bluuebunny/crossref_metadata_2025 huggingface dataset:
Final outcome analysis from the phase II TUXEDO-1 trial of trastuzumab-deruxtecan in HER2-positive breast cancer patients with active brain metastases
Authors: Bartsch Rupert , Berghoff Anna Sophie , Furtner Julia , Marhold Maximilian , Bergen Elisabeth Sophie , Roider-Schur Sophie , Mair Maximilian Johannes , Starzer Angelika Martina , Forstner Heidrun , Rottenmanner Beate , Aretin Marie-Bernadette , Dieckmann Karin , Bago-Horvath Zsuzsanna , Haslacher Helmuth , Widhalm Georg , Ilhan-Mutlu Aysegül , Minichsdorfer Christoph , Fuereder Thorsten , Szekeres Thomas , Oehler Leopold , Gruenberger Birgit , Pfeiler Georg , Singer Christian , Weltermann Ansgar , Berchtold Luzia , Preusser Matthias
Published: July 2024

Background

Brain metastases (BM) are a devastating complication of HER2-positive metastatic breast cancer (BC) and treatment strategies providing optimized local and systemic disease control are urgently required. The antibody-drug conjugate trastuzumab deruxtecan (T-DXd) improved progression-free survival (PFS) and overall survival (OS) over trastuzumab emtansine but data regarding intracranial activity is limited. In the primary outcome analysis of TUXEDO-1, a high intracranial response rate (RR) was reported with T-DXd. Here, we report the final PFS and OS results.

Patients and Methods

TUXEDO-1 accrued adult patients with HER2-positive BC and active BM (newly diagnosed or progressing) without indication for immediate local therapy. The primary endpoint was intracranial RR; secondary endpoints included PFS, OS, safety, quality-of-life (QoL), and neurocognitive function. PFS and OS were estimated with the Kaplan-Meier method and analyzed in the per-protocol population.

Results

At 26.5 months median follow-up, median PFS was 21 months (95% CI: 13.3–n.r.) and median OS was not reached (95% CI: 22.2–n.r.). With longer follow-ups, no new safety signals were observed. The most common grade 3 adverse event was fatigue (20%). Grade 2 interstitial lung disease and a grade 3 symptomatic drop of left-ventricular ejection fraction were observed in one patient each. QoL was maintained over the treatment period.

Conclusions

T-DXd yielded prolonged intra- and extracranial disease control in patients with active HER2-positive BC BM in line with results from the pivotal trials. These results support the concept of antibody-drug-conjugates as systemic therapy for active BM.
Rights That
Authors: Eldridge Eleanor
Published: July 2024

Hohfeld was acutely aware of the ‘potent tendency [of words] to control thought’. He was perhaps less aware of the power of syntax to do the same. Hohfeld’s tendency to express the content of duties and liberties in the syntactically restrictive to ϕ form has allowed a corrupted version of his analytical scheme to take root. That version takes as axiomatic that the content of any duty or liberty is the action or inaction of the duty bearer or liberty holder. Yet duties and liberties can (and do) pertain to matters other than the action or inaction of the duty bearer or liberty holder. This insight has a range of doctrinal implications.
The stromal side of the cytochrome b6f complex regulates state transitions
Authors: Riché Alexis , Dumas Louis , Malesinski Soazig , Bossan Guillaume , Madigou Céline , Zito Francesca , Alric Jean
Published: July 2024

In oxygenic photosynthesis, state transitions distribute light energy between PSI and PSII. This regulation involves reduction of the plastoquinone pool, activation of the state transitions 7 (STT7) protein kinase by the cytochrome (cyt) b6f complex, and phosphorylation and migration of light harvesting complexes II (LHCII). In this study, we show that in Chlamydomonas reinhardtii, the C-terminus of the cyt b6 subunit PetB acts on phosphorylation of STT7 and state transitions. We used site-directed mutagenesis of the chloroplast petB gene to truncate (remove L215b6) or elongate (add G216b6) the cyt b6 subunit. Modified complexes are devoid of heme ci and degraded by FTSH protease, revealing that salt bridge formation between cyt b6 (PetB) and Subunit IV (PetD) is essential to the assembly of the complex. In double mutants where FTSH is inactivated, modified cyt b6f accumulated but the phosphorylation cascade was blocked. We also replaced the arginine interacting with heme ci propionate (R207Kb6). In this modified complex, heme ci is present but the kinetics of phosphorylation are slower. We show that highly phosphorylated forms of STT7 accumulated transiently after reduction of the PQ pool and represent the active forms of the protein kinase. The phosphorylation of the LHCII targets is favored at the expense of the protein kinase, and the migration of LHCII toward PSI is the limiting step for state transitions.
RESISTANCE TO PHYTOPHTHORA1 promotes cytochrome b559 formation during early photosystem II biogenesis in Arabidopsis
Authors: Che Li-Ping , Ruan Junxiang , Xin Qiang , Zhang Lin , Gao Fudan , Cai Lujuan , Zhang Jianing , Chen Shiwei , Zhang Hui , Rochaix Jean-David , Peng Lianwei
Published: July 2024

As an essential intrinsic component of photosystem II (PSII) in all oxygenic photosynthetic organisms, heme-bridged heterodimer cytochrome b559 (Cyt b559) plays critical roles in the protection and assembly of PSII. However, the underlying mechanisms of Cyt b559 assembly are largely unclear. Here, we characterized the Arabidopsis (Arabidopsis thaliana) rph1 (resistance to Phytophthora1) mutant, which was previously shown to be susceptible to the oomycete pathogen Phytophthora brassicae. Loss of RPH1 leads to a drastic reduction in PSII accumulation, which can be primarily attributed to the defective formation of Cyt b559. Spectroscopic analyses showed that the heme level in PSII supercomplexes isolated from rph1 is significantly reduced, suggesting that RPH1 facilitates proper heme assembly in Cyt b559. Due to the loss of RPH1-mediated processes, a covalently bound PsbE–PsbF heterodimer is formed during the biogenesis of PSII. In addition, rph1 is highly photosensitive and accumulates elevated levels of reactive oxygen species under photoinhibitory-light conditions. RPH1 is a conserved intrinsic thylakoid protein present in green algae and terrestrial plants, but absent in Synechocystis, and it directly interacts with the subunits of Cyt b559. Thus, our data demonstrate that RPH1 represents a chloroplast acquisition specifically promoting the efficient assembly of Cyt b559, probably by mediating proper heme insertion into the apo-Cyt b559 during the initial phase of PSII biogenesis.
Neuropsychiatric drugs and a neurophysiological marker as predictors of health-related quality of life in patients with phantom limb pain
Authors: Costa Valton , Pacheco-Barrios Kevin , Gianlorenço Anna Carolyna , Fregni Felipe
Published: July 2024

Objective

To explore the relationship between sociodemographic, clinical, and neurophysiological variables and health-related quality of life (HR-QOL) of patients with phantom limb pain (PLP).

Methods

This is a cross-sectional analysis of a previous clinical trial. Univariate and multivariate linear and logistic regression analyses were used to model the predictors of HR-QOL. We utilized a sequential modeling approach with increasing adjustment levels, controlling for age and sex, and other relevant clinical variables (time since amputation, level of amputation, and pain). HR-QOL was assessed by the SF-36 Health Survey and its 8 subdomains.

Results

We analyzed baseline data from 92 patients with lower-limb amputations. They were mostly male (63%), 45.2 ± 15.6 years, with a mean time since amputation of 82.7 ± 122.4 months, and an overall SF-36 score of 55.9 ± 21.5. We found an association between intracortical facilitation (ICF) in the affected hemisphere, gabapentin usage, and HR-QOL. ICF is a predictor of better HRQOL, whereas gabapentin usage was associated with a poorer HR-QOL, with the main model explaining 13.4% of the variance in the outcome. For the SF-36 subdomains, ICF was also a positive predictor for social functioning, bodily pain, and vitality, while medication usage was associated with lower scores in mental health, general health perception, bodily pain, and vitality.

Conclusion

We found firsthand 2 new independent predictors of HR-QOL in individuals with PLP, namely, the neurophysiological metric ICF and gabapentin usage. These results highlight the role of the motor cortex excitability in the HR-QOL and stress the need for treatments that favor the neuroplastic adaptation after amputation, for which ICF may be used as a possible marker.
Safe and effective degradation of aflatoxins by food-grade culture broth of Aspergillus oryzae
Authors: Choi Dasol , Alshannaq Ahmad F , Yu Jae-Hyuk
Published: July 2024

Aflatoxins (AFs) are carcinogenic fungal toxins contaminating up to 25% of the global food supply. Over half of the world's population is exposed to unmonitored levels of AFs, mostly aflatoxin B1 (AFB1). Despite numerous efforts over the past 60 years, there are no solutions to remove AFs safely from food. Here, we present a safe and effective AF-degrading product called “D-Tox”, a filtered culture broth of Aspergillus oryzae grown in a food-grade liquid medium. When 5 ppm of AFB1 is added to D-Tox, ∼90% is degraded at 48 and 24 hr at room temperature and 50°C, respectively. Moreover, when varying amounts (0.1 ppm ∼ 100 ppm) of AFB1 are added to D-Tox at 100°C, over 95% of AFB1 is degraded in 1 hr, suggesting a nonenzymatic process. Examining degradation of 100 ppm AFB1 reveals that aflatoxin D1 (AFD1) is the major transient degradant of AFB1, indicating that degradation occurs irreversibly by lactone ring hydrolysis followed by decarboxylation. D-Tox further degrades AFD1 to unknown fragmented products. Importantly, the practical application of D-Tox is also demonstrated, as more than 70% of AFB1 is degraded when wheat, corn, and peanuts naturally contaminated with high levels of AFB1 (0.3 ∼ 4.5 ppm) are boiled in D-Tox for 1 hr. Additionally, D-Tox can degrade other lactone-ring containing mycotoxins, including patulin and ochratoxin. D-Tox exhibits no cytotoxicity under the conditions tested in MCF-7 breast cancer cell lines. In summary, D-Tox is a safe and effective AF-detoxifying product that can enhance global food safety.
What is to reproduce? On the overlap, development, and persistence account of reproduction
Authors: Palacios-González César
Published: July 2024

Monika Piotrowska has defended a new account of reproduction. Her account seems able to answer the question of whether reproduction takes place, and who reproduces, when we employ biotechnologies that bear little to no resemblance to naturally occurring human sexual reproduction. Piotrowska's account also seems to increase our understanding of biological individuality and seems to be compatible with the theory of evolution via natural selection. In this paper, I do two things. First, I show that Piotrowska's account is found wanting, because it is extensionally inadequate. Second, I show that her criticism of James Grisemer's account of reproduction is mistaken.
A Comparison of the Socioeconomic and Gendered Organization of Social Reproduction in the United States and the United Kingdom, 1973–2013
Authors: Moos Katherine A , Gonalons-Pons Pilar
Published: July 2024

Drawing on both gender regime theory and social reproduction theory, this article compares the socioeconomic and gendered organization of social reproduction in the United States and the United Kingdom from 1973 to 2013. Integrating data from the Luxembourg Income Study, the Multinational Time-Use Study, and additional sources, we examine how men and women of different socioeconomic groups contribute to social reproduction through household production, paid work, and government social benefits. Our results demonstrate that household social reproduction has not been universally refamilialized, marketized, or desocialized in either country. While there is some evidence of degendering, questions remain about its feminist implications.
Weissella paramesenteroidesNRIC1542 inhibits dextran sodium sulfate‐induced colitis in mice through regulating gut microbiota and SIRT1/NF‐κB signaling pathway
Authors: Li Shuang , Chen Junyang , Zheng Yang , Zhang Yun
Published: July 2024

Inflammatory bowel disease (IBD) is a kind of recurrent inflammatory disorder of the intestinal tract. The purpose of this study was to investigate the effects of Weissella paramesenteroides NRIC1542 on colitis in mice. A colitis model was induced by adding 1.5% DSS to sterile distilled water for seven consecutive days. During this process, mice were administered different concentrations of W. paramesenteroides NRIC1542. Colitis was assessed by DAI, colon length and hematoxylin–eosin staining of colon sections. The expressions of NF‐κB signaling proteins and the tight junction proteins ZO‐1 and occludin were detected by western blotting, and the gut microbiota was analyzed by 16S rDNA. The results showed that W. paramesenteroides NRIC1542 significantly reduced the degree of pathological tissue damage and the levels of TNF‐α and IL‐1β in colonic tissue, inhibiting the NF‐κB signaling pathway and increasing the expression of SIRT1, ZO‐1 and occludin. In addition, W. paramesenteroides NRIC1542 can modulate the structure of the gut microbiota, characterized by increased relative abundance of Muribaculaceae_unclassified, Paraprevotella, Prevotellaceae_UCG_001 and Roseburia, and decrease the relative abundance of Akkermansia and Alloprevotella induced by DSS. The above results suggested that W. paramesenteroides NRIC1542 can protect against DSS‐induced colitis in mice through anti‐inflammatory, intestinal barrier maintenance and flora modulation.
Adverse effects of anti-cancer biologics on the ocular surface
Authors: Shawer Riham , Solomon Abraham
Published: July 2024

Purpose of review

Cancer immunotherapy is one of the most emerging and rapidly growing fields.

Ocular side effects associated with these therapies are common and can be present in up to 70% of patients.

The cornea may be involved in different pathogenic mechanisms triggered by different immunotherapeutic agents, and corneal disease varies from mild symptoms to severe corneal ulceration and melting with visual loss.

We aimed to review the incidence, mechanism, and management of ocular surface side effects in cancer patients receiving immunotherapy.

Recent findings

With the recent use of immunotherapeutic agents in cancer patients, in particular immune checkpoint inhibitors (ICIs) and epidermal growth factor receptor (EGFR) inhibitors, ocular surface and corneal involvement are common side effects.

These patients can be at risk of sight threatening complications that warrant prompt diagnosis and careful monitoring and management.

Immunotherapy- related corneal complications in cancer patients are associated with a decreased quality of life. Prompt recognition and an interdisciplinary approach between ophthalmologists and oncologists are crucial to handle immune related ocular adverse events in these patients, in order to maintain ocular surface integrity and avoid a vision threatening complication.
Life-threatening bilateral internal carotid artery and unilateral vertebral artery total occlusion presenting with dizziness: a case report
Authors: Jobran Afnan W.M. , Warasna Haya Jebreen Mohammad , Awad Mohammad Yaser Hasan , Awad Bashar Yaser Hasan , Shahin Farah Bilal Yousef , Alhadad Baha , Amr Bajis , Abuturki Abdelwadod A , Smerat Mohammad I.
Published: July 2024

Introduction:

It is well known that whereas bilateral occlusion is less common, unilateral internal carotid artery blockage happens regularly. Asymptomatic to fatal ischemic stroke can be the clinical presentation, depending on whether there is adequate collateral blood flow. Internal carotid artery occlusion is often associated with significant neurologic events, both at the time of initial occlusion and during follow-up.

Case presentation:

The authors describe a patient’s experience of dizziness followed by a fall. The hyperdense position of the basilar artery near its bifurcation was identified following a computed tomography (CT) scan. Furthermore, the pons, midbrain, and medial parts of the right temporal lobe showed numerous small hypodensities suggestive of an ischemic injury. The patient had medical treatment without surgery after it was determined that they had bilateral internal carotid arteries and a blocked right vertebral artery. After taking dual anti-platelet therapy for 5 days, the patient recovered without incident and was discharged from the hospital.

Discussion:

In a young patient with bilateral internal carotid arteries occlusion (BICAO), the authors highlighted the significance of prompt diagnosis of stroke-like symptoms, diagnostic possibilities, and treatment options. Options for diagnosis include brain MRI and CT head to check for ischemia and CT angiography (CTA) head and neck to assess for artery obstruction. Options for treatment include severe medical and surgical treatments, such as carotid endarterectomy, stent implantation, or balloon angioplasty, or medical management alone, such as dual anti-platelet medication and thrombolysis.

Conclusion:

BICAO is associated with a grave prognosis and significant cerebrovascular complications. High-quality studies are needed to establish the best treatment strategy, considering the complex and individualized nature of the condition.
Embryoid Bodies and Related Proliferations in Ovarian Germ Cell Tumors
Authors: Devins Kyle M. , Young Robert H.
Published: July 2024

We investigated the frequency and associated pathology of embryoid bodies in ovarian tumors by evaluating neoplasms in which they are known to occur: 100 immature teratomas, 125 malignant mixed germ cell tumors, and 6 polyembryomas. Three immature teratomas contained a single relatively well-formed embryoid body, whereas these and 11 others showed foci we categorized as embryoid body remnants consisting of microscopic aggregates of embryonal or yolk sac-type epithelium associated with spaces consistent with yolk sac or amniotic cavity but lacking a classic embryoid body structure. Teratomas with these foci were all high grade. A well-formed embryoid body was found in only 1 malignant mixed tumor, but embryoid body remnants were present in 25%, invariably associated with foci of immature teratoma (100%) and often with yolk sac tumor (97%), embryonal carcinoma (35%), or both (32%). These foci usually took the form of round to oval aggregates, often well-circumscribed, for which the term “polyembryoma background” has been proposed. The polyembryomas were typically grossly hemorrhagic and occurred in patients from 9 to 43 years of age. The embryoid bodies in them generally grew in lobules within an edematous to occasionally myxoid stroma. Four tumors contained liver-like cells, 4 numerous glands likely recapitulating the allantois, 3 syncytiotrophoblast cells, 2 prominent cysts, and 2 striking vascular proliferations. This study indicates that (1) typical embryoid bodies are rare in immature teratomas but about 14% of them have embryoid body remnants. (2) Embryoid body remnants are seen in 25% of malignant mixed germ cell tumors with a teratomatous component and often proliferate to form yolk sac tumor and embryonal carcinoma. (3) Well-formed embryoid bodies growing in a confluent manner (polyembryoma) are rare, and minor foci of teratoma, yolk sac tumor, or embryonal carcinoma are almost always present, indicating that these are fundamentally malignant mixed germ cell tumors but the polyembryoma component is dominant and distinctive which, in our opinion, justifies its own nomenclature. (4) Embryoid bodies are not a feature of other germ cell tumors.
Auricular Deformational Anomalies Detected in Human Fetal Cadavers
Authors: Elvan Özlem , Bobuş Örs Alev , Güneş Evrim
Published: July 2024

The aim of the study was to investigate the incidence and diversity of deformational auricular anomalies in human fetuses based on their morphologic appearances. A total of 100 auricles from 56 formalin-fixed fetuses (32 female and 24 male), gestational ages ranging from 17 to 36 weeks, were examined. The auricles were categorized according to the morphologic deformities outlined in existing literature. Of the samples analyzed, 67% exhibited auricular deformities, while the remaining 33% showed no auricle anomalies. Among the auricles with deformities, 73% displayed a single type of deformity: Conchal crus, 22%; Stahl’s ear, 13%; inverted conchal bowl, 13%; lidding ear, 12%; cup ear, 7%; and constricted ear, 6%. In addition, 27% of the auricles exhibited 2 different deformities on the same side: Conchal crus with lidding ear, 10%; conchal crus with Stahl’s ear, 5%; conchal crus with the antihelix 3rd crus, 3%; constricted ear with lidding ear, 5%; constricted ear with cup ear, 2%; and constricted ear with inverted conchal bowl, 2%. The most prevalent deformity was conchal crus, whereas cup ear was the least. Among the fetuses, 10 had bilaterally normal auricles, 8 had unilaterally normal auricles, 12 exhibited the same deformity bilaterally, and 14 displayed different deformities on each side. Auricular deformational variations can vary in shape and symmetry, even in morphologically normal fetuses. Identifying these deformities can contribute to accurate diagnosis and treatment planning for such anomalies in newborns.
Effects of Footbath on Pain, Anxiety, Sleep, and Comfort Levels in Patients With Postlaparoscopic Cholecystectomy: A Randomized Controlled Study
Authors: Gürçayir Dilek , Karabulut Neziha
Published: July 2024

Purpose:

The aim of the study is to determine the effect of of hot footbaths on the pain, anxiety, sleep, and comfort levels of patients who underwent laparoscopic cholecystectomy.

Design:

The study is a randomized controlled designed.

Methods:

This study was conducted in surgery clinic of a university hospital between January 2022 and November 2022. The research was completed with 54 patients in the experimental group and 54 patients in the control group.

Findings:

The mean state anxiety score and VAS-Sleep score of the patients in the experimental group 120 minutes after the application was 31.07±4.70 and 612.62±82.37, respectively, which was statistically significantly lower than that of the patients in the control group (P<0.05). On the other hand, at the 120th minutes after the application, the mean VAS-Comfort scores of the patients in the experimental group were statistically significantly higher than those of the patients in the control group (P<0.05). A positive relationship was found between the mean VAS-Pain and VAS-Sleep scores of the patients in the experimental group, and a significant negative relationship was found between the mean VAS-Comfort and state anxiety scores.

Conclusions:

Foot bath is effective in reducing the pain and anxiety levels of patients undergoing laparoscopic cholecystectomy surgery.
Patterns of Injury in a Gaza War Hospital
Authors: Alsalqawi Abdalkarim , Villar Richard
Published: July 2024

This study describes the patterns of injury observed in a Gaza war hospital, focusing on 110 consecutive patients. Of these, two had conditions unrelated to trauma, so the analysis was of the remaining 108 casualties. No military personnel were seen. The data reveal clear trends, including a high prevalence of explosive injuries (86.36%), a low prevalence of gunshot wounds (8.18%), a notable proportion of female (34.55%) and child (23.64%) casualties, and the occurrence of multiple injuries (1.73 injuries/patient) because of the use of high explosive. There were 187 injuries identified including 128 fractures. Of these fractures, 64.84% were of the lower limb and 28.91% of the upper limb. Of the 128 fractures, 79 (61.72%) were clinically and/or radiologically infected. The most frequently infected fracture was the compound tibial and fibular fracture, which showed an infection rate of 92.86%. These findings highlight the unique and tragic nature of the Gaza conflict, the increasing injuries to civilians, including women and children, and the long-term healthcare that will be needed.
Association of serum adiponectin and leptin levels with inner retinal thickness among individuals with or without elevated HbA1c
Authors: Koseoglu Neslihan D , Wang Jiangxia , Anokye-Danso Frederick , Moreno Jose Amezcua , Cha Eumee , Fuchs Franklin , Teed Jacqueline , Yao Jianing , Zhang Yan , Ahima Rexford S , Sachdeva Mira M
Published: July 2024

Inner retinal thinning precedes clinical evidence of retinopathy in prediabetes and diabetes mellitus (DM), and may contribute to retinopathy development and progression. Serum levels of the adipokines leptin and adiponectin are inversely related in the setting of impaired glucose homeostasis, but their potential association with inner retinal thickness is unknown. In this prospective study, both eyes from 24 individuals with prediabetes or type 2 DM (glycated hemoglobin [HbA1c] ≥5.7) and 16 controls (HbA1c<5.7) underwent spectral-domain optical coherence tomography imaging of the macula, and thickness of the nerve fiber layer (NFL) and ganglion cell layer-inner plexiform layer (GCL-IPL) was analyzed in each subfield of the Early Treatment Diabetic Retinopathy Study grid. Serum samples were collected and metabolic factors, including adiponectin and leptin, were measured. Adjusted regression analyses revealed inverse associations of these adipokines with NFL thickness that did not differ between prediabetes/DM and controls, but differential positive associations of adiponectin with GCL-IPL thickness only in the prediabetes/DM group. The results of our pilot study suggest opposing roles for adiponectin and leptin in the retina, similar to their relationship in systemic disease, and suggest that serum adiponectin may represent a potential clinical biomarker for inner retinal thickness in patients with elevated HbA1c.
Precision Medicine in Cardiology: An Evolving Understanding of Biomarkers in Coronary Artery Disease Prevention a 10-year Thematic Review
Authors: Borges Julian Yin Vieira
Published: July 2024

Background

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Precision medicine, utilizing biomarkers for early detection and prevention of CAD, has emerged as a promising approach to improve patient outcomes. This systematic review aims to summarize the current state of knowledge regarding biomarkers in CAD prevention, focusing on the most promising and well-studied biomarkers over the past decade.

Methods

Following PRISMA guidelines, a systematic review was conducted. PubMed, Embase, and Cochrane Library databases were searched for relevant studies published between 2013 and 2023. Inclusion criteria were original research articles, systematic reviews, or meta-analyses focusing on biomarkers in CAD prevention, with sufficient data on biomarker performance. Exclusion criteria were case reports, editorials, conference abstracts, and studies on biomarkers in established CAD. The STARD “Standards for Reporting Diagnostic accuracy studies” 2015 guideline criteria for assessing diagnostic tools was also utilized to ensure the precision of the methodology and help readers to appraise the applicability of the study findings and the validity of conclusions and recommendations. The main outcome assessed was the association between biomarkers and CAD risk, using various statistical methods.

Findings

The search identified 2,345 articles, of which 40 met the inclusion criteria, including 32 original research articles, 6 systematic reviews, and 2 meta-analyses. The biomarkers studied included traditional risk factors (lipid profiles and blood pressure), novel biomarkers (high-sensitivity C-reactive protein, homocysteine, and adipokines), and imaging biomarkers (coronary artery calcium scores and carotid intima-media thickness). Several studies demonstrated the association between these biomarkers and increased CAD risk, independent of traditional risk factors. Multi-marker approaches combining various biomarkers showed improved accuracy in CAD risk assessment compared to traditional risk factors alone. The risk of bias and variability between studies were assessed and reported.

Interpretation

This systematic review provides a comprehensive overview of the current landscape of biomarkers in CAD prevention. While traditional risk factors remain important, novel and imaging biomarkers have shown promise in improving risk stratification and guiding personalized prevention strategies.

However, challenges remain in translating biomarker research into clinical practice, including the need for standardized guidelines, cost-effectiveness analyses, and further research on multi-marker approaches and personalized prevention strategies. Addressing these challenges and developing evidence-based guidelines for biomarker use in CAD prevention can improve risk assessment accuracy, tailor prevention strategies, and ultimately reduce the global burden of CAD.
Effectiveness of XBB.1.5 Vaccines Against Omicron Subvariants
Authors: Lin Dan-Yu , Du Yi , Xu Yangjianchen , Paritala Sai , Donahue Matthew , Maloney Patrick
Published: July 2024

Background

The updated Moderna, Pfizer-BioNTech, and Novavax COVID-19 vaccines containing the SARS-CoV-2 omicron XBB.1.5 strain have replaced their predecessors in the United States and in other countries since the fall of 2023. The clinical impact of these vaccines on currently circulating variants was unknown.

Aims

We aimed to assess the effectiveness of the updated XBB.1.5 vaccines against currently circulating omicron subvariants.

Methods

We examined data on the administration of XBB.1.5 vaccines and the incidence of COVID-19 between September 11 and November 27, 2023 for approximately 2 million persons by linking records from the Nebraska Electronic Disease Surveillance System and the Nebraska State Immunization Information System. We used Cox regression to estimate the effects of XBB.1.5 vaccines on the risk of COVID-19, as a function of time elapsed since vaccination, while adjusting for demographic factors, previous infection history, and previous vaccination history.

Results

The effectiveness (i.e., proportionate reduction of risk) for XBB.1.5 vaccines against SARS-CoV-2 infection was 63.0% (95% confidence interval [CI], 48.6 to 73.4) 4 weeks after vaccination and 67.1% (95% CI, 49.9 to 78.4) 6 weeks after vaccination; vaccine effectiveness started to decline after 6 weeks. Vaccine effectiveness was broadly similar across subgroups defined by age, sex, race and ethnicity, socioeconomic status, and previous immunity status.

Conclusion

XBB.1.5 vaccines were effective against currently circulating variants, regardless of age, sex, race and ethnicity, socioeconomic status, or previous immunity status. These findings can be used to develop effective prevention strategies against COVID-19.
Leveraging machine learning to streamline the development of liposomal drug delivery systems
Authors: Eugster Remo , Orsi Markus , Buttitta Giorgio , Serafini Nicola , Tiboni Mattia , Casettari Luca , Reymond Jean-Louis , Aleandri Simone , Luciani Paola
Published: July 2024

Drug delivery systems efficiently and safely administer therapeutic agents to specific body sites. Liposomes, spherical vesicles made of phospholipid bilayers, have become a powerful tool in this field, especially with the rise of microfluidic manufacturing during the COVID-19 pandemic. Despite its efficiency, microfluidic liposomal production poses challenges, often requiring laborious, optimization on a case-by-case basis. This is due to a lack of comprehensive understanding and robust methodologies, compounded by limited data on microfluidic production with varying lipids. Artificial intelligence offers promise in predicting lipid behaviour during microfluidic production, with the still unexploited potential of streamlining development. Herein we employ machine learning to predict critical quality attributes and process parameters for microfluidic-based liposome production. Validated models predict liposome formation, size, and production parameters, significantly advancing our understanding of lipid behaviour. Extensive model analysis enhanced interpretability and investigated underlying mechanisms, supporting the transition to microfluidic production. Unlocking the potential of machine learning in drug development can accelerate pharmaceutical innovation, making drug delivery systems more adaptable and accessible.
Limitations of Current Machine-Learning Models in Predicting Enzymatic Functions for Uncharacterized Proteins
Authors: de Crécy-Lagard Valérie , Dias Raquel , Friedberg Iddo , Yuan Yifeng , Swairjo Manal A.
Published: July 2024

Thirty to seventy percent of proteins in any given genome have no assigned function and have been labeled as the protein “unknome”. This large knowledge gap prevents the biological community from fully leveraging the plethora of genomic data that is now available. Machine-learning approaches are showing some promise in propagating functional knowledge from experimentally characterized proteins to the correct set of isofunctional orthologs. However, they largely fail to predict enzymatic functions unseen in the training set, as shown by dissecting the predictions made for over 450 enzymes of unknown function from the model bacteriaEscherichia coliuxgsing the DeepECTransformer platform. Lessons from these failures can help the community develop machine-learning methods that assist domain experts in making testable functional predictions for more members of the uncharacterized proteome.

Article Summary

Many proteins in any genome, ranging from 30 to 70%, lack an assigned function. This knowledge gap limits the full use of the vast available genomic data. Machine learning has shown promise in transferring functional knowledge from proteins of known functions to similar ones, but largely fails to predict novel functions not seen in its training data. Understanding these failures can guide the development of better machine-learning methods to help experts make accurate functional predictions for uncharacterized proteins.
Genetic architecture of the thermal tolerance landscape ofDrosophila melanogaster
Authors: Soto Juan , Pinilla Francisco , Olguín Patricio , Castañeda Luis E.
Published: July 2024

Increased environmental temperatures associated with global warming strongly impact the natural populations of ectothermic species. Therefore, it is crucial to understand the genetic foundations and evolutionary potential of heat tolerance. However, heat tolerance and its genetic components depend on the methodology, making it difficult to predict the adaptive responses to global warming. Here, we measured the knockdown time for 100 lines from theDrosophilaGenetic Reference Panel (DGRP) at four different static temperatures, and we estimated their thermal death time (TDT) curves, which incorporate the magnitude and the time of exposure to thermal stress. Through quantitative genetic analyses, it was observed that the knockdown time showed a significant heritability at different temperatures and that its genetic correlations decreased as temperatures were dissimilar. Significant genotype-by-sex and genotype-by-environment interactions were noted for knockdown time. We also discovered heritable variation for the two parameters of TDT:CTmaxand thermal sensitivity. Taking advantage of the DGRP, we performed a GWAS and identified multiple variants positively associated with the TDT parameters, which map to genes related to signaling and developmental functions. We performed functional validations for some candidate genes using RNAi, which revealed that genes such asmam,KNCQ,orrobo3affect the knockdown time at a specific temperature but are not associated with the TDT parameters. Ultimately, the thermal tolerance landscape must possess the ability to adapt to the selective pressures caused by global warming. Genetic variation of phenotypic plasticity and sexually antagonistic pleiotropy should also facilitate the adaptive process and maintain the genetic diversity inDrosophilapopulations.
A diverse high-fibre plant-based dietary intervention improves gut microbiome composition, gut symptoms, energy and hunger in healthy adults: a randomised controlled trial
Authors: Creedon Alice C. , Bernard Hannah , Amati Federica , Segata Nicola , Wallace Meg , Arrè Alberto , Smith Harry A. , Platts Alex , Bulsiewicz William J. , Bermingham Kate M. , Capdevila Pujol Joan , Piperni Elisa , Roomans Ledo Ana , Johnson Claire , Caro Catherine , Karimjee Nafisa , Linenberg Inbar , Giordano Francesca , Davies Richard , Wolf Jonathan , Asnicar Francesco , Spector Tim D. , Berry Sarah E.
Published: July 2024

Diets low in diverse fibre-rich plant foods are a major factor in the rise of chronic diseases globally. The BIOME study (NCT06231706) was a 6-week, parallel design randomised controlled trial in 399 healthy adults in the UK, investigating a simple dietary intervention containing 30+ whole-food ingredients high in plant polyphenolic compounds, fibre and micronutrients. Participants were randomised to the primary intervention (prebiotic blend; 30g/d) or control (bread croutons; 28g/d; isocaloric functional equivalent) or a daily probiotic (L. rhamnosus). The primary outcome was change in ‘favourable’ and ‘unfavourable’ microbiome species compared to control, secondary outcomes included changes in blood metabolites, gut symptoms, stool output, anthropometric measures, subjective hunger, sleep, energy and mood. A crossover test meal challenge sub-study was conducted in 34 participants, investigating postprandial glucose responses, subjective hunger, satiety and mood.

In the 349 male and female participants (mean age 50yrs) included in the analysis (intention-to-treat), self-reported adherence was high (> 98% for all treatments). Following the prebiotic blend, significant improvements were seen in the change and ranking of ‘favourable’ and ‘unfavourable’ species as well as beta diversity (weighted-UniFrac measure), but not in the control or probiotic group. There were significantly greater improvements in self reported indigestion, constipation, heartburn, flatulence and energy, following the prebiotic vs control, and hunger following the prebiotic vs probiotic. Addition of the prebiotic to a high carbohydrate test meal challenge resulted in significant improvements in subjective hunger, fullness, and energy (3h incremental area under the curve). No other significant differences between groups were observed.

This prebiotic blend is a simple dietary strategy that benefits gut microbiome composition, gut symptoms and self-reported energy and hunger.

Graphical abstract
Predicting diagnostic progression to schizophrenia or bipolar disorder via machine learning applied to electronic health record data
Authors: Hansen Lasse , Bernstorff Martin , Enevoldsen Kenneth , Kolding Sara , Damgaard Jakob Grøhn , Perfalk Erik , Nielbo Kristoffer L. , Danielsen Andreas A. , Østergaard Søren D.
Published: July 2024

Importance

The diagnosis of schizophrenia and bipolar disorder is often delayed several years despite illness typically emerging in late adolescence or early adulthood, which impedes initiation of targeted treatment.

Objective

To investigate whether machine learning models trained on routine clinical data from electronic health records (EHRs) can predict diagnostic progression to schizophrenia or bipolar disorder among patients undergoing treatment in psychiatric services for other mental illness.

Design

Cohort study based on data from EHRs.

Setting

The psychiatric services of the Central Denmark Region.

Participants

All patients between ≥15 and <60 years with at least one contact with the psychiatric services of the Central Denmark Region between 2011 and 2021. Patients with only a single contact were removed, leaving a total of 24,449 eligible patients with 398,922 outpatient contacts with the psychiatric services.

Exposures

Predictors based on EHR data, including medications, diagnoses, and clinical notes.

Main Outcomes and Measures

Diagnostic transition to schizophrenia or bipolar disorder within 5 years, predicted one day before outpatient contacts by means of regularized logistic regression and Extreme Gradient Boosting (XGBoost) models.

Results

Transition to the first occurrence of either schizophrenia or bipolar disorder was predicted by the XGBoost model with an area under the receiver operating characteristics curve (AUROC) of 0.70 on the training set, and 0.64 on the test set which consisted of two held-out hospital sites. At a predicted positive rate of 4%, the XGBoost model had a sensitivity of 9.3%, a specificity of 96.3%, and a positive predictive value of 13.0%. Predicting schizophrenia and bipolar disorder separately yielded AUROCs of 0.80 and 0.62, respectively, on the test set.

The clinical notes proved particularly informative for prediction.

Conclusions and relevance

It is possible to predict diagnostic transition to schizophrenia and bipolar disorder from routine clinical data extracted from EHRs, with schizophrenia being notably easier to predict than bipolar disorder.

Key Points

Question

Can diagnostic progression to schizophrenia or bipolar disorder be accurately predicted from routine clinical data extracted from electronic health records?

Findings

In this study, which included all patients aged between ≥15 and <60 years with contacts to the psychiatric services of the Central Denmark Region between 2011 and 2021, progression to schizophrenia was predicted with high accuracy, with bipolar disorder proving a more difficult target.

Meaning

Detecting progression to schizophrenia through machine learning based on routine clinical data is feasible. This may reduce diagnostic delay and duration of untreated illness.
Disability Inclusion in National Surveys
Authors: Cerilli Caroline , Varadaraj Varshini , Choi Jennifer , Sweeney Fiona , Castro Franz , Landes Scott D. , Swenor Bonnielin K.
Published: July 2024

National surveys are important for understanding the disparities that disabled people experience across social determinants of health; however, limited research has examined the methods used to include disabled people in these surveys. This study reviewed nationally representative surveys administered by the Centers for Disease Control and Prevention (CDC) and the U.S. Census Bureau that collected data in the past five years and sampled adults ≥18 years. Data from both publicly available online survey documents and a questionnaire emailed to survey administrators were used to determine whether surveys: 1) oversampled disabled people; 2) had a data accessibility protocol to support data collection; and 3) provided multiple data collection modalities (e.g., phone, paper). Of the 201 surveys identified, 30 met the inclusion criteria for the study. Of these 30 surveys, one oversampled disabled people, none had a data collection accessibility protocol, and 21 provided multiple data collection modalities. This study highlights barriers and opportunities to including disabled people in national surveys, which is essential for ensuring survey data are generalizable to the U.S. population.
Prevalence and factors associated with incompletion of measles and rubella vaccine routine immunization among children aged 18-59 months in Kilimanjaro region, Tanzania
Authors: Gichogo David M. , Mbezi Abdul A. , Sasi Sasi K. , Magogo Vailet , Shewiyo Edwin J. , Nkenguye William , Tinuga Florian , Msuya Sia E.
Published: July 2024

Background

In Tanzania Measles and Rubella (MR) vaccination coverage of 90% in 90% of the regions was achieved in 2018. However, there are councils lagging in MR1 coverage, 38 (19%) councils out of 195 had <90% coverage by the end of 2019 while MR2 coverage is struggling with 99 (51%) of councils having a coverage of <90% at the end of 2019. Kilimanjaro region is among the regions with some councils having MR coverage of <80%. There is a need for information on why a significant proportion of eligible children are not receiving the second dose of MR vaccine.

Objective

To determine prevalence and factors associated with incompletion of MR vaccination among children aged 18-59 months in two districts of Kilimanjaro region.

Methodology

This study was a cross-sectional study conducted in Moshi urban and rural councils, two out of the seven councils in Kilimanjaro region. The study population was children aged 18-59 months whose parents/ caregivers have been the residents of the respective districts for at least 3 past years. Interviews using questionnaires were used for data collection. Data was entered and analyzed using SPSS version 20.

Results

A total of 415 children aged 18-59 months were enrolled. The proportion of children with incomplete MR2 vaccination was 14.2%. Only 33% of the 415 caregivers knew MR vaccine is given at 9 and 18 months and 24% reported unavailability of vaccine at their scheduled visit. Children from Moshi rural council (AOR=2.53, 95% CI =1.36-4.73) had higher odds of MR incompletion. Lower odds of MR vaccine incompletion were among caregivers who were aware on the time for MR vaccination; 9 and 18 months (AOR=0.27, 95% CI=0.10-0.73), caregivers who had knowledge that MR vaccine protects measles, and those who had health promotion talk on the vaccination day.

Conclusion

Nearly one in ten (14.2%) children do not complete the recommended two doses of MR vaccines. Strategies to improve awareness and knowledge on timing, frequency and advantage of MR and other vaccines is needed among parents/ caregivers in this setting. Further, improvement in ordering and supply of vaccines at health facilities needs to be improved.
Variation in albumin glycation rates in birds suggests resistance to relative hyperglycaemia rather than conformity to the pace of life syndrome hypothesis
Authors: Moreno-Borrallo Adrián , Jaramillo-Ortiz Sarahi , Schaeffer-Reiss Christine , Quintard Benoît , Rey Benjamin , Bize Pierre , Viblanc Vincent A. , Boulinier Thierry , Chastel Olivier , Gutiérrez Jorge S. , Masero Jose A. , Bertile Fabrice , Criscuolo François
Published: July 2024

The pace of life syndrome hypothesis (POLS) suggests that organisms’ life history, physiological and behavioural traits should co-evolve. In this framework, how glycaemia (i.e., blood glucose levels) and its reaction with proteins and other compounds (i.e. glycation) covary with life history traits remain relatively under-investigated, despite the well documented consequences of glucose and glycation on ageing, and therefore potentially on life history evolution. Birds are particularly relevant in this context given that they have the highest blood glucose levels within vertebrates and still higher mass-adjusted longevity when compared to organisms with similar physiology as mammals. We thus performed a comparative analysis on glucose and albumin glycation rates of 88 bird species from 22 orders, in relation to life history traits (body mass, clutch mass, maximum lifespan and developmental time) and diet. Glucose levels correlated positively with albumin glycation rates in a non-linear fashion, suggesting resistance to glycation in species with higher glucose levels. Plasma glucose levels decreased with increasing body mass but, contrary to what is predicted to the POLS hypothesis, glucose levels increased with maximum lifespan before reaching a plateau. Finally, terrestrial carnivores showed higher albumin glycation compared to omnivores despite not showing higher glucose, which we discuss may be related to additional factors as differential antioxidant levels or dietary composition in terms of fibres or polyunsaturated fatty acids. These results increase our knowledge about the diversity of glycaemia and glycation patterns across birds, pointing towards the existence of glycation resistance mechanisms within comparatively high glycaemic birds.