bluuebunny/crossref_metadata_2025 huggingface dataset:
Fractures in women with type 2 diabetes are associated with marked deficits in cortical parameters and trabecular plates
Authors: Agarwal Sanchita , Germosen Carmen , Rosillo Isabella , Bucovsky Mariana , Colon Ivelisse , Kil Nayoung , Wang Zexi , Dinescu Andreea , Guo Xiang-Dong Edward , Walker Marcella
Published: June 2024

The basis for increased fracture risk in type 2 diabetes (T2DM) is not well understood. In this multi-ethnic, population-based study (n = 565), we investigated bone microstructure, trabecular plate/rod morphology, and mineralization in women with T2DM (n = 175) with and without fracture using a second-generation HRpQCT and individual trabecula segmentation and mineralization (ITS; ITM). Covariate-adjusted aBMD was 3.0%-6.5% higher at all sites (all p<.005) in T2DM vs controls. By HRpQCT, T2DM had higher covariate-adjusted trabecular vBMD (5.3%-6.4%) and number (3.8%-5.1%) and greater cortical area at the radius and tibia. Covariate-adjusted cortical porosity was 10.0% higher at the tibia only in T2DM vs controls, but failure load did not differ. Among women with T2DM, those with adult atraumatic fracture (n = 59) had 5.2%-8.5% lower adjusted aBMD at all sites by DXA compared with those without fracture (n = 103). By HRpQCT, those with fracture had lower adjusted total vBMD and smaller cortical area (10.2%-16.1%), lower cortical thickness (10.5-15.8%) and lower cortical vBMD associated with 18.1 and 17.2% lower failure load at the radius and tibia, respectively (all p<.05); plate volume and thickness were 5.7% and 4.7% lower, respectively, (p<.05) while rod volume fraction was 12.8% higher in the fracture group at the tibia only. Sodium glucose cotransporter 2 inhibitor users (SGLT2i; n = 19), tended to have lower radial rod tissue mineral density by ITS (p=.06). GLP1 agonist users (n = 19) had trabecular deficits at both sites and higher cortical porosity and larger pores at the distal tibia. In summary, T2DM is associated with increased cortical porosity while those with T2DM and fracture have more marked cortical deficits and fewer trabecular plates associated with lower failure load.
Introducing the SPS Agreement
Authors: Gruszczynski Lukasz
Published: June 2024

This chapter introduces the Agreement on the Application of Sanitary and Phytosanitary Measures (the SPS Agreement). According to the agreement’s preamble, the agreement is conceived as an elaboration of the original General Agreement on Tariffs and Trade (GATT) exception. Sanitary and phytosanitary measures are those which apply to protect human, animal, plant life or health, or to prevent other damage within the territory of an importing Member.

In the above context, the chapter examines the scope of the SPS Agreement’s application, and its relationship to other parts of the WTO package, in particular the GATT and the Agreement on Technical Barriers to Trade. The chapter concludes by introducing the idea of Member autonomy in determining the appropriate level of SPS protection pursued. Later chapters will consider the extent to which this so-called right has, in practice, been undermined by the pronouncements of the WTO dispute settlement bodies.
Science and SPS
Authors: Gruszczynski Lukasz
Published: June 2024

This chapter discusses the science-based provisions of the Agreement on the Application of Sanitary and Phytosanitary Measures (the SPS Agreement), including the core obligation in Article 2.2 and the closely related obligations in Articles 5.1 (requirement of risk assessment). The usage of science as a benchmark in the agreement marks a radical departure from the predominantly discrimination-based approach of the General Agreement on Tariffs and Trade (GATT). It includes a careful discussion of the panel’s and AB’s reading of these obligations. It considers the nature of the scientific thresholds constructed by the dispute settlement bodies and, building upon Chapter 1, it considers the extent to which Members really do retain autonomy in defining their own ‘appropriate level of protection’.
The SPS Agreement and Developing Countries
Authors: Gruszczynski Lukasz
Published: June 2024

This chapter discusses of the developing country dimension of the Agreement on the Application of Sanitary and Phytosanitary Measures (the SPS Agreement). In this context, it elaborates on the key concepts of special and differential (S&D) treatment and technical assistance as well as related proposals for reform. The chapter also considers private standards as a challenge for developing countries. It then looks into the contrast between the high politics of systemic reform and the concrete achievements secured in the less high-profile world of the Committee governance.
Determination method for binary fractions using the integrated spectrum
Authors: Zhang F , Li L , Han Z , Wang X
Published: June 2024

We need to resolve the individual stars for binary-fraction determinations of stellar systems. Therefore, it is not possible to obtain the binary fractions for dense or distant stellar systems. We propose a method to determine the binary fraction of a dense or distant stellar system: this method is first to determine the binary-fraction variation for any two adjacent regions and then to add up those binary-fraction variations along the radial direction to obtain the binary fraction for a stellar system. The binary-fraction variation is derived using 10 binary-fraction-sensitive spectral absorption feature indices (SAFIs) and the binary-fraction variation calibrations in terms of these SAFIs. Using this method, we first present the binary-fraction variations for 21 Galactic globular clusters (GCs). By comparison, we find that they agree well with the binary fractions based on the main-sequence fiducial line method from previous studies. This verifies that the above-mentioned method is feasible. Next, we present the binary-fraction variations of 13 Galactic GCs. We give the relationships between the binary fraction and various parameters, and find that the binary fraction is negatively correlated with NHB and NRR, the binary fraction of some studies is not strongly correlated with NBS, and the number of GCs with large binary fraction is greater for the extreme blue horizontal branch population ratio. Finally, if we want to obtain a more accurate binary fraction, we suggest that spectroscopic and photometric observations are conducted at an appropriate area interval for a stellar system.
High-throughput neural stem cell-based drug screening identifies S6K1 inhibition as a selective vulnerability in sonic hedgehog-medulloblastoma
Authors: Zhou Leilei , van Bree Niek , Boutin Lola , Ryu Jinhye , Moussaud Simon , Liu Mingzhi , Otrocka Magdalena , Olsson Magnus , Falk Anna , Wilhelm Margareta
Published: June 2024

Background

Medulloblastoma (MB) is one of the most common malignant brain tumors in children. Current treatments have increased overall survival but can lead to devastating side effects and late complications in survivors, emphasizing the need for new, improved targeted therapies that specifically eliminate tumor cells while sparing the normally developing brain.

Methods

Here, we used a sonic hedgehog (SHH)-MB model based on a patient-derived neuroepithelial stem cell system for an unbiased high-throughput screen with a library of 172 compounds with known targets. Compounds were evaluated in both healthy neural stem cells (NSCs) and tumor cells derived from the same patient. Based on the difference of cell viability and drug sensitivity score between normal cells and tumor cells, hit compounds were selected and further validated in vitro and in vivo.

Results

We identified PF4708671 (S6K1 inhibitor) as a potential agent that selectively targets SHH-driven MB tumor cells while sparing NSCs and differentiated neurons. Subsequent validation studies confirmed that PF4708671 inhibited the growth of SHH-MB tumor cells both in vitro and in vivo, and that knockdown of S6K1 resulted in reduced tumor formation.

Conclusions

Overall, our results suggest that inhibition of S6K1 specifically affects tumor growth, whereas it has less effect on non-tumor cells. Our data also show that the NES cell platform can be used to identify potentially effective new therapies and targets for SHH-MB.
Epigenetically rewiring metabolic genes via SIRT6 orchestrates MSC fate determination
Authors: Liao Xueyang , Li Feifei , Yu Fanyuan , Ye Ling
Published: June 2024

SIRT6 owns versatile types of enzymatic activities as a multitasking protein, including ribosyltransferase and deacetylase. To investigate the epigenetic regulations of SIRT6 on MSC fate determination via histone deacetylation, we used allosteric small molecules specifically controlling its histone 3 deacetylation activities. Results showed that enhanced deacetylation of SIRT6 promoted the ossific lineage commitment of MSC and finally achieved anabolic effects on hard tissues. Mechanistically, H3K9ac and H3K56ac, governed by SIRT6, in MSC orchestrated the transcriptions of crucial metabolic genes, mediating MSC fate determination. Most importantly, our data evidenced that modulating the epigenetic regulations of SIRT6, specifically via enhancing its deacetylation of H3K9ac and H3K56ac, was a promising choice to treat bone loss diseases and promote dentin regeneration. In this study, we revealed the specific roles of SIRT6’s histone modification in MSC fate determination. These findings endow us with insights on SIRT6 and the promising therapeutic choices through SIRT6’s epigenetic functions for hard tissues regeneration.
Disaggregation of canopy photosynthesis among tree species in a mixed broadleaf forest
Authors: Stojanović Marko , Jocher Georg , Kowalska Natalia , Szatniewska Justyna , Zavadilová Ina , Urban Otmar , Čáslavský Josef , Horáček Petr , Acosta Manuel , Pavelka Marian , Marshall John D
Published: June 2024

Carbon dioxide sequestration from the atmosphere is commonly assessed using the eddy covariance method. Its net flux signal can be decomposed into gross primary production and ecosystem respiration components, but these have seldom been tested against independent methods. In addition, eddy covariance lacks the ability to partition carbon sequestration among individual trees or species within mixed forests. Therefore, we compared gross primary production from eddy covariance versus an independent method based on sap flow and water-use efficiency, as measured by the tissue heat balance method and δ13C of phloem contents, respectively. The latter measurements were conducted on individual trees throughout a growing season in a mixed broadleaf forest dominated by three tree species, namely English oak, narrow-leaved ash and common hornbeam (Quercus robur L., Fraxinus angustifolia Vahl, and Carpinus betulus L., respectively). In this context, we applied an alternative ecophysiological method aimed at verifying the accuracy of a state-of-the-art eddy covariance system while also offering a solution to the partitioning problem. We observed strong agreement in the ecosystem gross primary production estimates (R2 = 0.56; P < 0.0001), with correlation being especially high and nearly on the 1:1 line in the period before the end of July (R2 = 0.85; P < 0.0001). After this period, the estimates of gross primary production began to diverge. Possible reasons for the divergence are discussed, focusing especially on phenology and the limitation of the isotopic data. English oak showed the highest per-tree daily photosynthetic rates among tree species, but the smaller, more abundant common hornbeam contributed most to the stand-level summation, especially early in the spring. These findings provide a rigorous test of the methods and the species-level photosynthesis offers avenues for enhancing forest management aimed at carbon sequestration.
Development of a TaqMan Assay for the Detection of ‘Candidatus Phytoplasma brasiliense’ and Assessment by High-Resolution Melt Curve Analysis
Authors: Lane Jeremy , Bloch Melody , Helmick Ericka E. , Krueger Robert R. , Bahder Brian W.
Published: June 2024

‘Candidatus Phytoplasma brasiliense’ (CPB) is a phytoplasma originally discovered in South America and is known to infect a wide variety of economically important crops. It is most prevalent in Hibiscus spp., where it causes witches broom symptoms, and papaya, where it causes bunchy top. Recently, CPB was documented for the first time in North America in a new host, globe sedge. In this study, two quantitative PCR assays are developed: one using high-resolution melt curve analysis (HRMA) based on the secA gene and the other a TaqMan assay based on the dnaK gene. The secA/HRMA and dnaK/TaqMan assay successfully amplified two of the three isolates of CPB. Both assays were screened against available isolates of 16SrI, 16SrII, and 16SrIV phytoplasmas. The secA/HRMA assay failed to amplify 16SrI and 16SrIV phytoplasmas but successfully amplified 16SrII phytoplasmas. The resulting melting point (Tm) products of CPB and 16SrII phytoplasmas displayed a difference of 0.5°C, easily distinguishing them by melt curves. The dnaK/TaqMan assay failed to amplify all non-CPB phytoplasma isolates in the study. The development of these assays provides a valuable tool that will significantly improve monitoring programs in Florida and will aid in developing a better fundamental understanding of the epidemiology of this phytoplasma.
DDB2 promotes melanoma cell growth by transcriptionally regulating the expression of KMT2A and predicts a poor prognosis
Authors: Zhang Changlin , Li Weizhao , Liu Lixiang , Li Miao , Sun Haohui , Zhang Chi , Zhong Li , Huang Jiajia , Li Tian
Published: June 2024

Identification of potential key targets of melanoma, a fatal skin malignancy, is critical to the development of new cancer therapies. Lysine methyltransferase 2A (KMT2A) promotes melanoma growth by activating the human telomerase reverse transcriptase (hTERT) signaling pathway; however, the exact mechanism remains elusive. This study aimed to reveal new molecular targets that regulate KMT2A expression and melanoma growth. Using biotin–streptavidin–agarose pull‐down and proteomics, we identified Damage‐specific DNA‐binding protein 2 (DDB2) as a KMT2A promoter‐binding protein in melanoma cells and validated its role as a regulator of KMT2A/hTERT signaling. DDB2 knockdown inhibited the expression of KMT2A and hTERT and inhibited the growth of melanoma cells in vitro. Conversely, overexpression of DDB2 activated the expression of KMT2A and promoted the growth of melanoma cells. Additionally, we demonstrated that DDB2 expression was higher in tumor tissues of patients with melanoma than in corresponding normal tissues and was positively correlated with KMT2A expression. Kaplan–Meier analysis showed a poor prognosis in patients with high levels of DDB2 and KMT2A. Overall, our data suggest that DDB2 promotes melanoma cell growth through the transcriptional regulation of KMT2A expression and predicts poor prognosis. Therefore, targeting DDB2 may regulate the effects of KMT2A on melanoma growth and progression, providing a new potential therapeutic strategy for melanoma.
A Question Answering Chatbot for Gastric Cancer Patients After Curative Gastrectomy
Authors: Kim Ae Ran , Park Hyeoun-Ae
Published: June 2024

Postoperative gastric cancer patients have many questions about managing their daily lives with various symptoms and discomfort. This study aimed to develop a knowledge-based question answering (QA) chatbot for their self-management and to evaluate the user experience and performance of the chatbot. To support the chatbot's natural language processing, we analyzed QA texts from an online self-help group, clinical guidelines, and refined frequently asked questions related to gastric cancer. We developed a named entity classification with seven superconcepts, 4544 subconcepts, and 1415 synonyms. We also developed a knowledge base by linking the users' classified question intents with the experts' answers and knowledge resources, including 677 question intents and scripts with standard QA pairs and similar question phrases. A chatbot called “GastricFAQ” was built, reflecting the question topics of the named entity classification and QA pairs of the knowledge base. User experience evaluation (N = 56) revealed the highest mean score for usefulness (4.41/5.00), with all other items rated 4.00 or higher, except desirability (3.85/5.00). The chatbot's accuracy, precision, recall, and F score ratings were 85.2%, 87.6%, 96.8%, and 92.0%, respectively, with immediate answers. GastricFAQ could be provided as one option to obtain immediate information with relatively high accuracy for postoperative gastric cancer patients.
Missed Nursing Care and Relationship to Burnout and Leave the Profession
Authors: Jafari-Koulaee Azar , Heidari Tahereh , Khorram Majid , Rezaei Soraya , Nikbakht Roya , Jafari Hedayat
Published: June 2024

Background/objective

Nurses are at high risk of burnout, desire to leave the profession, and possibly missed nursing care due to the exhausting nature of caring. Missed nursing care may also affect nurses’ burnout and desire to leave the profession. Therefore, the objective of this study was to determine the missed nursing care and its relationship with burnout and desire to leave the profession among intensive care unit nurses.

Subjects/Methods

The participants of this descriptive analytical study were 249 Iranian nurses working in intensive care units in 2022. The data were collected using a Demographic Information Questionnaire, Kalish’s Missed Nursing Care Questionnaire, Maslach Burnout Inventory, and desire to leave the profession questionnaire.

Results

The majority of nurses (71%) were females. The generalized linear regression model showed that there was a significant relationship between missed care with gender (B = 5.55, P < .001), marital status (B = −7.37, P = .04), working shift (B = 7.80, P < .001), and employment status (B = −2.87, P = .02). Using structural equation modeling, it was found that the effect of missed care on burnout was significant.

Conclusions

Considering the effect of missed care on burnout among nurses working in intensive care units, it seems that creating better working conditions, providing sufficient resources for nurses, supporting them, and changing the factors affecting missed care in order to improve the conditions can reduce the possibility of missing nursing care and, finally, burnout.
When Life-Supporting Interventions Lead to Moral Distress
Authors: Hudgins Kerstin
Published: June 2024

Moral distress can impact nurses and the care team significantly. A profession dedicated to the principles of caring and compassion is often subjected to patients receiving futile treatment. With the proliferation of extreme life-prolonging measures come the difficulties in the withdrawal of those medical modalities. If a prognosis is poor and care is perceived as curative rather than palliative, providers may often feel conflicted and distressed by their interventions. The American Association of Colleges of Nursing has expressed growing concern about an increase in the use of inappropriate life-support treatments related to futile care. The compelling case of a severely beaten 69-year-old homeless man who had cardiac-arrested and was resuscitated after an unknown amount of down-time, provides the contextual framework for this report. Ethical conflicts can become very challenging, which inevitably increases the suffering of the patient and their caregivers. Research findings suggest that health care organizations can benefit from enacting processes that make ethical considerations an early and routine part of everyday clinical practice. A proactive approach to ethical conflicts may improve patient care outcomes and decrease moral distress.
Nicotine Screening and Cessation Education Among Patients Awaiting Total Joint Arthroplasty
Authors: Appleton Lindsay , Barnes Joshua , Ray Hollis , Thompson Julie , Zychowicz Michael
Published: June 2024

Orthopedic surgical patients who use nicotine are at a high risk for postoperative complications including infection, respiratory failure, cardiac arrest, and death. Periprosthetic joint infections may result from nicotine-induced immunosuppression and microvascular changes, increasing perioperative morbidity and mortality. These complications result in higher health care costs, increased length of stay, and loss of reimbursement due to readmissions. Four weeks of nicotine cessation prior to arthroplasty decreases these risks; however, perioperative teams may lack reliable nicotine screening and cessation education methods. This project identified inconsistencies in nicotine screening and cessation counseling in the preoperative setting, which contributed to surgery cancellations among patients who required to demonstrate nicotine cessation preoperatively. Standardization of preoperative nicotine screening and patient cessation education resources can improve the identification of orthopedic patients who use nicotine and provide concrete, proven methods of achieving nicotine cessation prior to elective primary arthroplasty. Investment from perioperative staff is essential to ensure success.
Factors That Influence Quality of Life in Postmenopausal Osteoporotic Women With Nonvertebral Fractures
Authors: Zannetti Emanuela Basilici , Cittadini Noemi , Iovino Paolo , De Maria Maddalena , D’Angelo Daniela , Pennini Annalisa , Vellone Ercole , Tarantino Umberto , Alvaro Rosaria
Published: June 2024

The knowledge of variables associated with quality of life in women with nonvertebral fractures is poor. The aim of this study was to examine the independent associations between sociodemographic and clinical factors, self-care, and quality of life in this specific population. We undertook a 3-year multicenter longitudinal study on a cohort of Italian postmenopausal osteoporotic women with three follow-ups at 1, 3, and 6 months. Nurses asked women to complete questionnaires on quality of life and self-care. The sample (n = 532) had a mean age of 74.78 years. The results showed that women taking more than two medications per day (p = .026) and those with nine or more years of education (p = .036) were more likely to exhibit better quality of life levels (p < .001) than their counterparts. Both self-care and quality of life scores improved over time in all participants. This study shows positive independent associations between quality of life and polypharmacy, education, and self-care behaviors, which were improved by educational interventions to attain a better quality of life in our participants.
HIV and Syphilis Co-Screening Rates Among Patients Tested for Gonorrhea and Chlamydia at a Large, Urban Hospital
Authors: Almirol Ellen , Meyer Makenna , Mason Joseph A. , Hazra Aniruddha , McNulty Moira C. , Stanford Kimberly A.
Published: June 2024

Background

Current guidelines recommend concurrent screening for HIV and syphilis with gonorrhea and chlamydia testing. Despite this, many patients are still not screened. This study describes trends in demographics and encounter locations associated with missed opportunities for HIV and syphilis screening among patients tested for gonorrhea or chlamydia.

Methods

This is a retrospective review of all encounters with gonorrhea or chlamydia testing in a large, urban hospital from November 1, 2018, to July 31, 2021. Demographic information and encounter location were extracted from the medical record. Encounters were categorized as including both HIV and syphilis (complete) screening, HIV screening only, or neither. Logistic regression was used to examine associations between demographics and encounter location and likelihood of complete screening.

Results

There were 42,791 patient encounters, of which 40.2% had complete screening, 6.2% had concurrent HIV screening only, and 53.6% had no concurrent screening. Increasing age, female sex (adjusted odds ratio [aOR], 0.58; 95% confidence interval [CI], 0.55–0.61; P < 0.01), non-Hispanic Black race (aOR, 0.52; 95% CI, 0.49–0.55; P < 0.01), and public insurance (aOR, 0.72; 95% CI, 0.69–0.75; P < 0.01) were associated with lower odds of complete screening. Emergency department (ED) encounters were most likely to include complete screening (aOR, 3.11; 95% CI, 2.96–3.26; P < 0.01).

Conclusions

This study found that a large proportion of patients tested for gonorrhea and chlamydia had missed opportunities for HIV and syphilis screening. Significant demographic disparities were found. The emergency department was most likely to screen for both HIV and syphilis. Decreasing disparities in screening could have profound effects on the HIV and syphilis epidemics.
Fatal Head Injury in a 1-Year-Old Child Secured in a Rear-Facing Child Seat by Offset Car-to-Car Collision
Authors: Taniguchi Hiroaki , Nagasawa Hiroki , Yanagawa Youichi
Published: June 2024

This case study describes a fatal head injury in a 1-year-old child involved in a motor vehicle accident in Japan. The child, secured in a rear-facing child seat, was a passenger in a car driven by their mother when the offset car-to-car collision occurred. The car rotated counterclockwise before coming to a stop. Despite remaining secured in the child seat, the child suffered severe head trauma, leading to cardiac arrest. Autopsy computed tomography revealed a right open depressed fracture, left head contusion, traumatic subarachnoid hemorrhage, intraventricular hemorrhage, and pneumocephalus. The injury mechanism involved the child’s head striking the right headrest, followed by a swing to the left, induced by the initial impact and subsequent rotational movement. This case highlights the importance of age-specific data in understanding pediatric injuries in motor vehicle accidents and improving child seat safety measures.
Rare Congenital Upper Lip Pit
Authors: Patel Milan , Ramamurthi Aishu , Jones Kelly , North Paula , Lin Kant Y.K.
Published: June 2024

Congenital lip pits are characterized by sinuses or fistulas in the lips that can occur in isolation or as part of a genetic disorder. A 6-year-old girl with a right upper lip lesion present at birth presented with recurrent swelling and occasional erythema. Examination revealed a mildly swollen punctum at the right upper wet/dry vermillion with expressible serous drainage. There were no other phenotypic or cognitive concerns. The lesion was surgically excised using vertical wedge resection. The postoperative course showed well well-healed incision. The pathology report confirmed a lip pit. The family was referred to genetics for further evaluation. Van der Woude syndrome (VWS) is a genetic disorder associated with abnormal development of the paramedian lip. Most congenital lip pits are primarily found on the lower lips, with paramedian lip pits being the most common. Upper lateral lip pits with or without accompanying lip pits are considerably rarer. Though VWS is commonly associated with mutations in the interferon regulatory factor 6 or grainyhead-like protein 3 genes, ~25% of affected individuals lack an identified genetic etiology. A high index of suspicion for VWS is warranted if lip pits are present in the absence of other phenotypic abnormalities and should prompt genetic testing for interferon regulatory factor 6 and grainyhead-like protein 3 mutations. Multidisciplinary teams should consider patient self-esteem, quality of life, and potential family planning when deciding on surgical intervention for lip pits. Surgical management of pits should entail tissue-preserving techniques such as vertical wedge resection and inverted T-lip reduction to prevent whistle-lip deformity.
Association between Complications and Death within 30 days after General Surgery
Authors: Park Lily J , Borges Flavia K , Ofori Sandra , Nenshi Rahima , Jacka Michael , Heels-Ansdell Diane , Bogach Jessica , Vogt Kelly , Chan Matthew TV. , Verghese Anish , Polanczyk Carisi A , Skinner David , Asencio JM , Paniagua Pilar , Rosen Michael , Serrano Pablo E , Marcaccio Michael J , Simunovic Marko , Thabane Lehana , Devereaux PJ
Published: June 2024

Objective:

To determine the epidemiology of post-operative complications among general surgery patients, inform their relationships with 30-day mortality, and determine the attributable fraction of death of each postoperative complication.

Background:

The contemporary causes of post-operative mortality among general surgery patients are not well characterized.

Methods:

VISION is a prospective cohort study of adult non-cardiac surgery patients across 28 centres in 14 countries, who were followed for 30 days after surgery. For the subset of general surgery patients, a cox proportional hazards model was used to determine associations between various surgical complications and post-operative mortality. The analyses were adjusted for preoperative and surgical variables. Results were reported in adjusted hazard ratios (HR) with 95% confidence intervals (CI).

Results:

Among 7950 patients included in the study, 240 (3.0%) patients died within 30 days of surgery. Five post-operative complications (myocardial injury after non-cardiac surgery [MINS], major bleeding, sepsis, stroke, and acute kidney injury resulting in dialysis) were independently associated with death. Complications associated with the largest attributable fraction (AF) of post-operative mortality (i.e., percentage of deaths in the cohort that can be attributed to each complication, if causality were established) were major bleeding (n=1454, 18.3%, HR 2.49 95%CI 1.87-3.33, P<0.001, AF 21.2%), sepsis (n=783, 9.9%, HR 6.52, 95%CI 4.72-9.01, P<0.001, AF 15.6%), and MINS (n=980, 12.3%, HR 2.00, 95%CI 1.50-2.67, P<0.001, AF 14.4%).

Conclusion:

The complications most associated with 30-day mortality following general surgery are major bleeding, sepsis, and MINS. These findings may guide the development of mitigating strategies, including prophylaxis for perioperative bleeding.
Potential role of Gut Bacteria in the development of hepatocellular carcinoma
Authors: Yan Bingqing , Wang Yuchao , Wang Ziqi , Huang Ailong , Jin Xiuxiu , Jiang Tiantian , Xue Hong , Shen Zheyu , Wang Shifang , Xu Haiyan , Zhu Renfei
Published: June 2024

Liver cancer is the fourth most deadly cancer, and early detection and timely treatment play a crucial role in it. Intestinal bacteria affect the development of liver cancer through various pathways, and in this study, we analyzed the gut bacteria of liver cancer patients in detail by using macro-genome sequencing technology. This work identified some of the bacterial species and metabolic pathways that may affect the development of liver cancer, in addition, the bacterial factors that may affect the tumor size and other important clinical indicators were also identified, which provides a scientific basis for the research related to the development of liver cancer and new insights for the clinical treatment of liver cancer.
Smallpox vaccination campaigns resulted in age-associated population cross-immunity against monkeypox virus
Authors: Dee Kieran , Manali Maria , Bissett Laura A. , Bone Jordan , Magill Callum , Davis Chris , Willett Brian J. , Murcia Pablo R.
Published: June 2024

Increased human-to-human transmission of monkeypox virus (MPXV) is cause for concern, and antibodies directed against vaccinia virus (VACV) are known to confer cross-protection against Mpox. We used 430 serum samples derived from the Scottish patient population to investigate antibody-mediated cross-neutralization against MPXV. By combining electrochemiluminescence immunoassays with live-virus neutralization assays, we show that people born when smallpox vaccination was routinely offered in the United Kingdom have increased levels of antibodies that cross-neutralize MPXV. Our results suggest that age is a risk factor of Mpox infection, and people born after 1971 are at higher risk of infection upon exposure.
Genetic variants predisposing to increased risk of kidney stone disease
Authors: Lovegrove Catherine E. , Goldsworthy Michelle , Haley Jeremy , Diane Smelser , Gorvin Caroline , Hannan Fadil M. , Mahajan Anubha , Mohnish Suri , Sadeghi-Alavijeh Omid , Moochhala Shabbir , Gale Daniel , Carey David , Holmes Michael V. , Furniss Dominic , Thakker Rajesh V. , Howles Sarah A.
Published: June 2024

Kidney stones (KS) are common, heritable, and associated with mineral metabolism abnormalities. We used Mendelian randomization and colocalization to identify variants predicted to increase KS risk via increased serum calcium or decreased serum phosphate (odds ratios for genomic regions=4.30-13.83 per 1 standard deviation alteration) that account for 11-19% of KS due to reduced calcium-sensing receptor (CaSR)-signal transduction, increased urinary phosphate excretion, and impaired 1,25-dihydroxyvitamin D inactivation via diacylglycerol kinase delta (DGKD), solute carrier family 34 member 1 (SLC34A1), and cytochrome P450 family 24 subfamily A member 1 (CYP24A1), respectively. In silico analyses revealed that targetingCASR,DGKD, orCYP24A1to decrease serum calcium, orSLC34A1to increase serum phosphate may reduce KS risk, and in vitro studies demonstrated that positive CaSR-allosteric modulation ameliorates CaSR-signal transduction impaired by reduced DGKδ expression or KS-associatedDGKDmissense variants. These studies suggest that genotyping individuals with KS may facilitate personalized risk stratification and pharmacomodulation.
MULT: An allometric body mass index (ABMI) reference to assess nutritional status of multi-ethnic children and adolescents
Authors: de Oliveira Mariane Helen , Mazzeti Camila Medeiros da Silva , Araújo Joana , Severo Milton , Ramos Elisabete , Rodrigues Kévin Allan Sales , Pereira Débora Borges dos Santos , Conde Wolney Lisboa
Published: June 2024

Objectives

To develop an allometric body mass index (ABMI) reference that adjusts the weight in relation to height, taking into account the changes during development (MULT ABMI reference), and to compare it with international BMI references.

Methods

The MULT ABMI reference was constructed through the LMS method, calculated with 65 644 ABMI observations of 17 447 subjects aged 5-22 years, from the United Kingdom, Ethiopia, India, Peru, Vietnam, Portugal, and Brazil. The M, S, and L curves of the MULT ABMI reference were compared with the curves of the MULT, World Health Organization (WHO), Centers for Disease Control and Prevention (CDC), International Obesity Task Force (IOTF), and Dutch Growth Study (DUTCH).

Results

The greater differences in the M curve between MULT ABMI and WHO, CDC, IOTF, DUTCH, and MULT BMI references were around puberty (138 to 150 months for boys; 114 to 132 for girls). MULT ABMI presented S values similar to IOTF and DUTCH BMI references for boys 60 to 114 months and then became higher, approaching the MULT BMI S values from 198 to 240 months. For girls the MULT ABMI S values were close to the IOTF, CDC, and DUTCH from 60 to 110 months, and then became higher, approaching the MULT BMI S values until 240 months.

Conclusion

MULT ABMI presented an advantage in comparison to the existing BMI references because it takes into account the growth changes during puberty and is a new option to assess the nutritional status of multi-ethnic populations.
Analysis of Mutations in Precision Oncology using The Automated, Accurate, and User-Friendly Web Tool PredictONCO
Authors: Khan Rayyan Tariq , Pokorna Petra , Stourac Jan , Borko Simeon , Dobias Adam , Planas-Iglesias Joan , Mazurenko Stanislav , Arefiev Ihor , Pinto Gaspar , Szotkowska Veronika , Sterba Jaroslav , Damborsky Jiri , Slaby Ondrej , Bednar David
Published: June 2024

Next-generation sequencing technology has created many new opportunities for clinical diagnostics, but it faces the challenge of functional annotation of identified mutations. Various algorithms have been developed to predict the impact of missense variants that influence oncogenic drivers. However, computational pipelines that handle biological data must integrate multiple software tools, which can add complexity and hinder non-specialist users from accessing the pipeline. Here, we have developed an online user-friendly web server tool PredictONCO that is fully automated and has a low barrier to access. The tool models the structure of the mutant protein in the first step. Next, it calculates the protein stability change, pocket level information, evolutionary conservation, and changes in ionisation of catalytic amino acid residues, and uses them as the features in the machine-learning predictor. The XGBoost-based predictor was validated on an independent subset of held-out data, demonstrating areas under the receiver operating characteristic curve (ROC) of 0.95 and 0.94, and the average precision from the precision-recall curve 0.98 and 0.94 for structure-based and sequence-based predictions, respectively. Finally, PredictONCO calculates the docking results of small molecules approved by regulatory authorities. We demonstrate the applicability of the tool by presenting its usage for variants in two cancer-associated proteins, cellular tumour antigen p53 and fibroblast growth factor receptor FGFR1. Our free web tool will assist with the interpretation of data from next-generation sequencing and navigate treatment strategies in clinical oncology:https://loschmidt.chemi.muni.cz/predictonco/.
Lysosomal signalling pathways influence heart rhythm, and regulate atrial function
Authors: Capel Rebecca A. , Akerman Emily , Rog-Zielinska Eva A. , Winbo Annika , Aston Daniel , Mu-u-min Razik Bin Abdul , Read Matthew J. , Bose Samuel J. , Swietach Pawel , Wang Jingyu , Corbett Alexander D. , Koschinski Andreas , Falter Florian , Calamaio Serena , Melgari Dario , Prevostini Rachele , Rivolta Ilaria , Ayagama Thamali , Jenkin Ifan , Simon Jillian N. , Fakuade Funsho E. , Pronto Julius R. , Sharma Parveen , Song Qianqian , Booth Martin J , Platt Frances M. , Lei Ming , Hester Svenja , Fischer Roman , Voigt Niels , Schotten Ulrich , Verheule Sander , Galione Antony , Keller Marco , Bracher Franz , Zaccolo Manuela , Terrar Derek A. , Burton Rebecca A. B.
Published: June 2024

In the heart, endogenous nicotinic acid adenine dinucleotide phosphate (NAADP) triggers lysosomal calcium (Ca2+) release to augment sarcoplasmic reticulum [1] Ca2+sequestration, producing larger Ca2+transients. However, the role of lysosomal Ca2+signals in pacemaker activity, a distinct Ca2+-operated function of the sinoatrial node (SAN), or in the atrial myocardium has not been investigated. Pharmacological or genetic ablation of the NAADP pathway inhibits the spontaneous beating rate response to β-adrenergic stimulation in intact SAN. We found intracellular signalling microdomains between lysosomes and neighboring SR or mitochondria in mouse, rabbit, goat, and human atrial tissue. The spatial relationship between lysosomes and other Ca2+-handling organelles are altered in goat and human atrial fibrillation. Furthermore, we demonstrate atrial myocytes produce 3′–5′-cyclic adenosine monophosphate in response to lysosomal signalling, adding a novel trigger for cyclic nucleotide signalling. Our findings support the hypothesis that lysosomal Ca2+signalling directly increases cardiomyocyte cAMP and modulates pacemaker activity.
Modeling differences in neurodevelopmental maturity of the reading network using support vector regression on functional connectivity data
Authors: Lasnick Oliver H.M. , Luo Jie , Kinnie Brianna , Kamal Shaan , Low Spencer , Marrouch Natasza , Hoeft Fumiko
Published: June 2024

The construction of brain growth charts trained to predict age based on morphometric and/or functional properties of the brain (‘brain-age prediction’) has the potential to inform neuroscientists and clinicians alike about children’s neurodevelopmental trajectories. When applied to both typically- and atypically-developing populations – such as those with specific learning disorders – results may be informative as to whether a particular condition is associated with atypical maturation of specific brain networks. Here, we focus on the relationship between reading disorder (RD) and maturation of functional connectivity (FC) patterns in the prototypical reading/language network across development using a cross-sectional sample of N = 742 participants aged 6-21 years. A support vector regression model is trained to predict chronological age from FC data derived from (1) a whole-brain model, as well as (2) multiple ‘reduced’ models, which are trained on FC data generated from a successively smaller number of regions in the brain’s reading network. We hypothesized that the trained models would show systematic underestimation of brain network maturity (i.e., lower FC-based age predictions) for poor readers, particularly for the models trained with reading/language regions. Exploratory results demonstrated that the most important whole-brain ROIs and connections are derived from the dorsal attention and somatosensory motor networks. Comparisons of the different models’ predictions reveal that while the whole-brain model outperforms the others in terms of overall prediction accuracy, all models are effective at predicting brain maturity, including the one trained with the smallest amount of FC data. In addition, all models demonstrate some degree of moderation in the reliability of their age predictions as a function of reading ability, with predictions for both poor and exceptional readers being more accurate relative to those for typical readers.

Key Points

A machine learning model trained to predict age from functional connectivity data has better predictive utility for children/adolescents with either low OR high reading ability, and performs less well for those with average reading ability

Both impaired and exceptional reading may be characterized as having lower variance in connectivity patterns on the population level compared to typical readers (rather than having delayed/accelerated network maturation)

Neural markers of reading and language are likely diffusely represented in the brain
Dynamics of pitch perception in the auditory cortex
Authors: Abrams Ellie Bean , Marantz Alec , Krementsov Isaac , Gwilliams Laura
Published: June 2024

The ability to perceive pitch allows human listeners to experience music, recognize the identity and emotion conveyed by conversational partners, and make sense of their auditory environment. A pitch percept is formed by weighting different acoustic cues (e.g., signal fundamental frequency and inter-harmonic spacing) and contextual cues (expectation). How and when such cues are neurally encoded and integrated remains debated. In this study, twenty-eight participants (16 female) listened to tone sequences with different acoustic cues (pure tones, complex missing fundamental tones, and tones with an ambiguous mixture), placed in predictable and less predictable sequences, while magnetoencephalography was recorded. Decoding analyses revealed that pitch was encoded in neural responses to all three tone types, in the low-to-mid auditory cortex and sensorimotor cortex bilaterally, with right-hemisphere dominance. The pattern of activity generalized across cue-types, offset in time: pitch was neurally encoded earlier for harmonic tones (∼85ms) than pure tones (∼95ms). For ambiguous tones, pitch emerged significantly earlier in predictable contexts than unpredictable. The results suggest that a unified neural representation of pitch emerges by integrating independent pitch cues, and that context alters the dynamics of pitch generation when acoustic cues are ambiguous.

Significance Statement

Pitch enables humans to enjoy music, understand the emotional intent of a conversational partner, distinguish lexical items in tonal languages, and make sense of the acoustic environment. The study of pitch has lasted over a century, with conflicting accounts of how and when the brain integrates spectrotemporal information to map different sound sources onto a single and stable pitch percept. Our results answer crucial questions about the emergence of perceptual pitch in the brain: namely, that place and temporal cues to pitch seem to be accounted for by early auditory cortex, that a common representation of perceptual pitch emerges early in the right hemisphere, and that the temporal dynamics of pitch representations are modulated by expectation.
Pathological axonal enlargement in connection with amyloidosis, lysosome destabilization and hemorrhage is a major defect in Alzheimer’s disease
Authors: Fu Hualin , Li Jilong , Zhang Chunlei , Gao Guo , Ge Qiqi , Guan Xinping , Cui Daxiang
Published: June 2024

Abstract

Alzheimer’s disease (AD) is a multi-amyloidosis disease with Aβ deposits in the cerebral blood vessels, microaneurysms and senile plaques. How Aβ amyloidosis affects axon pathology is not well-examined. We studied Aβ-related axonal phenotypes with histochemistry, immunohistochemistry and fluorescence imaging methods. Widespread axonal amyloidosis with distinctive axonal enlargement was observed in AD. Aβ-positive axon diameters in AD brains were 1.72 times of control brain axons by average. Axonal amyloidosis also associated with MAP2 reduction, Tau phosphorylation, lysosome destabilization and hemorrhagic markers such as ApoE, HBA, HbA1C and Hemin. Lysosome destabilization in AD was also clearly identified in the neural soma, associating with the co-expression of Aβ and Cathepsin D, HBA, ACTA2 and ColIV, implicating exogeneous hemorrhagic protein intake might influence neural lysosome stability. The data showed that Aβ-containing lysosomes were 2.23 times as large as the control lysosomes. Furthermore, under rare conditions, axon breakages were observed, which likely resulted in Wallerian degeneration. In summary, axonal enlargement associated with amyloidosis, chronic microhemorrhage and lysosome destabilization is a major defect in Alzheimer’s disease.
A comprehensive multi-omics study reveals potential prognostic and diagnostic biomarkers for colorectal cancer
Authors: Mahajan Mohita , Dhabalia Subodh , Dash Tirtharaj , Sarkar Angshuman , Mondal Sukanta
Published: June 2024

Background

Colorectal cancer (CRC) is a complex disease with diverse genetic alterations and causes 10% of cancer-related deaths worldwide. Understanding its molecular mechanisms is essential for identifying potential biomarkers and therapeutic targets for its effective management.

Method

We integrated copy number alterations (CNA) and mutation data via their differentially expressed genes termed as candidate genes (CGs) computed using bioinformatics approaches. Then, using the CGs, we perform Weighted correlation network analysis (WGCNA) and utilise several hazard models such as Univariate Cox, Least Absolute Shrinkage and Selection Operator (LASSO) Cox and multivariate Cox to identify the key genes involved in CRC progression. We used different machine-learning models to demonstrate the discriminative power of selected hub genes among normal and CRC (early and late-stage) samples.

Results

The integration of CNA with mRNA expression identified over 3000 CGs, including CRC-specific driver genes likeMYCandAPC. In addition, pathway analysis revealed that the CGs are mainly enriched in endocytosis, cell cycle, wnt signalling and mTOR signalling pathways. Hazard models identified four key genes,CASP2, HCN4, LRRC69andSRD5A1, that were significantly associated with CRC progression and predicted the 1-year, 3-years, and 5-years survival times. WGCNA identified seven hub genes:DSCC1, ETV4, KIAA1549, NOP56, RRS1, TEAD4andANKRD13B, which exhibited strong predictive performance in distinguishing normal from CRC (early and late-stage) samples.

Conclusions

Integrating regulatory information with gene expression improved early versus latestage prediction. The identified potential prognostic and diagnostic biomarkers in this study may guide us in developing effective therapeutic strategies for CRC management.