gaps in conventional therapy. Nonetheless, challenges exist in designing these games to prevent potential pitfalls, such as excessive stress arising from the SVGs themselves or potential gaming addiction. Further studies will also be required to assess the long-term benefits of SVGs as well as explore their potential preventive, and not just curative, effects on disordered eating.

Responses of dinoflagellate cells to ultraviolet-C irradiation.

Dinoflagellates are important aquatic microbes and major harmful algal bloom (HAB) agents that form invasive species through ship ballast transfer. UV-C installations are recommended for ballast treatments and HAB controls, but there is a lack of knowledge in dinoflagellate responses to UV-C. We report here dose-dependent cell cycle delay and viability loss of dinoflagellate cells irradiated with UV-C, with significant proliferative reduction at 800 Jm-2 doses or higher, but immediate LD50 was in the range of 2400-3200 Jm-2 . At higher dosages, some dinoflagellate cells surprisingly survived after days of recovery incubation, and continued viability loss, with samples exhibiting DNA fragmentations per proliferative resumption. Sequential cell cycle postponements, suggesting DNA damages were repaired over one cell cycle, were revealed with flow cytometric analysis and transcriptomic analysis. Over a sustained level of other DNA damage repair pathways, transcript elevation was observed only for several components of base pair repair and mismatch repair. Cumulatively, our findings demonstrated special DNA damage responses in dinoflagellate cells, which we discussed in relation to their unique chromo-genomic characters, as well as indicating resilience of dinoflagellate cells to UV-C.

The politics of universal health coverage.

The UN has declared universal health coverage an urgent global goal. Efforts to achieve this goal have been supported by rigorous research on the scientific, technical, and administrative aspects of health systems design. Yet a substantial portion of the world's population does not have access to essential health services. There is growing recognition that achieving universal health coverage is a political challenge. However, fundamental concepts from the political science discipline are often overlooked in the health literature. This Series paper draws on political science research to highlight the ways in which politics can facilitate, or stymie, policy reform. Specifically, we present a framework of analysis that explores how interests, ideas, and institutions shape universal health coverage. We then examine key considerations relating to the implementation of relevant policies. This Series paper shows that a political understanding of universal health coverage is needed to achieve health for all.

Evaluating the Initiation of Sodium/Glucose Cotransporter 2 Inhibitors within 2 Weeks of an Acute Hospital Admission: A Systematic Review and Meta-Analysis of Nine Clinical Trials.

OBJECTIVE: Recent studies have increasingly shown the benefits of using sodium/glucose cotransporter 2 inhibitor (SGLT2i). However, there are concerns regarding the initiation of SGLT2i during acute hospital admissions due to the potential increased risk of complications. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of SGLT2i initiation within 2 weeks of an acute hospital admission. METHODS: Four electronic databases (PubMed, Embase, Cochrane, and Scopus) were searched for articles published from inception up to 27 March 2021 that evaluated the efficacy and/or safety of SGLT2i initiation within 2 weeks of an acute hospital admission. Random-effects pair-wise meta-analysis models were utilized to summarize the studies. The protocol was registered with PROSPERO (CRD42021245492). RESULTS: Nine clinical trials were included with a combined cohort of 1,758 patients. Patients receiving SGLT2i had a mean increase in 24-h urine volume of +487.55 mL (95% CI 126.86-848.25; p = 0.008) compared to those not started on SGLT2i. Patients with heart failure treated with SGLT2i had a 27% relative risk reduction in rehospitalizations for heart failure, compared to controls (risk ratio 0.73; p = 0.005). There were no differences in other efficacy and safety outcomes examined. CONCLUSION: There was no increased harm with initiation of SGLT2i within 2 weeks of an acute hospital admission, and its use reduced the relative risk of rehospitalizations for heart failure in patients with heart failure. It was also associated with increased urine output. However, current evidence pool is limited, especially in specific population subtypes.

Novel assays to investigate the mechanisms of latent infection with HIV-2.

Although there have been great advancements in the field of HIV treatment and prevention, there is no cure. There are two types of HIV: HIV-1 and HIV-2. In addition to genetic differences between the two types of HIV, HIV-2 infection causes a slower disease progression, and the rate of new HIV-2 infections has dramatically decreased since 2003. Like HIV-1, HIV-2 is capable of establishing latent infection in CD4+ T cells, thereby allowing the virus to evade viral cytopathic effects and detection by the immune system. The mechanisms underlying HIV latency are not fully understood, rendering this a significant barrier to development of a cure. Using RT-ddPCR, we previously demonstrated that latent infection with HIV-1 may be due to blocks to HIV transcriptional elongation, distal transcription/polyadenylation, and multiple splicing. In this study, we describe the development of seven highly-specific RT-ddPCR assays for HIV-2 that can be applied to the study of HIV-2 infections and latency. We designed and validated seven assays targeting different HIV-2 RNA regions along the genome that can be used to measure the degree of progression through different blocks to HIV-2 transcription and splicing. Given that HIV-2 is vastly understudied relative to HIV-1 and that it can be considered a model of a less virulent infection, application of these assays to studies of HIV-2 latency may inform new therapies for HIV-2, HIV-1, and other retroviruses.