bluuebunny/crossref_metadata_2025 huggingface dataset:
Healthcare Disparities Among Older Adults: Exploring Social Determinants of Health and Cognition Levels
Authors: Rahemi Zahra , Bacsu Juanita-Dawne R. , Shalhout Sophia Z. , Sadafipoor Maryam S. , Smith Matthew Lee , Adams Swann Arp
Published: July 2024

Background

The purpose was to investigate the impact of sociodemographic factors on healthcare utilization among adults with different cognition levels (normal and impairment/dementia).

Methods

We used cross-sectional data from the Health and Retirement Study (N=17,698) to assess healthcare utilization: hospital stay, nursing home stay, hospice care, and doctor visits.

Results

A cohort comparison between normal and dementia/impaired cognition groups revealed significant differences. The dementia/impaired group had lower education levels, higher single/widowed status, and more racial and ethnic minorities. They experienced longer hospital and nursing home stays, varied doctor visit frequencies, and had higher mean age, greater loneliness scores, and lower family social support scores. Differences in hospitalization, nursing home, hospice care, and doctor visits were influenced by factors such as race, age, marital status, education, and rurality.

Conclusion

There were disparities in healthcare utilization based on participants’ characteristics and cognition levels, especially in terms of race/ethnicity, education, and rural location.
PARP14 mediated SQSTM1/p62 cysteine ADP-ribosylation is counteracted by the SARS-CoV-2 macrodomain
Authors: Kubon David , Leslie Pedrioli Deena M. , Hottiger Michael O.
Published: July 2024

Several ADP-ribosyltransferases are upregulated during viral infections and are crucial for the cellular immune response. While interferon-induced PARP14 ADP-ribosylates various substrates, viruses such as SARS-CoV-2 counteract this by reversing ADP-ribosylation. The exact mechanism of PARP14’s antiviral activity and the targets of viral macrodomains remain unknown. Here, we observe that PARP14 mono-ADP-ribosylates the selective autophagy adaptor SQSTM1/p62 at cysteine residues 113, 289/90, and 331 following interferon treatment. This correlates with the ADP-ribosylation of cytoplasmic p62 foci that colocalize with ubiquitin and PARP14 but not with LC3, thereby distinguishing them from classical autophagosomes. Moreover, the SARS-CoV-2 macrodomain effectively prevented this p62 modification, suggesting an antiviral function for this ADP-ribosylated target. Furthermore, our results indicate that TRIM21 prevents the autophagic degradation of ADP-ribosylated p62, suggesting that the identified p62 foci may have autophagy-independent roles. This study contributes to our understanding of the molecular dynamics involved in host-virus interactions and highlights the potential role of ADP-ribosylation in the regulation of innate immunity.
Awake prone positioning effectiveness in moderate to severe COVID-19 a randomized controlled trial
Authors: Phong Nguyen Thanh , Duc Du Hong , Hai Ho Bich , Nguyen Thanh Nguyen , Khoa Le Dinh Van , Khanh Le Thuy Thuy , Tran Luu Hoai Bao , Linh Nguyen Thi My , Van Cao Thi Cam , Thao Dang Phuong , Trinh Nguyen Thi Diem , Kieu Pham Tieu , Truong Nguyen Thanh , Hoang Vo Tan , Ngoc Nguyen Thanh , Vien Tran Thi Dong , Ly Vo Trieu , Khoa Tran Dang , Beane Abigail , Anibal James ,   Oucru Covid Reseach Group, Thwaites Guy E , Geskus Ronald B , Clifton David , Dung Nguyen Thi Phuong , Kestelyn Evelyne , Glover Guy , Tan Le Van , Yen Lam Minh , Tung Nguyen Le Nhu , Dung Nguyen Thanh , Thwaites C Louise
Published: July 2024

Objectives

We evaluated the efficacy and acceptability of awake-prone positioning (APP) in a randomised controlled trial, using a dedicated APP implementation team and wearable continuous-monitoring devices to monitor position and oximetry.

Methods

The trial was performed at a tertiary level hospital in Ho Chi Minh City, Vietnam, recruiting adults (≥18 years) hospitalised with moderate or severe COVID-19 and receiving supplemental oxygen therapy via nasal/facemask systems or high-flow nasal canulae. Participants were randomized (1:1) to standard care or APP. The primary outcome was escalation of respiratory support within 28 days of randomisation.

Results

Ninety-three patients were enrolled between March 2022 and March 2023; 80 (86%) had received ≥2 doses of SARS-CoV2 vaccine. Significantly greater mean daily APP times were achieved in those allocated to APP, although most did not achieve the target 8 hours/day. We did not detect significant differences in the primary outcome (RR 0.85, 95% CI 0.40-1.78, p=0.67) or secondary outcomes, including intubation rate and 28-day mortality. Particpants reported prone positioning was comfortable, although almost all preferred supine positioning. No adverse events associated with the intervention were reported.

Conclusions

APP was not associated with benefit, but was safe. Continuous monitoring with wearable devices was feasible and acceptable to patients.

Clinical Trials Registration

NCT05083130

Funding

Wellcome Trust Grant 089276/B/09/7, 217650/Z/19/Z and FDCO/Wellcome Trust 225437/Z/22/Z
Women’s Health And Manifestos (WHAM): UK General Election 2024, a rapid voter information study
Authors: Mullins E , Womersley K , Abdi Fardowsa , Donovan-Bradley Celestine , Ekechi Christine , Hazard Leah , Hirst Jane , Nana Melanie , Perry Alison , Pinho-Gomes Ana-Catarina , Ripullone Katherine , Williams Stephanie
Published: July 2024

Background

The UK 2024 general election manifestos publicly set out the political parties’ priorities for the eventuality that they are voted into government. We determined to evaluate whether already agreed, evidenced and promoted issues affecting women’s health in the UK had been included in the major parties’ manifestos.

Methods

We curated a longlist of priorities and recommendations drawn from major women’s health reports, white papers, national inquiries and health strategies published in the UK over the last 10 years which are publicly available and invited our public contributors to suggest additional topics. We selected the shortlist of women’s health-related priorities – our top 15 ‘asks’ –using a Delphi process. We then devised a scoring system whereby manifestos were marked against the 15 priorities with a maximum of 2 points for each priority. We tested inter-rater reliability on the 2019 Manifesto.

Results

Overall, the limited inclusion of prominent issues for women’s health in party manifestos was disappointing across the board. There was little difference between most major parties’ coverage of women’s health in their manifestos. All were limited. Most parties addressed two issues well: childcare and women returning to work after pregnancy; and violence against women and girls and the prosecution of perpetrators.

Several other issues, including assurance that all policy is built in consultation with women; decriminalisation and access to abortion; and women’s health hubs for reproductive, menopause and lifelong health, were considered by none or only one of the major parties.

Discussion

Women’s health remains a fringe issue in UK politics, despite the efforts of patients, advocates and healthcare professionals to highlight the suffering that many women live with every day, and at particularly vulnerable and high risk periods of their life such as in pregnancy and the postpartum.

Our analysis highlights the importance of developing previous efforts in women’s health to strengthen existing infrastructure, collaboration and innovation. The next government should build on the work in progress, such as delivering the Women’s Health Strategy (2022) rather than starting afresh.
Knot Guilty? An Examination of Testicular Torsion Litigation Trends from 2014 to 2022
Authors: Menshawey Rahma , Menshawey Esraa
Published: July 2024

Background

Testicular torsion is a true urological emergency that occurs when the testes twists around the spermatic cord, cutting off its blood supply. The failure to diagnose testicular torsion is a common medicolegal pitfall due to the uncertainty and urgency of the diagnosis and the potential for testicular loss. In this study, we examined the current medicolegal cases that involved testicular torsion using the LexisNexis database for all cases from 2014 to 2022, using the search terms “testicular torsion” and “medical malpractice”. Our final examination included a total of 20 cases.

Results

Trends reveal that Emergency doctors and urologists are the most commonly named defendants. Adults and incarcerated persons are common plaintiffs. The average time from presentation to diagnosis of testicular torsion was 8 ±13 days. The right testicle was the most commonly implicated, and a misdiagnosis was a commonly cited. The average time from testicular torsion diagnosis to filing a case was 4.35 years.

Conclusions

Trends reaffirm that testicular torsion remains a high risk of litigation diagnosis, and continued training and education may be needed to remedy the medicolegal pitfalls for this emergency condition.
Cross-sectional and longitudinal associations of smoking behavior with central arterial hemodynamic measures: The Framingham Heart Study
Authors: Cooper Leroy L. , Majid Sana , Wang Na , Fetterman Jessica L. , Palmisano Joseph N. , Benjamin Emelia J. , Vasan Ramachandran S. , Mitchell Gary F. , Hamburg Naomi M.
Published: July 2024

Background

Cigarette smoking is a leading modifiable cardiovascular disease risk factor. Cross-sectional studies demonstrated variable relations of smoking behavior with measures of vascular function. Additionally, the impact of persistent versus changes in smoking behaviors on alterations in central arterial function is unclear.

Methods and Results

We assessed associations of smoking behavior and intensity with measures of central arterial hemodynamics in 6597 participants (51.5% never smoked, 34.8% formerly quit, 4.3% recent quit, and 9.3% currently smoking) of the Framingham Heart Study (N=3606 [55%] women). In cross-sectional models, central vascular measures were different across categories of smoking behavior. For example, augmentation index was higher among participants who formerly quit smoking (least squares mean±standard error=14.1±0.4%;P<0.001) and were currently smoking (18.1±0.5%;P<0.001) compared to participants who never smoked (12.6±0.3%). Among participants who were currently smoking, higher cigarettes per day (estimatedB=1.41; 95% CI, 0.47—2.34;P=0.003) was associated with higher augmentation index. Among participants who had quit smoking, higher pack-years was associated with higher augmentation index (est.B=0.85; 95% CI, 0.60—1.14) and central pulse pressure (est.B=0.84; 95% CI, 0.46—1.21). Using restricted cubic splines, we observed a negative linear association for augmentation index, but a distinct nonlinear association for characteristic impedance and central pulse pressure, with higher time since quit (allP<0.001). In longitudinal models, we observed higher increases in augmentation index among participants who persistently quit (4.62±0.41%;P<0.001) and persistently smoked (5.48±0.70%;P=0.002) compared to participants who persistently never smoked (3.45±0.37%).

Conclusion

Central arterial measures are sensitive to smoking status and intensity and changes in smoking behavior. Longer smoking cessation may partially revert central arterial measures to levels comparable to those with lower smoking exposure.
Longitudinal trajectories of muscle impairments in growing boys with Duchenne muscular dystrophy
Authors: Vandekerckhove Ines , Hauwe Marleen Van den , Dewit Tijl , Molenberghs Geert , Goemans Nathalie , Waele Liesbeth De , Campenhout Anja Van , Groote Friedl De , Desloovere Kaat
Published: July 2024

Background

Insights into the progression of muscle impairments in growing boys with Duchenne muscular dystrophy (DMD) remains incomplete due to the frequent oversight of normal maturation as confounding factor, thereby restricting the delineation of sole pathological processes.

Objective

To establish longitudinal trajectories for a comprehensive integrated set of muscle impairments, including muscle weakness, contractures and muscle size alterations, whilst correcting for normal maturation, in DMD.

Methods

Thirty-five boys with DMD (aged 4.3-17 years) were included. Fixed dynamometry, goniometry and 3D freehand ultrasound were used to repeatedly asses lower limb muscle strength, passive range of motion (ROM) and muscle size, resulting in 165, 182 and 67 assessments for the strength, ROM and ultrasound dataset, respectively. To account for natural strength development, ROM reduction and muscle growth in growing children, muscle impairments were converted to unit-less z-scores calculated in reference to typically developing (TD) peers. This allows the interpretation of the muscle impairments as deficits or alterations with respect to TD. Mixed-effect models estimated the longitudinal change in muscle impairments.

Results

The pathological trajectories of most muscle impairments with age followed a similar non-linear, piecewise pattern, characterized by an initial phase of improvement or stability lasting until 6.6-9.5 years, and a subsequent decline after these ages. The muscle strength outcomes and several ROMs showed already initial deficits at young ages. General muscle weakness and plantar flexion contractures exhibited the steepest declines, resulting in large deficits at older ages. The muscle size alterations with age were muscle-specific.

Conclusions

The established longitudinal trajectories of muscle impairments will serve as the basis to enhance understanding of their relationship with the progressive gait pathology in DMD. Our study provides outcome measures, which will be useful for future clinical trials that assess the efficacy of novel therapeutic strategies.
Challenges and benefits associated with educational materials: experiences of the Ghanaian nurse trainees
Authors: Adabre James Agamah , Bam Victoria Bubunyo
Published: July 2024

Background

Educational Materials (EMs) are vital in teaching and learning activities and contribute significantly to the acquisition of knowledge and skills for an enhanced performance. The right educational resources help stimulate, reinforce and make it more impact and beneficial.

AIM

This study’s main goal is to identify the learning materials that are used regularly in nursing training schools and analyze the experiences of nurse trainees on their impact on the achievement of academic objectives. And to guide stakeholders in nursing education policy formulation.

SETTING

This study was conducted in four (4) Nursing and Midwifery Training institutions in Ghana.

Methods

A descriptive method was used for this study. An online survey was used to collect data from 47 nurse educators and 374 student nurses and analyzed using Stata version 16.0. The Kwame Nkrumah University of Science and Technology’s Committee on Human Research, Publication, and Ethics (CHRPE) was consulted for ethical approval.

Results

The common available EMs were handouts (80.1%), recommended textbooks (55.9%), and smartphones (54.6%). The EMs that were commonly used by students were the handout (58.6%), recommended textbooks (39.6%), and both internet information and PowerPoint slides (18.8%) each. Majority of the students (64.1%) reported that the commonly used EMs made good contributions towards their academic performance and 22.6% indicated that the used EMs made excellent contributions to their academic performance. Example e-books has OR of 0.43 and a p-value of 0.021.

Conclusion

Modern Ems such as reliable internet access, 3D animation videos should be made readily available in schools to greatly help to improve the standards of nursing education and contribute to quality healthcare workforce.

Contributions

Educational materials plays a vital role in health trainees’ education, increases nurses knowledge, and output on health care delivery.
Expanding Risks: Medicaid Expansion and Data Security
Authors: Clement Jeffrey , Greenwood Brad N , D’Arcy John , Angst Corey
Published: July 2024

The Patient Protection and Affordable Care Act of 2010 led to the largest expansion of healthcare coverage since the instantiation of Medicare and Medicaid in 1965. Yet, limited attention has been given to the security aftereffects of the statute, specifically the potential for malfeasance in the form of consumer fraud and identity theft resulting from the vast influx of new patient data residing in various and highly dispersed sources. In this work, we fill this gap by exploiting the phased expansion of Medicaid into different states at different times. Using a difference in difference approach, we explore the data security-related aftereffects of the law. Results indicate a significantdecreasein claims of consumer fraud after the expansion of Medicaid, with no robust effect on identity theft. In empirical extensions, we find a material drop in data breaches and compromised records after the expansion of Medicaid. Taken in sum, these findings suggest that the expansion of Medicaid had a consequential effect on the security of consumer data and created significant positive externalities for consumers.
Combined pre-dialysis systolic blood pressure and pulse rate assessment for all-cause and cardiovascular mortalities: A nationwide cohort study on patients undergoing haemodialysis
Authors: Joki Nobuhiko , Toida Tatsunori , Niihata Kakuya , Inanaga Ryohei , Nakata Kenji , Abe Masanori , Hanafusa Norio , Kurita Noriaki
Published: July 2024

Background and Aims

The prognostic utility of the combined assessment of pre-haemodialysis systolic blood pressure (SBP) and pulse rate (PR) compared with their individual assessment is unclear. This study aimed to determine whether the combined assessment could enhance the prognostic utility in patients on haemodialysis.

Methods

This nationwide cohort study involved patients undergoing maintenance haemodialysis using the Japanese Renal Data Registry database. Exposure was defined as a combination of SBP and PR. Forty-eight levels of exposure groups were created: SBP (six levels; <100, 100-<120, 120-<140, 140-<160 [reference], 160-<180, and ≥180 mmHg) and PR (eight levels; <50, 50-<60, 60-<70 [reference], 70-<80, 80-<90, 90-<100, 100-<110, and ≥110 per minute). The primary and secondary outcomes were one-year all-cause and cardiovascular mortalities, respectively. Multivariate Cox proportional hazards models were used, and multiplicative interactions were assessed to determine the superiority of the combined model over the individual models. Additive interactions were assessed using relative excess risk due to interactions (RERI).

Results

The combined model explained mortality and cardiac mortality better than the individual SBP and PR models (P<0.001 andP<0.002, respectively). A lower SBP was associated with a higher risk of all-cause mortality regardless of the PR. Most categories of lower SBP or higher PR vs. the 120-<140 mmHg and 70-<80/min category had positive RERIs. Similar findings were also observed for cardiac mortality.

Conclusions

The combined assessment of pre-dialysis SBP and PR may help in the simple stratification of patients with excess risks that cannot be identified by individual SBP or PR assessment.
Differential action modes of Neutrophil Extracellular Trap-targeted drugs define T cell responses in SARS-CoV-2 infection
Authors: Bonilha Caio Santos , Veras Flavio Protasio , Ramos Anderson dos Santos , Gomes Giovanni Freitas , Lemes Robertha Mariana Rodrigues , Arruda Eurico , Alves-Filho José Carlos , Cunha Thiago Mattar , Cunha Fernando Queiroz
Published: July 2024

Neutrophil extracellular traps (NETs) play a dual role in SARS-CoV-2 infection, aiding early immune defense but also contributing to lung damage. While NET targeting may improve clinical outcomes in SARS-CoV-2 infection, its impact on adaptive immunity, crucial for fighting the virus, remains unclear. Our study demonstrates that both recombinant human DNase (rhDNase), degrading NET structure, and GSK484, inhibiting NET formation, reduce lung NET concentration and improve clinical outcomes in infected mice, yet they differ in their influence on T cell responses. We show that rhDNase does not impact T cell responses, whereas GSK484 diminishes virus-specific T cell responses.In vitro, GSK484 decreases dendritic cell antigen presentation by impairing antigen uptake and reduces IL-2 signaling by affecting its production by T cells. In a model of lung inflammation, GSK484 diminishes antigen-specific T cell activation and proliferation, while rhDNase shows a potential to boost T cell responses via the presence of NET fragments that reduce T cell activation threshold. Our findings suggest that NET targeting with rhDNase or GSK484 holds therapeutic potential for treating SARS-CoV-2 infection, while their distinct modes of action shape T cell responses during the infection.
β-1,6-glucan plays a central role in the structure and remodeling of the bilaminate fungal cell wall
Authors: Bekirian Clara , Valsecchi Isabel , Bachellier-Bassi Sophie , Scandola Cyril , Guijarro J. Iñaki , Chauvel Murielle , Mourer Thierry , Gow Neil A.R. , Aimanianda Vishukumar , d’Enfert Christophe , Fontaine Thierry
Published: July 2024

The cell wall of human fungal pathogens plays critical roles as an architectural scaffold and as a target and modulator of the host immune response. Although the cell wall of the pathogenic yeastCandida albicansis intensively studied, one of the major fibrillar components in its cell wall, β-1,6- glucan, has been largely neglected. Here, we show that β-1,6-glucan is essential for bilayered cell wall organization, cell wall integrity and filamentous growth. For the first time, we show that β-1,6- glucan production compensates the defect in mannan elongation in the outer layer of the cell wall. In addition, β-1,6-glucan dynamics are also coordinated by host environmental stimuli and stresses with wall remodeling, where the regulation of β-1,6-glucan structure and chain length is a crucial process. As we point out that β-1,6-glucan is exposed at the yeast surface and modulate immune response, β-1,6-glucan must be considered a key factor in host-pathogen interactions.
Efficient Generation ofSOCS2Knock-out Sheep by Electroporation of CRISPR-Cas9 Ribonucleoprotein Complex with Dual-sgRNAs
Authors: Mahdi Ahmed K. , Fitzpatrick Devon S. , Hagen Darren E. , McNabb Bret R. , Beach Tara Urbano , Muir William M. , Werry Nicholas , Van Eenennaam Alison L. , Medrano Juan F. , Ross Pablo J.
Published: July 2024

Knock-out (KO) sheep were produced using CRISPR-Cas9 ribonucleoprotein complexes in zygotes targeting an 85 bp section of the first exon of the Suppressor of Cytokine Signalling-2 (SOCS2) gene. Electroporation was performed 6 hours post-fertilization with dual-guide CRISPR-Cas9 ribonucleoproteins (RNPs). Fifty-two blastocysts were transferred to 13 estrus-synchronized recipients, yielding five live lambs and one stillborn. These lambs were all compound heterozygotes with mutations predicted to result inSOCS2KO. Three lambs carried large deletion alleles (259 bp, 1694 bp, and 2127 bp) that evaded initial detection via initial PCR screening. Off-target analysis identified a small number of mutations which may have been the result of off-target activity in regions with some homology to the guides, but notably such mutations were also observed in unedited controls. Further, we observed several orders of magnitude more mutations outside of these regions of homology in both edited animals and controls. Western blot and RT-PCR analysis of cell lines from SOCS2 KO lambs showed trace levels ofSOCS2mRNA and SOCS2 protein. In conclusion, combining IVF and electroporation of dual-guide CRISPR-Cas9 RNPs was effective at generating KO sheep.
Inhibition of serine racemase prevents diabetic retinopathy
Authors: Jiang Haiyan , Zhou Piansi , Jiang Xue , Wu Xiong , Mao Yandie , Liu Shuyi , Tang Shiqi , Zhou Jing , Zhang Zhiwen , Ren Bingbing , Shan Ge , Qu Jia , Wu Shengzhou
Published: July 2024

Retinal diabetic neuropathy (RDN) precedes retinal microvascular pathology in diabetic retinopathy (DR), but the therapy by antagonizing RDN to stall DR is rare. Emerging evidence including ours suggest that serine racemase (SRR) drives DR at least by promoting RDN. Thus, we explore the therapy by antagonizing SRR to stall and treat DR. We herein indicate that inhibition of SRR by oral gavage of l-aspartic acid β-hydroxymate (L-ABH), a competitive inhibitor of SRR, mitigated photoreceptor dysfunction, loss of retinal ganglion cells (RGC) and retinal endothelial cell and pericyte in db/db mice, a type II diabetes model. To dissect the mechanism, intravitreal injection of L-ABH mitigates glutamate-induced neurotoxicity in the retina. In the whole body, gastrointestinal-based delivery of L-ABH maintained euglycemia and improved glucose tolerance either in db/db mice or in diet-induced obesity mice. In conclusion, inhibition of SRR prevented retinal neurovascular abnormalities in diabetic animals through executing neuroprotection in the retina and maintaining glucose homeostasis in the system. Our study reveals a novel strategy to prevent DR.
Treatment recommendations based on Network Meta-Analysis: rules for risk-averse decision-makers
Authors: Ades A E , Pedder Hugo , Davies Annabel L , Thom H , Phillippo David M , Downing Beatrice , Caldwell Deborah M , Welton Nicky J
Published: July 2024

Background

The treatment recommendation based on a Network Meta-analysis (NMA) is usually the single treatment with the highest Expected Value (EV) on an evaluative function. We explore approaches which recommend multiple treatments and which penalize uncertainty, making them suitable for risk-averse decision makers.

Methods

We introduce Loss-adjusted EV (LaEV) and compare it to GRADE and three probability-based rankings. We define the properties of a valid ranking under uncertainty and other desirable properties of ranking systems. A two-stage process is proposed: the first selects treatments superior to the reference treatment; the second identifies those that are also within a Minimal Clinically Important Difference (MCID) of the best treatment. Decision rules and ranking systems are compared on stylized examples and 10 NMAs used in NICE Guidelines.

Results

Only LaEV reliably delivers valid rankings under uncertainty and has all the desirable properties. In 10 NMAs comparing between 4 and 40 treatments, an EV decision maker would recommend 4-14 treatments, and LaEV 0-3 (median 2) fewer. GRADE rules give rise to anomalies, and, like the probability-based rankings, the number of treatments recommended depends on arbitrary probability cutoffs. Among treatments that are superior to the reference, GRADE privileges the more uncertain ones, and in 3/10 cases GRADE failed to recommend the treatment with the highest EV and LaEV.

Conclusions

A two-stage approach based on MCID ensures that EV- and LaEV-based rules recommend a clinically appropriate number of treatments. For a risk-averse decision maker, LaEV is conservative, simple to implement, and has an independent theoretical foundation.

Highlights

What is already known?

A risk-neutral decision-maker should make treatment decisions based on Expected Value (EV), meaning that the single treatment with the highest expected efficacy from a network meta-analysis should be recommended, regardless of uncertainty. In practice, decision makers may recommend several treatments, and take uncertainty into account on anad hocbasis.

What is new?

We introduce Loss-adjusted EV (LaEV) as a mechanism for risk-averse decision making, and set out desirable properties of ranking systems. We define a ranking as valid under uncertainty if a higher EV is ranked above a lower one at the same uncertainty and a lower uncertainty above a higher one at the same EV. We compare LaEV to GRADE and probabilistic rankings. Of the methods examined, only LaEV provides a valid ranking under uncertainty and has all the desirable properties.

Implications

For a risk-averse decision maker, LaEV is a reliable, conservative, and easy-to-implement decision metric, with an independent theoretical foundation. Adoption of a risk-averse stance might focus attention on more accurate quantification of uncertainty, and encourage generation of better quality evidence.
Using Family History Data to Improve the Power of Association Studies: Application to Cancer in UK Biobank
Authors: Wilcox Naomi , Tyrer Jonathan P. , Dennis Joe , Yang Xin , Perry John R. B. , Gardner Eugene J. , Easton Douglas F.
Published: July 2024

In large cohort studies the number of unaffected individuals outnumbers the number of affected individuals, and the power can be low to detect associations for outcomes with low prevalence. We consider how including recorded family history in regression models increases the power to detect associations between genetic variants and disease risk. We show theoretically and using Monte-Carlo simulations that including family history of the disease, with a weighting of 0.5 compared to true cases, increases the power to detect associations. This is a powerful approach for detecting variants with moderate effects, but for larger effect sizes a weighting of >0.5 can be more powerful. We illustrate this both for common variants and for exome sequencing data for over 400,000 individuals in UK Biobank to evaluate the association between the burden of protein-truncating variants in genes and risk for 4 cancer types.
Simulating 500 million years of evolution with a language model
Authors: Hayes Thomas , Rao Roshan , Akin Halil , Sofroniew Nicholas J. , Oktay Deniz , Lin Zeming , Verkuil Robert , Tran Vincent Q. , Deaton Jonathan , Wiggert Marius , Badkundri Rohil , Shafkat Irhum , Gong Jun , Derry Alexander , Molina Raul S. , Thomas Neil , Khan Yousuf , Mishra Chetan , Kim Carolyn , Bartie Liam J. , Nemeth Matthew , Hsu Patrick D. , Sercu Tom , Candido Salvatore , Rives Alexander
Published: July 2024

More than three billion years of evolution have produced an image of biology encoded into the space of natural proteins. Here we show that language models trained on tokens generated by evolution can act as evolutionary simulators to generate functional proteins that are far away from known proteins. We present ESM3, a frontier multimodal generative language model that reasons over the sequence, structure, and function of proteins. ESM3 can follow complex prompts combining its modalities and is highly responsive to biological alignment. We have prompted ESM3 to generate fluorescent proteins with a chain of thought. Among the generations that we synthesized, we found a bright fluorescent protein at far distance (58% identity) from known fluorescent proteins. Similarly distant natural fluorescent proteins are separated by over five hundred million years of evolution.
A stabilized MERS-CoV spike ferritin nanoparticle vaccine elicits robust and protective neutralizing antibody responses
Authors: Powell Abigail E. , Caruso Hannah , Park Soyoon , Chen Jui-Lin , O’Rear Jessica , Ferrer Brian J. , Belnap David M. , Walker Audrey , Bruening Anneliese , Hartwig Airn , Ahyong Vida , Dougherty Cristy S. , Bowen Richard , Ledgerwood Julie E. , Kay Michael S. , Weidenbacher Payton A.-B. , Palanski Brad A.
Published: July 2024

Middle East respiratory syndrome coronavirus (MERS-CoV) was first identified as a human pathogen in 2012 and causes ongoing sporadic infections and outbreak clusters. Despite case fatality rates (CFRs) of over 30% and the pandemic potential associated with betacoronaviruses, a safe and efficacious vaccine has not been developed for prevention of MERS in at-risk individuals. Here we report the design, in vitro characterization, and preclinical evaluation of MERS-CoV antigens. Our lead candidate comprises a stabilized spike ectodomain displayed on a self-assembling ferritin nanoparticle that can be produced from a high-expressing, stable cell pool. This vaccine elicits robust antibody titers in BALB/c mice as measured by MERS- CoV pseudovirus and live-virus neutralization assays. Immunization of non-human primates (NHPs) with a single dose of Alhydrogel-adjuvanted vaccine elicits >103geometric mean titer (GMT) of pseudovirus neutralizing antibodies that can be boosted with a second dose. These antibody levels are durable, with GMTs that surpass the post-prime levels for more than 5 months post-boost. Importantly, sera from these NHPs exhibit broad cross-reactivity against lentiviruses pseudotyped with spike proteins from MERS-CoV clades A, B, and C as well as a more distant pangolin merbecovirus. In transgenic mice expressing human DPP4, immunization provided dose-dependent protection against MERS-CoV lethal challenge, and in an established alpaca challenge model, immunization fully protected against MERS-CoV infection. This protein-based MERS-CoV nanoparticle vaccine is a promising candidate for advancement to clinical development to protect at-risk individuals and for future use in a potential outbreak setting.
Essential Roles of RodA Peptidoglycan Polymerase and PBP2 Transpeptidase in Expression of Cell Wall-Spanning Supramolecular Organelles and ModulatingSalmonellaVirulence
Authors: Doble Anne C. , Gollan Bethany C , Clark-Corrigall John , Bulmer David M. , Daniel Richard A , Mastroeni Pietro , Khan C. M. Anjam
Published: July 2024

The increased spread of multidrug-resistant bacteria no longer sensitive to commonly used antibiotics poses a major threat to human health. The search for potential new drug targets is critical in disease control and prevention. Whilst several components of the cell wall synthesis machinery are already targeted by beta-lactam antibiotics, other elements of this machinery present opportunities for novel drug targets. Landmark studies revealed RodA exhibits peptidoglycan polymerase activity inBacillus subtilisandEscherichia coli,highlighting RodA as a prime for the next generation of antimicrobial drugs. However, the role of RodA in virulence remains unexplored. Through targeted mutagenesis, virulence gene reporter assays, and phenotypic screening, we demonstrate that the presence of RodA or PBP2, is intrinsically linked to the regulation of virulence gene expression inSalmonella. Specifically, deletion of either of these components causes both disruption in cell morphology and a complete downregulation in major cell invasion-associated virulence factorsin vitro,and attenuated virulencein vivo. Significantly, this study highlights the importance of RodA and PBP2 in both the biology and virulence of an important bacterial pathogen, identifying them as promising targets for developing new antibiotics.
Porphyromonas gingivalisactivates Heat-Shock-Protein 27 to drive a LC3C-specific probacterial form of select autophagy that is redox sensitive for intracellular bacterial survival in human gingival mucosa
Authors: Wellslager Bridgette , Roberts JoAnn , Chowdhury Nityananda , Madan Lalima , Orellana Elsy , Yilmaz Özlem
Published: July 2024

Porphyromonas gingivalis, a major oral pathobiont, evades canonical host pathogen clearance in human primary gingival epithelial cells (GECs) by initiating a non-canonical variant of autophagy consisting of Microtubule-associated protein 1A/1B-light chain 3 (LC3)-rich autophagosomes, which then act as replicative niches. Simultaneously,P. gingivalisinhibits apoptosis and oxidative-stress, including extracellular-ATP (eATP)-mediated reactive-oxygen-species (ROS) production via phosphorylating Heat Shock Protein 27 (HSp27) with the bacterial nucleoside-diphosphate-kinase (Ndk). Here, we have mechanistically identified thatP. gingivalis-mediated induction of HSp27 is crucial for the recruitment of the LC3 isoform, LC3C, to drive the formation of liveP. gingivalis-containing Beclin1-ATG14-rich autophagosomes that are redox sensitive and non-degrading. HSp27 depletions of both infected GECs and gingiva-mimicking organotypic-culture systems resulted in the collapse ofP. gingivalis-mediated autophagosomes, and abolishedP. gingivalis-induced LC3C-specific autophagic-flux in a HSp27-dependent manner. Concurrently, HSp27 depletion accompanied by eATP treatment abrogated protracted Beclin 1-ATG14 partnering and decreased live intracellularP. gingivalislevels. These events were only partially restored via treatments with the antioxidant N-acetyl cysteine (NAC), which rescued the cellular redox environment independent of HSp27. Moreover, the temporal phosphorylation of HSp27 by the bacterial Ndk results in HSp27 tightly partnering with LC3C, hindering LC3C canonical cleavage, extending Beclin 1-ATG14 association, and halting canonical maturation. These findings pinpoint how HSp27 pleiotropically serves as a major platform-molecule, redox regulator, and stepwise modulator of LC3C duringP. gingivalis-mediated non-canonical autophagy. Thus, our findings can determine specific molecular strategies for interfering with the host-adaptedP. gingivalis’ successful mucosal colonization and oral dysbiosis.
Identification of mCMQ069, a novel antimalarial with potential for a single-dose cure and/or 28-day chemoprevention
Authors: Gupta Anil K. , Pedroarena James , Nazarian Armen , Antonova-Koch Jenya , Weiss Frank , Kumpornsin Krittikorn , Chi Victor , Woods Ashley K. , Lee Kyoung-Jin , Joseph Sean B. , Li Shuangwei , Brittain Jason , De Hostos Eugenio , Duffy James , Cooper Anne , Schultz Peter G. , McNamara Case W. , Chatterjee Arnab K.
Published: July 2024

In efforts towards eliminating malaria, a discovery program was initiated to identify a novel antimalarial using KAF156 as a starting point. Following the most recent TCP/TPP guidelines, we have identified mCMQ069 with a predicted single oral dose for treatment (∼40-106 mg) and one-month chemoprevention (∼96-216 mg). We have improved unbound MPC and predicted human clearance by 18-fold and 10-fold respectively when compared to KAF156.
High Throughput Repurposing Screen Reveals Compounds with Activity Against Toxoplasma gondii Bradyzoites
Authors: Uddin Taher , Xia Jing , Fu Yong , McNamara Case W , Chatterjee Arnab K , Sibley L. David
Published: July 2024

Toxoplasma gondii causes widespread chronic infections that are not cured by current treatments due to inability to affect semi-dormant bradyzoite stages within tissue cysts. To identify compounds to eliminate chronic infection, we developed a HTS using a recently characterized strain of T. gondii that undergoes efficient conversion to bradyzoites in intro. Stage-specific expression of luciferase was used to selectively monitor growth inhibition of bradyzoites by the Library of Pharmacological Active Compounds, consisting of 1,280 drug-like compounds. We identified 44 compounds with >50% inhibitory effects against bradyzoites, including new highly potent compounds, several of which have precedent for antimicrobial activity. Subsequent characterization of the compound Sanguinarine sulfate revealed potent and rapid killing against in vitro produced bradyzoites and bradyzoites harvested from chronically infected mice. These findings provide a platform for expanded screening and identify promising compounds for further preclinical development against T. gondii bradyzoites responsible for chronic infection.
Differential expression ofCCD4(4B)drives natural variation in fruit carotenoid content in strawberry (Fragariaspp.)
Authors: Amaya Iraida , Roldán-Guerra F. Javier , Ordóñez-Díaz José L. , Torreblanca Rocío , Wagner Henning , Veronika Waurich , Olbricht Klaus , Moreno-Rojas José M. , Sánchez-Sevilla José F. , Castillejo Cristina
Published: July 2024

Pigments, mainly anthocyanins and carotenoids, are important contributors to fruits’ visual appearance and nutritional properties. In strawberry (Fragariaspp.), the genetic and molecular mechanisms regulating fruit carotenoid biosynthesis and its natural variation remain largely unexplored. In this study, we sought to identify genomic loci contributing to variation in yellow flesh pigmentation. A major QTL,qYellow Flesh-4B, accounting for 82% of the total phenotypic variation was identified onF. ×ananassachromosome 4B. Following a candidate gene approach, we determined thatCCD4(4B),a carotenoid cleavage dioxygenase (CCD), was the underlying gene. Specific polymorphisms onCCD4(4B)promoter region were associated with the yellow flesh phenotype and with differential regulation ofCCD4(4B)expression during fruit ripening. Furthermore,CCD4(4B)expression levels were negatively correlated with violaxanthin, lutein, zeaxanthin, β-carotene and total carotenoid content. The role of CCD4(4B) in carotenoid turnover was confirmed by transient overexpression inF.×ananassafruits, which led to a decrease in carotenoid accumulation. Notably, a −35 C>T SNP identified inCCD4(4B)promoter was found to be predictive forCCD4(4B)expression, and carotenoid content in fruits of a diverse germplasm collection, which included different octoploidFragariaspecies. Taken together, these results provide important genetic insights into the natural variation of carotenoid content in strawberry. The High-Resolution Melting (HRM) DNA test here developed offers a fast and reliable method to predict high fruit carotenoid content, representing a useful tool for breeding projects aiming to enhance the nutritional value of this crop.
Implementing total quality management in a virtual organisation: thoughts and lessons from an interventionist approach
Authors: Norberto Carneiro Welington , Mendonça Neto Octavio Ribeiro de , Afonso Paulo , Oyadomari Jose Carlos Tiomatsu , Dultra-de-Lima Ronaldo Gomes
Published: July 2024

Purpose

This article aims to understand the challenges and key takeaways of implementing total quality management (TQM) in a virtual organisation.

Design/methodology/approach

An interventionist research (IVR) methodology combined with a qualitative critical event analysis was used to evaluate the challenges and concerns faced during the company’s adoption of TQM and understand the roles of the key players involved.

Findings

Standard process tools such as desktop procedures (DTP), focused teams, and service-level agreements (SLAs) were fundamental to implementing TQM in the company. These processes require the right leaders, but external agents may also be influential, acting as accelerators of change in adopting and using management practices in small companies. Indeed, the researcher acted as a problem solver, bringing innovative solutions to the firm using a hands-on iterative approach.

Practical implications

This research underscores the importance of critical success factors (CSF), such as employee engagement, training, and project management tools. These factors are not just important but crucial for the success of TQM in organisations seeking to adopt the industry’s best practices.

Originality/value

This study, conducted as a virtual IVR for TQM implementation, provides novel insights for practitioners and academics. It elucidates the pivotal role of some quality management tools in the journey towards TQM and the role of both internal and external critical players in the process, particularly in small virtual organisations based on innovative business models.
Sensitivity analysis with various parameters in undermoded reverberation chambers
Authors: Kenderes Anett , Gyimóthy Szabolcs , Benk Péter Tamás
Published: July 2024

Purpose

The purpose of this paper is to investigate the influence of measurement uncertainties and the environment characteristics themselves on the desired field uniformity (FU) in reverberation chambers (RCs) by means of state-of-the-art global sensitivity analysis techniques. There are many quantities to describe the FU. The authors attempted to inspect many of the most important ones in two different orientations of the stirrer (horizontal, vertical).

Design/methodology/approach

Surrogate modelling techniques are involved to compute the Sobol’ indices efficiently with a modest number of required electromagnetic (EM) simulations. This can be only achieved if the behaviour of an appropriately chosen output quantity is predictable in such a way, which enables to extract useful information. Therefore, this choice should be made with extra care of the stochastic fluctuations, which have to be as low as possible. To this end, in this paper, various figures of merit are investigated.

Findings

This method can provide useful knowledge in the lower frequency range, where the ideal properties of the EM field in RCs cannot be established, and the importance of the setup parameters can vary from configuration to configuration.

Originality/value

Considering the current research tendencies related to RCs, the application of the method of Sobol’ indices to RCs is unique, which has only been done by the authors of this work so far. The main contribution presented in the paper is the thorough investigation of the effect of configuration parameters on the statistical properties of RCs through many output quantities describing the FU.
The role of financial literacy in enhancing firm’s sustainable performance through Fintech adoption: a moderated mediation analysis
Authors: Hidayat-ur-Rehman Imdadullah
Published: July 2024

Purpose

This study aims to explore the intricate relationship between financial literacy, digital transformation, Fintech adoption, competitiveness and sustainable firm performance, particularly focusing on how financial literacy empowers firms in the evolving digital landscape. Leveraging technological innovation systems (TIS) and resource-based view (RBV), this research suggests a model that incorporates these concepts, focusing on the moderating role of financial literacy in essential interactions.

Design/methodology/approach

This study employed a survey-based methodology, collecting data from employees across five major Pakistani banks. The survey yielded 426 responses, from which 387 valid ones were selected for analysis. The analysis utilized partial least squares-structural equation modeling (PLS-SEM), complemented by the Hayes Process Model for moderated mediation analysis. This approach ensured robust examination of the relationships between the constructs of the proposed model.

Findings

The study's findings validate that digital transformation significantly enhances sustainable performance, with Fintech adoption and competitiveness acting as crucial mediators. Financial literacy is highlighted as a key moderator, influencing the effects of digital transformation on Fintech adoption and competitiveness, although its direct impact on sustainable performance is less pronounced. This comprehensive analysis underscores the complex interplay among these factors in driving sustainable performance in the banking sector.

Originality/value

This research enriches the theoretical and practical comprehension of how digital transformation and Fintech integration, underpinned by financial literacy, bolster sustainable business outcomes. It sheds light on the synergy between technology, strategy and organizational success, offering key insights for the banking industry's navigation through the digital era's challenges.