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The objective of this observational study was to estimate partial direct costs of dry cow antibiotic therapy (DCT) protocols used on 37 large dairy herds in Wisconsin and to estimate the potential monetary savings and reduction in antimicrobial usage (AMU) if selective DCT was used. Partial direct costs of DCT were calculated using costs of intramammary (IMM) antimicrobials and teat sealants. Data were retrospectively collected on 37 large dairy farms for a period of 1 yr and included the total number of cows dried off, types of IMM antimicrobial used, and product prices (obtained from farm invoices). A single farm visit was performed to verify data. Clinical mastitis (CM) and SCC history across lactation were used as the criteria to identify cows eligible to receive only teat sealants (no antibiotic DCT) based on adoption of a hypothetical selective DCT program. Descriptive statistics were performed using PROC MEANS to summarize continuous herd and cow characteristics. Differences in costs among IMM antibiotic products and eligibility to not receive antibiotics at dry-off by parity were analyzed using ANOVA. Differences in milk yield at the last test-day and DIM at dry-off based on eligibility for selective DCT were analyzed using PROC MIXED. A total of 35,691 cows were dried off across all herds (n = 37) and most of the herds used IMM antibiotic DCT at dry-off in most of the cows. Teat sealant was used as part of the dry-off protocol in all but 3 herds. Of the enrolled farms, 30 used blanket antibiotic DCT in all quarters of all cows and 7 herds used selective DCT with no administration of antibiotics given to 0.8% to 58% of the dry cows within the herd. Across all farms, the average cost of products given per dried cow was $19.57 ± 0.64 (mean ± SE) and ranged from $8.72 to $24.04. As expected, the cost per dried cow was greater ($23.45 ± $0.38) in herds that used higher cost IMM antibiotics as compared with herds that used lower cost IMM antibiotics ($16.64 ± $0.40). When using an algorithm based on udder health records to hypothetically select cows that would be eligible to receive teat sealants only (no antibiotic DCT), eligibility ranged from 27.3% to 93.3% within-herds and varied by parity, milk yield at last test-day, and DIM at dry-off. If a selective DCT program based on udder health records was used, an overall reduction of $5.37 (27% of total costs) per dry cow would be expected. Likewise, adoption of selective DCT based on udder health records would reduce AMU at dry-off by approximately 51%. However, neither of these estimates included potential adverse health complications (such as increased CM) that can occur if selective DCT programs are not effectively performed. Variations in partial direct costs at dry-off were observed among herds based on treatment protocols. In herds that have good udder health management and contagious mastitis pathogens controlled, adoption of selective DCT based on SCC and history of CM can reduce AMU and partial direct costs of dry cow management.

ABSTRACT: Negative associations of health disorders with reproductive performance, often measured with pregnancy per AI or the risk of pregnancy loss, have been demonstrated extensively. Most studies investigated common clinical diseases but did not include subclinical disorders comprehensively. They often evaluated cows subjected to hormonal synchronization protocols for timed AI, limiting the ability to understand how disease may affect spontaneous reproductive function, which is essential for targeted management programs with selective hormonal intervention. It is plausible that metabolic and inflammatory disorders have short- and long-term detrimental effects on different features of reproductive function that result in or contribute to reduced fertility. These may include: (1) re-establishment of endocrine function to promote follicular growth and first ovulation postpartum, (2) corpus luteum (CL) function, (3) estrus expression, and (4) uterine environment, fertilization, and embryonic development. In this narrative literature review, we discuss insights and knowledge gaps linking health disorders with these processes of reproductive function. A growing set of observational studies with adequate internal validity suggest that these outcomes may be affected by metabolic and inflammatory disorders that are common in the early postpartum period. A better characterization of these risk factors in multisite studies with greater external validity is warranted to develop decision-support tools to identify subgroups of cows that are more or less likely to be successful in targeted reproductive management programs.

Lung cancer, highly prevalent and the leading cause of cancer-related death globally, persists as a significant challenge due to the lack of definitive tumor markers for early diagnosis and personalized therapeutic interventions. Recently, extracellular vesicles (EVs), functioning as natural carriers for intercellular communication, have received increasing attention due to their ability to traverse biological barriers and deliver diverse biological cargoes, including cytosolic proteins, cell surface proteins, microRNA, lncRNA, circRNA, DNA, and lipids. EVs are increasingly recognized as a valuable resource for non-invasive liquid biopsy, as well as drug delivery platforms, and anticancer vaccines for precision medicine in lung cancer. Herein, given the diagnostic and therapeutic potential of tumor-associated EVs for lung cancer, we discuss this topic from a translational standpoint. We delve into the specific roles that EVs play in lung cancer carcinogenesis and offer a particular perspective on how advanced engineering technologies can overcome the current challenges and expedite and/or enhance the translation of EVs from laboratory research to clinical settings.

ABSTRACT: Our objective was to investigate the effects of intravenous (IV) or intrauterine (IU) lipopolysaccharide (LPS) challenge at 5 or 40 d postpartum (DPP) on clinical signs, systemic and uterine inflammation, dry matter intake (DMI), and milk yield (MY). Holstein cows at 5 DPP (n = 23) or at 40 DPP (n = 24) were blocked by parity and randomly assigned to 1 of 3 treatments: (1) IV-LPS (0.0625 μg/kg BW [5 DPP] or 0.1 μg/kg BW [40 DPP] over 1h), (2) IU-LPS (100 μg [5 DPP] or 300 μg [40 DPP] in 20 mL of saline), or (3) 20 mL of saline IU (IU-SAL; same for 5 and 40 DPP). The proportion of polymorphonuclear (PMN) cells was measured by endometrial cytology at d −1, 1, 4, and 7 relative to treatment. Blood haptoglobin (Hp), serum amyloid A (SAA), and LPS-binding protein (LBP), DMI, and MY were measured from d −1 through d 7. Data were analyzed separately for each DPP group in multivariable linear regression models accounting for repeated measures. Both DPP groups showed increases in rectal temperature and heart and respiratory rates, and decrease in rumination rate following IV-LPS, but not following IU-LPS. At 5 DPP, endometrial PMN proportion was similar in IU-LPS and IU-SAL. Serum Hp was unaffected by LPS challenge, SAA was greater in IV-LPS from 12 h to 24 h after challenge, and LBP was greater in IV-LPS from 8 h to 24 h. At 40 DPP, PMN was greater in IU-LPS (37 ± 4%) than in IU-SAL (15 ± 4%) 1 d after LPS challenge. Serum Hp was greater from 24 h to 72 h after challenge in IV-LPS than in the other groups, SAA was greater in IV-LPS from 6 h to 48 h, and LBP was greater in IV-LPS from 8 h to 24 h. At both 5 and 40 DPP, treatment did not affect DMI, but MY was lesser in IV-LPS cows at 12 h and 24 h than in IU-SAL or IU-LPS. The IV-LPS challenge resulted in more pronounced changes in clinical signs and acute phase protein (APP) concentrations than IU-LPS or IU-SAL at 40 DPP, but more subtle or inconsistent changes at 5 DPP. These may be due to the different doses of LPS used at 5 and 40 DPP or possibly due to the high variation in baseline clinical signs and APP observed in all groups at 5 DPP. The IU-LPS increased uterine PMN 1 d after challenge at 40 DPP but not at 5 DPP. At each time, IU-LPS did not produce changes in clinical signs or markers of systemic inflammation.

ABSTRACT: The objective of this prospective cohort study was to determine if progesterone (P4) profiles differed between dairy cows with or without inflammatory disorders early postpartum. A total of 708 cows from 2 commercial herds were enrolled 3 wk before parturition and examined for clinical health disorders (difficult calving, retained placenta, metritis, displaced abomasum, mastitis, or lameness) until 5 wk postpartum. Serum haptoglobin (Hp) was measured in blood at 2 and 6 DIM (range ±2 d); metritis was assessed at 4, 8, 11, and 15 DIM; and purulent vaginal discharge and endometritis (≥6% PMN in endometrial cytology sampled by cytobrush) were assessed at 35 ± 3 DIM. As Hp ≥0.8 g/L or endometritis were associated with ovarian dysfunction in previous studies, cows with serum Hp ≥0.8 g/L at either time point and endometritis, regardless of clinical disease, were classified as the cohort with inflammatory disorders (INFLAM; n = 139). Clinically healthy cows without difficult calving, with singleton birth, with Hp

Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rarely described in the pregnant population, and knowledge of their impact on the mother/fetus is limited. Objective: To describe SJS/TEN in pregnant women and to investigate the risk factors for developing SJS/TEN in pregnancy. Methods: We utilized hospitalization data from the 2009–2020 National Inpatient Sample. Pregnancy hospitalizations and SJS/TEN involvement were identified by ICD-9/10 codes and analyzed by chi-square and logistic regression. Results: We identified 650 pregnancies complicated by SJS/TEN requiring hospitalization. The median age was 28 years, and most were non-Hispanic White (55.2%). There were ≤10 cases associated with mortality. Most SJS/TEN cases (73.9%) occurred during the third trimester. HIV infection (OR = 9.49; P = .030), herpes simplex virus infection (OR = 2.49; P = .021), genitourinary tract infections (OR = 3.80; P

Summary: Background: Since the beginning of May 2022, cases of mpox have been reported in several European and American countries where the disease is nonendemic. We performed a retrospective genomic characterisation of the 2022 mpox outbreak in Belgium, and assessed the in vitro sensitivity of three antiviral compounds to a monkeypox virus (MPXV) strain from the 2022 outbreak. Methods: We sequenced the complete genomes of MPXV isolated from skin-, throat-, anorectal- and genital swab samples using the Oxford Nanopore Technologies (ONT) GridION. We subsequently analysed high-quality complete MPXV genomes and conducted a genomic analysis of MPXV complete genomes from this study with all other complete MPXV genomes available on GISAID up to October 28th, 2022. The in vitro activity of tecovirimat, brincidofovir, and cidofovir was also tested in human and monkey cell lines. Findings: We produced 248 complete MPXV genomes. Phylogenetic analysis of the complete MPXV genomes revealed that they all belong to MPXV Clade IIb B.1. Surprisingly, through phylogeographic analysis we identified a minimum number of 79 introduction events into Belgium, along with sustained local transmission. We also demonstrated the superior in vitro efficacy and selectivity of tecovirimat to the 2022 MPXV clinical strain. Interpretation: The number of sequences provides sufficient information about the MPXV lineages that were circulating in Belgium. The 2022 mpox outbreak, in Belgium, was mainly characterised by many introduction events that were promptly contained and resulted in limited human-to-human transmission of MPXV. The in vitro efficacy of antivirals against a 2022 MPXV Belgian strain highlights the potent activity and specificity of tecovirimat and its ability to prevent the formation of the extracellular enveloped viruses. Funding: None.

Baroreflex activation therapy (BAT) is an emerging device-based treatment for patients with heart failure with a reduced ejection fraction refractory to maximally tolerated goal-directed medical therapy. Currently, there is sparse literature on the critical role that vascular surgeons serve in the delivery of this novel therapy. This single-institution series describes the creation of a BAT program and elaborates on the function of vascular surgeons in the multidisciplinary heart failure team. The preoperative evaluation, perioperative care, and postoperative course of patients receiving BAT from March 2022 to August 2023 were retrospectively analyzed. Eleven patients were evaluated by a dedicated heart failure cardiologist for medical eligibility and assessed by a vascular surgeon for technical feasibility. Of the 11 patients, 7 were men (63.6%). The median age was 60.5 years (range, 44-73 years). No patient (0.00%) had existing carotid artery disease, and one patient (9.1%) had undergone previous neck radiation therapy. All 11 patients (100%) had an existing cardiac implantable electronic device, and BAT implantation was performed on the same side as the cardiac implantable electronic device in two patients (18.1%). Four patients (36.4%) required preoperative hospital admission for medical optimization before surgery. The median length of surgery was 82 minutes (range, 58-113 minutes), and the median length of stay in the hospital after surgery was 1 day (range, 0-6 days). No major adverse neurologic or cardiovascular events, cranial nerve injuries, device complications requiring reintervention, or heart failure-related mortality at 6 months occurred. Three patients (27.3%) experienced extraneous stimulations, which affected BAT tolerability. Within 6 months after BAT implantation, no significant improvements were observed for several heart failure disease burden markers compared with 6 months before BAT implantation. Our early results demonstrate that BAT implantation is a safe procedure with rare complications. Vascular surgeons play an important role in the multidisciplinary delivery of this novel device-based therapy. More data are needed to understand whether BAT is beneficial in the treatment of heart failure with a reduced ejection fraction refractory to maximally tolerated goal-directed medical therapy.

Summary: Background: Incarcerated people are at high risk of blood-borne virus infections, particularly HCV, and a priority population for elimination efforts. This national bio-behavioural survey evaluated blood-borne virus prevalence and HCV testing-and-treatment uptake amongst people in Australian prisons. Methods: Randomly-selected participants from 23 representative prisons nationally were offered point-of-care testing for HIV and HCV (anti-HCV) antibodies, hepatitis B surface antigen (HBsAg), and HCV RNA (if anti-HCV positive). Demographic data and previous HCV testing and treatment were collected by structured interview. Findings: 1599 individuals participated (98% participation; 89%male; median age 35 years; 49% ever injected drugs). Prevalence estimates were: 31.7% (95% CI:28.8–34.8) for anti-HCV; 8.0%for HCV RNA (95% CI:6.4–9.9); 0.5% (95% CI:0.2–1.1) for HBsAg, and 0.8% (95% CI: 0.4–1.7) for HIV antibody. Among participants who had ever injected drugs (n = 787), HCV RNA prevalence was highest among those injecting and sharing needles/syringes within the past month [27.9%; adjusted odds ratio (aOR):4.54 (95% CI:2.65–7.77). Among participants (n = 1599), 70.4% (95% CI: 67.4–73.2) had ever been tested for HCV (62.6% in prison). The highest likelihood of having had HCV testing was observed among participants who injected drugs in the past month (aOR = 10.37, 95% CI:5.72–0.18.78). Among those eligible (n = 318), 84.6% (95% CI:79.2–88.7) had ever received HCV treatment (75.0% in prison), and 67.8% (95% CI:61.7–73.4) were cured. The likelihood of HCV treatment was higher among those previously imprisoned, (aOR = 2.67, 95% CI:1.20–5.93). Interpretation: Despite high overall HCV testing and treatment uptake, the lower uptake and substantial ongoing HCV disease burden in some sub-populations highlights the need for continued prison-based elimination efforts with population-specific interventions. Funding: The AusHep study was funded by the Australian Government Department of Health and Aged Care.

Phenomics is the acquisition of high-dimensional data on an individual-wide scale and is proving transformational in areas of biological research related to human health including medicine and the crop sciences. However, more broadly, a lack of accessible transferrable technologies and research approaches is significantly hindering the uptake of phenomics, in contrast to molecular-omics for which transferrable technologies have been a significant enabler. Aquatic embryos are natural models for phenomics, due to their small size, taxonomic diversity, ecological relevance, and high levels of temporal, spatial and functional change. Here, we present LabEmbryoCam, an autonomous phenotyping platform for timelapse imaging of developing aquatic embryos cultured in a multiwell plate format, and while optimised for embryos, the instrument is extremely versatile. The LabEmbryoCam capitalises on 3D printing, single board computers, consumer electronics and stepper motor enabled motion. We combine these into a compact and modular laboratory insturment to provide X, Y and Z motion of a camera and lens, a web application streamlined for rapid setup of experiments, user email notifications and a humidification chamber to reduce evaporation over prolonged acquisitions. Downstream analyses are provided, enabling automated embryo segmentation, heartrate measurement, motion tracking, and energy proxy trait (EPT) measurement. The LabEmbryoCam is a scalable, and flexible laboratory instrument, that leverages embryonic and early life stage organisms to tackle key global challenges including biological sensitivity assessment, toxicological screening, but also to support broader engagement with the earliest stages of life.

This study provides a comprehensive investigation into the antioxidant and antibacterial properties of Hibiscus flower extracts, highlighting their potential for future applications in functional foods. The research addressed key challenges by employing a multi-faceted approach, including four distinct methods for evaluating antioxidant potential: DPPH and FRAP assays, reducing power, and chelating ability of Fe ions. Total phenolic content was quantified using the Folin–Ciocalteu method, while tannins and flavonoids were assessed via vanillin–HCl and aluminum chloride assays. Additional analyses included spectrophotometric measurement of total flavonols and anthocyanins. Antibacterial activity was determined using a modified agar disk diffusion method, with results indicating significant inhibition of Salmonella typhimurium and Staphylococcus aureus by both aqueous and methanolic extracts. Colorimetric analysis revealed a reduction in chroma and hue angles, while FTIR spectroscopy identified key functional groups, such as suberin, lipids, and polysaccharides. Notably, the antioxidant efficacy varied depending on the solvent used, with aqueous extracts showing higher total phenolic content (4325.12 mg GAE/100 g) compared to methanolic extracts (3487.05 mg GAE/100 g). The study concludes that Hibiscus flower extracts, rich in antioxidants like tannins and anthocyanins, possess significant potential for use as natural preservatives and colorants in food products, supporting their role in developing novel functional foods.

Summary: Background: The Narrative Experiences Online (NEON) Intervention provides self-managed web-based access to mental health recovery narratives (n = 659). We evaluated effectiveness and cost-effectiveness in improving quality of life for adults resident in England with mental health problems and recent psychosis experience. Methods: Prospectively registered pragmatic parallel-group randomised trial controlling for usual care, recruiting from statutory mental health services and through community engagement activities, with a 52-week primary endpoint (ISRCTN11152837). All trial procedures and the NEON Intervention were delivered by an integrated web-application. Randomisation was through an independently generated list (no stratification). Allocation was masked for statistical staff and the Chief Investigator but not participants. Intervention arm participants received immediate NEON Intervention access. Control arm participants received access after completing primary endpoint questionnaires. The primary outcome was quality of life through the Manchester Short Assessment (MANSA). Serious Adverse Events (SAEs) were collected through web-based safety report forms and identified from health service usage data. The primary analysis was by a prospectively described Intention To Treat principle excluding participants who had registered multiple times, with multiple imputation for missing data. Findings: Between 9 March 2020 and 1 March 2021, 739 participants were randomised (intervention:370; control: 369), providing more than 90% power to detect a baseline-adjusted difference of 0.25 in the MANSA score. Mean age was 34.8 years (standard deviation (SD) 12.0), 561 (75.9%) were white British, 443 (59.9%) were female, 609 (82.4%) had accessed specialist care mental health services, and 698 (94.5%) had accessed primary care mental health services. Mean baseline MANSA score was 3.7 for control and intervention arms (SD 0.9 and 1.0). 565 (76.5%) participants provided primary endpoint MANSA data with a mean score of 4.1 (SD 1.0) for both arms. We found no significant difference in Quality of Life between the two arms at the primary endpoint (baseline-adjusted difference 0.07, 95% CI −0.07 to 0.21, p = 0.35). The incremental cost-effectiveness ratio (£110,501 per quality-adjusted life-year (QALY)) exceeded the prospectively defined cost-effectiveness threshold (£30,000 per QALY). 158 (42.8%) control arm and 194 (52.4%) intervention arm participants accessed narratives outside of the NEON Intervention. There were no related serious adverse events (SAEs). 116 unrelated SAEs were reported by control arm participants, and 107 by intervention arm participants. Interpretation: Our findings do not indicate NEON Intervention access for all people with psychosis experience. Future research should consider a) evaluation with current mental health services users; b) optimisation to enable users to find hope-promoting narratives. Funding: National Institute for Health and Care Research (NIHR).

Light, porous, and highly absorbent organic materials have emerged as new renewable and sustainable development materials for electromagnetic wave absorber materials. This study aimed to synthesize electromagnetic wave absorber materials from bamboo activated carbon (BAC), clitoria ternatea powder (CTP), and a combination of them. The powder materials of three materials were put into a mold/holder, and compacted under a conventional compaction method. The results showed that the CTP material produced optimal electromagnetic wave absorption with the smallest return loss value of −17.32 dB. It can be a beneficial reference for the development of electromagnetic wave absorber research in the future.

Summary: Antibody-oligonucleotide conjugates (AOCs) are a fast-expanding modality for targeted delivery of therapeutic oligonucleotides to tissues. Here, we present a protocol to generate, purify, and analyze AOCs from off-the-shelf antibodies. We describe steps to conjugate single/double-stranded oligonucleotides bearing amine handles to linkers and, then, to antibodies using well-established chemistry. In addition, we provide details regarding the purification techniques and analytical methods suitable for AOC. This protocol can be applied for several purposes where AOC is a modality of interest.For complete details on the use and execution of this protocol, please refer to Rady et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Blood parasites of the genus Leucocytozoon commonly infect many bird species worldwide and are particularly prevalent in birds of prey. As a vector-borne parasitic disease, the infection occurrence overlaps with that of the dominant vectors: blackflies (Diptera, Simuliidae). These blood-sucking insects are dependent on habitats with flowing freshwaters for the development of their larval stages. We investigated the correlation between the proximity to flowing waters and Leucocytozoon infection probability in common buzzard (Buteo buteo) broods, as well as the occurrence of adult blackflies directly at the nests. In addition, we investigated the survival of captured simuliids in relation to host infection intensity. In total in 2019, we examined 112 different nests, including 297 common buzzard nestlings, with a Leucocytozoon prevalence of 56.6% among the nestlings and of 80.3% at brood level. We found no significant association of Leucocytozoon infection probability with nestling age, the distance to the nearest stream and the sum of the length of streams within a radius of 200 and 1000 m around each nest. The number of blackflies caught around the nest showed a tentative correlation with the probability of Leucocyozoon infection of the nestlings. Among the subsample of 218 blackfly individuals that survived day one after capture, survival averaged 6.2 days. Our results suggest that Leucocytozoon transmission is complex and requires consideration of many factors, related to habitat and vector prevalence, especially given their temporal variation.

Hydrogen peroxide (H2O2) sensing has been widely investigated using various electrochemical methods, yet the challenge of finding an imaging technique capable of real-time, spatially resolved detection remains. Addressing this, we introduce a Prussian blue (PB) nanofilm-sensitized plasmonic electrochemical microscopy (PEM) technique that successfully visualizes the localized delivery of H2O2. The PB nanofilm was carefully characterized, and its sensing capability towards H2O2 was demonstrated in amperometric mode. Employing a precise micromanipulator system, we controlled a micropipette to create a localized concentration gradient on the sensor surface and monitored the gradient through the PB nanofilm-sensitized PEM. The accuracy of the obtained concentration values was further validated by numerical simulations based on finite-element methods. Our technique ensures dependable localized detection, and we anticipate that advancements in film uniformity will further improve the resolution. The potential applications of this technique are broad and significant, including the opportunity to investigate single-cell exocytosis with neurotransmitters like dopamine, thus offering a promising avenue for future biomedical research.

This paper explores the implications of carbon-taxing policies on food supply chain affordability and competitiveness in Canada. Initiated with Alberta’s 2007 carbon levy, Canada’s approach to carbon taxation aims to mitigate greenhouse gas emissions while addressing the economic impacts on the food sector. With the federal carbon price set to rise to CAD $170 per ton by 2030, the study investigates the potential for increased food prices and the challenges to food affordability as well as identify the current gaps in understanding the intricacies of Carbon Taxing Policies on the Food Supply Chain in Canada. Graphic analyses and forecasts were created using data from Statistics Canada and the U.S. Census Bureau. The main findings of the analyses reveal shifts in wholesale and industrial prices since the carbon tax’s implementation. Findings suggest that carbon pricing may be affecting every level of the food supply chain, highlighting the need for further research to understand its full impact on food affordability and security.

Background: The impact of nonneutralizing antibodies (NNAs) in moderate hemophilia is elusive. Objectives: To explore the presence of NNAs in Nordic persons with moderate hemophilia A (MHA) and B (MHB) in relation to treatment modality, clinical outcome, history of inhibitor, and the corresponding factor VIII (FVIII)/factor IX (FIX) gene mutation. Methods: A cross-sectional multicenter study covering persons with MHA and MHB in Sweden, Finland, and Norway. Inhibitors were analyzed with the Bethesda assay, and NNAs were detected by enzyme-linked immunosorbent assay. Results: Plasma samples from 137 MoHem study participants (median age 29 years; Q1-Q3, 15-54) were analyzed. NNAs were present in 11 of 82 (13%) of people with MHA and 7 of 55 (13%) of those with MHB irrespective of prophylactic or on-demand treatment, most frequently after 150 exposure days (EDs). Three NNA positive patients had a history of high-titer inhibitor, but current analyses were negative (

Summary: Background: As temperatures rise, the transmission and incidence of enteric infections such as those caused by Salmonella and Campylobacter increase. This study aimed to review and synthesise the available evidence on the effects of exposure to ambient temperatures on non-typhoidal Salmonella and Campylobacter infections. Methods: A systematic search was conducted for peer-reviewed epidemiological studies published between January 1990 and March 2024, in PubMed, Scopus, Embase, and Web of Science databases. Original observational studies using ecological time-series, case-crossover or case-series study designs reporting the association between ambient temperature and non-typhoidal Salmonella and Campylobacter infections in the general population were included. A random-effects meta-analysis was performed to pool the relative risks (RRs) per 1 °C temperature increase, and further meta regression, and subgroup analyses by climate zone, temperature metrics, temporal resolution, lag period, and continent were conducted. The Navigation Guide systematic review methodology framework was used to assess the quality and strength of evidence. The study protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO). Findings: Out of 3472 results, 44 studies were included in this systematic review encompassing over one million cases each of Salmonella and Campylobacter infections. Geographically, the 44 studies covered 27 countries across five continents and most of the studies were from high income countries. The meta-analysis incorporated 23 Salmonella studies (65 effect estimates) and 15 Campylobacter studies (24 effect estimates). For each 1 °C rise in temperature, the risk of non-typhoidal Salmonella and Campylobacter infections increased by 5% (RR: 1.05, 95% CI: 1.04–1.06), and 5% (RR: 1.05, 95% CI: 1.04–1.07%), respectively, with varying risks across different climate zones. The overall evidence was evaluated as being of “high” quality, and the strength of the evidence was determined to be “sufficient” for both infections. Interpretation: These findings emphasise the relationship between temperature and the incidence of Salmonella and Campylobacter infections. It is crucial to exercise caution when generalising these findings, given the limited number of studies conducted in low and middle-income countries. Nevertheless, the results demonstrate the importance of implementing focused interventions and adaptive measures, such as the establishment of localised early warning systems and preventive strategies that account for climatic fluctuations. Furthermore, our research emphasises the ongoing need for surveillance and research efforts to monitor and understand the changing dynamics of temperature-related enteric infections in the context of climate change. Funding: Australian Research Council Discovery Projects grant (ARC DP200102571) Program.

This review delves into the effects of carbon pricing policies on food affordability and the performance of the agri-food sector, with a specific focus on Canada. Against the backdrop of the widespread adoption of carbon pricing as a crucial tool in reducing greenhouse gas (GHG) emissions, the discussion acknowledges potential economic repercussions, particularly for lower-income households. Findings reveal that the implementation of a mandated carbon tax across all provinces in Canada by 2019 led to reduced GHG emissions and an increase in food prices. In addition, this review positions Canada within the global context by examining actions taken by other countries and their impacts. Crucial research gaps are also identified, ultimately serving as a guide for future studies and policy formulation aimed at balancing the necessity of carbon tax implementation with considerations of food affordability.

This study investigated the relationship between MiPs, antibiotic resistance genes (ARGs), and water quality in the Red River Delta. MiPs were collected from water samples at four locations: Hanoi, Ha Nam, Nam Dinh, and Cat Ba Island. Bacteria isolated from MiPs and the surrounding water were analyzed for β-lactamase genes. Polyethylene terephthalate (PET) and polytridecanolactone (PTDL) exhibited notable correlations with coefficients with microbial abundance on MiPs. Aeromonas (99.2 % of all isolates) were the most common bacteria isolated from MiPs, with a fewer Escherichia coli (0.83 %). Of 207 bacterial strains isolated from microplastic, 23 (~11 % of total) were found to carry antibiotic resistance genes, mostly blaTEM (13/23; 56.5 %), blaSHV (9/23; 39.1 %) and blaCTXM-9 (1/23; 4.3 %). All seven environmental factors measured were found to affect the distribution of ARGs and ARBs on MiP surfaces. Chlorophyll-a showed a strong positive correlation with ARB abundance, suggesting a potential link between primary productivity and bacterial colonization. This study is one of the first to report the association of MPs with antibiotic-resistant microbiota and genes. The presence of ARGs on MiPs in areas with high human population highlights the need for effective pollution management strategies to mitigate the risks associated with AMR.

Working memory (WM) enables the temporary storage of limited information and is a central component of higher order cognitive function. Irrelevant and/or distracting information can have a negative impact on WM processing and suppressing such incoming stimuli is critical to maintaining adequate performance. However, the neural mechanisms and dynamics underlying such distractor inhibition remain poorly understood. In the current study, we enrolled 46 healthy adults (Mage: 27.92, Nfemale: 28) who completed a Sternberg type WM task with high- and low-distractor conditions during magnetoencephalography (MEG). MEG data were transformed into the time-frequency domain and significant task-related oscillatory responses were imaged to identify the underlying anatomical areas. Whole-brain paired t-tests, with cluster-based permutation testing for multiple comparisons correction, were performed to assess differences between the low- and high-distractor conditions for each oscillatory response. Across conditions, we found strong alpha and beta oscillations (i.e., decreases relative to baseline) and increases in theta power throughout the encoding and maintenance periods. Whole-brain contrasts revealed significantly stronger alpha and beta oscillations in bilateral prefrontal regions during maintenance in high- compared to low-distractor trials, with the stronger beta oscillations being centered on the left dorsolateral prefrontal cortex and right inferior frontal gyrus, while those for alpha being within the right anterior prefrontal cortices and the right middle frontal gyrus. These findings suggest that alpha and beta oscillations in the bilateral prefrontal cortices play a major role in the inhibition of distracting information during WM maintenance. Our results also contribute to prior research on cognitive control and functional inhibition, in which prefrontal regions have been widely implicated.

A study was conducted to evaluate the antimicrobial effect of TiO2 incorporated polylactic acid (PLA) films, activated by pulsed light (PL). TiO2-PLA films with 0, 0.5, 5, 10, and 20 % TiO2/PLA ratio were developed by the solvent casting method. Populations of Escherichia coli and Listeria on film surfaces were determined after the films were PL-treated in three ways: PL treatment on the inoculated film surface; PL treatment from the reverse side of the inoculated film surface; PL treatment before the inoculation on the film surface. A 5 s PL treatment reduced E. coli populations on PLA film from 6.2 to 2.5 log CFU/cm2 and on TiO2-PLA film from 6.2 to 1.1 log CFU/cm2, indicating the combined antibacterial effect of PL and TiO2. Light-activated TiO2-PLA films maintained antibacterial activity against E. coli and L. innocua for 2 h after the 5 s PL treatment, as the activated TiO2-PLA films were still able to reduce bacterial populations by up to 2.5 log CFU/cm2. These findings suggest that pre-activated TiO2-PLA films have potential for packaging foods that are sensitive to UV light.

Despite effective antiretroviral therapy, cognitive impairment remains prevalent among people with HIV (PWH) and decrements in executive function are particularly prominent. One component of executive function is cognitive flexibility, which integrates a variety of executive functions to dynamically adapt one's behavior in response to changing contextual demands. Though substantial work has illuminated HIV-related aberrations in brain function, it remains unclear how the neural oscillatory dynamics serving cognitive flexibility are affected by HIV-related alterations in neural functioning. Herein, 149 participants (PWH: 74; seronegative controls: 75) between the ages of 29–76 years completed a perceptual feature matching task that probes cognitive flexibility during high-density magnetoencephalography (MEG). Neural responses were decomposed into the time-frequency domain and significant oscillatory responses in the theta (4–8 Hz), alpha (10–16 Hz), and gamma (74–98 Hz) spectral windows were imaged using a beamforming approach. Whole-brain voxel-wise comparisons were then conducted on these dynamic functional maps to identify HIV-related differences in the neural oscillatory dynamics supporting cognitive flexibility. Our findings indicated group differences in alpha oscillatory activity in the cingulo-opercular cortices, and differences in gamma activity were found in the cerebellum. Across all participants, alpha and gamma activity in these regions were associated with performance on the cognitive flexibility task. Further, PWH who had been treated with antiretroviral therapy for a longer duration and those with higher current CD4 counts had alpha responses that more closely resembled those of seronegative controls, suggesting that optimal clinical management of HIV infection is associated with preserved neural dynamics supporting cognitive flexibility.

Background & Aims: Biochemical response to ursodeoxycholic acid (UDCA) therapy is associated with good prognosis in people living with primary biliary cholangitis (PBC). Biochemical response is typically assessed early in disease and it is not known what proportion of patients lose previously attained biochemical response, nor whether this impacts long-term liver transplant (LT)-free survival. Methods: We identified all UDCA-treated patients with PBC from the Canadian Network for Autoimmune Liver disease with biochemical measurements at 1 year, and evaluated their liver biochemistry over time. Inadequate biochemical response was defined as serum alkaline phosphatase ≥1.67x the upper limit of normal or abnormal serum total bilirubin at 1 year of UDCA therapy and all time points thereafter. Multistate Markov models were used to estimate transition rates between biochemical response states and from each state to LT or death. Results were validated in an external cohort (GLOBAL PBC registry). Results: A total of 823 patients from eight centers were included. Mean age at diagnosis was 53 years, 91% were female, 33% had inadequate biochemical response to UDCA at 1 year (n = 269). Patients who retained initial adequate response had lower rates of LT or death compared to patients who subsequently lost response (relative rate 0.102, 95% CI 0.047-0.223). Patients who regained adequate response had lower rates than patients who did not (0.016, 95% CI 0.001-0.568), and patients who lost response once more (0.010, 95% CI 0.001-0.340). Patients who regained adequate response for a third time also had lower rates than patients who did not (0.151, 95% CI 0.040-0.566). Analyses in the GLOBAL PBC registry (n = 2,237) validated these results. Conclusion: Loss of biochemical response at any time is associated with heightened risks of LT or death in people living with PBC. Achievement of biochemical response is an important goal throughout follow-up, regardless of biochemical response profile early in therapy. Impact and implications:: Early biochemical response to ursodeoxycholic acid is associated with good prognosis in patients with primary biliary cholangitis (PBC). Our work demonstrates that patients with PBC transition between biochemical response states over time, and that these transitions correspond with changes in risk of liver transplantation or death. Clinicians should re-evaluate risk and optimize treatment decisions for patients with PBC throughout follow-up, regardless of early biochemical response to therapy.

Summary: Background: The inflammatory response in patients with traumatic brain injury (TBI) offers opportunities for stratification and intervention. Previous unselected approaches to immunomodulation in patients with TBI have not improved patient outcomes. Methods: Serum and plasma samples from two prospective, multi-centre observational studies of patients with TBI were used to discover (Collaborative European NeuroTrauma Effectiveness Research [CENTER-TBI], Europe) and validate (Transforming Research and Clinical Knowledge in Traumatic Brain Injury [TRACK-TBI] Pilot, USA) individual variations in the immune response using a multiplex panel of 30 inflammatory mediators. Mediators that were associated with unfavourable outcomes (Glasgow outcome score-extended [GOS-E] ≤ 4) were used for hierarchical clustering to identify patients with similar signatures. Findings: Two clusters were identified in both the discovery and validation cohorts, termed early-inflammatory and pauci-inflammatory. The early-inflammatory phenotype had higher concentrations of interleukin-6 (IL-6), IL-15, and monocyte chemoattractant protein 1 (MCP1). Patients with the early-inflammatory phenotype were older and more likely to have an unfavourable GOS-E at 6 months. There were no differences in the baseline injury severity scores between patients in each phenotype. A combined IL-15 and MCP1 signature identified patients with the early-inflammatory phenotype in both cohorts. Inflammatory processes mediated outcomes in older patients with moderate-severe TBI. Interpretation: Our findings offer a precision medicine approach for future clinical trials of immunomodulation in patients with TBI, by using inflammatory signatures to stratify patients. Funding: CENTER-TBI study was supported by the European Union 7th Framework Programme. TRACK-TBI is supported by the National Institute of Neurological Disorders and Stroke.

Background and purpose: No best practices currently exist for achieving high quality radiation therapy (RT) treatment plan adaptation during magnetic resonance (MR) guided RT of prostate cancer. This study validates the use of machine learning (ML) automated RT treatment plan adaptation and benchmarks it against current clinical RT plan adaptation methods. Materials and methods: We trained an atlas-based ML automated treatment planning model using reference MR RT treatment plans (42.7 Gy in 7 fractions) from 46 patients with prostate cancer previously treated at our institution. For a held-out test set of 38 patients, retrospectively generated ML RT plans were compared to clinical human-generated adaptive RT plans for all 266 fractions. Differences in dose-volume metrics and clinical objective pass rates were evaluated using Wilcoxon tests (p

Background: The clinical value of therapeutic drug monitoring (TDM) for newer anti-seizure medications (ASMs) remains uncertain. This study aimed to assess the impact of newer ASM TDM on clinical decision making in patients with epilepsy. Methods: We retrospectively identified all plasma requests for newer ASM level measurement as part of routine clinical management in the outpatient departments of seven medical institutes across Taiwan between September 2016 and May 2019. Data collected from reviewed medical records included clinical and medication details, indications for TDM requests, test results, interpretation, and impact on patient management. Results: A total of 682 visits with 1051 plasma samples were included. The most frequently analyzed ASMs were levetiracetam (36.1%), oxcarbazepine (18.4%), and lamotrigine (12.0%). Reasons for TDM included poorly controlled seizures (55.3%), concerns about drug-drug interactions (12.3%), and suspicion of drug overdose (10.6%). 68.8% of samples were within the orienting therapeutic range, even for patients with poorly controlled seizures. TDM for non-adherence concerns showed 54.3% below the orienting therapeutic range, while ASM-related adverse events assessment only 8.9% showed levels exceeding the orienting therapeutic range. Following TDM results, 64.2% of cases had medication adjustments, mainly dosage increases. Overall, 55.9% of newer ASM TDM visits showed improved outcomes, including reduced seizures (47.5%) and fewer ASM-related side effects (8.4%). Conclusions: These findings suggest that appropriate utilization of TDM for newer ASMs provides clinical benefits in adjunct to complement clinical decision making in the management of epilepsy patients in a real-world clinical setting.

Background: The Global Burden of Disease (GBD) 2021 study updated methods for attributing burden to physical inactivity, to include all conditions from fasting plasma glucose (FPG) due to physical inactivity. However, physical inactivity influences several additional GBD risk factors that also effect other diseases. This study estimated effects of physical activity on high blood pressure (hypertension), FPG (as diabetes), osteoporosis, and LDL-cholesterol, to enable mediation effects modelling. Methods: MEDLINE, ProQuest Central, Scopus, EMBASE, SPORTDiscus, and Cochrane Library databases were searched from inception to 29 June 2024 for systematic reviews reporting total physical activity levels as an exposure and at least one of the above GBD risk factors or BMI as outcomes. Results: There were 25 systematic reviews that met the inclusion criteria (3 for hypertension, 5 for diabetes, 1 for osteoporosis, and 16 for LDL-cholesterol). Physical activity reduced levels of the risk factors investigated, with dose–response effects observed for blood pressure (6 % for every 600 MET-min/week; 19 % for high versus low activity level) and diabetes (14–28 % if active versus being inactive). Relative to adults not reporting any activity, approximately 600 METs/week reduced levels of LDL-cholesterol by 3.2 % (95 % CI: 1.0 % to 5.4 %) and reduced low bone mineral density by an odds ratio of 0.76 (0.64 to 0.91). No studies of high BMI were identified. Conclusion: Current risk factor models do not comprehensively assess indirect effects of physical activity through all of the relevant biomedical risk factors. Our study estimated input parameters that can be used to assess these indirect pathways.

Summary: Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (

Video-assisted thoracoscopy surgical diaphragmatic plication is the standard of care for diaphragmatic eventration. However, it is associated with complications like injuries to the bowel, liver, spleen, and lung parenchyma. We report life-threatening cardiac tamponade after Video-assisted thoracoscopy surgical diaphragmatic plication. The mechanisms contributing to the injury are described as well.

Open Radio Access Network (RAN) is an important architecture design shift for 5G and next generation telecommunications networks. With open RAN, mobile network operators would be able to mix and match multi-vendor RAN solutions as long as the solutions comply with open standards. O-RAN Alliance is the global leader in standardizing the open RAN architecture, where RAN Intelligent Controller (RIC) is positioned centrally as the brain of a RAN to manage and optimize the RAN operations. Open-source projects play a key role in accelerating the adoption of open RAN architecture, especially the use of RIC. However, the fast pace of development and the lack of documentation in open-source projects create steep learning curve for beginners. In this paper, we first provide an overview of widely used open-source RIC projects and discuss their pros and cons. We then share our first-hand experience to use RIC in our campus 5G network that consists of commercial-grade RAN solutions. In particular, we developed a suite of three RAN control applications (i.e., energy efficiency, interference management, and predictive maintenance) on an open-source RIC, and we deploy and evaluate them on a commercial-grade 5G network in a university campus. For these RIC applications, we design and evaluate different ML models based on real-world data collected from our 5G network, which we publish together with this paper. Our experimental results show that AI-based RIC applications can achieve more than 90% of accuracy in inferring the situation of the RAN for each given task. Our energy-saving RIC application can reduce 65% of energy consumption of the RAN over a simulated period of one year. Our project also validates the feasibility to interfacing an open-source RIC with existing commercial-grade 5G solutions.

As additive manufacturing gains widespread adoption across various industries, its application to traditional materials such as bronze remains relatively underexplored. Through a comprehensive assessment, this research investigates the extrusion-based additive manufacturing of bronze, utilizing a CuSn10/Polylactic Acid (PLA) composite filament for printing bronze green parts, followed by thermal debinding and sintering processes to produce metal parts. By systematically varying 3D printing, debinding, and sintering parameters, optimized conditions for manufacturing bronze metal parts are identified. The study evaluates key material properties including density, ultimate tensile strength, surface morphology, and electrical conductivity of the produced metal parts. Additionally, the influence of printing parameters on dimensional deviation and shrinkage for both bronze green and metal parts is analyzed. Overall, this research highlights the potential of additive manufacturing to revolutionize bronze production, offering valuable insights into optimized process parameters and the enhancement of bronze component properties for a wide range of industrial applications.

Background: The trajectories of all-cause deaths linked to omicron infections are rarely studied, especially in relation to the efficacy of booster shots. For assessing three epidemiological death trajectories, including dying from COVID-19, dying with COVID-19, and non-COVID-19 death, we offer a new COVID-19-and-death competing risk model that deals with the primary pathway (e.g., dying from COVID-19) competing with two other pathways. Methods: We applied this model to track three trajectories: deaths directly from COVID-19, deaths with COVID-19 as a contributing factor, and indirect non-COVID-19 deaths. The study used data from a Taiwanese cohort, covering periods of Omicron subvariants BA.2, BA.5, and BA.2.75. It focused on the effectiveness of monovalent and bivalent booster vaccines against these death trajectories. Results: The highest mortality was observed during the BA.2 phase, which decreased in the BA.5 period and increased again in the BA.2.75 period. Analyzing each trajectory, we noted similar trends in deaths directly from and with COVID-19, while non-COVID-19 deaths remained stable across subvariants. Booster vaccines reduced all-cause mortality by 58% (52%−62%) for BA.2, 70% (65%−75%) for BA.5%, and 75% (70%−80%) for BA.2.75, compared to incomplete vaccination. The reduction in deaths directly from COVID-19 was 66% (61%−72%) for BA.2, 78% (72%−84%) for BA.5%, and 85% (76%−93%) for BA.2.75. For deaths with COVID-19, the figures were 46% (36%−55%), 76% (68%−84%), and 90% (86%−95%). Additionally, the booster shots decreased non-COVID-19 deaths by 64% (63%−66%) for BA.2, 38% (36%−40%) for BA.5, and 19% (17%−21%) for BA.2.75. Conclusion: Our competing risk analysis is effective for monitoring all-cause death trajectories amidst various Omicron infections. It provides insights into the impact of booster vaccines, especially bivalent ones, and highlights the consequences of inadequate healthcare for vulnerable groups.

Adolescence is a period of profound biopsychosocial development, with pubertally-driven neural reorganization as social demands increase in peer contexts. The explosive increase in social media access has fundamentally changed peer interactions among youth, creating an urgent need to understand its impact on neurobiological development and mental health. Extant literature indicates that using social media promotes social comparison and feedback seeking (SCFS) behaviors in youth, which portend increased risk for mental health disorders, but little is known about its impact on neurobiological development. We assessed social media behaviors, mental health symptoms, and spontaneous cortical activity using magnetoencephalography (MEG) in 80 typically developing youth (8–16 years) and tested how self-reported pubertal stage moderates their relationship. More mature adolescents who engaged in more SCFS showed weaker fusiform/parahippocampal alpha and medial prefrontal beta activity, and increased symptoms of anxiety and attention problems. Engaging in SCFS on social media during adolescence may thus relate to developmental differences in brain regions that undergo considerable development during puberty. These results are consistent with works indicating altered neurodevelopmental trajectories within association cortices surrounding the onset of many mental health disorders. Importantly, later pubertal stages may be most sensitive to the detrimental effects of social media use.

Introduction: The germline human leukocyte antigen (HLA) status has been found to be associated with immunotherapy outcomes in patients with NSCLC, but its correlation to immunotherapy-induced pneumonitis and prognostic impact in the Asian population remains largely unknown. Methods: We evaluated the HLA genotype of the germline and available tumor samples in 42 patients with programmed death-ligand 1 expression of 50% or higher undergoing pembrolizumab immunotherapy. The HLA allele expression was correlated with tumor response, disease survival, and the occurrence of pneumonitis. Results: It was observed that the germline HLA-C homozygosity and HLA-DRB1∗13 expression were related to a worse progression-free survival and treatment response. Importantly, all patients (7/7 patients) who developed pneumonitis in our cohort expressed the HLA-DPB1∗02 allele, and the incidence of pneumonitis was 31.8% (7/22 patients) in patients expressing this allele compared with 0% (0/20 patients) in those without this allele (p = 0.009). Investigation of the tumor samples from 15 patients revealed some degree of HLA loss in the HLA class I loci in 40% (6/15) of patients, and no significant difference in tumor mutation burden was found among patients with different treatment responses. Conclusion: Taken together, this study evaluated the impact of HLA status in both germline and tumor samples in patients with NSCLC with high programmed death-ligand 1 expression, and the high incidence of immunotherapy-induced pneumonitis in patients expressing the HLA-DPB1∗02 allele may suggest a routine HLA typing and closer monitoring in this patient subset.

Introduction: Artificial intelligence (AI) has the potential to improve healthcare quality when thoughtfully integrated into clinical practice. Current evaluations of AI solutions tend to focus solely on model performance. There is a critical knowledge gap in the assessment of AI–clinician interactions. We systematically reviewed existing literature to identify interaction traits that can be used to assess the quality of AI–clinician interactions. Methods: We performed a systematic review of published studies to June 2022 that reported elements of interactions that impacted the relationship between clinicians and AI-enabled clinical decision support systems. Due to study heterogeneity, we conducted a narrative synthesis of the different interaction traits identified from this review. Two study authors categorised the AI–clinician interaction traits based on their shared constructs independently. After the independent categorisation, both authors engaged in a discussion to finalise the categories. Results: From 34 included studies, we identified 210 interaction traits. The most common interaction traits included usefulness, ease of use, trust, satisfaction, willingness to use and usability. After removing duplicate or redundant traits, 90 unique interaction traits were identified. Unique interaction traits were then classified into seven categories: usability and user experience, system performance, clinician trust and acceptance, impact on patient care, communication, ethical and professional concerns, and clinician engagement and workflow. Discussion: We identified seven categories of interaction traits between clinicians and AI systems. The proposed categories may serve as a foundation for a framework assessing the quality of AI–clinician interactions.

Costs/benefits research to support active transport/electric micromobility investments are needed for optimal investment of public funds. This systematic review provides an evidence base of the economic effects of active transport and electric micromobility modes. Previous reviews including non-health benefits of active transport have been limited to Europe. Twenty-three studies from both the academic and grey literature were included in the review. Values for walking ranged from USD −0.25 ∼ 4.25/km, values for cycling ranged from USD −1.00 ∼ 1.95/km, and values for e-bike and e-scooter ranged from USD −0.44 ∼ 1.15/km. The largest benefit for active transport was due to health parameters. There were large variations in monetised benefits; some studies incorporated only certain types of benefits. Research gaps included inconsistent evidence for assumptions and a lack of data especially for electric micromobility modes. The quality of grey literature also varied.

Novel biochar-based fertilizers, produced by combining biochar particles with chemical fertilizers, have strong potential to enrich soil with carbon (C) and nitrogen (N), and to increase plant productivity. Application of biochar-based fertilizers modifies soil microbial community compositions, thereby influencing greenhouse gas emissions, including methane (CH4) fluxes. Due to the improved aeration in soils amended with biochar particles, we hypothesized that biochar-based urea would decrease CH4 production and increase CH4 oxidation, leading to increase of total CH4 uptake by soil. A three-year field experiment was conducted in a subtropical Moso bamboo forest to compare the impacts of biochar-based urea and traditional urea on seasonal CH4 uptake by soil, as well as on soil physicochemical and microbial attributes. Urea application lowered the annual soil CH4 uptake by 6 % and 16 % at 100 and 300 kg N/ha, respectively, within the first year. Biochar-based urea application at 300 kg N/ha increased the annual CH4 uptake by 12 % in both the first and second years, whereas the effects weakened over time. Soil CH4 uptake was positively correlated with CH4 oxidation rate but negatively with CH4 production rate. The urea-induced decrease in CH4 uptake was attributed to the increased NH4+ and NO3− contents and mcrA gene abundance as well as decreased pmoA/mcrA ratio, thereby increasing CH4 production rate. The biochar-based urea increased CH4 uptake by enhanced soil aeration and labile C supply, which created favorable conditions for methanotrophs. This resulted in increased pmoA gene abundance and the pmoA/mcrA ratio, thereby accelerating CH4 oxidation. Overall, these findings underscore the potential of biochar-based fertilizers in augmenting CH4 uptake within subtropical forest soils. Notably, the transition from traditional urea to biochar-based urea in China Moso bamboo forests alone has the potential to lift annual soil CH4 uptake by an estimated 4450 t.

Summary: Within the penile microbiome, bacteria associated with seroconversion, immunology, and cells (BASIC species) enhance HIV susceptibility in heterosexual uncircumcised men by inducing foreskin inflammation and HIV target cell recruitment. This phase 1/2 clinical trial randomizes HIV-uninfected Ugandan men (n = 125) to either oral tinidazole, topical metronidazole, topical clindamycin, or topical hydrogen peroxide to define impact on ex vivo foreskin HIV susceptibility, penile immunology, and BASIC species density. Antimicrobials are well tolerated, and 116 (93%) participants complete the protocol. Topical metronidazole and oral tinidazole reduce the inner foreskin tissue density of HIV-susceptible CD4+ T cells (predefined primary endpoint). Antimicrobials also have varying but substantial effects on reducing prepuce inflammation and BASIC species density, reducing density of foreskin T cell subsets, and increasing foreskin epithelial integrity. Immune alterations correlate strongly with changes in the abundance of BASIC species. Clinical interventions targeting the penile microbiota, particularly topical metronidazole, may reduce HIV susceptibility in uncircumcised men.

ABSTRACT: Background: Spinal Infection (SI) is associated with various comorbidities. The interaction of these comorbidities and their impact on costs and complexity of care has not been fully assessed. Methods: This is a retrospective cohort study of SI patients in an urban hospital system to characterize comorbidities and outcomes in adult patients with SI. Adult patients in our hospital system who were hospitalized with an initial diagnosis of SI between July 1, 2017 and June 30, 2019 were included. Outcomes measures included length of stay (LOS) of the index hospitalization for SI, charges and payments for the index hospitalization, and hospital readmissions within one year after discharge from the index hospitalization. Data was obtained by querying our Electronic Data Warehouse (EDW) using ICD-10-CM and CPT procedure codes. Spearman's correlation was used to summarize the relationships between LOS, charges, and payments. Multivariable linear regression was used to evaluate associations of demographics, comorbidities, and other factors with LOS. Multivariable Cox regression was used to evaluate associations of demographics, comorbidities, and other factors with hospital readmissions. Results: 403 patients with a first diagnosis of SI were identified. The average number of comorbidities per patient was 1.3. 294 (73%) had at least 1 medical comorbidity, and 54 (13%) had 3 or more comorbidities. The most common medical comorbidities were diabetes mellitus (26%), intravenous drug use (IVDU, 26%), and malnutrition (20%). 112 patients (28%) had a surgical site infection (SSI). DM (p

Summary: In cancer research, murine models play a crucial role as highly valuable preclinical tools. Here, we present a protocol to generate a murine model of glioblastoma through the direct intracranial injection of tumor cells. We describe steps for cell culture, intracranial implantation, and standard-of-care treatments. We then detail procedures for monitoring tumor growth using bioluminescent imaging.For complete details on the use and execution of this protocol, please refer to Pelizzari-Raymundo et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Summary: Background: Traumatic brain injury is conventionally categorised as mild, moderate, or severe on the Glasgow Coma Scale (GCS). Recently developed biomarkers can provide more objective and nuanced measures of the extent of brain injury. Methods: Exposure–response relationships were investigated in 2479 patients aged ≥16 enrolled in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) prospective observational cohort study. Neurofilament protein-light (NFL), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and glial fibrillary acidic protein (GFAP) were assayed from serum sampled in the first 24 h; concentrations were divided into quintiles within GCS severity groups. Relationships with the Glasgow Outcome Scale-Extended were examined using modified Poisson regression including age, sex, major extracranial injury, time to sample, and log biomarker concentration as covariates. Findings: Within severity groups there were associations between biomarkers and outcomes after adjustment for covariates: GCS 13–15 and negative CT imaging (relative risks [RRs] from 1.28 to 3.72), GCS 13–15 and positive CT (1.21–2.81), GCS 9–12 (1.16–2.02), GCS 3–8 (1.09–1.94). RRs were associated with clinically important differences in expectations of prognosis. In patients with GCS 3 (RRs 1.51–1.80) percentages of unfavourable outcome were 37–51% in the lowest quintiles of biomarker levels and reached 90–94% in the highest quintiles. Similarly, for GCS 15 (RRs 1.83–3.79), the percentages were 2–4% and 19–28% in the lowest and highest biomarker quintiles, respectively. Interpretation: Conventional TBI severity classification is inadequate and underestimates heterogeneity of brain injury and associated outcomes. The adoption of circulating biomarkers can add to clinical assessment of injury severity. Funding: European Union 7th Framework program (EC grant 602150), Hannelore Kohl Stiftung, One Mind, Integra LifeSciences, Neuro-Trauma Sciences, NIHR Rosetrees Trust.

Summary: The Hippo signaling pathway is an important regulator of organ growth and differentiation, and its deregulation contributes to the development of cancer. The activity of its downstream targets YAP/TAZ depends on adherens junctions. Plakophilin 4 (PKP4) is a cell-type specific adherens junction protein expressed in the proliferating cells of the epidermis. Here, we show that PKP4 diminishes proliferation as well as differentiation. Depletion of PKP4 increased proliferation but at the same time induced premature epidermal differentiation. PKP4 interacted with several Hippo pathway components, including the transcriptional co-activators YAP/TAZ, and promoted nuclear YAP localization and target gene expression. In differentiated keratinocytes, PKP4 recruited LATS and YAP to cell junctions where YAP is transcriptionally inactive. YAP depletion, on the other hand, reduced PKP4 levels and keratinocyte adhesion indicative of a feedback mechanism controlling adhesion, proliferation, and differentiation by balancing YAP functions.

Modeling dynamic interactions among network components is crucial to uncovering the evolution mechanisms of complex networks. Recently, spatio-temporal graph learning methods have achieved noteworthy results in characterizing the dynamic changes of inter-node relations (INRs). However, challenges remain: The spatial neighborhood of an INR is underexploited, and the spatio-temporal dependencies in INRs’ dynamic changes are overlooked, ignoring the influence of historical states and local information. In addition, the model’s explainability has been understudied. To address these issues, we propose an explainable spatio-temporal graph evolution learning (ESTGEL) model to model the dynamic evolution of INRs. Specifically, an edge attention module is proposed to utilize the spatial neighborhood of an INR at multi-level, i.e., a hierarchy of nested subgraphs derived from decomposing the initial node-relation graph. Subsequently, a dynamic relation learning module is proposed to capture the spatio-temporal dependencies of INRs. The INRs are then used as adjacent information to improve the node representation, resulting in comprehensive delineation of dynamic evolution of the network. Finally, the approach is validated with real data on brain development study. Experimental results on dynamic brain networks analysis reveal that brain functional networks transition from dispersed to more convergent and modular structures throughout development. Significant changes are observed in the dynamic functional connectivity (dFC) associated with functions including emotional control, decision-making, and language processing.

Summary: Reactive changes of glial cells during neuroinflammation impact brain disorders and disease progression. Elucidating the mechanisms that control reactive gliosis may help us to understand brain pathophysiology and improve outcomes. Here, we report that adult ablation of autism spectrum disorder (ASD)-associated CHD8 in astrocytes attenuates reactive gliosis via remodeling chromatin accessibility, changing gene expression. Conditional Chd8 deletion in astrocytes, but not microglia, suppresses reactive gliosis by impeding astrocyte proliferation and morphological elaboration. Astrocyte Chd8 ablation alleviates lipopolysaccharide-induced neuroinflammation and septic-associated hypothermia in mice. Astrocytic CHD8 plays an important role in neuroinflammation by altering the chromatin landscape, regulating metabolic and lipid-associated pathways, and astrocyte-microglia crosstalk. Moreover, we show that reactive gliosis can be directly mitigated in vivo using an adeno-associated virus (AAV)-mediated Chd8 gene editing strategy. These findings uncover a role of ASD-associated CHD8 in the adult brain, which may warrant future exploration of targeting chromatin remodelers in reactive gliosis and neuroinflammation in injury and neurological diseases.

Summary: Background: Globally, fall-related injuries are a substantial problem, and 80% of fatal falls occur in low-income and middle-income countries. We aimed to measure time from injury to hip-fracture surgery in people aged 50 years or older living in low-income and middle-income regions, as well as to measure the proportion of patients with surgical stabilisation of their hip fracture within 72 h of admission to hospital and to identify risk factors associated with surgical delay. Methods: For this secondary analysis, we analysed data collected from Africa, Latin America, China, India, and Asia (excluding China and India) for the International Orthopaedic Multicentre Study in Fracture Care (INORMUS) between March 29, 2014, and June 15, 2022. Patients from INORMUS were included in this analysis if they were aged 50 years or older and had an isolated, primary hip fracture sustained from a ground-level fall. Staff at participating hospitals identified patients with musculoskeletal injury and referred them for assessment of eligibility. We report time from injury to surgery as three distinct time periods: time from injury to hospital admission, time from admission to surgery, and a total time from injury to surgery. Date and time of injury were self-reported by patients at the time of study recruitment. If time to hospital admission after injury exceeded 24 h, patients reported the primary reason for delayed admission. Reasons for surgery, no surgery, and surgical delay were reported by the treating team. For patients undergoing surgery, multivariable regression analyses were used to identify risk factors for surgical delay. Findings: 4486 adults aged 50 years or older with an isolated, primary hip fracture were enrolled in INORMUS from 55 hospitals in 24 countries. Countries were grouped into five regions: Africa (418 [9·3%] of 4486), Latin America (558 [12·4%]), China (1680 [37·4%]), India (1059 [23·6%]) and Asia (excluding China and India; 771 [17·2%]). Of 4486 patients, 3805 (84·8%) received surgery. The rate of surgery was similar in all regions except in Africa, where only 193 (46·3%) of 418 patients had surgery. Overall, 2791 (62·2%) of 4486 patients were admitted to hospital within 24 h of injury. However, 1019 (22·7%) of 4486 patients had delayed hospital admission of 72 h or more from injury. The two most common reasons for delayed admission of more than 24 h were transfer from another hospital (522 [36·2%] of 1441) and delayed care-seeking because patients thought the injury would heal on its own (480 [33·3%]). Once admitted to hospital, 1451 (38·1%) of 3805 patients who received surgery did so within 72 h (median 4·0 days [IQR 1·7–6·0]). Regional variation was seen in the proportion of patients receiving surgery within 72 h of hospital admission (92 [17·9%] of 514 in Latin America, 53 [27·5%] of 193 in Africa, 454 [30·9%] of 1471 in China, 318 [44·4%] of 716 in Asia [excluding China and India], and 534 [58·6%] of 911 in India). Of all 3805 patients who received operative treatment, 2353 (61·8%) waited 72 h or more from hospital admission. From time of injury, the proportion of patients who were surgically stabilised within 72 h was 889 (23·4%) of 3805 (50 [9·7%] of 517 in Latin America, 31 [16·1%] of 193 in Africa, 277 [18·8%] of 1471 in China, 189 [26·4%] of 716 in Asia [excluding China and India], and 342 [37·5%] of 911 in India). Interpretation: Access to surgery within 72 h of hospital admission was poor, with factors that affected time to surgery varying by region. Data are necessary to understand existing pathways of hip-fracture care to inform the local development of quality-improvement initiatives. Funding: The National Health and Medical Research Council of Australia, the Canadian Institutes of Health Research, McMaster Surgical Associates, Hamilton Health Sciences, and the US National Institutes of Health.

Summary: Background: We estimated the health gains and health inequality impacts for the Australian population alive in 2021 (n = 25.0 million) in the next 20 years and over their remaining lifespan, from shifting everyone above a BMI of 25 kg/m2 to 25 kg/m2 compared to the BMI distribution in 2021 persisting into the future. Methods: National Health Survey 2017–2018 was used to estimate BMI distributions by sex, age and, socio-economic status (Socio-Economic Indexes for Areas; SEIFA). A proportional multistate life table linking BMI to 19 associated diseases and allowing for time lags and competing morbidity and mortality, was used to estimate the future stream of health adjusted life years (HALYs) gained from eradicating high BMI. Findings: Undiscounted health gains in the first 20 years and lifetime of the population were, respectively, 2.00 million (95% uncertainty interval 1.70–2.32) and 20.4 million (17.0–24.2) (at a 3% annual discount rate, HALY gains were 1.37 and 5.77 million, respectively). Reductions in the incidence of cardio metabolic diseases contributed 61% (95% UI: 54%–68%) of the undiscounted health gains in the first 20 years, musculoskeletal diseases contributed 26% (20%–32%) and cancer 5% (3%–8%). HALY gains in the first 20 years and lifetime, per person alive in 2021, were 2.5 (2.4–2.5) and 1.9 (1.9–2.0) times higher for the most compared to the least deprived SEIFA quintile. Interpretation: The total theoretical envelope of health gains, and health inequality reductions, through eradication of BMI is substantial. Our modeling infrastructure can be used to estimate the health impacts and cost effectiveness of many actual interventions. Funding: No funding was received for the study.

Introduction: Yeo’s Index, product of the mitral leaflet separation index and dimensionless index, is a novel measure of the severity of rheumatic mitral stenosis (MS). We assess Yeo’s index in patients with rheumatic MS with or without mixed valve disease. Methods: In a retrospective cohort study, Yeo’s index was measured in 237 cases of rheumatic MS − 124 in a transthoracic echocardiography validation cohort using mitral valve area (MVA) by pressure half-time and planimetry as comparator and 113 in a transesophageal echocardiography (TEE) validation cohort using TEE three-dimensional MVA as comparator. Patients were considered to have mixed valve disease if they had MS and concomitant mitral regurgitation or aortic valve disease. Results: There were 113 patients with isolated MS and 124 patients with mixed valve disease. Overall, Yeo’s index ≤ 0.26 cm showed 93.0 % sensitivity and 87.5 % specificity for identifying severe MS (MVA ≤ 1.5 cm2). In isolated MS, Yeo’s index ≤ 0.26 cm showed sensitivity of 94.6 % and specificity of 90.0 % for identifying severe MS, while in mixed valve disease sensitivity was 90.6 % and specificity 86.7 %. Overall, Yeo’s index ≤ 0.15 cm showed 83.6 % sensitivity and 94.3 % specificity for very severe MS (MVA ≤ 1.0 cm2). In isolated MS, the threshold of ≤0.15 cm showed sensitivity of 84.4 % and specificity of 92.6 % for very severe MS, while in mixed valve disease sensitivity was 81.3 % and specificity 95.3 %. The presence of atrial fibrillation did not influence the performance of Yeo’s index. Conclusion: Yeo’s Index accurately differentiates severity of rheumatic MS with or without mixed valve disease.