bluuebunny/crossref_metadata_2025 huggingface dataset:
Saponin-mediated and microwave-assisted biosynthesis of silver nanoparticles: preparations and anticancer assessment
Authors: Murugan Sesha Subramanian , Dalavi Pandurang Appana , Gupta Pramod K , Hur Won , Pillappan Ramkumar , Venkatesan Jayachandran , Seong Gi Hun
Published: September 2024

Silver nanoparticles have been extensively studied and used for biological and biomedical applications due to its antimicrobial properties. In this study, we have developed silver nanoparticles with saponin (S-AgNPs) using microwave-mediated methodology and physiochemically characterised and evaluated its anticancer potential. According to UV–visible spectroscopy, S-AgNPs exhibited a maximum absorption peak at a wavelength of 420 nm. DLS analysis revealed that S-AgNPs have an average diameter of around 133.8 ± 10 nm. HR-TEM analysis confirms the spherical morphology of S-AgNPs. Further, the anticancer effect of S-AgNPs was validated using A459 lung cancer cells by in vitro cell interaction tests such as the MTT assay, staining assay, and flow cytometry assay. The IC50 value of S-AgNPs against A549 cells was 30 μg ml−1, and Calcein-EtBr and Annexin V/PI staining results confirm the presence of apoptotic cells after treatment S-AgNPs. Hence, biosynthesized S-AgNPs can play a vital role in developing anticancer drugs for cancer treatment.
Initial data sets with dominant energy condition admitting no smooth DEC spacetime extension
Authors: Glöckle Jonathan
Published: September 2024

There are two versions of the dominant energy condition (=DEC): The original one for Lorentzian manifolds and an associated one for initial data sets. If a Lorentzian manifold satisfies DEC, then so does the induced initial set on any embedded spacelike hypersurface. In this article, we discuss the question of a potential converse of this: Is every DEC initial data set the induced one on a spacelike hypersurface within a suitably chosen DEC Lorentzian manifold? We provide an example showing that in general the answer is no if we require all structures to be smooth.
Spatiotemporal Forecasting of Opioid-Related Fatal Overdoses: Towards Best Practices for Modeling and Evaluation
Authors: Heuton Kyle , Kapoor Jyontika , Shrestha Shikhar , Stopka Thomas J , Hughes Michael C
Published: September 2024

To inform public health interventions, researchers have developed models to forecast opioid-related overdose mortality. These efforts often have limited overlap in the models and datasets employed, presenting challenges to assessing progress in this field. Furthermore, common error-based performance metrics, such as root mean squared error (RMSE), cannot directly assess a key modeling purpose: the identification of priority areas for interventions. We recommend a new intervention-aware performance metric, Percentage of Best Possible Reach (%BPR). We compare metrics for many published models across two distinct geographic settings, Cook County, Illinois and Massachusetts, assuming the budget to intervene in 100 census tracts out of 1000s in each setting. The top-performing models based on RMSE recommend areas that do not always reach the most possible overdose events. In Massachusetts, the top models preferred by %BPR could have reached 18 additional fatal overdoses per year in 2020-2021 compared to models favored by RMSE. In Cook County, the different metrics select similar top-performing models, yet other models with similar RMSE can have significant variation in %BPR. We further find that simple models often perform as well as recently published ones. We release open code and data for others to build upon.
Impact of Baseline SARS-CoV-2 Load in Plasma and Upper Airways on the Incidence of Acute Extrapulmonary Complications of COVID-19: A Multicentric, Prospective, Cohort Study
Authors: Jensen Tomas O , Harper Katrina , Gupta Shaili , Liu Sean T , Dharan Nila J , Baker Jason V , Pett Sarah L , Shaw-Saliba Kathryn , Esmail Aliasgar , Ho Minh Q , Almasri Eyad , Dewar Robin L , Lundgren Jens , Vock David M
Published: September 2024

Background

Extrapulmonary complications (EPCs) are common in patients hospitalized for coronavirus disease 2019 (COVID-19), but data on their clinical consequences and association with viral replication and systemic viral dissemination are lacking.

Methods

Patients hospitalized for COVID-19 and enrolled in the Therapeutics for Inpatients with COVID-19 (TICO) platform trial at 114 international sites between August 2020 and November 2021 were included in a prospective cohort study. We categorized EPCs into 39 event types within 9 categories and estimated their frequency through day 28 and their association with clinical outcomes through day 90. We analyzed the association between baseline viral burden (plasma nucleocapsid antigen [N-Ag] level and upper airway viral load) and EPCs, adjusting for other baseline factors.

Results

A total of 2625 trial participants were included in the study. Their median age was 57 years (interquartile range, 46–68 years), 57.7% were male, and 537 (20.5%) had ≥1 EPC. EPCs were associated with higher day-90 all-cause mortality rate (hazard ratio, 9.6 [95% confidence interval, 7.3–12.7]) after adjustment for other risk factors. The risk of EPCs increased with increasing baseline plasma N-Ag level (hazard ratio, 1.21 per log10 ng/L increase [95% confidence interval, 1.09–1.34]), and upper airway viral load (1.12 per log10 copies/mL increase [1.04–1.19), after adjustment for comorbid conditions, disease severity, inflammatory markers, and other baseline factors. Trial treatment allocation had no effect on EPC risk.

Conclusions

Systemic viral dissemination as evidenced by high plasma N-Ag level and high respiratory viral burden are associated with development of EPCs in COVID-19, which in turn are associated with higher 90-day mortality rates.
Competition and Industrial Policies: Complementary Action for EU Competitiveness
Authors: Piechucka Joanna , Sauri-Romero Lluis , Smulders Ben
Published: September 2024

This paper contributes to the current debate about competition and industrial policies, by illustrating their complementary role in fostering competitiveness and economic growth. Further market integration combined with effective competition policy can unleash the long-term competitive potential of EU firms. Effective competition in domestic markets contributes to the global competitiveness of firms, by incentivizing them to be more efficient and innovative. Preventing inefficient exercise of market power benefits final consumers as well as firms that have access to inputs of higher quality at lower costs. Pro-competitive industrial policies are required to realize the competitive potential of EU firms, notably in the areas of innovation, technological adoption, and decarbonization, characterized by externalities, miscoordination, public goods, and uncertainty. Similarly, public intervention is required to achieve greater economic resilience efficiently, while considering inevitable interdependencies in the global economy. A balance must be struck between avoiding harmful trade wars and supporting EU firms in a challenging international environment.
Frequentist Prediction Sets for Species Abundance using Indirect Information
Authors: Bersson Elizabeth , Hoff Peter D
Published: September 2024

Citizen science databases that consist of volunteer-led sampling efforts of species communities are relied on as essential sources of data in ecology. Summarising such data across counties with frequentist-valid prediction sets for each county provides an interpretable comparison across counties of varying size or composition. As citizen science data often feature unequal sampling efforts across a spatial domain, prediction sets constructed with indirect methods that share information across counties may be used to improve precision. In this article, we present a nonparametric framework to obtain precise prediction sets for a multinomial random sample based on indirect information that maintain frequentist coverage guarantees for each county. We detail a simple algorithm to obtain prediction sets for each county using indirect information where the computation time does not depend on the sample size and scales nicely with the number of species considered. The indirect information may be estimated by a proposed empirical Bayes procedure based on information from auxiliary data. Our approach makes inference for under-sampled counties more precise, while maintaining area-specific frequentist validity for each county. Our method is used to provide a useful description of avian species abundance in North Carolina, USA based on citizen science data from the eBird database.
Imprint of massive neutrinos on Persistent Homology of large-scale structure
Authors: Jalali Kanafi M H , Ansarifard S , Movahed S M S
Published: September 2024

Exploiting the Persistent Homology technique and its complementary representations, we examine the footprint of summed neutrino mass ($M_{\nu }$) in the various density fields simulated by the publicly available Quijote suite. The evolution of topological features by utilizing the superlevel filtration on three-dimensional density fields at zero redshift, reveals a remarkable benchmark for constraining the cosmological parameters, particularly $M_{\nu }$ and $\sigma _8$. The abundance of independent closed surfaces (voids) compared to the connected components (clusters) and independent loops (filaments), is more sensitive to the presence of $M_{\nu }$ for $R=5$ Mpc $h^{-1}$ irrespective of whether using the total matter density field (m) or cold dark matter + baryons field ($\mathrm{ \mathrm{cb}}$). Reducing the degeneracy between $M_{\nu }$ and $\sigma _8$ is achieved via Persistent Homology for the m field but not for the $\mathrm{cb}$ field. The uncertainty of $M_{\nu }$ at $1\sigma$ confidenc interval from the joint analysis of Persistent Homology vectorization for the m and $\mathrm{cb}$ fields smoothed by $R=5$ Mpc $h^{-1}$ at $z=0$ reaches 0.0152 and 0.1242 eV, respectively. Noticing the use of the three-dimensional underlying density field at $z=0$, the mentioned uncertainties can be treated as the theoretical lower limits.
Compliance Rate With Triage Test and Treatment for Participants Screening Positive in Cervical Cancer Screening Programs
Authors: Wang Minmin , Maimaitiming Mailikezhati , Bi Yanxin , Jin Yinzi
Published: September 2024

OBJECTIVE:

To assess the rates of adherence to triage testing after positive screening results and referral to treatment for precancerous lesions in global cervical cancer screening programs.

DATA SOURCES:

We searched three electronic databases (Medline, EMBASE, and Web of Science) for articles published in the English language from January 1, 2018, to December 31, 2023. We included studies reporting the compliance rate of triage testing and precancer treatment in cervical cancer screening programs. ClinicalTrials.gov was reviewed, and no more studies were identified.

METHODS OF STUDY SELECTION:

The combined search strategies identified 1,673 titles, of which 858 titles and abstracts were screened and 113 full-text articles were assessed for eligibility. A total of 33 studies met the inclusion criteria and were included in the meta-analysis.

TABULATION, INTEGRATION, AND RESULTS:

Thirty-three studies were included in the systematic review and meta-analysis. The average compliance rate for women screening positive was 77.1% for triage testing and 69.4% for referral to treatment. Compliance varied by country income level, screening guideline approach, and target population.

CONCLUSION:

The current compliance rate was lower than the 90% target set by the World Health Organization's global strategy to eliminate cervical cancer. Inadequate follow-up of participants screening positive revealed a gap between the screening program and clinical care.
Global burden of thyroid cancer in 2022: Incidence and mortality estimates from GLOBOCAN
Authors: Lyu Zhangyan , Zhang Yu , Sheng Chao , Huang Yubei , Zhang Qiang , Chen Kexin
Published: September 2024

Background:

Thyroid cancer (TC) is the most common malignancy of the endocrine system. This study aimed to assess the global distribution of TC incidence and mortality in 2022, as well as to predict the burden for the year 2050.

Methods:

Data from the GLOBOCAN 2022 database were used to analyze the age-standardized incidence and mortality rates of TC by sex, age group (<55 years and ≥55 years), country, world region, and level of Human Development Index (HDI) for 185 countries. The predicted incidence and mortality burden for 2050 was calculated based on demographic projections.

Results:

In 2022, an estimated 821,214 new TC cases and 47,507 TC-related deaths occurred worldwide. The age-standardized incidence rates (ASIRs) and age-standardized mortality rates (ASMRs) were higher in women (ASIR: 13.60 per 100,000; ASMR: 0.53 per 100,000) than in men (ASIR: 4.60 per 100,000; ASMR: 0.35 per 100,000). The ASIR in high HDI countries was approximately ten times higher than that in low HDI countries for both sexes, with relatively similar ASMR across regions. Among 185 countries, China had the largest number of TC cases (accounting for 56.77% of total cases) and TC-related deaths (accounting for 24.35% of global TC-related deaths), with the highest ASIR in men (13.30 per 100,000). Worldwide, approximately 64.63% of TC cases occurred in populations under 55 years old, while nearly 82.99% of TC-related deaths occurred in populations aged 55 years and above. If the rates stay the same as in 2022, it is projected that approximately 1,100,000 new TC cases and 91,000 TC-related deaths will occur in 2050, indicating a 34.15% and 89.58% increase, respectively.

Conclusions:

TC is a highly frequent cancer worldwide with disparities across regions, genders, and age groups. Our results provide light on the worldwide TC disease burden and facilitate regionally customized prevention measures.
Prophylactic Buried Dermal Flap: A Simple Method for Axillary Reconstruction after Lymph Node Dissection
Authors: Fallah Kasra N. , Ahmed Shahnur , Venardi Andrew S. , Hulsman Luci A. , Fisher Carla S. , Ludwig Kandice K. , Lester Mary E. , Hassanein Aladdin H.
Published: September 2024

Breast cancer–related lymphedema is characterized by progressive limb enlargement and occurs in up to 30% of breast cancer patients following axillary lymph node dissection (ALND). Immediate lymphatic reconstruction (ILR) is a preventative technique used to reduce lymphedema rates by performing lymphovenous anastomoses of disrupted afferent lymphatics. This study presents a novel method of axillary reconstruction following ALND using a buried dermal flap that provides local tissue with intact subdermal lymphatics to the axillary dead space. A single-center retrospective review was performed to assess breast cancer patients who underwent modified radical mastectomy without reconstruction between 2018 and 2023. Groups were divided into those who had ILR alone (group 1) and those who had buried dermal flap with attempted ILR (group 2). There were 31 patients included in this study: 18 patients in group 1 and 13 patients in group 2. Patient demographics, comorbidities, and breast cancer history were similar between the groups. There was no significant difference in the mean number of lymphovenous anastomoses performed (1.6 versus 1.7, P = 0.84). Mean operative time of 224.4 ± 51.9 minutes in group 1 was similar to 223.4 ± 30.4 minutes in group 2 (P = 0.95). We introduce a novel method of axillary reconstruction following ALND using a buried dermal flap that is inset into the axillary dissection space and over the area of ILR. We propose that it is an efficient accessory procedure to augment ILR by providing supplementary intact lymphatic channels to the area of lymphatic injury, while obliterating the axillary dead space.
Association Between Sports Team Participation and Sunburn Among U.S. High School Students, National Youth Risk Behavior Survey, 2021
Authors: Holman Dawn M. , Jones Sherry Everett , Cornett Kelly A. , Mouhanna Farah
Published: September 2024

Sunburn during adolescence increases a person's lifetime skin cancer risk. This study examines the association between sports team participation and sunburn prevalence among U.S. high school students. Using cross-sectional data from the 2021 National Youth Risk Behavior Survey, we compared sunburn prevalence among students who participated in one or more sports teams during the past 12 months to those who did not. Nationwide, 64.4% of high school students experienced one or more sunburns during the past 12 months, and 49.1% had played on one or more sports teams during the past 12 months. Sports team participation was associated with higher sunburn prevalence overall (adjusted prevalence ratio [aPR], 1.2; 95% CI [1.2, 1.3]) and among female (aPR, 1.2; 95% CI [1.2, 1.3]) and male (aPR, 1.2; 95% CI [1.1, 1.3]) students. Sunburn prevalence is higher among student athletes than those who do not participate on sports teams. Evidence-based organizational policies and practices are available to help keep student athletes sun-safe while allowing them to enjoy the benefits of sports participation. Future research could examine the contexts in which high school students experience sunburn and why student athletes are at an increased risk.
Laryngeal mask vs. laryngeal tube trial in paediatric patients (LaMaTuPe): a single-blinded, open-label, randomised-controlled trial
Authors: Katzenschlager Stephan , Mohr Stefan , Kaltschmidt Nikolai , Peterstorfer Franziska , Weilbacher Frank , Günther Patrick , Ries Markus , Weigand Markus A. , Popp Erik
Published: September 2024

Background

In hypoxemic children with difficult airway, or for minor elective procedures, the use of a supraglottic airway device may be preferred to endotracheal intubation, whether with a laryngeal mask or laryngeal tube. Second-generation laryngeal masks may offer a better safety profile. Whether they should be preferred to laryngeal tubes is unknown. This study aimed to compare the efficacy and safety of second-generation laryngeal masks and laryngeal tubes in children.

Methods

This randomised-controlled trial was conducted in a single university hospital in children <18 years undergoing elective anaesthesia in urology, minor paediatric surgery and gynaecology. Patients were 1 : 1 randomised to the laryngeal mask or laryngeal tube group. Children were allocated a second-generation laryngeal tube or a second-generation laryngeal mask as the primary airway device. The primary endpoint was insertion time. Secondary endpoints included first-attempt success, overall success and complications, which included hypoxia (SpO2 < 90%), laryngospasm, bronchospasm, aspiration and bleeding.

Results

In total, 135 patients were randomised, with 61 allocated to the laryngeal tube and 74 to the laryngeal mask group, with a median age of 5.4 and 4.9 years, respectively. Median insertion time was significantly longer in the laryngeal tube group (37 vs. 31 s; difference of medians: 6.0 s; 95% confidence interval: 0.0–13.0). The laryngeal tube had a significantly lower first-attempt (41.0%) and overall success rate (45.9%) than the laryngeal mask (90.5% and 97.3%, respectively). Those allocated to the laryngeal tube group had a higher ratio of complications (27.8%) compared to the laryngeal mask group (2.7%).

Conclusion

This randomised-controlled trial reported that in children undergoing elective anaesthesia, the use of a laryngeal tube was associated with a longer insertion time.
Evaluation of jaw pathologies of patients with medication-related osteonecrosis of the jaw using a computer program to assess the bone scan index: comparison of standardized uptake values with bone SPECT/CT
Authors: Shirai Ai , Ogura Ichiro
Published: September 2024

Objectives

The aim of this study is to investigate the jaw pathologies of patients with medication-related osteonecrosis of the jaw (MRONJ) using a computer program to assess the bone scan index (BSI), especially comparison of standardized uptake values (SUVs) with bone single-photon emission-computed tomography/computed tomography (SPECT/CT).

Methods

Sixty-three patients with MRONJ underwent bone SPECT/CT in this prospective study. BSI and high-risk hot spot as bone metastases in the patients with MRONJ were evaluated using a computer program for BSI that scanned SPECT/CT and automatically defined the data. The maximum and mean SUVs with SPECT/CT were obtained using commercially available software. Statistical analyses were performed by Pearson chi-square test, Mann–Whitney U-test, or one-way analysis of variance with Tukey’s honestly significant difference test. A P value lower than 0.05 was considered statistically significant.

Results

The maximum and mean SUVs for a high-risk hot spot of the jaw with MRONJ [28.2 ± 10.2 and 11.7 ± 3.8; n = 6 (6/63 : 9.5%)] were significantly higher than those for a low-risk hot spot [18.5 ± 6.4 and 6.2 ± 1.9; n = 23 (23/63 : 36.5%)] and no-risk hot spot [14.2 ± 9.4 and 5.3 ± 5.1; n = 34 (34/63 : 54.0%)], respectively.

Conclusion

The computer program for BSI indicated that 9.5% of the jaw with MRONJ were false positive of bone metastases. The study suggests that high-risk hot spots of the jaw with MRONJ depend on the SUVs.
Epidemiology of Chronic Hepatitis B Virus Infection, Alameda County, California, 2017-2021
Authors: Yette Emily , Marusinec Rachel , Conlon Craig , Pham Thi T. Hang , Toy Mehlika , So Samuel , Wong Robert J. , Chitnis Amit S.
Published: September 2024

Context

In the United States, chronic hepatitis B (CHB) virus infection predominantly affects ethnic minorities and vulnerable populations.

Objective

We analyzed surveillance data to describe CHB epidemiology to guide hepatitis B virus (HBV) elimination efforts in Alameda County.

Design

Persons with CHB during 2017-2021 were identified by ≥2 positive HBV tests (ie, HBsAg, HbeAg, and HBV DNA) ≥180 days apart using data from California Reportable Disease Information Exchange. Persons with CHB were stratified by age, race/ethnicity, zip code-based Healthy Places Index (HPI), and federally designated Medically Underserved Areas (MUA). Comparisons of reported CHB prevalence between groups utilized z test; comparisons between MUA regions utilized chi-square testing.

Results

A total of 8122 persons with CHB were identified; reported 5-year CHB prevalence was 0.53% (95% confidence interval: 0.52%–0.54%). Reported CHB 5-year prevalence was significantly higher among persons aged 50 to 69 years old than persons aged 30 to 49 years old (0.99%, 0.78%; P < .001) and Asians, Native Hawaiian/Pacific Islanders, African Americans compared to Whites (1.22%, 0.56%, 0.18%, 0.06%; P < .001). Reported CHB 5-year prevalence in the 2 lowest and most disadvantaged HPI quartiles was significantly higher than the 2 highest quartiles (0.55%, 0.68%, 0.37%, 0.42%; P < .001). The 1918 persons with CHB in MUA, compared to 5859 non-MUA persons, were significantly more likely to be African American (7%, 3%; P < .001) and from the lowest HPI quartile (79%, 19%; P < .001).

Conclusions

Reported CHB 5-year prevalence in Alameda County was 1.5 times the national prevalence estimates, and reported prevalence was highest among Asians and persons in more disadvantaged areas. Analysis of local CHB surveillance data can guide public health efforts toward HBV elimination.
Decompressive nerve surgery associated with low diabetic foot ulcer rate and high-risk bias: A systematic review and meta-analysis
Authors: Louca Milton , Meares Charles , Dusseldorp Joseph R.
Published: September 2024

Background:

Diabetic sensorimotor polyneuropathy (DSPN) occurs in 50% of diabetes mellitus (DM) patients. Up to 70% of DM patients incur diabetic foot ulcer(s) (DFU). Of those with DSPN, 20% develop DFU and medical therapy remains challenging. Decompression nerve surgery (DNS) purportedly improves DSPN and DFU. Currently, there is no accurate, pooled DFU incidence post-DNS. Thus, this systematic review meta-analyses DFU incidence post-DNS. Given the 60% global DFU incidence, we hypothesised a lower, pooled DFU incidence following DNS.

Methods:

Two authors searched six databases (MEDLINE/PubMed/Web of Science/Embase/Scopus/Cochrane/Google Scholar) to July 2023 for DNS clinical studies. Primary tracked outcomes were new and recurrent DFU incidence post-DNS. Inclusion criteria: clinical studies, adult DM patients, DNS of tibial nerve(s) at minimum, three-month minimum follow-up, and reported new/recurrent DFU incidence post-DNS. Exclusion criteria: non-clinical, non-human studies. GRADE and MINORS instrument(s) evaluated evidence. With random-effects model, DFU incidence was meta-analysed.

Results:

For inclusion, 1074 studies were identified and 208 screened. Thirteen studies yielded 2466 and 540 new and recurrent patients with DFU incidence(s) of 1% and 5%, respectively. Primary studies had low-level evidence and high-risk bias, including selection bias using Cochrane Collaboration Bias Risk Tool. A sub-analysis of sample size (new:0% and recurrent:2%) and follow-up length (new:1% and recurrent:7%) produced similar results. Additional analyses based on further co-variables was precluded because of incomplete primary study data.

Conclusions:

Overall, despite low DFU incidence post-DNS, clinical studies provide too low-level evidence and high-risk bias for any recommendations. Future randomized, control trials may validate DNS for DFU management.
Association of cardiovascular disease risk with liver steatosis and fibrosis in people with HIV in low- and middle-income countries
Authors: Kuniholm Mark H. , Murenzi Gad , Shumbusho Fabienne , Brazier Ellen , Plaisy Marie K. , Mensah Ephrem , Wandeler Gilles , Riebensahm Carlotta , Chihota Belinda V. , Samala Niharika , Diero Lameck , Semeere Aggrey S. , Chanyachukul Thida , Borse Rohidas , Nguyen Dung T.H. , Perazzo Hugo , Lopez-Iniguez Alvaro , Castilho Jessica L. , Maruri Fernanda , Jaquet Antoine
Published: September 2024

Objective:

The aim of this study was to understand the relationship between cardiovascular disease (CVD) risk and liver steatosis and fibrosis among people with HIV (PLWH) at least 40 years of age on antiretroviral therapy (ART) in low and middle-income countries (LMIC).

Design:

We used cross-sectional behavioral and clinical data collected during study enrollment visits in 2020–2022 for the Sentinel Research Network of International epidemiology Databases to Evaluate AIDS (SRN of IeDEA).

Methods:

Ten-year CVD risk was calculated using 2019 WHO nonlaboratory and laboratory models. Transient elastography was used to assess liver disease. Presence of steatosis and significant fibrosis were defined by controlled attenuation parameter (CAP) at least 248 dB/m and liver stiffness measurement (LSM) at least 7.1 kPa, respectively. Participants with viral hepatitis, hazardous alcohol consumption, and unsuppressed HIV viral load were excluded from the analysis. Logistic regression was used to estimate odds ratios, adjusting for study site, CD4+ T cell count, stavudine and didanosine exposure, and in models stratified by sex and geographic region.

Results:

There were 1750 participants from nine LMIC. Median CVD risk was 3% for both nonlaboratory and laboratory-based models. Adjusted odds ratios (ORs) for steatosis and significant fibrosis associated with laboratory CVD risk (≥10 vs. <5%) were OR = 1.83 [95% confidence interval (95% CI) = 1.21–2.76; P = 0.004] and OR = 1.62 (95% CI = 0.85–3.07; P = 0.14), respectively. Associations of CVD risk with steatosis were stronger in men and among participants at study sites outside Africa.

Conclusion:

Higher CVD risk was associated with steatosis but not with significant fibrosis in PWH in our LMIC cohort.
To PE or Not to PE
Authors: Ali Aamir , Gopal Akilan , Lu Yang
Published: September 2024

A 41-year-old woman with metastatic breast cancer presented with dyspnea, hypoxia, and elevated d-dimer. Perfusion planar imaging followed by SPECT/CT of the chest was performed due to the patient’s iodinated contrast allergy. Planar images showed multiple pleural-based wedge-shaped defects concerning for bilateral pulmonary embolism (PE). Perfusion SPECT/CT of the chest confirmed multiple areas of perfusion defects but was considered negative for PE and attributed the perfusion defects to the compressing of pulmonary vasculature from metastatic lymph nodes and pulmonary masses. Given the high pretest probability of PE, a CT pulmonary angiogram was performed after premedication for contrast allergy confirming absence of PE.
The first comparative metagenomic analysis of diarrheal and non-diarrheal gut microbiome leading to the identification of prospective prognostic markers and probiotics to protect from diarrhea: A Brief Report
Authors: De Rituparna , Kanungo Suman , Mukhopadhyay Asish K. , Dutta Shanta
Published: September 2024

Introduction: Diarrhea is a leading contributor of mortality. Its disease burden can be assuaged using enhanced prognostics and therapeutics. A cross-sectional gut microbiome analysis  of  non-diarrheal  and   diarrheal  fecal  samples was conducted to meet the goals of the Global Action Plan for Pneumonia and Diarrhea.
Hypothesis: Next-generation Sequencing as a tool for epidemiological surveillance helps in the comparison of structural diversity of the gut microbiome of diarrheal and non-diarrheal samples and can identify prognostic and therapeutic candidates. Aim: The pilot study was designed to identify taxa that are enriched in non-diarrheal samples and to predict gut microbial interactions. Methodology: 16SrRNA amplicon sequencing  and  analysis  were deployed for taxonomic  profiling  and  abundance  interpretation  of  OTUs (Operational Taxonomic Units). Results: The findings suggested significant  differences  in structural composition between  the  two  groups. Firmicutes was the  most  abundant  phylum in most samples. B/F ratio was consistently <1 in all diarrheal samples. Proteobacteria  was    more  abundant  in    diarrheal  samples.  Prevotellaceae  was  the  most  abundant  family  in  non-diarrheal  samples.  Streptococcaceae  was  the  most  abundant  family  in  60%  diarrheal  samples.Where  Streptococcaceae  was  suppressed,  Bacteroideaceae  and  Nocardeaceae  were  the  most  abundant.    In  non-diarrheal  samples  where  Bifidobacteriaceae  was  the  most  abundant  other  families  were significantly low.  A  negative  correlation  was  observed  between  Prevotellaceae  and  Bacteroideaceae  in    non-diarrheal  samples.  Prevotella  copri  was  the  most  abundant  species  in  70%  non-diarrheal  samples  and  was  significantly  suppressed  in  diarrheal  samples.  Proteus  mirabilis  was  identified  in  all  the  non-diarrheal  samples  and  were  absent in  diarrheal  samples.  Conclusion: The OTUs  associated  with  diarrheal  dysbiosis  can  serve  as  prognostic  markers.  This is the first report on the comparative analysis of diarrheal and non-diarrheal microbiome.  The study addressed  gut microbiome dysbiosis from the context that can lead to the development of prognostic markers and probiotics for protecting the endemic population from diarrhea and help in reaching Sustainable Development Goals 2 and 3.
Liquid–liquid phase inclusion bodies in acute and persistent parainfluenaza virus type 5 infections
Authors: Wignall-Fleming E. B. , Carlos T. S. , Randall R. E.
Published: September 2024

Cytoplasmic inclusion bodies (IBs) are a common feature of single-stranded, non-segmented, negative-strand RNA virus (Mononegavirales) infections and are thought to be regions of active virus transcription and replication. Here we followed the dynamics of IB formation and maintenance in cells infected with persistent and lytic/acute variants of the paramyxovirus, parainfluenza virus type 5 (PIV5). We show that there is a rapid increase in the number of small inclusions bodies up until approximately 12 h post-infection. Thereafter the number of inclusion bodies decreases but they increase in size, presumably due to the fusion of these liquid organelles that can be disrupted by osmotically shocking cells. No obvious differences were observed at these times between inclusion body formation in cells infected with lytic/acute and persistent viruses. IBs are also readily detected in cells persistently infected with PIV5, including in cells in which there is little or no ongoing virus transcription or replication. In situ hybridization shows that genomic RNA is primarily located in IBs, whilst viral mRNA is more diffusely distributed throughout the cytoplasm. Some, but not all, IBs show incorporation of 5-ethynyl-uridine (5EU), which is integrated into newly synthesized RNA, at early times post-infection. These results strongly suggest that, although genomic RNA is present in all IBs, IBs are not continuously active sites of virus transcription and replication. Disruption of IBs by osmotically shocking persistently infected cells does not increase virus protein synthesis, suggesting that in persistently infected cells most of the virus genomes are in a repressed state. The role of IBs in PIV5 replication and the establishment and maintenance of persistence is discussed.
Geographic characterization of RPE structure and lipid changes in the PEX1-p.Gly844Asp mouse model for Zellweger spectrum disorder
Authors: Omri Samy , Argyriou Catherine , Pryce Rachel , Di Pietro Erminia , Chaurand Pierre , Braverman Nancy
Published: September 2024

Peroxisome Biogenesis Disorders-Zellweger Spectrum (PBD-ZSD) are a heterogenous group of autosomal recessive disorders caused by defects inPEXgenes whose proteins are required for peroxisome assembly and function. Peroxisomes are ubiquitous organelles that play a critical role in complex lipid metabolism. Dysfunctional peroxisomes in ZSD cause multisystem effects, with progressive retinal degeneration (RD) leading to childhood blindness being one of the most frequent clinical findings. Despite progress in understanding the role of peroxisomes in normal cellular functions, much remains unknown about how their deficiency causes RD, and there is no treatment. To study RD pathophysiology in this disease, we used the knock-in PEX1-p.GlyG844Asp (G844D) mouse model of milder ZSD, which represents the common human PEX1-p.Gly843Asp allele. We previously reported diminished retinal function, functional vision, and neural retina structural defects in this model. Beyond the neural retina, structural defects in retinal pigment epithelium (RPE) have been reported in ZSD patients and murine models with single peroxisome enzyme deficiency, suggesting that RPE degeneration may contribute to overall RD progression in this disease. Here, we investigate the RPE phenotype in our PEX1-G844D mouse model, observing morphological, inflammatory, and lipid changes at 1, 3, and 6 months of age. We report that RPE cell degeneration appears at 3 months of age and worsens with time, starts in the dorsal pole, and is accompanied by subretinal inflammatory cell infiltration. We match these events with lipid remodelling using imaging mass spectrometry which allowed regional analysis specific to the RPE cell layer. We identified 47 lipid alterations that precede structural changes, 10 of which are localized to the dorsal pole. 32 of these lipid alterations persist to 3 months, with remodelling of the lipid signature at the dorsal pole. 14 new alterations occur concurrent with histological changes. Changes in peroxisome-dependent lipids detected by liquid chromatography tandem mass spectrometry (reduced docosahexanoic acid and increased very long chain lysophosphatidylcholines) are exacerbated over time. This study represents the first characterization of RPE in any animal model of ZSD, and the firstin situlipid analysis in any peroxisome-deficient tissue. Our findings reveal candidate lipid drivers that could be targeted to alleviate RD progression in ZSD, as well as candidate biomarkers that could be used to evaluate retinopathy progression and response to therapy.
Association between maternal depressive symptoms and hair cortisol concentration during pregnancy with corpus callosum integrity in newborns
Authors: Mariani Wigley Isabella L.C , Mustonen Paula , Karlsson Linnea , Nolvi Saara , Scheinin Noora M , Kortesluoma Susanna , Pastore Massimiliano , Tervahartiala Katja , Coimbra Bárbara , Rodrigues Ana João , Sousa Nuno , Karlsson Hasse , Tuulari Jetro J
Published: September 2024

Background

Maternal prenatal depressive symptoms are linked to neurodevelopmental impairments in offspring. Maternal cortisol levels are hypothesized to moderate this association, but its relationship with depressive symptoms is inconsistent. This study examined how maternal prenatal depressive symptoms and cortisol levels predict infant brain development, focusing on neonatal corpus callosum (CC) integrity.

Methods

Using data from the FinnBrain Birth Cohort Study, we analyzed 37 mother-infant dyads. MRI data were collected from 2 to 5 weeks old infants, and DTI imaging estimated fractional anisotropy (FA) in CC regions (Genu, Body, and Splenium). Maternal cortisol levels were assessed through hair cortisol concentration (HCC) from a 5cm hair segment, reflecting cortisol over the last five months of pregnancy. A factor score of maternal depressive symptoms was computed from EPDS questionnaire data collected at gestational weeks 14, 24, and 34. We employed multivariate regression models with a Bayesian approach for statistical testing, controlling for maternal and infant attributes.

Results

Results indicated that maternal prenatal depressive symptoms and HCC interact negatively in predicting infants’ FA across all CC regions. Infants exposed to high prenatal depressive symptoms and low HCC (1 SD below the mean) showed higher FA in all CC regions.

Conclusions

These findings highlight the complex dynamics between maternal prenatal cortisol levels and depressive symptoms, revealing a nuanced impact of those factors on the structural integrity of infants’ CC.
Decidual natural killer cells promote extravillous trophoblast developmental pathways: evidence from trophoblast organoid co-cultures
Authors: Zych Morgan , Lo Natalie , Patton Kate A , Wang Kewei , Cox Brian J
Published: September 2024

The placenta an essential extraembryonic organ that supports the fetus throughout gestation. The interactions between the placenta and the maternal immune system during the first trimester have not been wholly characterized despite their close physical association and hemi-allogeneic relationship. The most abundant type of immune cell in the uterus in the first trimester is the decidual natural killer cell (dNK). Despite their name, dNKs play supportive roles during pregnancy by remodelling uterine spiral arteries. We present evidence suggesting that the matrix metalloproteinases (MMPs) that dNKs secrete to promote this remodelling also drive placental development. This study used a novel co-culture system of dNKs and trophoblast organoids, which are mini-organs representing two to three different cell types of the human placenta. We found that co-cultures for one week led to significant (p=0.020) increases in the organoid area. We also observed significant decreases in trophoblast stemness markers and upregulation of gene sets associated with extravillous trophoblast (EVT) development through bulk RNA sequencing and immunohistochemical examinations. These changes were accompanied by significant (p<0.001) increases in collagen subunit gene expression in the organoids, with simultaneous significant decreases (p<0.001) in the proportion of organoid area occupied by collagen as determined through Massons Trichrome. Cultures containing dNKs also contained significantly higher MMP1, 3, 9, and 10 levels in their culture media, each of which can break down collagen. These findings demonstrate that dNKs promote changes concordant with trophoblast differentiation towards EVTs and villous branching morphogenesis.
Synaptic inhibition in the accessory olfactory bulb regulates pheromone location learning and memory
Authors: Marathe Shruti D. , Abraham Nixon M.
Published: September 2024

Pheromone signaling is pivotal in driving social and reproductive behaviors of rodents. Learning and memorizing the pheromone locations involve olfactory subsystems. To study the neural basis of this behavior, we trained female heterozygous knockouts of GluA2 (AMPAR subunit) and NR1 (NMDAR subunit), targeting GAD65 interneuron population, in a pheromone place preference learning assay. We observed memory loss of pheromone locations on early and late recall periods, pointing towards the possible role of ionotropic glutamate receptors (iGluRs), and thereby the synaptic inhibition in pheromone location learning. Correlated changes were observed in the expression levels of activity-regulated cytoskeletal (Arc)protein, which is critical for memory consolidation, in the associated brain areas. Further, to probe the involvement of main olfactory bulb (MOB) and accessory olfactory bulb (AOB) in pheromone location learning, we knocked out NR1 and GluA2 from MOB and/or AOB neuronal circuits by stereotaxic injection of Cre-dependent AAV5 viral particles. Perturbing the inhibitory circuits of MOB and AOB & AOB-alone resulted in the loss of pheromone location memory. These results confirm the role of iGluRs and the synaptic inhibition exerted by the interneuron network of AOB in regulating learning and memory of pheromone locations.
Quantification of electron transport-related oxidative signals by time and wavelength-resolved redox biosensors and chlorophyll fluorescence
Authors: Hipsch Matanel , Lampl Nardy , Lev Raz , Rosenwasser Shilo
Published: September 2024

Reductive and oxidative signals transmitted from the photosynthetic electron chain to target proteins through the redox signaling network are key regulators of carbon assimilation and downstream metabolism. However, despite their crucial role in activating and inhibiting photosynthetic activity, their relation to photosynthetic efficiency is hardly quantified due to the methodological gap between traditional spectroscopic approaches for investigating photosynthesis and biochemical analyses used in the redox regulation field. Here, we simultaneously quantified redox signals and photosynthetic activity by exploring time and wavelength-resolved fluorescence spectra that capture biosensor and chlorophyll fluorescence signals. Using a set of potato plants expressing genetically encoded redox biosensors, we demonstrated how reductive and oxidative signals are amplified with elevated light intensities and revealed the tight connection between electron transport rate (ETR) and the generation of peroxiredoxin-related oxidative signals. These results demonstrate how full spectrum analysis can pave the way for the integration of genetically encoded biosensors in photosynthesis research and demonstrate light-dependent activation of inhibitory oxidative signals in major crop plants.
Widespread naturally variable human exons aid genetic interpretation
Authors: Jacobs Hannah , Gorissen Bram L. , Guez Jeremy , Kanai Masahiro , Finucane Hilary K. , Karczewski Konrad J. , Burge Christopher B.
Published: September 2024

Most mammalian genes undergo alternative splicing. The splicing of some exons has been acquired or lost in specific mammalian lineages, but differences in splicing within the human population are poorly characterized. Using GTEx tissue transcriptomes from 838 individuals, we identified 56,415 exons which are included in mRNAs in some individuals but entirely excluded from others, which we term “naturally variable exons” (NVEs). NVEs impact three quarters of protein-coding genes, occur at all population frequencies, and are often absent from reference annotations. NVEs are more abundant in genes depleted of genetic loss-of-function mutations and aid in the interpretation of causal genetic variants. Genetic variants modulate the splicing of many NVEs, and 5’UTR and coding-region NVEs are often associated with increased and decreased gene expression, respectively. Together, our findings characterize abundant splicing variation in the human population, with implications for a range of human genetic analyses.
Adaptive protein synthesis in genetic models of copper deficiency and childhood neurodegeneration
Authors: Lane Alicia R. , Scher Noah E. , Bhattacharjee Shatabdi , Zlatic Stephanie A. , Roberts Anne M. , Gokhale Avanti , Singleton Kaela S. , Duong Duc M. , McKenna Mike , Liu William L. , Baiju Alina , Moctezuma Felix G Rivera , Tran Tommy , Patel Atit A. , Clayton Lauren B. , Petris Michael J. , Wood Levi B. , Patgiri Anupam , Vrailas-Mortimer Alysia D. , Cox Daniel N. , Roberts Blaine R. , Werner Erica , Faundez Victor
Published: September 2024

Rare inherited diseases caused by mutations in the copper transportersSLC31A1(CTR1) orATP7Ainduce copper deficiency in the brain, causing seizures and neurodegeneration in infancy through poorly understood mechanisms. Here, we used multiple model systems to characterize the molecular mechanisms by which neuronal cells respond to copper deficiency. Targeted deletion of CTR1 in neuroblastoma cells produced copper deficiency that was associated with a metabolic shift favoring glycolysis over oxidative phosphorylation. Proteomic and transcriptomic analysis of CTR1 KO cells revealed simultaneous upregulation of mTORC1 and S6K signaling and reduced PERK signaling. Patterns of gene and protein expression and pharmacogenomics show increased activation of the mTORC1-S6K pathway as a pro-survival mechanism, ultimately resulting in increased protein synthesis. Spatial transcriptomic profiling ofAtp7aflx/Y:: Vil1Cre/+mice identified upregulated protein synthesis machinery and mTORC1-S6K pathway genes in copper-deficient Purkinje neurons in the cerebellum. Genetic epistasis experiments inDrosophilademonstrated that copper deficiency dendritic phenotypes in class IV neurons are partially rescued by increased S6k expression or 4E-BP1 (Thor) RNAi, while epidermis phenotypes are exacerbated by Akt, S6k, or raptor RNAi. Overall, we demonstrate that increased mTORC1-S6K pathway activation and protein synthesis is an adaptive mechanism by which neuronal cells respond to copper deficiency.

Significance

Copper deficiency is present in rare conditions such as Menkes disease and CTR1 deficiency and in more common diseases like Alzheimer’s. The mechanisms of resilience and ultimate susceptibility to copper deficiency and associated pathology in the brain remain unknown.

We demonstrate that in a human cell line,Drosophila, and the mouse cerebellum, copper-deficient neuronal cells exhibit increased protein synthesis through mTORC1 activation and decreased PERK (EIF2AK3) activity.

Upregulation of protein synthesis facilitates resilience of neuronal cells to copper deficiency, including partial restoration of dendritic arborization. Our findings offer a new framework for understanding copper deficiency-related pathology in neurological disorders.
Spontaneously regenerative corticospinal neurons in mice
Authors: Fait Benjamin W , Cotto Bianca , Murakami Tatsuya C. , Hagemann-Jensen Michael , Zhan Huiqing , Freivald Corinne , Turbek Isadora , Gao Yuan , Yao Zizhen , Way Sharon W. , Zeng Hongkui , Tasic Bosiljka , Steward Oswald , Heintz Nathaniel , Schmidt Eric F
Published: September 2024

The spinal cord receives inputs from the cortex via corticospinal neurons (CSNs). While predominantly a contralateral projection, a less-investigated minority of its axons terminate in the ipsilateral spinal cord. We analyzed the spatial and molecular properties of these ipsilateral axons and their post-synaptic targets in mice and found they project primarily to the ventral horn, including directly to motor neurons. Barcode-based reconstruction of the ipsilateral axons revealed a class of primarily bilaterally-projecting CSNs with a distinct cortical distribution. The molecular properties of these ipsilaterally-projecting CSNs (IP-CSNs) are strikingly similar to the previously described molecular signature of embryonic-like regenerating CSNs. Finally, we show that IP-CSNs are spontaneously regenerative after spinal cord injury. The discovery of a class of spontaneously regenerative CSNs may prove valuable to the study of spinal cord injury. Additionally, this work suggests that the retention of juvenile-like characteristics may be a widespread phenomenon in adult nervous systems.