Integrating the Memory Support Intervention into the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C): can improving memory for treatment in midlife and older adults improve patient outcomes? Study protocol for a randomized controlled trial.

BACKGROUND: Poor memory for treatment is associated with poorer treatment adherence and poorer patient outcomes. The memory support intervention (MSI) was developed to improve patient memory for treatment with the goal of improving patient outcomes. The aim of this study protocol is to conduct a confirmatory efficacy trial to test whether a new, streamlined, and potent version of the MSI improves outcomes for midlife and older adults. This streamlined MSI is comprised of constructive memory supports that will be applied to a broader range of treatment content. The platform for this study is the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C). We will focus on midlife and older adults who are low income and experiencing mobility impairments. METHODS: Participants (N = 178) will be randomly allocated to TranS-C + MSI or TranS-C alone. Both intervention arms include eight 50-min weekly sessions. Assessments will be conducted at pre-treatment, post-treatment, 6-, and 12-month follow-up (6FU and 12FU). Aim 1 will compare the effects of TranS-C + MSI versus TranS-C alone on sleep and circadian functioning, daytime functioning, well-being, and patient memory. Aim 2 will test whether patient memory for treatment mediates the relationship between treatment condition and patient outcomes. Aim 3 will evaluate if previously reported poor treatment response subgroups will moderate the relationship between treatment condition and (a) patient memory for treatment and (b) treatment outcome. Exploratory analyses will compare treatment condition on (a) patient adherence, patient-rated treatment credibility, and patient utilization of treatment contents, and (b) provider-rated acceptability, appropriateness, and feasibility. DISCUSSION: This study has the potential to provide evidence for (a) the efficacy of a new simplified version of the MSI for maintaining health, well-being, and functioning, (b) the wider application of the MSI for midlife and older adults and to the treatment of sleep and circadian problems, and (c) the efficacy of the MSI for sub-groups who are likely to benefit from the intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT05986604. Registered on 2 August 2023.

T lymphocyte recruitment to melanoma brain tumors depends on distinct venous vessels.

To improve immunotherapy for brain tumors, it is important to determine the principal intracranial site of T cell recruitment from the bloodstream and their intracranial route to brain tumors. Using intravital microscopy in mouse models of intracranial melanoma, we discovered that circulating T cells preferably adhered and extravasated at a distinct type of venous blood vessel in the tumor vicinity, peritumoral venous vessels (PVVs). Other vascular structures were excluded as alternative T cell routes to intracranial melanomas. Anti-PD-1/CTLA-4 immune checkpoint inhibitors increased intracranial T cell motility, facilitating migration from PVVs to the tumor and subsequently inhibiting intracranial tumor growth. The endothelial adhesion molecule ICAM-1 was particularly expressed on PVVs, and, in samples of human brain metastases, ICAM-1 positivity of PVV-like vessels correlated with intratumoral T cell infiltration. These findings uncover a distinct mechanism by which the immune system can access and control brain tumors and potentially influence other brain pathologies.

A Bayesian incorporated linear non-Gaussian acyclic model for multiple directed graph estimation to study brain emotion circuit development in adolescence.

Emotion perception is essential to affective and cognitive development which involves distributed brain circuits. Emotion identification skills emerge in infancy and continue to develop throughout childhood and adolescence. Understanding the development of the brain's emotion circuitry may help us explain the emotional changes during adolescence. In this work, we aim to deepen our understanding of emotion-related functional connectivity (FC) from association to causation. We proposed a Bayesian incorporated linear non-Gaussian acyclic model (BiLiNGAM), which incorporated association model into the estimation pipeline. Simulation results indicated stable and accurate performance over various settings, especially when the sample size was small. We used fMRI data from the Philadelphia Neurodevelopmental Cohort (PNC) to validate the approach. It included 855 individuals aged 8-22 years who were divided into five different adolescent stages. Our network analysis revealed the development of emotion-related intra- and intermodular connectivity and pinpointed several emotion-related hubs. We further categorized the hubs into two types: in-hubs and out-hubs, as the center of receiving and distributing information, respectively. In addition, several unique developmental hub structures and group-specific patterns were discovered. Our findings help provide a directed FC template of brain network organization underlying emotion processing during adolescence.

Our study introduces a novel method for analyzing directed graphs across multiple groups and demonstrates its effectiveness through a series of simulation studies. This method is applied to investigate the development of directed functional connectivity for emotion processing across diverse adolescent periods. Our findings unveil a notable increase in interfunctional connectivity with age, specifically involved with the executive control and memory retrieval, indicating the maturation of emotion processing function. Additionally, significant development of intraconnectivity in the subcortical areas emerges in early adolescence, whereas development of cerebellum emerges in the very end of adolescence. These insights offer valuable contributions to our understanding of the dynamic neural processes underlying emotion regulation during adolescence.

Prenatal exposure to ambient air pollution and subsequent risk of lower respiratory tract infections in childhood and adolescence: A systematic review.

BACKGROUND: Pregnancy represents a critical window of vulnerability to the harmful effects of air pollution on health. However, long-term consequences such as risk of having lower respiratory tract infections (LRTIs) are less explored. This systematic review aims to synthesize previous research on prenatal exposure to ambient (outdoor) air pollution and LRTIs in childhood and adolescence. METHODS: We systematically searched Embase, MEDLINE, Web of Science Core Collection, CINAHL, and Global Health up to May 17, 2024. We included peer-reviewed publications of studies which investigated the association between prenatal exposure to ambient air pollution and LRTIs up to the age of 19. We excluded conference abstracts, study protocols, review articles, and grey literature. Screening and data extraction was conducted by two reviewers independently. We used the Office of Health Assessment and Translation tool to assess risk of bias and conducted a narrative synthesis. RESULTS: The search yielded 6056 records, of which 16 publications describing 12 research studies were eligible for the synthesis. All studies were conducted in high- or upper-middle-income countries in Europe or Asia. Half (6) of the studies focused on LRTIs occurring within the first three years of life, and the others also included LRTIs in older children (up to age 14). Air pollutants investigated included nitrogen dioxide, sulphur dioxide, particulate matter (PM2.5: diameter ≤2.5 µm and PM10: diameter ≤10 µm), carbon monoxide, ozone, and benzene. Findings on a potential association between prenatal ambient air pollution exposure and LRTIs were inconclusive, without a clear and consistent direction. There was some suggestion of a positive association with prenatal PM2.5 exposure. The small number of studies identified, their poor geographical representation, and their methodological limitations including concerns for risk of bias preclude more definitive conclusions. CONCLUSION: The available published evidence is insufficient to establish whether prenatal exposure to ambient air pollution increases risk of LRTIs in children and adolescents. With many populations exposed to high levels of air pollution, there is an urgent need for research in more diverse settings, more transparent reporting of methods, and exploring how, when, and for whom prenatal exposure to ambient air pollution leads to the greatest health risks. PROSPERO REGISTRATION NUMBER: CRD42023407689.

Theoretical Study of Co-Doping Effects with Different Ions on the Multiferroic Properties of BiFeO3 Nanoparticles.

Using a microscopic model and the Green's function theory, the size and co-doping effects on the multiferroic and optical (band gap) properties of BiFeO3 (BFO) nanoparticles are investigated. The magnetization increases, whereas the band gap energy decreases with decreasing nanoparticle size. The substitution with Co/Mn, Nd/Sm, Ce/Ni, and Cd/Ni is discussed and explained on a microscopic level. By the ion co-doping appear different strains due to the difference between the doping and host ionic radii, which leads to changes in the exchange interaction constants for tuning all properties. It is observed that by co-doping with Nd/Sm at the Bi site or with Co/Mn at the Fe site, the multiferroic properties are larger than those by doping with one ion. Moreover, by doping with Ni, the multiferroic properties are reduced. But by adding another ion (for example Ce or Cd), an increase in these properties is obtained. This shows the advantages of the co-doping, its flexibility, and its greater possibility of tuning the multiferroic properties compared to single ion substitution. The band gap energy decreases for all co-dopants. The polarization increases with increasing magnetic field. This is evidence of magnetoelectric coupling, which is enhanced by co-doping with Co/Mn. The observed theoretical results are in good qualitative agreement with the existing experimental data.

Rewilded horses in European nature conservation - a genetics, ethics, and welfare perspective.

In recent decades, the integration of horses (Equus ferus) in European rewilding initiatives has gained widespread popularity due to their potential for regulating vegetation and restoring natural ecosystems. However, employing horses in conservation efforts presents important challenges, which we here explore and discuss. These challenges encompass the lack of consensus on key terms inherent to conservation and rewilding, the entrenched culture and strong emotions associated with horses, low genetic diversity and high susceptibility to hereditary diseases in animals under human selection, as well as insufficient consideration for the social behaviour of horses in wild-living populations. In addition, management of wild-living horses involves intricate welfare, ethics and legislative dimensions. Anthropocentric population-control initiatives may be detrimental to horse group structures since they tend to prioritise individual welfare over the health of populations and ecosystems. To overcome these challenges, we provide comprehensive recommendations. These involve a systematic acquisition of genetic information, a focus on genetic diversity rather than breed purity and minimal veterinary intervention in wild-living populations. Further, we advise allowing for natural top-down and bottom-up control - or, if impossible, simulating this by culling or non-lethal removal of horses - instead of using fertility control for population management. We advocate for intensified collaboration between conservation biologists and practitioners and enhanced communication with the general public. Decision-making should be informed by a thorough understanding of the genetic makeup, common health issues and dynamics, and social behaviour in wild-living horse populations. Such a holistic approach is essential to reconcile human emotions associated with horses with the implementation of conservation practices that are not only effective but also sustainable for the long-term viability of functional, biodiverse ecosystems, while rehabilitating the horse as a widespread wild-living species in Europe.

Detection of EPEC and STEC strains isolated from children with diarrhea in Argentina.

Rectal swabs (122) from pediatric patients were analyzed by polymerase chain reaction (PCR) for the detection of EPEC and STEC. STEC isolates were tested for the presence of stx1, stx2, eae, saa and ehxA. All eae-positive samples were tested for the presence of bfpA, and antigen O was determined using the agglutination test. Int1 and Int2 were detected to identify the presence of integrons class 1 and 2, respectively. Escherichia coli was detected in 68% of the samples, of which 18.8% were STEC (2.45%) and EPEC (16.3%). Serogroups STEC O145 and EPEC O130, O113 and O157 were observed, while three strains were non-typable. None of the EPEC strains carrying tbfpA and class 1 and 2 integrons was detected in any of the samples. The results obtained are important considering the virulence profiles found in the isolated EPEC and STEC strains and the serogroups associated with disease in humans.

Mirtazapine to alleviate severe breathlessness in patients with COPD or interstitial lung diseases (BETTER-B): an international, multicentre, double-blind, randomised, placebo-controlled, phase 3 mixed-method trial.

BACKGROUND: Breathlessness frequently becomes severe among people with respiratory disease. Mirtazapine, a widely used antidepressant, has shown promise in the modulation of respiratory sensation and the response to it, as well as reducing feelings of panic, which often accompanies breathlessness. We aimed to determine the effectiveness of mirtazapine to alleviate severe persisting breathlessness. METHODS: This international, multicentre, phase 3, parallel-group, double-blind, randomised, placebo-controlled trial across 16 centres in seven countries (Australia, Germany, Ireland, Italy, New Zealand, Poland, and the UK), recruited adults with chronic obstructive pulmonary disease (COPD), interstitial lung diseases, or both, and grade 3 or 4 of the modified Medical Research Council breathlessness scale. Consenting participants were randomly assigned (1:1) to receive oral mirtazapine or matching placebo for 56 days. Randomisation was by minimisation. The initial mirtazapine dose was 15 mg, escalating to a maximum of 45 mg per day, tapered at treatment end. Participants, caregivers, assessors, and investigators were masked to group assignment. The primary outcome was worst breathlessness in the preceding 24 h measured on a 0-10 numerical rating scale (NRS), at 56 days post-treatment start, with follow-up to 180 days. The primary analysis was performed in the modified intention-to-treat population using multivariable multi-level repeated measures model. This trial was registered with ISRCTN (ISRCTN10487976 and ISRCTN15751764 [Australia and New Zealand]) and EudraCT (2019-002001-21) and is complete. FINDINGS: Between Feb 4, 2021 and March 28, 2023, we enrolled 225 eligible participants (148 men and 77 women, 113 to the mirtazapine group and 112 to the placebo group). The median age was 74 years (IQR 67-78). No evidence of a difference was found in worst breathlessness at day 56 between mirtazapine and placebo (difference in adjusted mean NRS score was 0·105 [95% CI -0·407 to 0·618]; p=0·69). Although the study was underpowered, the primary endpoint effect did not reach the pre-specified treatment effect of 0·55 for worst breathlessness score reduction that the study was powered to detect for the primary analysis. There were 215 adverse reactions in 72 (64%) of 113 participants in the mirtazapine group versus 116 in 44 (40%) of 110 participants in the placebo group; 11 serious adverse events in six (5%) participants in the mirtazapine group versus eight in seven (6%) participants in the placebo group; and one (1%) suspected unexpected serious adverse reaction in the mirtazapine group. At day 56, there were three deaths in the mirtazapine group and two deaths in the placebo group. At day 180, there were seven deaths in the mirtazapine group and 11 deaths in the placebo group. INTERPRETATION: Our findings suggested that mirtazapine of doses 15 to 45 mg daily over 56 days does not improve severe breathlessness among patients with COPD or interstitial lung diseases and might cause adverse reactions. Based on these findings, we do not recommend mirtazapine as a treatment to alleviate severe breathlessness. FUNDING: EU Horizon 2020 (grant agreement No. 825319); Cicely Saunders International Breathlessness Programme; National Institute for Health and Care Research Applied Research Collaboration South London; Australian National Health and Medical Research Council-EU (application ID: APP1170731).

Improving Circulation Half-Life of Therapeutic Candidate N-TIMP2 by Unfolded Peptide Extension.

Matrix metalloproteinases (MMPs) are significant drivers of many diseases, including cancer, and are established targets for drug development. Tissue inhibitors of metalloproteinases (TIMPs) are endogenous MMP inhibitors and are being pursued for the development of anti-MMP therapeutics. TIMPs possess many attractive properties for drug candidates, such as complete MMP inhibition, low toxicity, low immunogenicity, and high tissue permeability. However, a major challenge with TIMPs is their rapid clearance from the bloodstream due to their small size. This study explores a method for extending the plasma half-life of the N-terminal domain of TIMP2 (N-TIMP2) by appending it with a long, intrinsically unfolded tail containing Pro, Ala, and Thr (PATylation). We designed and produced two PATylated N-TIMP2 constructs with tail lengths of 100 and 200 amino acids (N-TIMP2-PAT100 and N-TIMP2-PAT200). Both constructs demonstrated higher apparent molecular weights and retained high inhibitory activity against MMP-9. N-TIMP2-PAT200 significantly increased plasma half-life in mice compared to the non-PATylated variant, enhancing its therapeutic potential. PATylation offers distinct advantages for half-life extension, such as fully genetic encoding, monodispersion, and biodegradability. It can be easily applied to N-TIMP2 variants engineered for high affinity and selectivity toward individual MMPs, creating promising candidates for drug development against MMP-related diseases.

Impact of E. muris infection on B. burgdorferi-induced joint pathology in mice.

Tick-borne infections are increasing in the United States and around the world. The most common tick-borne disease in the United States is Lyme disease caused by infection with the spirochete Borrelia burgdorferi (Bb), and pathogenesis varies from subclinical to severe. Bb infection is transmitted by Ixodes ticks, which can carry multiple other microbial pathogens, including Ehrlichia species. To address how the simultaneous inoculation of a distinct pathogen impacted the course of Bb-induced disease, we used C57BL/6 (B6) mice which are susceptible to Bb infection but develop only mild joint pathology. While infection of B6 mice with Bb alone resulted in minimal inflammatory responses, mice co-infected with both Bb and the obligate intracellular pathogen Ehrlichia muris (Em) displayed hematologic changes, inflammatory cytokine production, and emergency myelopoiesis similar to what was observed in mice infected only with Em. Moreover, infection of B6 mice with Bb alone resulted in no detectable joint inflammation, whereas mice co-infected with both Em and Bb exhibited significant inflammation of the ankle joint. Our findings support the concept that co-infection with Ehrlichia can exacerbate inflammation, resulting in more severe Bb-induced disease.

Noninvasive vs invasive respiratory support for patients with acute hypoxemic respiratory failure.

BACKGROUND: Noninvasive respiratory support modalities are common alternatives to mechanical ventilation in acute hypoxemic respiratory failure. However, studies historically compare noninvasive respiratory support to conventional oxygen rather than mechanical ventilation. In this study, we compared outcomes in patients with acute hypoxemic respiratory failure treated initially with noninvasive respiratory support to patients treated initially with invasive mechanical ventilation. METHODS: This is a retrospective observational cohort study between January 1, 2018 and December 31, 2019 at a large healthcare network in the United States. We used a validated phenotyping algorithm to classify adult patients (≥18 years) with eligible International Classification of Diseases codes into two cohorts: those treated initially with noninvasive respiratory support or those treated invasive mechanical ventilation only. The primary outcome was time-to-in-hospital death analyzed using an inverse probability of treatment weighted Cox model adjusted for potential confounders. Secondary outcomes included time-to-hospital discharge alive. A secondary analysis was conducted to examine potential differences between noninvasive positive pressure ventilation and nasal high flow. RESULTS: During the study period, 3177 patients met inclusion criteria (40% invasive mechanical ventilation, 60% noninvasive respiratory support). Initial noninvasive respiratory support was not associated with a decreased hazard of in-hospital death (HR: 0.65, 95% CI: 0.35-1.2), but was associated with an increased hazard of discharge alive (HR: 2.26, 95% CI: 1.92-2.67). In-hospital death varied between the nasal high flow (HR 3.27, 95% CI: 1.43-7.45) and noninvasive positive pressure ventilation (HR 0.52, 95% CI 0.25-1.07), but both were associated with increased likelihood of discharge alive (nasal high flow HR 2.12, 95 CI: 1.25-3.57; noninvasive positive pressure ventilation HR 2.29, 95% CI: 1.92-2.74). CONCLUSIONS: These data show that noninvasive respiratory support is not associated with reduced hazards of in-hospital death but is associated with hospital discharge alive.

Vγ6/Vδ1+ γδ T cells protect from angiotensin II effects on blood pressure and endothelial function in mice.

OBJECTIVES: γδ T cells mediate angiotensin II (AngII)-induced hypertension and vascular injury. γδ T cells expressing specific T-cell receptor (TCR) variable (V) γ chains develop in several waves in the thymus and migrate to specific or diverse tissues. We hypothesized that γδ T cells expressing specific Vγ subtypes in perivascular tissue mediate AngII hypertensive effects. METHODS: C57BL/6J male mice were infused or not with AngII (490 ng/kg/min, subcutaneously) for 14 days. γδ T-cell Vγ subtypes were profiled by flow cytometry in the spleen, descending thoracic aorta with adherent perivascular adipose tissue (DTAo/PVAT) and mesenteric vessels (MV)/PVAT. Other sets of AngII-infused mice were injected with control or specific anti-Vγ6 or Vγ4 antibodies. Blood pressure (BP) was determined by telemetry, and mesenteric artery function and remodeling by pressurized myography. RESULTS: Vγ6/Vδ1+ γδ T cells represented more than 50% of the γδ T-cell Vγ subtypes in DTAo/PVAT and MV/PVAT, whereas Vγ1/2+, Vγ4+ and Vγ6/Vδ1+ γδ T cells were the most abundant Vγ subtypes in the spleen. The frequency of Vγ6/Vδ1+ γδ T cells was increased at least 1.5-fold in the spleen and DTAo/PVAT, and tended to increase in MV/PVAT by AngII. A majority of Vγ6/Vδ1+ γδ T cells were activated in perivascular tissues. Vγ6/Vδ1+ γδ T-cell neutralization caused a steeper BP elevation and greater mesenteric artery endothelial dysfunction in mice infused with AngII. This was associated with more than three-fold increase in activated Vγ6/Vδ1- γδ T cells in perivascular tissues. Depletion of Vγ4+ γδ T cells did not alter AngII detrimental effects. CONCLUSION: Vγ6/Vδ1+ γδ T cells reduce the BP elevation and endothelial dysfunction induced by AngII infusion.

Proteasome inhibition enhances the anti-leukemic efficacy of chimeric antigen receptor (CAR) expressing NK cells against acute myeloid leukemia.

BACKGROUND: Relapsed and refractory acute myeloid leukemia (AML) carries a dismal prognosis. CAR T cells have shown limited efficacy in AML, partially due to dysfunctional autologous T cells and the extended time for generation of patient specific CAR T cells. Allogeneic NK cell therapy is a promising alternative, but strategies to enhance efficacy and persistence may be necessary. Proteasome inhibitors (PI) induce changes in the surface proteome which may render malignant cells more vulnerable to NK mediated cytotoxicity. Here, we investigated the potential benefit of combining PIs with CAR-expressing allogeneic NK cells against AML. METHODS: We established the IC50 concentrations for Bortezomib and Carfilzomib against several AML cell lines. Surface expression of class-I HLA molecules and stress-associated proteins upon treatment with proteasome inhibitors was determined by multiparameter flow cytometry. Using functional in vitro assays, we explored the therapeutic synergy between pre-treatment with PIs and the anti-leukemic efficacy of NK cells with or without expression of AML-specific CAR constructs against AML cell lines and primary patient samples. Also, we investigated the tolerability and efficacy of a single PI application strategy followed by (CAR-) NK cell infusion in two different murine xenograft models of AML. RESULTS: AML cell lines and primary AML patient samples were susceptible to Bortezomib and Carfilzomib mediated cytotoxicity. Conditioned resistance to Azacitidine/Venetoclax did not confer primary resistance to PIs. Treating AML cells with PIs reduced the surface expression of class-I HLA molecules on AML cells in a time-and-dose dependent manner. Stress-associated proteins were upregulated on the transcriptional level and on the cell surface. NK cell mediated killing of AML cells was enhanced in a synergistic manner. PI pre-treatment increased effector-target cell conjugate formation and Interferon-γ secretion, resulting in enhanced NK cell activity against AML cell lines and primary samples in vitro. Expression of CD33- and CD70-specific CARs further improved the antileukemic efficacy. In vivo, Bortezomib pre-treatment followed by CAR-NK cell infusion reduced AML growth, leading to prolonged overall survival. CONCLUSIONS: PIs enhance the anti-leukemic efficacy of CAR-expressing allogeneic NK cells against AML in vitro and in vivo, warranting further exploration of this combinatorial treatment within early phase clinical trials.

Evaluation of Skin of Color Curricular Content for Physician Assistant Education.

INTRODUCTION: Physician assistants (PAs) are often members of dermatologic care teams. Adequate knowledge of dermatologic conditions in skin of color (SOC) is crucial to proper diagnosis, treatment, and patient satisfaction. The objective of this study was to increase PA students' objective knowledge of and comfort level with evaluating dermatologic conditions in SOC. METHODS: Eligible participants included 36 PA students at a major metropolitan medical center during the 2022 to 2023 academic year. A preintervention survey, immediate postintervention survey, and 7-month follow-up postintervention survey were administered before and after a SOC lecture. The surveys concluded with a 10-question, image-based, multiple-choice examination. RESULTS: There was a significant increase in accurate diagnoses of acne scarring, eczema, psoriasis, rosacea, and seborrheic dermatitis in SOC (59.4% preintervention to 76.9% postintervention, P = .029). Student confidence, as rated on a scale of 1 (minimally confident) to 5 (extremely confident), in diagnosing these conditions increased from 2.97 to 3.52 (P = .036). DISCUSSION: Implementation of a SOC-specific dermatology lecture significantly increased the accuracy and confidence with which PA students diagnosed dermatologic conditions.

Phase ordering in binary mixtures of active nematic fluids.

We use a continuum, two-fluid approach to study a mixture of two active nematic fluids. Even in the absence of thermodynamically driven ordering, for mixtures of different activities we observe turbulent microphase separation, where domains form and disintegrate chaotically in an active turbulent background. This is a weak effect if there is no elastic nematic alignment between the two fluid components, but is greatly enhanced in the presence of an elastic alignment or substrate friction. We interpret the results in terms of relative flows between the two species which result from active anchoring at concentration gradients. Our results may have relevance in interpreting epithelial cell sorting and the dynamics of multispecies bacterial colonies.

Phospholipase-catalyzed degradation drives domain morphology and rheology transitions in model lung surfactant monolayers.

Lung surfactant is inactivated in acute respiratory distress syndrome (ARDS) by a mechanism that remains unclear. Phospholipase (PLA2) plays an essential role in the normal lipid recycling processes, but is present in elevated levels in ARDS, suggesting it plays a role in ARDS pathophysiology. PLA2 hydrolyzes lipids such as DPPC-the primary component of lung surfactant-into palmitic acid (PA) and lyso-PC (LPC). Because PA co-crystallizes with DPPC to form rigid, elastic domains, we hypothesize that PLA2-catalyzed degradation establishes a stiff, heterogeneous rheology in the monolayer, and suggests a potential mechanical role in disrupting lung surfactant function during ARDS. Here we study the morphological and rheological changes of DPPC monolayers as they are degraded by PLA2 using interfacial microbutton microrheometry coupled with fluorescence microscopy. While degrading, domain morphology passes through qualitatively distinct transitions: compactification, coarsening, solidification, aggregation, network percolation, network erosion, and nucleation of PLA2-rich domains. Initially, condensed domains relax to more compact shapes, and coarsen via Ostwald ripening and coalescence up until the domains solidify, marked by a distinct roughening of domain boundaries that does not relax. Domains aggregate and eventually form a percolated network, whose elements then erode and whose connections are broken as degradation continues. The relative enzymatic activity of PLA2, set by the age of the sample, impacts the order and the duration of morphology transitions. The fresher the PLA2, the faster the overall degradation, and the earlier the onset of domain solidification: domains solidify before aggregating with fresh PLA2 samples, but aggregate and percolate before solidification with aged PLA2. Irrespective of the activity of the PLA2, all measured linear viscoelastic surface shear moduli obey the same dependence on condensed phase area fraction (log|G*| ∝ ϕ) throughout monolayer degradation. Moreover, the onset of domain solidification coincides with the time when the relative surface elasticity begins to increase.

Cardiac remodeling and inflammation detected by magnetic resonance imaging in COVID-19 survivors.

Background: Concerns have been raised about cardiac inflammation in patients with long COVID-19, particularly those with myocardial injury during the acute phase of the disease. This study was conducted to examine myopericardial involvement, detected by cardiac magnetic resonance (CMR) imaging in patients hospitalized for COVID-19. Methods: Adult patients hospitalized with COVID-19 who presented myocardial injury or increased D-dimers were enrolled in this prospective study. All patients were invited to undergo CMR imaging examination after discharge. During follow-up, patients with nonischemic myocardial or pericardial involvement detected on the first CMR imaging examination underwent second examinations. CMR imaging findings were compared with those of a control group of healthy patients with no comorbidity. Results: Of 180 included patients, 53 underwent CMR imaging examination. The mean age was 58.4 ± 18.3 years, and 73.6 % were male. Myocardial and pericardial LGE was reported in 43.4 % and 35.8 % of patients, respectively. Nonischemic myocardial or pericardial involvement was reported in 26 (49.1 %) patients. The prevalence of pericardial LGE was associated inversely with the interval between hospital discharge and CMR. COVID-19 survivors had higher end-systolic volume indices (ESVis) and lower left-ventricular ejection fractions than did healthy controls. Seventeen patients underwent follow-up CMR imaging; the end-diastolic volume index, ESVi, and prevalence of pericardial LGE, but not that of nonischemic LGE, were reduced. Conclusion: Among COVID-19 survivors with myocardial injury during the acute phase of the disease, the incidences of nonischemic myocardial and pericardial LGE and CMR imaging-detected signs of cardiac remodeling, partially reversed during follow-up, were high.

Self-reported follow-up care needs can be met in both facility and self-managed abortion: Evidence from low- and middle-income countries.

OBJECTIVES: To understand in-facility follow-up care-seeking behavior among both people who self-managed medication abortions and those who obtained facility-managed care in low-and-middle-income countries. We explore factors that contribute to meeting individual self-reported follow-up care needs, core to person-centered care. STUDY DESIGN: We conducted a qualitative, codebook thematic analysis of 67 in-depth interviews conducted with people who self-managed medication abortions or obtained facility-managed medication abortion care. We first classified individuals as having their follow-up care needs met (not seeking care when the participant felt confident that additional care was not warranted or desired or receiving care if it was desired) or not. Our a priori analytic domains came from the Anderson model of health services utilization - predisposing, enabling, or need factors (perceived and evaluated need for health services) that contributed to having follow-up care needs met or not. We also describe emergent themes within each domain. RESULTS: Most participants (n=59, 88%) had their follow-up care needs met; half (n=33, 49%) sought follow-up care in a facility. Prior birth or abortion experiences emerged as predisposing factors for having follow-up care needs met. Having accompaniment support (from activists or hotlines who provide abortion guidance outside of clinical settings), knowing what to expect, and information sources were key enabling factors for having follow-up care needs met. Need factors included flexible follow-up care guidelines. Those who did not have their follow-up care needs met described predisposing negative health system experiences; enabling factors including health system challenges, stigma from providers, and legal risk; and need factors of required follow-up care guidelines. CONCLUSIONS: Medication abortion follow-up care experiences are diverse, and individual needs can be met both in and outside of health facilities. Understanding prior experiences, enabling accompaniment support, and considering flexible follow-up care guidelines can support meeting individual follow-up care needs, which is essential to person-centered abortion care. IMPLICATIONS: Follow-up care needs, essential to ensuring access to high-quality abortion services, can be met in both self-managed and in-facility medication abortion models. Policies that require follow-up care when it is not needed or desired by the person can reinforce ideas that self-managed abortion is not safe or effective, despite existing evidence.

Isolation and comparative genotoxicity screening of trichokonins VI and VIII on CHO-K1 cells.

Peptaibols are fungal peptides that exhibit efficacy against pathogen microorganisms. Trichokonin VI (TK-VI) and trichokonin VIII (TK-VIII) are known peptaibols isolated from the endolichenic fungi Hypocrea sp. Previous investigations reported that trichokonin VI presents antiproliferative effects on tumor cells. This study is pioneering in elucidating the genotoxic effects of TK-VI and TK-VIII, contributing to the thorough assessment of their safety as potential therapeutic agents. The present investigation aimed to evaluate the genotoxicity of TK-VI and TK-VIII on CHO-K1 cells. Cytotoxicity was evaluated using the XTT assay and clonogenic survival assays, followed by evaluation of DNA damage using the comet assay and micronucleus test conducted in vitro. The XTT assay results indicated IC50 values of 10.30 µM and 9.89 µM for TK-VI and TK-VIII, respectively. The clonogenic survival assay indicated that concentrations of 10 µM or higher completely inhibited the cell colony formation. In the comet assay, both TK-VI and TK-VIII increased the DNA damage score and the frequency of comet nuclei in all tested concentrations. In the micronucleus assay, TK-VI and TK-VIII at 10 µM increased the frequency of MN in CHO-K1 cells. Both TK-VI and TK-VIII exhibited genotoxic effects. Our findings underscore the importance of considering the genotoxicological safety of peptaibols, particularly when assessing their potential for other biological activities.