bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk Factors for Infection-Attributable Mortality in Patients With Staphylococcus aureus Bacteremia: A Competing Risk Analysis
Authors: Bae Seongman , Kook Min Soo , Chang Euijin , Jung Jiwon , Kim Min Jae , Chong Yong Pil , Kim Sung-Han , Choi Sang-Ho , Lee Sang-Oh , Kim Yang Soo
Published: December 2024

Background

Identifying risk factors for mortality in patients with Staphylococcus aureus bacteremia (SAB) is crucial due to its high fatality. However, data on risk factors for infection-attributable deaths considering competing risk events such as non-infection-attributable deaths remain limited. We performed a competing risk analysis to elucidate risk factors associated with 30-day infection-attributable mortality in a large cohort of patients with SAB.

Methods

This retrospective cohort study included adult patients diagnosed with SAB at a tertiary hospital from August 2008 to December 2019. Competing risk analysis was performed using Fine and Gray models to estimate subdistribution hazard ratios (sHRs) for 30-day infection-attributable death.

Results

Among 1936 patients, 444 (22.9%) died within 30 days. Of these, 338 (76.1%) were infection-attributable and 106 (23.9%) were non-infection-attributable deaths. The multivariable Fine and Gray model identified significant risk factors for 30-day infection-attributable death (sHRs with 95% confidence intervals): an increase in age by 10 years (1.14 [1.02–1.26]), presence of malignancy (1.54 [1.17–2.02]), liver cirrhosis (2.15 [1.56–2.97]), corticosteroid use (1.61 [1.19–2.17]), septic shock (3.28 [1.98–5.42]), elevated C-reactive protein (1.60 [1.19–2.14]), pneumonia (1.81 [1.21–2.72]), persistent bacteremia (1.73 [1.31–2.30]), and failure to remove the eradicable focus (2.40 [1.38–4.19]) or absence of an eradicable focus (1.49 [1.08–2.04]). Except for age and malignancy, these factors were not significantly associated with non-infection-related death.

Conclusions

Specific risk factors for infection-attributable death in patients with SAB were identified, distinct from those for nonattributable death. These findings can aid in the early identification of patients at risk for SAB-attributable mortality.
Epidemiology and Genotype Dynamics of Dengue in Hospitalized Patients in Northern Vietnam Between 2020 and 2022
Authors: Anh Do Duc , The Nguyen Trong , My Truong Nhat , Linh Le Thi Kieu , Hoan Nghiem Xuan , Kremsner Peter G , Toan Nguyen Linh , Song Le Huu , Velavan Thirumalaisamy P
Published: December 2024

Background

Arboviruses, including Dengue (DENV), Zika, and chikungunya, cause recurrent outbreaks of varying intensity in tropical countries. This study aimed to investigate other arboviruses, including Zika and chikungunya, in patients clinically suspected of Dengue and to characterize the circulating Dengue serotypes and genotypes in Northern Vietnam from 2020 to 2022. To date, information on this topic in the region has been limited.

Methods

Multiplex real-time polymerase chain reaction (PCR) was used to detect Dengue, Zika, and chikungunya RNA, and DENV serotypes were identified via real-time reverse transcriptase PCR from 426 clinically Dengue suspected patients. Patients were screened for NS1 antigen and anti-DENV immunoglobulin (Ig) G/IgM antibodies. Phylogenetic analysis of DENV Capsid-premembrane gene sequences was performed to investigate genotype distribution.

Results

Dengue was confirmed in 95% of cases, with no Zika or chikungunya RNA detected. DENV-2 was the predominant serotype (61%), followed by DENV-1 (31%) and DENV-4 (7%). Coinfections were observed, with DENV-1 and DENV-2 being the most common. In 2022, a high incidence of Dengue cases with warning signs and severe Dengue was observed, accompanied by elevated liver enzyme levels and reduced platelet counts. Phylogenetic analysis revealed that the DENV-1 and DENV-4 serotypes clustered with previously reported regional virus, while DENV-2 showed a shift from genotype Asian I to Cosmopolitan over the study period.

Conclusions

This study underscores a significant rise in Dengue severity and shifts in DENV genotypes in recent years in Northern Vietnam, emphasizing the importance of understanding genotype dynamics and clinical dynamics for improving outbreak preparedness and response strategies.
Beyond Energy: Teleporting Current, Charge, and More
Authors: Ikeda Kazuki
Published: December 2024

As an homage to Quantum Energy Teleportation, we generalize the idea to arbitrary physical observables, not limited to energy, and prove a rigorous upper bound on the activated (“teleported”) quantity. The essence of this protocol is a quantum feedback control applied to an entangled ground state of a quantum many-body system. To illustrate the concept, we investigate a (1+1)-dimensional Dirac system and apply feedback control based on fermion chirality to activate electric current and charge. One of the most significant results is the creation of long-range correlations across the system after applying control operations only to one local site. Consequently but surprisingly, the induced charge susceptibility fully reconstructs the phase diagram, despite the model initially having no charge. Moreover, we find an activation of novel chiral dynamics induced by feedback control operations, which can be experimentally confirmed using trapped ions and neutral atoms.
Consumer Surplus of Alternative Payment Methods
Authors: Alvarez Fernando , Argente David
Published: December 2024

This paper estimates the consumer surplus from using alternative payment methods. We use evidence from Uber rides in Mexico, where riders have the option to use cash or cards to pay for rides. We design and conduct three large-scale field experiments, which involved approximately 400,000 riders. We also build a structural model which, disciplined by our new experimental data, allows us to estimate the loss of private benefits for riders when a ban on cash payments is implemented. We find that Uber riders who use cash as means of payment either sometimes or exclusively suffer an average loss of approximately 40–50% of their total trip expenditures paid in cash before the ban. The magnitude of these estimates reflects the intensity with which cash is used in the application, the shape of the demand curve for Uber rides, and the imperfect substitutability across means of payments. Welfare losses fall mostly on the least-advantaged households, who rely more heavily on the cash payment option.
Using the Perspectives of Advanced Practice Providers to Design Strategies to Increase Engagement of Surgical Patients in Advance Care Planning
Authors: Johnson Christopher L. , Barnes Katherine E. , Colley Alexis , Broering Jeanette , Yee Alisa , Bongiovanni Tasce , Roman Sanziana , Wick Elizabeth C.
Published: December 2024

Objective:

Advanced practice providers (APPs) are essential members of surgical teams. We sought to understand the barriers and facilitators they perceive when participating in advanced care planning (ACP) discussions with patients and use this knowledge to design strategies to promote interprofessional ACP uptake for surgical services and potentially extend ACP discussions and documentation to more patients.

Background:

ACP has been challenging to integrate into surgical practice despite being endorsed by national societies and payors as an essential aspect of caring for older adults.

Methods:

Using qualitative and quantitative methods, we surveyed and interviewed APPs at a single tertiary academic medical center. A previously validated Likert scale survey of clinician knowledge, attitudes, and experiences with ACP was adapted to include demographic information and details about practice experience.

Results:

Of the 88 APPs who were sent our surveys, 46 (52%) responded. Eighty-eight percent of respondents believed APPs play an important role in ACP discussions, 80% believed that ACP information was helpful in guiding clinical care discussions, 71% expressed comfort with discussing ACP with patients, and 59% endorsed comfort with communicating a prognosis to patients. Twelve interviews yielded 3 main themes: (1) clinical and professional benefits of ACP; (2) barriers to APP involvement in ACP; (3) proposed interventions to integrate APPs into ACP.

Conclusions:

To increase surgical ACP uptake by APPs, data on proposed ACP interventions must focus on establishing a multi-disciplinary team-based workflow, addressing competing clinical demands, opportunities for additional education, and clarifying the scope of work.
Ambulatory Surgery Ensemble: Predicting Adult and Pediatric Same-Day Surgery Cases Across Specialties
Authors: Howell Thomas Clark , Zaribafzadeh Hamed , Sumner Maxwell D. , Rogers Ursula , Rollman John , Buckland Daniel M. , Kent Michael , Kirk Allan D. , Allen Peter J. , Rogers Bruce
Published: December 2024

Objective:

To develop an ensemble model using case-posting data to predict which patients could be discharged on the day of surgery.

Background:

Few models have predicted which surgeries are appropriate for day cases. Increasing the ratio of ambulatory surgeries can decrease costs and inpatient bed utilization while improving resource utilization.

Methods:

Adult and pediatric patients undergoing elective surgery with any surgical specialty in a multisite academic health system from January 2021 to December 2023 were included in this retrospective study. We used surgical case data available at the time of case posting and created 3 gradient-boosting decision tree classification models to predict case length (CL) less than 6 hours, postoperative length of stay (LOS) less than 6 hours, and home discharge disposition (DD). The models were used to develop an ambulatory surgery ensemble (ASE) model to predict same-day surgery (SDS) cases.

Results:

The ASE achieved an area under the receiver operating characteristic curve of 0.95 and an average precision of 0.96. In total, 139,593 cases were included, 48,464 of which were in 2023 and were used for model validation. These methods identified that up to 20% of inpatient cases could be moved to SDS and identified which specialties, procedures, and surgeons had the most opportunity to transition cases.

Conclusions:

An ensemble model can predict CL, LOS, and DD for elective cases across multiple services and locations at the time of case posting. While limited in its inclusion of patient factors, this model can systematically facilitate clinical operations such as strategic planning, surgical block time, and case scheduling.
Comminuted Suprasyndesmotic Ankle Fractures are Associated with a High Rate of Anterolateral Plafond Involvement
Authors: Wahlig Brian D. , Khanna Ankur , MacInnis Bailey R. , Copp Jonathan , Cross 3rd William W. , Sems Stephen A. , Yuan Brandon J. , Hidden Krystin A.
Published: December 2024

Objectives:

This study aimed to identify the rate at which the anterolateral tibial plafond is affected in comminuted suprasyndesmotic ankle fractures (AO/OTA 44C2) and to assess how its involvement affects clinical outcomes.

Methods:

Design: Retrospective review

Setting:

Level 1 Trauma Center

Patient Selection Criteria:

Patients with a pre-operative computed tomography (CT) treated surgically for AO/OTA 44C2 fractures from January 2005 to December 2021.

Outcome Measures and Comparisons:

The primary outcome measure was the prevalence of anterolateral plafond impaction or a displaced Tillaux-Chaput fracture. Secondary outcome measures included reoperation rate (excluding hardware removal), rate of new-onset ankle osteoarthritis, rate of ankle osteoarthritis progression, Single Assessment Numeric Evaluation (SANE) score, and the Olerud Molander Ankle Score (OMAS).

Results:

Fifty-three patients met inclusion criteria. The average age was 50 years (range 18-100), and 53% were female. The anterolateral plafond was involved in 26 patients (49%), with anterolateral plafond impaction in 11 patients (21%) and a displaced Tillaux-Chaput fragment in 15 patients (28%). Five patients (19%) received independent fixation of the anterolateral plafond, and three of these patients had anterolateral plafond impaction addressed. Thirty-eight patients (72%) had clinical follow-up of at least 6 months. Patients with anterolateral plafond impaction had a higher rate of reoperation (excluding hardware removal) compared to those without any anterolateral plafond involvement (HR = 8.3, 95% CI: 1.4-15.3, p=0.022) as well as a higher rate of new-onset ankle osteoarthritis (83% vs 23%, p=0.013). There was no difference in the rate of reoperation (11% vs 9%, p=0.748) or new-onset osteoarthritis (63% vs 23%, p=0.078 when comparing those with a displaced Tillaux-Chaput fracture to those without anterolateral plafond involvement. There were no differences in SANE (75% vs. 78% vs. 85%, p = 0.661) or OMAS (70 points vs. 69 points vs. 81 points, p=0.517) scores when comparing those with anterolateral plafond impaction, those with Tillaux-Chaput fragments, and those with no anterolateral plafond involvement.

Conclusion:

CT evaluation is recommended in patients with comminuted suprasyndesmotic fibula fractures (AO/OTA 44C2) given their high association with anterolateral plafond impaction and Tillaux-Chaput fracture. Patients with anterolateral plafond impaction have a higher reoperation rate and new-onset ankle osteoarthritis compared to those without anterolateral plafond involvement.

Level of Evidence:

Level IV
Scoliosis in Rett syndrome: a comparative analysis of postoperative complications
Authors: Chi Jialun , Song Xiangwei , Liu Ju , Oh Eunha G. , Zhang Zhichang , Xu Zhiwen , Yang Hanzhi , Yuan Hui , Zhang Yi
Published: December 2024

Rett syndrome, a neurodevelopmental disorder primarily affecting females, presents unique challenges in managing associated scoliosis. This study aims to evaluate the efficacy and challenges of posterior spinal fusion (PSF) in Rett syndrome patients by analyzing postoperative complications. A retrospective cohort study was conducted using a large national database. We included Rett syndrome patients aged 10–18 years who underwent PSF between 2010 and 2020. Outcomes such as medical and surgical complications, emergency department visits, readmissions, mortality, and reoperation rates up to 5 years were compared with a matched neuromuscular scoliosis (NMS) group. The study identified 195 Rett syndrome patients and 973 NMS patients. Post-surgery, Rett syndrome patients showed a significantly higher incidence of pneumothorax (56.9%, P < 0.001), respiratory failure (24.6%, P = 0.013), and pneumonia (26.2%, P < 0.001). Additionally, ileus (7.2%, P = 0.041), acute kidney injury (14.9%, P = 0.029), and urinary tract infections (14.9%, P < 0.001) were also significantly more frequent in the Rett syndrome group. Rett syndrome group also had higher rates of transfusion (11.3%, P = 0.004). Interestingly, the incidence of pseudarthrosis, implant complications, junctional failures, and the necessity for reoperation did not significantly differ at postoperative year 2. Mid-term follow-up showed that the reoperation rates over a 5-year period did not significantly differ between the Rett syndrome and NMS groups. Rett syndrome is associated with increased immediate postoperative complications, necessitating tailored preoperative planning, and intensive postoperative care. Despite these challenges, the mid-term surgical outcomes are comparable to those in NMS patients.
Global, regional, and national burden of pancreatic cancer from 1990 to 2021, with projections for 25 years: a systematic analysis for the Global Burden of Disease Study 2021
Authors: Wang Qihong , Liu Jiao , Yang Zhuo
Published: December 2024

This study examines the global burden of pancreatic cancer from 1990 to 2021 and projects future trends, aiming to provide insights for health policy and resource allocation to mitigate the disease’s impact. We assessed the pancreatic cancer burden globally and by subgroups, employing linear regression models to analyze trends from 1990 to 2021. Cluster analysis was used to evaluate burden patterns across Global Burden of Disease regions. Forecasting was conducted using the age-period-cohort model and its Bayesian variant. Additionally, we evaluated risk factor contributions to the pancreatic cancer burden and used frontier analysis to explore the relationship between sociodemographic advancements and cancer rates. In 2021, pancreatic cancer accounted for 508 533 new cases, 439 001 prevalent cases, 505 752 deaths, and 11 316 963 disability-adjusted life years (DALYs). High-risk groups included males and middle-aged to older adults, with high-risk areas identified in regions with higher sociodemographic index (SDI). From 1990 to 2021, both pancreatic cancer cases and age-standardized rates (ASR) increased. Notably, high fasting plasma glucose surpassed tobacco as a leading risk factor for pancreatic cancer. Frontier analysis revealed an inverse relationship between SDI and pancreatic cancer ASR, plateauing at an SDI of 0.60. The global burden of pancreatic cancer continues to rise, with significant disparities across demographic and geographic segments. These findings highlight the need for targeted interventions and resource allocations to address this growing public health challenge.
Old age decreases the risk of lymph node metastasis in T1-2 hypopharynx squamous cell carcinoma patients
Authors: Li Yujiao , Hu Chaosu
Published: December 2024

Cervical lymph node metastasis (LNM) is an important prognostic factor for hypopharynx squamous cell carcinoma (SCC) patients, which can be detected in a large fraction of clinically diagnosed early hypopharynx SCC patients; however, the importance of knowing the risk of LNM in the younger/older patients has not been well defined. The objective of this study is to assess the effect of age and LNM in T1-2 hypopharynx SCC patients. Patients with T1-2 hypopharynx SCC were extracted from the Surveillance, Epidemiology and End Results database between 2005 and 2014. Univariate and multivariate logistic regression models were produced to recognize the association between age and risk factors of LNM. A total of 1018 patients were analyzed. Older patients have a lower risk of LNM compared with their younger peers (P < 0.01). In multivariate analyses, older age was associated with a significantly lower risk of LNM. Compared with patients aged 80–93 years old, the hazard ratios for patients aged 31–49, 50–59, 60–69, and 70–79 years old were 2.464 [95% confidence interval (CI): 1.338–4.537], 2.668 (95% CI: 1.638–4.346), 3.192 (95% CI: 1.957–5.205), and 1.564 (95% CI: 0.945–2.588), respectively. Subgroup analysis shows that the effect of older age was significantly associated with a higher risk of LNM in Caucasian male who harbored moderately/poorly differentiated tumors. Our study demonstrates that older patients with T1-2 hypopharynx SCC had a lower risk of LNM than their younger peers, especially males with moderately/poorly differentiated tumors. More accurate assessments of LNM and prophylactic neck dissection or prophylactic adjuvant radiation therapy to the neck will be imperative for reducing recurrence in younger T1-2 hypopharynx SCC.
What Motivates Older Sedentary People Living With HIV in the United States to Participate in an Exercise Trial? A Qualitative Study
Authors: Iriarte Evelyn , Webel Allison R. , Cook Paul F. , Turner Ashley , Ditzenberger Grace L. , Erlandson Kristine M. , Jankowski Catherine
Published: December 2024

Although exercise supports the physical function and health of older people living with HIV (PLWH), less than half of PLWH globally achieve recommended levels of activity. A qualitative descriptive design was used to determine what motivates sedentary PLWH, 50 years and older, to participate in an exercise trial. Interviews were conducted with PLWH who participated in an exercise trial (n = 30) and PLWH who declined enrollment in the same exercise trial (n = 4). The theory of planned behavior (TPB) guided a directed content analysis of the interviews. Data analysis identified four themes: (a) intention or motivation (perceived benefits, maintaining the exercise behavior over time), (b) attitudes (goals and preferences), (c) perceived behavioral control (barriers, facilitators, and self-efficacy), and (d) subjective norms (pressure from health care providers and social networks). Findings from our study contribute to informing the development of future exercise interventions or trials and to planning care to encourage a physically active lifestyle.
Trends in syphilis case rates among women of reproductive age — United States, 2013–2022
Authors: Anand Priyanka , Quilter Laura A. S. , Learner Emily R. , Barbee Lindley A. , Jackson David A.
Published: December 2024

We analyzed syphilis case notifications in reproductive age women during 2013–2022. Late/unknown duration syphilis grew faster after 2020 (45.8% versus 17.9% annual growth pre-2020). Increased screening, inaccurate staging, delayed diagnosis, or increased incidence following clinical and partner services gaps during 2020 may contribute to rises in late/unknown duration cases.
Estimating the incidence of antimicrobial resistant Neisseria gonorrhoeae in the United States among men and women aged 15-39 years, 2008-2019
Authors: Pondo Tracy , Nielsen Karen E. , Schmerer Matthew W. , Spicknall Ian H. , Pollock Emily D. , Kreisel Kristen M. ,   Antimicrobial-Resistant Neisseria gonorrhoeae Working Group
Published: December 2024

Background

The Gonococcal Isolate Surveillance Project (GISP) was established to monitor antimicrobial resistance (AR) in N. gonorrhoeae in the United States. Isolates collected in GISP undergo antimicrobial susceptibility testing allowing for estimates of resistance, based on exceeding minimum inhibitory concentrations (MICs), to be calculated.

Methods

We estimated the annual number and proportion of gonococcal infections with antibiotic resistance or elevated MICs (AR/eMICs) against six antibiotics for men and women aged 15 to 39 years in the US using male urethral specimens collected in GISP during 2008–2019. Although GISP only measured MICs for male gonococcal infections, this study estimated AR/eMICs in women using data from men with female sex partners. GISP data were weighted against national gonorrhea case report data based on four variables (age group, year of report, US Census region, and race/Hispanic ethnicity) to estimate annual, national proportions of gonococcal infections with AR/eMICs. These weighted proportions were then multiplied by national estimates of incident gonococcal infections to calculate the number of incident gonococcal infections with AR/eMICs nationally.

Results

Women had a higher estimated number of cases with AR/eMICs compared with men (440,900 vs. 387,200 in 2019) although the estimated percentage of gonococcal infections with AR/eMICs was lower in women (50.7% vs. 54.4% in 2019). Elevated MICs to ceftriaxone remained below 1% throughout the study period.

Conclusions

Our analysis indicates that there are more women with AR/eMICs gonorrhea than men. Although the proportion of cases that are resistant to any one antimicrobial is increasing, eMICs to ceftriaxone remains low.
Trends in Demographic Characteristics and Risk Factors among Individuals with Syphilis in Colorado from 2011-2020
Authors: Bianchini Monica L. , Rowan Sarah E. , Frost Holly M. , Valuck Robert , McQueen R. Brett , Anderson Heather D.
Published: December 2024

Background

Identify opportunities to improve syphilis screening by describing changes in patient characteristics and risk factors among individuals with syphilis and by comparing cases with and without an indication for syphilis screening.

Methods

This retrospective cohort study used Colorado public health surveillance data to identify 8,326 syphilis diagnoses from 2011-2020. Demographics, clinical characteristics, and risk factors were compared across 2-year groups and between individuals with and without an indication for screening. Indications for screening were based on national guidelines and included men who have sex with men, persons living with HIV, pregnant individuals, those who test positive for chlamydia, gonorrhea, or HIV, and partners of those who test positive for syphilis.

Results

Across study years, there was a 234% increase in the proportion of syphilis cases that were females (5.3% to 17.7%; p < .01), a 78% increase in the proportion of cases living in rural areas (3.6% to 6.4%; p < .01), and a 15% increase in the proportion of cases among non-White individuals (47.9% to 54.9%; p < .01). The proportion of patients that had a guideline-recommended indication for screening decreased from 88% in 2011-2012 to 59% in 2019-2020 (p < .01). Females represented 5.5% of cases with an indication for screening and 29.8% of cases without an indication for screening (p < .01).

Conclusions

Syphilis cases increased annually from 2011-2020 yet the proportion of cases detected under current screening recommendations decreased. These findings reveal opportunities to expand syphilis screening.
Review of Functional Cranioplasty and Implantable Neurotechnology
Authors: Gordon Chad R. , Perez Colleen F.
Published: December 2024

Cranioplasty for secondary reconstruction of cranial defects has historically focused on simply replacing the missing cranial bone to restore cerebral protection and fluid dynamics, but recent innovations have led to the development of customized cranial implants that address both bone and soft tissue deficits while avoiding postoperative complications such as temporal hollowing. In addition, customized cranial implants have incorporated implantable neurotechnology like ventriculostomy shunts, intracranial pressure monitoring devices, and medicine delivery systems within low-profile designs to convert previously “basic” implants into “smart” implants for added functionality. These “smart” implants aim to reduce complications and improve patient outcomes by leveraging the cranial space to house advanced technologies, providing benefits such as real-time biosensing, and treatment of chronic neurological conditions. This review outlines the progression of cranioplasty from basic bone replacement to functional implants with embedded neurotechnologies, highlighting the multidisciplinary approaches that enhance surgical outcomes and patient quality of life.
The quantum optics of media
Authors: Barnett Stephen M.
Published: December 2024

The quantum theory of light in real media requires attention to a number of physical features. Even in near-transparent dielectrics, we have to incorporate dispersion, losses and the effects of interfaces. Here, we review the quantization of light in a dielectric and see how this affects radiative processes and light propagation. In the second half of the paper, we turn to optical forces and momentum. There we show why there are two rival force densities in a medium and also why there
must be
two distinct optical momenta. In the process, this resolves the century-old Abraham–Minkowski dilemma.

This article is part of the theme issue ‘The quantum theory of light’.
Covalent inhibitors of the RAS binding domain of PI3Kα impair tumor growth driven by RAS and HER2
Authors: Klebba Joseph E. , Roy Nilotpal , Bernard Steffen M. , Grabow Stephanie , Hoffman Melissa A. , Miao Hui , Tamiya Junko , Wang Jinwei , Berry Cynthia , Esparza-Oros Antonio , Lin Richard , Liu Yongsheng , Pariollaud Marie , Parker Holly , Mochalkin Igor , Rana Sareena , Snead Aaron N. , Walton Eric J. , Wyrick Taylor E. , Aitichson Erick , Bedke Karl , Brannon Jacyln C. , Chick Joel M. , Hee Kenneth , Horning Benjamin D. , Ismail Mohamed , Lamb Kelsey N. , Lin Wei , Metzger Justine , Pastuszka Martha K. , Pollock Jonathan , Sigler John J. , Tomaschko Mona , Tran Eileen , Kinsella Todd M. , Molina-Arcas Miriam , Simon Gabriel M. , Weinstein David S. , Downward Julian , Patricelli Matthew P.
Published: December 2024

Genetic disruption of the RAS binding domain (RBD) of PI 3-kinase (PI3K) prevents the growth of mutant RAS driven tumors in mice and does not impact PI3K’s role in insulin mediated control of glucose homeostasis. Selectively blocking the RAS-PI3K interaction may represent an attractive strategy for treating RAS-dependent cancers as it would avoid the toxicity associated with inhibitors of PI3K lipid kinase activity such as alpelisib. Here we report compounds that bind covalently to cysteine 242 in the RBD of PI3K p110α and block the ability of RAS to activate PI3K activity. These inhibitors have a profound impact on the growth of RAS mutant and also HER2 over-expressing tumors, particularly when combined with other inhibitors of the RAS/MAPK pathway, without causing hyperglycemia.
Loss of olfaction reduces caterpillar performance and increases susceptibility to a natural enemy
Authors: Wang Qi , Jia Yufei , Smid Hans M. , Weldegergis Berhane T. , Greenberg Liana O. , Jongsma Maarten , Dicke Marcel , Haverkamp Alexander
Published: December 2024

Insect herbivores such as caterpillars, are under strong selection pressure from natural enemies, especially parasitoid wasps. Although the role of olfaction in host-plant seeking has been investigated in great detail in parasitoids and adult lepidopteran, the caterpillar olfactory system and its significance in tri-trophic interactions remains poorly understood. In this study, we investigated the olfactory system ofPieris brassicaecaterpillars and the importance of olfactory information in the interactions among this herbivore, its host-plantBrassica oleraceaand its primary natural enemyCotesia glomerata. To examine the role of olfaction, we utilized CRISPR/Cas9 to knock out the odorant receptor co-receptor (Orco). This knockout (KO) impaired olfactory detection and primary processing in the brain.OrcoKO caterpillars exhibited reduced weight and lost preference for their optimal food plant. Interestingly, the KO caterpillars also experienced reduced weight when challenged by the parasitoidC. glomeratawhose ovipositor had been removed, and the mortality of the KO caterpillars under the attack of unmanipulated parasitoids increased. We then investigated the behavior ofP. brassicaecaterpillars in response to volatiles from plants attacked by conspecific caterpillars and volatiles from plants on which the caterpillars were themselves attacked byC. glomerata. After analyzing the volatile compounds involved in these interactions, we concluded that olfactory information enables caterpillars to locate suitable food sources more efficiently as well as selecting enemy-free spaces. Our results reveal the crucial role of olfaction in caterpillar feeding and natural enemy avoidance, highlighting the significance of chemoreceptor genes in shaping ecological interactions.
Undiagnosed hypertension and its associated factors in India: A rural-urban contrast from the National Family Health Survey (2019-21)
Authors: Das Aritrik , Bhandari Yukti , Singh Angad , Kishore Jugal , Goel Sonu
Published: December 2024

Undiagnosed hypertension extracts significant social cost, with money spent on complications already accounting for one-fifths of total health expenditure. Widespread socioeconomic disparities and inequity in health care access between rural and urban areas is expected. It is important to identify the different factors associated with undiagnosed hypertension in the working age population (15-49-years) residing in urban and rural areas, both of whom are vital to the economic development of our country. Data from the National Family Health Survey-5 (2019-21) for men and women aged 15-49 years was extracted and analysed. Operational definitions were prepared to identify known and undiagnosed hypertension. Distribution of undiagnosed hypertension according to sociodemographic, anthropometric and health-related behaviour was studied using frequencies and weighted proportions. Choropleth maps were used to depict state-wise distribution of undiagnosed hypertension. Multivariable logistic regression was used to find risk factors and protective factors for undiagnosed hypertension for men and women in rural and urban areas. The prevalence of undiagnosed hypertension was 11.7%. among men and 7.2% among women. The proportion of men with undiagnosed hypertension (66.3%) was significantly higher than the proportion of women (41.4%). Urban-rural differences were noted in various states. Education and empowerment of rural women through provision of means of socioeconomic enhancement and strengthening of community-based screening and referral under the national programme were some of the major policy implications of our findings. Future research is warranted in areas such as health insurance coverage, working away from home, owning a mobile telephone and other interventions to improve health-seeking behaviour in the rural areas.
Parental kynurenine 3-monooxygenase genotype in mice directs sex-specific behavioral outcomes in offspring
Authors: Milosavljevic Snezana , Piroli Maria V , Sandago Emma J , Piroli Gerardo G , Smith Holland H , Beggiato Sarah , Frizzell Norma , Pocivavsek Ana
Published: December 2024

Background: Disruptions in brain development can impact behavioral traits and increase the risk of neurodevelopmental conditions such as autism spectrum disorder, attention-deficit/hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder, often in sex-specific ways. Dysregulation of the kynurenine pathway (KP) of tryptophan metabolism has been implicated in cognitive and neurodevelopmental disorders. Increased brain kynurenic acid (KYNA), a neuroactive metabolite implicated in cognition and sleep homeostasis, and variations in the Kmo gene, which encodes kynurenine 3-monooxygenase (KMO), have been identified in these patients. We hypothesize that parental Kmo genetics influence KP biochemistry, sleep behavior and brain energy demands, contributing to impairments in cognition and sleep in offspring through the influence of parental genotype and genetic nurture mechanisms. Methods: A mouse model of partial Kmo deficiency, Kmo heterozygous (HET-Kmo+/-), was used to examine brain KMO activity, KYNA levels, and sleep behavior in HET-Kmo+/- compared to wild-type control (WT-Control) mice. Brain mitochondrial respiration was assessed, and KP metabolites and corticosterone levels were measured in breast milk. Behavioral assessments were conducted on wild-type offspring from two parental groups: i) WT-Control from WT-Control parents, ii) wild-type Kmo (WT-Kmo+/+) from Kmo heterozygous parents (HET-Kmo+/-). All mice were C57Bl/6J background strain. Adult female and male offspring underwent behavioral testing for learning, memory, anxiety-like behavior and sleep-wake patterns. Results: HET-Kmo+/- mice exhibited reduced brain KMO activity, increased KYNA levels, and disrupted sleep architecture and electroencephalogram (EEG) power spectra. Mitochondrial respiration (Complex I and complex II activity) and electron transport chain protein levels were impaired in the hippocampus of HET-Kmo+/- females. Breast milk from HET-Kmo+/- mothers increased kynurenine exposure during lactation but corticosterone levels were unchanged. Compared to WT-Control offspring, WT-Kmo+/+ females showed impaired spatial learning, heightened anxiety, reduced sleep and abnormal EEG spectral power. WT-Kmo+/+ males had deficits in reversal learning but no sleep disturbances or anxiety-like behaviors. Conclusions: These findings suggest that Kmo deficiency impacts KP biochemistry, sleep behavior, and brain mitochondrial function. Even though WT-Kmo+/+ inherit identical genetic material as WT-Control, their development might be shaped by parental physiology, behavior, or metabolic state influenced by their Kmo genotype, leading to phenotypic sex-specific differences in offspring.
From Weak Interactions to Strong Affinity: Deciphering the Streptavidin-Biotin Interaction through NMR and Computational Analysis
Authors: Ptaszek Aleksandra L. , Kratzwald Sarah , Sagan Filip , Migotti Mario , Sánchez-Murcia Pedro A. , Konrat Robert , Platzer Gerald
Published: December 2024

Understanding weak interactions in protein-ligand complexes is essential for advancing drug design. Here, we combine experimental and quantum mechanical approaches to study the streptavidin-biotin complex, one of the strongest known protein-ligand binders. Using a monomeric streptavidin mutant, we analyze1H NMR chemical shift perturbations (CSPs) of biotin upon binding, identifying unprecedented upfield shifts of up to -3.2 ppm. Quantum chemical calculations attribute these shifts primarily to aromatic ring currents, with additional contributions from charge transfer effects linked to weak interactions. The agreement between experimental and computed chemical shifts validated the X-ray structure as a reliable basis for detailed computational analyses. Energy decomposition analysis reveals that electrostatics dominate the biotin-streptavidin interaction, complemented by significant orbital and dispersion contributions. Notably, weak non-covalent interactions—such as CH· · · S, CH· · ·π, and CH· · · HC contacts—driven by London dispersion forces, contribute ∼44% to the complex’s stability.
Common and rare genetic variation intersects with ancestry to influence human skin and plasma carotenoid concentrations
Authors: Han Yixing , Mwesigwa Savannah , Wu Qiang , Laska Melissa N. , Jilcott Pitts Stephanie B. , Moran Nancy E. , Hanchard Neil A.
Published: December 2024

Carotenoids are dietary bioactive compounds with health effects that are biomarkers of fruit and vegetable intake. Here, we examine genetic associations with plasma and skin carotenoid concentrations in two rigorously phenotyped human cohorts (n=317). Analysis of genome-wide SNPs revealed heritability to vary by genetic ancestry (h²=0.08–0.44) with ten SNPs at four loci reaching genome-wide significance (P<5E-08) in multivariate models, including atRAPGEF1(rs3765544, P=8.86E-10, beta=0.75) with α-carotene, and nearIGSF11(rs80316816, P=6.25E-10, beta=0.74), with cryptoxanthin; these were replicated in the second cohort (n=110). Multiple SNPs nearIGSF11demonstrated genotype-dependent dietary effects on plasma cryptoxanthin. Deep sequencing of 35 candidate genes revealed associations between thePKD1L2-BCO1locus and plasma β-carotene (Padj=0.04, beta=-1.3 to -0.3), and rare, ancestry-restricted, damaging variants inCETP(rs2303790) andAPOA1(rs756535387) in individuals with high skin carotenoids. Our findings implicate novel loci in carotenoid disposition and indicate the importance of including cohorts of diverse genetic ancestry.
Neural Ordinary Differential Equations Inspired Parameterization of Kinetic Models
Authors: van Lent Paul , Bunkova Olga , Planken Lèon , Schmitz Joep , Abeel Thomas
Published: December 2024

Motivation

Metabolic kinetic models are widely used to model biological systems. Despite their widespread use, it remains challenging to parameterize these Ordinary Differential Equations (ODE) for large scale kinetic models. Recent work on neural ODEs has shown the potential for modeling time-series data using neural networks, and many methodological developments in this field can similarly be applied to kinetic models.

Results

We have implemented a simulation and training framework for Systems Biology Markup Language (SBML) models using JAX/Diffrax, which we namedjaxkineticmodel. JAX allows for automatic differentiation and just-in-time compilation capabilities to speed up the parameterization of kinetic models. We show the robust capabilities of training kinetic models using this framework on a large collection of SBML models with different degrees of prior information on parameter initialization. Finally, we showcase the training framework implementation on a complex model of glycolysis. These results show that our framework can be used to fit large metabolic kinetic models efficiently and provides a strong platform for modeling biological systems.

Implementation

Implementation ofjaxkineticmodelis available as a Python package athttps://github.com/AbeelLab/jaxkineticmodel.

Author summary

Understanding how metabolism works from a systems perspective is important for many biotechnological applications. Metabolic kinetic models help in achieving understanding, but there construction and parametrization has proven to be complex, especially for larger metabolic networks. Recent success in the field of neural ordinary differential equations in combination with other mathematical/computational techniques may help in tackling this issue for training kinetic models. We have implemented a Python package namedjaxkineticmodelthat can be used to build, simulate and train kinetic models, as well as compatibility with the Systems Biology Markup Language. This framework allows for efficient training of kinetic models on time-series concentration data using a neural ordinary differential equation inspired approach. We show the convergence properties on a large collection of SBML models, as well as experimental data. This shows a robust training process for models with hundreds of parameters, indicating that it can be used for large-scale kinetic model training.
Food-entrainment of circadian timekeeping in the dorsal vagal complex
Authors: Chrobok Lukasz , Muir Charlotte , Kaur Tanya Chonkria , Veneri Iliana , Hitrec Timna , Ambler Michael , Pickering Anthony Edward , Piggins Hugh David
Published: December 2024

The dorsal vagal complex (DVC) is a multi-component brainstem satiety centre which has gained attention as a key target of anti-obesity pharmacotherapies. Our recent studies revealed its circadian timekeeping properties, with molecular and electrophysiological 24h rhythms persisting independently of the primary hypothalamic clock. However, the factors entraining these brainstem oscillators, and the downstream transcriptional targets of the DVC molecular clock remain unclear. Here, using fluorescentin situhybridisation, we demonstrate core clock gene expression in inhibitory and excitatory neuronal populations of the DVC, as well as in its output cholinergic vagal neurons. We further reveal that the molecular clock is associated with rhythmic expression of numerous neurotransmitter receptor genes in the DVCin vivo, with the phase of both clock and clock-controlled gene expression tightly regulated by meal timing. These findings uncover food-entrained circadian rhythms in the DVC and have important implications for clinical studies targeting brainstem satiety mechanisms.
Lipids modulate open probability of RyR1 under cryo-EM conditions
Authors: Li Chenyao , Efremov Rouslan G.
Published: December 2024

Ryanodine receptors (RyRs) are intracellular tetrameric ion channels responsible for Ca2+release from the sarcoplasmic and endoplasmic reticulum. Among the three known mammalian RyR isoforms, RyR1 is critical for muscle contraction and has been studied most extensively. The cytoplasm-exposed multidomain fragment of RyRs integrates multiple cellular signals that regulate channel gating and small deviations from the physiological open probability of RyRs leads to life-threatening diseases. While cryo-EM has been instrumental in revealing near-atomic details of RyR gating mechanisms, the open probability of RyR1 under cryo-EM conditions is notably lower than that observed in electrophysiological studies, complicating structural investigations of RyR1 gating modulation. Here, we present a cryo-EM study examining the open probability of RyR1 solubilized in CHAPS with varying lipid concentrations. We found that increasing lipid concentration from 0.001% to 0.05% raised the RyR1 open probability from 16 to 84%; however, RyR1 reconstituted into lipid nanodiscs remained closed. We modelled 72 lipid molecules in the map reconstructed at the highest lipid concentration. These findings demonstrate critical role of lipids in modulating RyR1 gating under cryo-EM conditions and suggest optimal lipid-mimetics for structural studies of RyR1 gating modulation.
Disruptions in Primary Visual Cortex Physiology and Function in a Mouse Model of Timothy Syndrome
Authors: Craddock Rosie , Tigaret Cezar M. , Sengpiel Frank
Published: December 2024

Timothy syndrome (TS) is a rare genetic disorder caused by mutations in theCACNA1Cgene which encodes the L-type calcium channel α-1 CaV1.2 subunit. While it is expressed throughout the body the most serious symptoms are cardiac and neurological. Classical TS1 and TS2 mutations cause prolonged action potentials (APs) in cardiomyocytes and in induced neurons derived from pluripotent stem cells taken from TS patients, but effects of TS mutations on neuronal function in vivo are not fully understood. TS is frequently associated with autistic traits, which in turn have been linked to altered sensory processing. Using the TS2-neo mouse model we analysed effects of the TS2 mutation on the visual system. We observed a widening of APs of pyramidal cells in ex vivo patch-clamp recordings and an increase in the density of parvalbumin positive (PV+) cells in the primary visual cortex. Neurons recorded extracellularly in vivo were less likely to respond to visual stimuli of low spatial frequency, but more likely to respond to visual stimuli of mid-to-high spatial frequency, compared to WT mice. These results point to a basic processing abnormality in the visual cortex of TS2-neo mice.
A continuation of the assembly of a G-quadruplex repair complex by the FANCJ DNA helicase
Authors: Campbell Laura , Lowran Kaitlin , Cismas Emma , Wu Colin G.
Published: December 2024

Nucleic acid sequences that are rich in guanines can form G-quadruplex (G4) structures, which can impede DNA replication or repair. The FANCJ helicase plays a role in maintaining genomic stability by facilitating DNA replication through regions of DNA that form G4 structures. This activity has been associated with an AKKQ motif in FANCJ and it is thought that this motif retains the ability to also target 8-oxoguanine-modified G4 (8oxoG4) structures. We hypothesize that the molecular recognition of FANCJ AKKQ to 8oxoG4s is dependent upon the position of DNA damage, sequence composition, and substrate stability. We previously demonstrated that reducing the loop length between guanine tetrads increased the affinity of FANCJ AKKQ when 8-oxoguanines (8oxoGs) were located at the first and fifth positions of the G4 structure. In this work, we use fluorescence spectroscopy to measure the affinities of a FANCJ AKKQ peptide for G4s formed by (GGGT)4, (GGGTT)4, and (TTAGGG)4. G4 conformations and thermal stability were determined via circular dichroism spectroscopy. We substituted 8oxoGs at the first (8oxo1), third (8oxo3), and fifth (8oxo5) positions of each G4 sequence and found that the most destabilized structures were (GGGT)48oxo1, (GGGTT)48oxo1, and (TTAGGG)48oxo5 in KCl. The most destabilized structures in NaCl were (GGGT)48oxo1, (GGGTT)48oxo5, and (TTAGGG)48oxo5. The binding affinities of FANCJ AKKQ differed for the distinct damage positions for (GGGT)4in KCl and for (TTAGGG)4in NaCl. These findings suggest that FANCJ AKKQ targets G4s and 8oxoG4s in a manner dependent upon sequence composition and damage position.