Novel high molecular weight polymerized hemoglobin in a non-obese model of cardiovascular and metabolic dysfunction.

The widespread adoption of high-calorie, high-fat, high-sucrose diets (HFHSD) has become a global health concern, particularly due to their association with cardiovascular diseases and metabolic disorders. These comorbidities increase susceptibility to severe outcomes from viral infections and trauma, with trauma-related incidents significantly contributing to global mortality rates. This context underscores the critical need for a reliable blood supply. Recent research has focused on high molecular weight (MW) polymerized human hemoglobin (PolyhHb) as a promising alternative to red blood cells (RBCs), showing encouraging outcomes in previous studies. Given the overlap of metabolic disorders and trauma-related health issues, it is crucial to assess the potential toxicity of PolyhHb transfusions, particularly in models that represent these vulnerable populations. This study evaluated the effects of PolyhHb exchange transfusion in guinea pigs that had developed metabolic disorders due to a 12-week HFHSD regimen. The guinea pigs, underwent a 20 % blood volume exchange transfusion with either PolyhHb or the lower molecular weight polymerized bovine hemoglobin, Oxyglobin. Results revealed that both PolyhHb and Oxyglobin transfusions led to liver damage, with a more pronounced effect observed in HFHSD-fed animals. Additionally, markers of cardiac dysfunction indicated signs of cardiac injury in both the HFHSD and normal diet groups following the Oxyglobin transfusion. This study highlights how pre-existing metabolic disorders can exacerbate the potential side effects of hemoglobin-based oxygen carriers (HBOCs). Importantly, the newer generation of high MW PolyhHb showed lower cardiac toxicity compared to the earlier generation low MW PolyhHb, known as Oxyglobin, even in models with pre-existing endothelial and metabolic challenges.

Tracking antimicrobial resistance transmission in urban and rural communities in Bangladesh: a One Health study of genomic diversity of ESBL-producing and carbapenem-resistant Escherichia coli.

Antimicrobial resistance (AMR) poses a significant threat to global health and sustainable development goals, especially in low- and middle-income countries (LMICs). This study aimed to understand the transmission of AMR between poultry, humans, and the environment in Bangladesh using a One Health approach. We analyzed the whole genome sequences (WGS) of 117 extended-spectrum ß-lactamase-producing Escherichia coli (ESBL-Ec) isolates, with 46 being carbapenem resistant. These isolates were obtained from human (n = 20) and poultry feces (n = 12), as well as proximal environments (wastewater) (n = 85) of three different study sites, including rural households (n = 48), rural poultry farms (n = 20), and urban wet markets (n = 49). The WGS of ESBL-Ec isolates were compared with 58 clinical isolates from global databases. No significant differences in antibiotic resistance genes (ARGs) were observed in ESBL-Ec isolated from humans with and without exposure to poultry. Environmental isolates showed higher ARG diversity than human and poultry isolates. No clonal transmission between poultry and human isolates was found, but wastewater was a reservoir for ESBL-Ec for both. Except for one human isolate, all ESBL-Ec isolates were distinct from clinical isolates. Most isolates (77.8%) carried at least one plasmid replicon type, with IncFII being the most prevalent. IncFIA was predominant in human isolates, while IncFII, Col(MG828), and p0111 were common in poultry. We observed putative sharing of ARG-carrying plasmids among isolates, mainly from wastewater. However, in most cases, bacterial isolates sharing plasmids were also clonally related, suggesting clonal spread was more probable than just plasmid transfer. IMPORTANCE: Our study underscores that wastewater discharged from households and wet markets carries antibiotic-resistant organisms from both human and animal sources. Thus, direct disposal of wastewater into the environment not only threatens human health but also endangers food safety by facilitating the spread of antimicrobial resistance (AMR) to surface water, crops, vegetables, and subsequently to food-producing animals. In regions with intensive poultry production heavily reliant on the prophylactic use of antibiotics, compounded by inadequate waste management systems, such as Bangladesh, the ramifications are particularly pronounced. Wastewater serves as a pivotal juncture for the dissemination of antibiotic-resistant organisms and functions as a pathway through which strains of human and animal origin can infiltrate the environment and potentially colonize new hosts. Further research is needed to thoroughly characterize wastewater isolates/populations and understand their potential impact on interconnected environments, communities, and wildlife.

Use of spectroscopic process analytical technology for rapid quality evaluation during preparation of CHO cell culture media.

Media preparation parameters contribute significantly to media quality, cell culture performance, productivity, and product quality. Establishing proper media preparation procedures is critical for ensuring a robust CHO cell culture process. Process analytical technology (PAT) enables unique ways to quantify assessments and improve media quality. Here, cell culture media were prepared under a wide range of temperatures (40-80°C) and pH (7.6-10.0). Media quality profiles were compared using three real-time PATs: Fourier-transform infrared (FTIR) spectroscopy, Raman spectroscopy, and excitation-emission matrix (EEM) spectroscopy. FTIR and Raman spectroscopies identified shifts in media quality under high preparation temperature (80°C) and at differing preparation pH which negatively impacted monoclonal antibody (mAb) production. In fed-batch processes for production of three different mAbs, viable cell density (VCD) and cell viability were mostly unaffected under all media preparation temperatures, while titer and cell specific productivity of mAb decreased when cultured in basal and feed media prepared at 80°C. High feed preparation pH alone was tolerated but cell growth and productivity profiles deviated from the control condition. Further, charge variants (main, acidic, basic species) and glycosylation (G0F, afucosylation, and high mannose) were examined. Statistically significant differences were observed for one or more of these quality attributes with any shifts in media preparation. In this study, we demonstrated strong associations between media preparation conditions and cell growth, productivity, and product quality. The rapid evaluation of media by PAT implementation enabled more comprehensive understanding of different parameters on media quality and consequential effects on CHO cell culture.

Different clinical characteristics and outcomes of adult hospitalized SARS-CoV-2 pneumonia patients complicated by cardiovascular events during the first, delta and omicron waves of COVID-19.

Background: The effects of SARS-CoV-2 have varied between significant waves of hospitalization. Research question: Are cardiovascular complications different among the first, delta and omicron waves of hospitalized COVID-19 pneumonia patients? Study design and methods: This was a multi-centre retrospective study of patients hospitalized with SARS-CoV-2 pneumonia: 632 were hospitalized during the first wave (March-July 2020), 1013 during the delta wave (September 2020-March 2021), and 323 during the omicron wave (January 2022-July 2022). Patients were stratified by wave and occurrence of cardiovascular events. Results: Among all hospitalized patients with cardiovascular events, patients in the omicron wave were younger (62.4 ± 14 years) than patients in the first wave (67.4 ± 7.8 years) and the delta wave (66.9 ± 12.6 years) and had a higher proportion of non-Hispanic White people than in the first wave (78.6% vs. 61.7%). For COVID-19 patients who suffered from cardiovascular events, the omicron wave patients had significantly higher neutrophil/lymphocyte ratio, white blood cell and platelet counts when compared to the first wave. Omicron wave patients had significantly lower albumin and B-type natriuretic peptide levels (only 5.8% of the first wave and 14.6% of the delta wave) when compared to either the first wave or delta wave patients. In COVID-19 patients who suffered cardiovascular events during hospitalization, mortality rate in the omicron wave (26.8%) was significantly lower than the first wave (48.3%), time to mortality for non-survivors of COVID-19 patients who suffered cardiovascular events was significantly longer in the omicron wave (median 16 days) than in the first wave (median 10 days). Conclusions: Younger and white patients were affected with cardiovascular complications more often by the omicron variant. Despite higher neutrophil/lymphocyte ratio and WBC counts, the omicron patients with cardiovascular events showed lower heart injuries, lower mortality and longer time to mortality for non-survivors when compared to the first and delta waves.

The hierarchical taxonomy of psychopathology in clinical high risk for psychosis: Validation and extension.

The Hierarchical Taxonomy of Psychopathology (HiTOP) consortium's transdiagnostic dimensional model of psychopathology has considerable support; however, this model has been underresearched in individuals at clinical high risk for psychosis (CHR-P), a population that may advance the model. CHR-P individuals not only have attenuated psychotic symptoms that vary in severity, but also have many comorbid diagnoses and varied clinical outcomes, including disorders with uncertain relations to HiTOP (e.g., obsessive-compulsive disorder). The present study used self-report and interview data from North American Prodrome Longitudinal Study-3 (710 CHR, 96 controls) to replicate the HiTOP model and test specific hypotheses regarding disorders with uncertain relations to its dimensions. Additionally, the present study examined the HiTOP model in relation to childhood trauma, declines in social functioning, and development of full psychosis. Confirmatory factor analysis indicated that the HiTOP model's fit was nearly adequate (e.g., comparative fit index = .89), though several theory-relevant modifications were indicated. Additionally, specific tests were conducted to gain a more fine-grained perspective on how disorders with less clear prior evidence were related to the HiTOP model. Notable findings from these analyses include bipolar spectrum disorders relating to the psychosis super spectrum (i.e., .39 loading), and obsessive-compulsive disorder showing a complex pattern of loadings (e.g., internalizing and psychosis). The final model parsimoniously accounted for childhood trauma (e.g., super spectra rs = .22-.32), associations with current functioning, and predicted future conversion to a psychotic disorder (e.g., super spectra R² = .13). Overall, these results inform the HiTOP model and suggest its promise for CHR-P research. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Amine Basicity of Quinoline ATP Synthase Inhibitors Drives Antibacterial Activity against Pseudomonas aeruginosa.

Pseudomonas aeruginosa (PA), a Gram-negative pathogen, is a common cause of nosocomial infections, especially in immunocompromised and cystic fibrosis patients. PA is intrinsically resistant to many currently prescribed antibiotics due to its tightly packed, anionic lipopolysaccharide outer membrane, efflux pumps, and ability to form biofilms. PA can acquire additional resistance through mutation and horizontal gene transfer. PA ATP synthase is an attractive target for antibiotic development because it is essential for cell survival even under fermentation conditions. Previously, we developed two lead quinoline compounds that were capable of selectively inhibiting PA ATP synthase and acting as antibacterial agents against multidrug-resistant PA. Herein we conduct a structure-activity relationship analysis of the lead compounds through the synthesis and evaluation of 18 quinoline derivatives. These compounds function as new antibacterial agents while providing insight into the balance of physical properties needed to promote cellular entry while maintaining PA ATP synthase inhibition.

Sensitivity to change of the Systemic Therapy Inventory of Change (STIC) intersession scales.

Objective: The Systemic Therapy Inventory of Change (STIC) is a systemic measurement feedback system that provides therapists with feedback regarding the multidimensional clinical change in individual, couple, and family therapy. The STIC Intersession scales include Individual Problems and Strengths (IPS), Relationship with Partner (RWP), Family/Household (FH), and Child Problems and Strengths (CPS). They are administered to clients before each therapy session. The purpose of the current study is to investigate the STIC Intersession scales' sensitivity to change, the ability to detect reliable and valid changes that occur after an intervention. Method: Participants (N = 583) who voluntarily received individual, couple, or family therapy services in a randomized clinical trial attended the study. Results: By comparing the changes in pre-therapy and post-therapy scores of the STIC Intersession scales with those of the corresponding reference measures, the external sensitivity to change of the STIC Intersession scales was supported. The IPS Intersession scale showed greater change than the Beck Anxiety Inventory. However, no evidence supported the discriminant validity of CPS's change scores. Conclusion: Thus, the STIC Intersession IPS, RWP, and FH can be validly used to assess multi-systemic changes in both research and clinical work.

Best practices for communication while wearing facemasks: A scoping review.

INTRODUCTION: Facemasks are an important piece of personal protective equipment (PPE) to mitigate the spread of respiratory illnesses, but they can impede communication between patients and healthcare providers. The purpose of this scoping review is to identify effective communication practices while wearing facemasks. DESIGN: Scoping review using a systematic search of articles from the PubMed, CINAHL, and Embase databases. METHODS: The PEO (population, exposure, outcome) methodology was selected for this systematic scoping review. The population of interest (P) includes humans of all ages (children, adults, and older adults); the exposure of interest (E) is PPE that covers the mouth (i.e., facemasks); and the outcome of interest (O) is successful or unsuccessful communication practices. The Johns Hopkins Evidence-Based Practice for Nurses and Healthcare Professionals appraisal guidelines were used to determine the level and quality of the research. RESULTS: Thirty-nine articles met the inclusion criteria. Seventeen of these were high- or good-quality research studies, and the remaining 22 were non-research articles included with separate analysis as part of the scoping review. The 17 articles encompassed 2656 participants. The highest quality evidence indicated that standard surgical masks have the least impact on speech perception compared to other non-transparent mask types, and that recognizing emotions is less accurate with facemasks, necessitating compensatory actions (i.e., reducing extraneous noise, using a microphone to amplify voice, and employing clear speech). Evidence was contradictory regarding the use of transparent masks. Evidence was of limited quality for other non-verbal and verbal communication strategies. CONCLUSION: Awareness of communication challenges is crucial when wearing facemasks. More high-quality studies are needed to evaluate communication techniques when speakers are wearing facemasks. Basic strategies such as selecting an appropriate mask type, reducing extraneous noise, using microphones, verbalizing emotions, and employing clear speech appear to be beneficial. CLINICAL RELEVANCE: The findings of this scoping review highlight the importance of considering communication challenges while wearing facemasks in the healthcare settings. The review suggests that selecting an appropriate mask type, reducing extraneous noise, verbalizing emotions, and employing clear speech are some strategies that may be effective in mitigating the impact of facemasks on communication between patients and healthcare providers.

Genome-wide association study of preserved ratio impaired spirometry (PRISm).

BACKGROUND: Preserved ratio impaired spirometry (PRISm) is defined as a forced expiratory volume in 1 s (FEV1) <80% predicted and FEV1/forced vital capacity ≥0.70. PRISm is associated with respiratory symptoms and comorbidities. Our objective was to discover novel genetic signals for PRISm and see if they provide insight into the pathogenesis of PRISm and associated comorbidities. METHODS: We undertook a genome-wide association study (GWAS) of PRISm in UK Biobank participants (Stage 1), and selected single nucleotide polymorphisms (SNPs) reaching genome-wide significance for replication in 13 cohorts (Stage 2). A combined meta-analysis of Stage 1 and Stage 2 was done to determine top SNPs. We used cross-trait linkage disequilibrium score regression to estimate genome-wide genetic correlation between PRISm and pulmonary and extrapulmonary traits. Phenome-wide association studies of top SNPs were performed. RESULTS: 22 signals reached significance in the joint meta-analysis, including four signals novel for lung function. A strong genome-wide genetic correlation (rg) between PRISm and spirometric COPD (rg=0.62, p<0.001) was observed, and genetic correlation with type 2 diabetes (rg=0.12, p=0.007). Phenome-wide association studies showed that 18 of 22 signals were associated with diabetic traits and seven with blood pressure traits. CONCLUSION: This is the first GWAS to successfully identify SNPs associated with PRISm. Four of the signals, rs7652391 (nearest gene MECOM), rs9431040 (HLX), rs62018863 (TMEM114) and rs185937162 (HLA-B), have not been described in association with lung function before, demonstrating the utility of using different lung function phenotypes in GWAS. Genetic factors associated with PRISm are strongly correlated with risk of both other lung diseases and extrapulmonary comorbidity.

The Relationship Between Rejection of Care Behaviors and Pain and Delirium Severity in Hospital Dementia Care.

Background and Objectives: Rejection of care is common in hospitalized persons living with dementia. However, distinguishing between rejection of care behaviors related to care practices or other causes, such as pain or delirium, is challenging. The purpose of this study is to further understand the relationship between rejection of care and pain and delirium in hospitalized patients with dementia by identifying which rejection of care behaviors are associated with pain and delirium. Research Design and Methods: Care encounters between hospitalized patients with dementia (n = 16) and nursing staff (n = 53) were observed on 88 separate occasions across 35 days. Rejection of care was measured using the 13 behaviors from the Resistiveness to Care Scale. Pain and delirium severity were measured using a variety of scales including the Pain Assessment in Advanced Dementia Scale, Checklist of Nonverbal Pain Indicators, and numeric rating scale for pain severity and the Confusion Assessment Method-Severity short form and Delirium Observation Screening Scale for delirium severity. Linear mixed modeling was used to determine the relationship between rejection of care behaviors and pain and delirium severity for each measure. Results: About 48.9% of the observations included rejection of care, 49.9% included a patient in pain, and 12.5% included a patient with delirium. Cry, push away, scream/yell, and turn away indicated a higher pain severity across pain measures. No rejection of care behaviors were found to indicate delirium severity. Discussion and Implications: Certain rejection of care behaviors may be helpful in identifying pain in hospitalized patients with dementia, suggesting that caregivers should be cognizant of pain when these rejection of care behaviors are present. However, in this sample rejection of care behaviors was not found to be useful for identifying delirium severity in hospital dementia care.

Impact of contrasting poultry exposures on human, poultry, and wastewater antibiotic resistomes in Bangladesh.

IMPORTANCE: Through the use of DNA sequencing, our study shows that there is no significant difference in the antibiotic resistance genes found in stool samples taken from individuals with high exposure to poultry routinely fed antibiotics and those without such exposure. This finding is significant as it suggests limited transmission of antibiotic resistance genes between poultry and humans in these circumstances. However, our research also demonstrates that commercially reared poultry are more likely to possess resistance genes to antibiotics commonly administered on medium-sized farms. Additionally, our study highlights the under-explored potential of wastewater as a source of various antibiotic resistance genes, some of which are clinically relevant.

Quinoline Compounds Targeting the c-Ring of ATP Synthase Inhibit Drug-Resistant Pseudomonas aeruginosa.

Pseudomonas aeruginosa (PA) is a Gram-negative, biofilm-forming bacterium and an opportunistic pathogen. The growing drug resistance of PA is a serious threat that necessitates the discovery of novel antibiotics, ideally with previously underexplored mechanisms of action. Due to their central role in cell metabolism, bacterial bioenergetic processes are of increasing interest as drug targets, especially with the success of the ATP synthase inhibitor bedaquiline to treat drug-resistant tuberculosis. Like Mycobacterium tuberculosis, PA requires F1Fo ATP synthase for growth, even under anaerobic conditions, making the PA ATP synthase an ideal drug target for the treatment of drug-resistant infection. In previous work, we conducted an initial screen for quinoline compounds that inhibit ATP synthesis activity in PA. In the present study, we report additional quinoline derivatives, including one with increased potency against PA ATP synthase in vitro and antibacterial activity against drug-resistant PA. Moreover, by expressing the PA ATP synthase in Escherichia coli, we show that mutations in the H+ binding site on the membrane-embedded rotor ring alter inhibition by the reported quinoline compounds. Identification of a potent inhibitor and its probable binding site on ATP synthase enables further development of promising quinoline derivatives into a viable treatment for drug-resistant PA infection.

A Metascientific Review of the Evidential Value of Acceptance and Commitment Therapy for Depression.

In the past three-and-a-half decades, nearly 500 randomized controlled trials (RCTs) have examined Acceptance and Commitment Therapy (ACT) for a range of health problems, including depression. However, emerging concerns regarding the replicability of scientific findings across psychology and mental health treatment outcome research highlight a need to re-examine the strength of evidence for treatment efficacy. Therefore, we conducted a metascientific review of the evidential value of ACT in treating depression. Whereas reporting accuracy was generally high across all trials, we found important differences in evidential value metrics corresponding to the types of control conditions used. RCTs of ACT compared to weaker controls (e.g., no treatment, waitlist) were well-powered, with sample sizes appropriate for detecting plausible effect sizes. They typically yielded stronger Bayesian evidence for (and larger posterior estimates of) ACT efficacy, though there was some evidence of significance inflation among these effects. RCTs of ACT against stronger controls (e.g., other psychotherapies), meanwhile, were poorly powered, designed to detect implausibly large effect sizes, and yielded ambiguous-if not contradicting-Bayesian evidence and estimates of efficacy. Although our review supports a view of ACT as efficacious for treating depression compared to weaker controls, future RCTs must provide more transparent reporting with larger groups of participants to properly assess the difference between ACT and competitor treatments such as behavioral activation and other forms of cognitive behavioral therapy. Clinicians and health organizations should reassess the use of ACT for depression if costs and resources are higher than for other efficacious treatments. Clinical trials contributing effects to our synthesis can be found at https://osf.io/qky35.

Genome-wide association study of thyroid-stimulating hormone highlights new genes, pathways and associations with thyroid disease.

Thyroid hormones play a critical role in regulation of multiple physiological functions and thyroid dysfunction is associated with substantial morbidity. Here, we use electronic health records to undertake a genome-wide association study of thyroid-stimulating hormone (TSH) levels, with a total sample size of 247,107. We identify 158 novel genetic associations, more than doubling the number of known associations with TSH, and implicate 112 putative causal genes, of which 76 are not previously implicated. A polygenic score for TSH is associated with TSH levels in African, South Asian, East Asian, Middle Eastern and admixed American ancestries, and associated with hypothyroidism and other thyroid disease in South Asians. In Europeans, the TSH polygenic score is associated with thyroid disease, including thyroid cancer and age-of-onset of hypothyroidism and hyperthyroidism. We develop pathway-specific genetic risk scores for TSH levels and use these in phenome-wide association studies to identify potential consequences of pathway perturbation. Together, these findings demonstrate the potential utility of genetic associations to inform future therapeutics and risk prediction for thyroid diseases.

Changes in oxygen delivery during experimental models of cerebral malaria.

Cerebral malaria (CM) is a severe manifestation of malaria that commonly occurs in children and is hallmarked by neurologic symptoms and significant Plasmodium falciparum parasitemia. It is currently hypothesized that cerebral hypoperfusion from impaired microvascular oxygen transport secondary to parasitic occlusion of the microvasculature is responsible for cerebral ischemia and thus disease severity. Animal models to study CM, are known as experimental cerebral malaria (ECM), and include the C57BL/6J infected with Plasmodium berghei ANKA (PbA), which is ECM-susceptible, and BALB/c infected with PbA, which is ECM-resistant. Here we sought to investigate whether changes in oxygen (O2) delivery, O2 flux, and O2 utilization are altered in both these models of ECM using phosphorescence quenching microscopy (PQM) and direct measurement of microvascular hemodynamics using the cranial window preparation. Animal groups used for investigation consisted of ECM-susceptible C57BL/6 (Infected, n = 14) and ECM-resistant BALB/c (Infected, n = 9) mice. Uninfected C57BL/6 (n = 6) and BALB/c (n = 6) mice were included as uninfected controls. Control animals were manipulated in the exact same way as the infected mice (except for the infection itself). C57BL/6 ECM animals at day 6 of infection were divided into two cohorts: Early-stage ECM, presenting mild to moderate drops in body temperature (>34 < 36 °C) and Late-stage ECM, showing marked drops in body temperature (<33 °C). Data taken from new experiments conducted with these animal models were analyzed using a general linear mixed model. We constructed three general linear mixed models, one for total O2 content, another for total O2 delivery, and the third for total O2 content as a function of convective flow. We found that in both the ECM-susceptible C57BL/6J model and ECM-resistant BALB/c model of CM, convective and diffusive O2 flux along with pial hemodynamics are impaired. We further show that concomitant changes in p50 (oxygen partial pressure for 50% hemoglobin saturation), only 5 mmHg in the case of late-stage CM C57BL/6J mice, and O2 diffusion result in insufficient O2 transport by the pial microcirculation, and that both these changes are required for late-stage disease. In summary, we found impaired O2 transport and O2 affinity in late-stage ECM, but only the former in either early-stage ECM and ECM-resistant strains.

Staying Ahead of the Game: How SARS-CoV-2 has Accelerated the Application of Machine Learning in Pandemic Management.

In recent years, machine learning (ML) techniques have garnered considerable interest for their potential use in accelerating the rate of drug discovery. With the emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, the utilization of ML has become even more crucial in the search for effective antiviral medications. The pandemic has presented the scientific community with a unique challenge, and the rapid identification of potential treatments has become an urgent priority. Researchers have been able to accelerate the process of identifying drug candidates, repurposing existing drugs, and designing new compounds with desirable properties using machine learning in drug discovery. To train predictive models, ML techniques in drug discovery rely on the analysis of large datasets, including both experimental and clinical data. These models can be used to predict the biological activities, potential side effects, and interactions with specific target proteins of drug candidates. This strategy has proven to be an effective method for identifying potential coronavirus disease 2019 (COVID-19) and other disease treatments. This paper offers a thorough analysis of the various ML techniques implemented to combat COVID-19, including supervised and unsupervised learning, deep learning, and natural language processing. The paper discusses the impact of these techniques on pandemic drug development, including the identification of potential treatments, the understanding of the disease mechanism, and the creation of effective and safe therapeutics. The lessons learned can be applied to future outbreaks and drug discovery initiatives.

Personality predicts pre-COVID-19 to COVID-19 trajectories of transdiagnostic anxiety and depression symptoms.

This study aimed to characterize within-person pre-COVID-19 and coronavirus pandemic (COVID-19) transdiagnostic anxiety and depression symptom trajectories in emerging adults and determine the roles of neuroticism and behavioral activation in predicting these COVID-19-related changes. We recruited a sample of 342 emerging adults (aged 18-19 at baseline) who were screened on neuroticism and behavioral activation and completed symptom questionnaires on multiple occasions before and after the start of the pandemic. We examined estimates of the symptom factors of General Distress, Anhedonia-Apprehension, and Fears at each wave. The stress amplification model predicts a multiplicative neuroticism-adversity interaction with those high on neuroticism showing the greatest symptom increases to the pandemic. The stably elevated negative affect model is an additive model and predicts that persons high on neuroticism will display elevated symptoms at every wave. General Distress and Anhedonia-Apprehension showed large increases from the pre-COVID-19 to COVID-19 transition then decreased thereafter. The increase brought the average General Distress score to clinical levels at the first COVID-19 wave. There was a small decrease in Fears from the pre-COVID-19 to COVID-19 transition followed by a large increase. Thus, COVID-19 was associated with both increases in psychological symptoms and some resilience. Neuroticism positively predicted the pre-COVID-19 to COVID-19 transition change in Fears but was associated with a dampening of increases in General Distress and Anhedonia-Apprehension. The results disconfirmed the stress amplification model of neuroticism but partially supported the stably elevated negative affect model. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Prony Analysis of Left Ventricle Pressure and Volume.

Direct measurement of cardiac pressure-volume (PV) relationships is the gold standard for assessment of ventricular hemodynamics, but few innovations have been made to "multi-beat" PV analysis beyond traditional signal processing. The Prony method solves the signal recovery problem with a series of dampened exponentials or sinusoids. It achieves this by extracting the amplitude, frequency, dampening, and phase of each component. Since its inception, application of the Prony method to biologic and medical signal has demonstrated a relative degree of success, as a series of dampened complex sinusoids easily generalizes to multifaceted physiological processes. In cardiovascular physiology, the Prony analysis has been used to determine fatal arrythmia from electrocardiogram signals. However, application of the Prony method to simple left ventricular function based on pressure and volume analysis is absent. We have developed a new pipeline for analysis of pressure volume signals recorded from the left ventricle. We propose fitting pressure-volume data from cardiac catheterization to the Prony method for pole extraction and quantification of the transfer function. We implemented the Prony algorithm using open-source Python packages and analyzed the pressure and volume signals before and after severe hemorrhagic shock, and after resuscitation with stored blood. Each animal (n = 6 per group) underwent a 50% hemorrhage to induce hypovolemic shock, which was maintained for 30 min, and resuscitated with 3-week-old stored RBCs until 90% baseline blood pressure was achieved. Pressure-volume catheterization data used for Prony analysis were 1 s in length, sampled at 1000 Hz, and acquired at the time of hypovolemic shock, 15 and 30 min after induction of hypovolemic shock, and 10, 30, and 60 min after volume resuscitation. We next assessed the complex poles from both pressure and volume waveforms. To quantify deviation from the unit circle, which represents deviation from a Fourier series, we counted the number of poles at least 0.2 radial units away from it. We found a significant decrease in the number of poles after shock (p = 0.0072 vs. baseline) and after resuscitation (p = 0.0091 vs. baseline). No differences were observed in this metric pre and post volume resuscitation (p = 0.2956). We next found a composite transfer function using the Prony fits between the pressure and volume waveforms and found differences in both the magnitude and phase Bode plots at baseline, during shock, and after resuscitation. In summary, our implementation of the Prony analysis shows meaningful physiologic differences after shock and resuscitation and allows for future applications to broader physiological and pathophysiological conditions.

GBT021601 improves red blood cell health and the pathophysiology of sickle cell disease in a murine model.

The pathophysiologic mechanism of sickle cell disease (SCD) involves polymerization of deoxygenated haemoglobin S (HbS), leading to red blood cell (RBC) sickling, decreased RBC deformability, microvascular obstruction, haemolysis, anaemia and downstream clinical complications. Pharmacological increase in the concentration of oxygenated HbS in RBCs has been shown to be a novel approach to inhibit HbS polymerization and reduce RBC sickling and haemolysis. We report that GBT021601, a small molecule that increases HbS-oxygen affinity, inhibits HbS polymerization and prevents RBC sickling in blood from patients with SCD. Moreover, in a murine model of SCD (SS mice), GBT021601 reduces RBC sickling, improves RBC deformability, prolongs RBC half-life and restores haemoglobin levels to the normal range, while improving oxygen delivery and increasing tolerance to severe hypoxia. Notably, oral dosing of GBT021601 in animals results in higher levels of Hb occupancy than voxelotor and suggests the feasibility of once-daily dosing in humans. In summary, GBT021601 improves RBC health and normalizes haemoglobin in SS mice, suggesting that it may be useful for the treatment of SCD. These data are being used as a foundation for clinical research and development of GBT021601.

Mendelian randomisation of eosinophils and other cell types in relation to lung function and disease.

RATIONALE: Eosinophils are associated with airway inflammation in respiratory disease. Eosinophil production and survival is controlled partly by interleukin-5: anti-interleukin-5 agents reduce asthma and response correlates with baseline eosinophil counts. However, whether raised eosinophils are causally related to chronic obstructive pulmonary disease (COPD) and other respiratory phenotypes is not well understood. OBJECTIVES: We investigated causality between eosinophils and: lung function, acute exacerbations of COPD, asthma-COPD overlap (ACO), moderate-to-severe asthma and respiratory infections. METHODS: We performed Mendelian randomisation (MR) using 151 variants from genome-wide association studies of blood eosinophils in UK Biobank/INTERVAL, and respiratory traits in UK Biobank/SpiroMeta, using methods relying on different assumptions for validity. We performed multivariable analyses using eight cell types where there was possible evidence of causation by eosinophils. MEASUREMENTS AND MAIN RESULTS: Causal estimates derived from individual variants were highly heterogeneous, which may arise from pleiotropy. The average effect of raising eosinophils was to increase risk of ACO (weighted median OR per SD eosinophils, 1.44 (95%CI 1.19 to 1.74)), and moderate-severe asthma (weighted median OR 1.50 (95%CI 1.23 to 1.83)), and to reduce forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) and FEV1 (weighted median estimator, SD FEV1/FVC: -0.054 (95% CI -0.078 to -0.029), effect only prominent in individuals with asthma). CONCLUSIONS: Broad consistency across MR methods may suggest causation by eosinophils (although of uncertain magnitude), yet heterogeneity necessitates caution: other important mechanisms may be responsible for the impairment of respiratory health by these eosinophil-raising variants. These results could suggest that anti-IL5 agents (designed to lower eosinophils) may be valuable in treating other respiratory conditions, including people with overlapping features of asthma and COPD.