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Abstract This study aims to explore the perspectives of community leaders (CL) on trusted sources of health information, examine their roles, challenges, and needs in disseminating COVID-19 health information, and identify opportunities to improve public health reach and access for underserved communities. This qualitative study included seven focus groups conducted via online video conferencing from April-June 2021. The participants (n = 9) were CL recruited from the Texas Community Engagement Alliance (CEAL) for their experience working with underserved communities in Dallas, Texas. Data were coded deductively and analyzed thematically. The analysis resulted in three themes: (1) Information fatigue, mistrust, and desensitization were experienced by community members and leaders; (2) CL were expected to process, verify, and share accurate and timely COVID-19 health information; (3) CL identified potential strategies to improve COVID-19 health info access and reach. CLs were critical in addressing mis/disinformation and fostering trust in public health communication, particularly in underserved communities. They acted as vital intermediaries for health information, striving to debunk mis/disinformation and disseminate accurate health information. Public health strategies could benefit from prioritizing the integration of CL in communicating health information during crises and rebuilding trust within historically and racially marginalized and underserved communities. Supporting CLs, for example, through resources and training programs to counter misinformation and provide access to culturally and linguistically tailored health resources, may significantly enhance the access and reach of evidence-based health communication during health crises.

Abstract CTNNB1 syndrome is a rare monogenetic disorder caused by CTNNB1 de novo pathogenic heterozygous loss-of-function variants that result in cognitive and motor disabilities. Treatment is currently lacking; our study addresses this critical need. CTNNB1 encodes β-catenin which is essential for normal brain function via its dual roles in cadherin-based synaptic adhesion complexes and canonical Wnt signal transduction. We have generated a Ctnnb1 germline heterozygous mouse line that displays cognitive and motor deficits, resembling key features of CTNNB1 syndrome in humans. Compared with wild-type littermates, Ctnnb1 heterozygous mice also exhibit decreases in brain β-catenin, β-catenin association with N-cadherin, Wnt target gene expression, and Na/K ATPases, key regulators of changes in ion gradients during high activity. Consistently, hippocampal neuron functional properties and excitability are altered. Most important, we identify a highly selective inhibitor of glycogen synthase kinase (GSK)3α,β that significantly normalizes the phenotypes to closely meet wild-type littermate levels. Our data provide new insights into brain molecular and functional changes, and the first evidence for an efficacious treatment with therapeutic potential for individuals with CTNNB1 syndrome.

Abstract Consequential STEM experiences in informal settings can address issues of equity by fully engaging historically marginalized high school students in complex socio-scientific issues. However, inclusive and effective programs are in high demand, and there is little research on what specific aspects, context, and timeframes are most important when scaling these experiences. Using a mixed method approach, this study demonstrates that students make significant gains, in the short and long term, through in-person and remote informal programs ranging between 22-h and 320-h. Progress across STEM learning constructs is attributed to authentic research experiences, students’ connections to STEM professionals, direct hands-on participation in projects, and group work. Relative to formal education settings, research-based informal STEM programs can be implemented with minimal resources, can maintain effectiveness while scaling, and work towards addressing the societal challenge of improving STEM learning and outcomes for high school students from historically marginalized communities.

Abstract Quantitative climate and conflict research has thus far considered the role of biophysical extreme weather impacts in conflict dynamics only to a limited extent. We do not fully understand if and if so how, extreme weather impacts can improve conflict predictions. Addressing this gap, we use the Generalized Random Forest (GRF) algorithm to evaluate whether detailed information on extreme weather impacts improves conflict forecasts made with well known conflict predictors such as socio-economic, governance, and history of conflict indicators. We integrate data on biophysical extreme weather impacts such as droughts, floods, crop production shocks, and tropical cyclones from the Inter-Sectoral Impact Model Intercomparison Project 2a (ISIMIP2a) project into predictive models of conflict in mainland Africa between 1994 and 2012. While we find that while extreme weather impacts alone predict violent conflicts modestly well, socio-economic and conflict history indicators remain the strongest individual predictors of conflicts. Finally, fully specified forecast models including conflict history, governance, and socio-economic variables are not improved by adding extreme weather impacts information. Some part of this can be explained by spatial correlations between extreme weather impacts and other socioeconomic and governance conditions. We conclude that extreme weather impacts do not contain any unique information for forecasting annual conflict incidence in Africa, which calls into question its usefulness for early warning.

Abstract The COVID-19 pandemic affected the world in various ways. In response to this, countries set up various interventions such as lockdowns, physical distancing, and mandatory face covering, among others. Governments also put in place measures to ensure compliance. However, the extent to which the various responses impacted the deaths and confirmed cases remains debatable. This paper explores this question by looking at how government stringency measures impacted deaths and cases in Malawi. We employ an instrumental variable (IV) approach to assess the impact of government action on confirmed COVID-19 cases and deaths. We measure government policy by the stringency index. By leveraging the IV approach, we circumvent potential endogeneity concerns between our main policy variable and the outcome variables. Our data comes from the University of Oxford COVID-19 project and spans a daily frequency from 20 February 2020 to 25 April 2022, covering multiple waves of the pandemic. Overall, the findings show that despite Malawi never having implemented a full lockdown, the government policies may have helped to reduce both cases and deaths related to COVID-19. Specifically, the IV shows that a unit increase in the government stringency index results in a drop of 179 cases and 6 deaths. All the results are statistically significant at 1% level and remain robust to the use of the ordinary least-squares method. This study demonstrates the efficacy of non-pharmaceutical tools implemented by the government to fight COVID-19. Thus, policymakers need to place more emphasis on the need for the public to adhere to these stringency measures in the event of new waves of the pandemic or similar outbreaks.

Abstract Clinical and preclinical studies established that supplementing diets with ω3 polyunsaturated fatty acids (PUFA) can reduce hepatic dysfunction in nonalcoholic steatohepatitis (NASH) but molecular underpinnings of this action were elusive. Herein, we used multi‐omic network analysis that unveiled critical molecular pathways involved in ω3 PUFA effects in a preclinical mouse model of western diet induced NASH. Since NASH is a precursor of liver cancer, we also performed meta‐analysis of human liver cancer transcriptomes that uncovered betacellulin as a key EGFR‐binding protein upregulated in liver cancer and downregulated by ω3 PUFAs in animals and humans with NASH. We then confirmed that betacellulin acts by promoting proliferation of quiescent hepatic stellate cells, inducing transforming growth factor–β2 and increasing collagen production. When used in combination with TLR2/4 agonists, betacellulin upregulated integrins in macrophages thereby potentiating inflammation and fibrosis. Taken together, our results suggest that suppression of betacellulin is one of the key mechanisms associated with anti‐inflammatory and anti‐fibrotic effects of ω3 PUFA on NASH.

Purpose: Modular cementless knee arthroplasty systems are capable of precise reconstruction of the mechanical axis. However, they are considered more susceptible to complications. In contrast, non-modular cemented systems are said to be more forgiving and show good long-term results. The aim of this study was to investigate the resulting leg axis after implantation of a non-modular cemented rotating hinged knee prosthesis. Furthermore, potential risk factors for the occurrence of malalignment and complications should be identified. Methods: Between 2005 and 2015, 115 patients could be included in this monocentric retrospective cohort study. All patients underwent primary hinged non-modular cemented total knee arthroplasty. Preoperative and postoperative standardized long radiographs were analysed to determine resulting leg axis. Furthermore, epidemiological and intraoperative data as well as perioperative complications were surveyed. Results: Average leg axis was 5.8° varus preoperatively and 0.6° valgus postoperatively. Considering an axis deviation of 3° as the target corridor, 27% of all cases examined were outside the desired range. 21% cases showed a femoral deviation from the target corridor and 15% showed a tibial deviation. There was a significant relationship between the preoperative mLDFA and the mechanical alignment of the femoral component (R = 0.396, p < 0.001) as well as between the preoperative mMPTA and the mechanical alignment of the tibial component (R = 0.187, p = 0.045). The mean operative duration was 96 min. No periprosthetic fractures were observed within the study cohort. Conclusion: The main result of the present work is that a non-modular cemented rotating hinged knee arthroplasty system can reconstruct the mechanical leg axis precisely and comparable to modular cementless and unconstrained total knee prostheses. Component malalignment is primarily dependent upon extraarticular deformity preoperatively. Periprosthetic fracture rates and duration of surgery were lower compared with current literature. Level of evidence: Level III: Retrospective cohort study. [ABSTRACT FROM AUTHOR]

E. innesii is a recently described Enterococcus species which may be difficult to differentiate from the more common E. casseliflavus. We present the first clinical report of invasive E. innesii infection, featuring two cases of biliary sepsis. Whole genome sequencing confirmed the taxonomic assignment and the presence of vanC-4. Analysis of public genomes identified 13 deposited E. innesii and 13 deposited E. casselifalvus/E.gallinarum genomes which could be reassigned as E. innesii. Improved laboratory diagnosis of E. innesii is expected to generate additional data concerning its clinical relevance and support the future diagnosis and treatment of this uncommon pathogen. [ABSTRACT FROM AUTHOR]

Abstract The DNA damage response (DDR) acts as a barrier to malignant transformation and is often impaired during tumorigenesis. Exploiting the impaired DDR can be a promising therapeutic strategy; however, the mechanisms of inactivation and corresponding biomarkers are incompletely understood. Starting from an unbiased screening approach, we identified the SMC5‐SMC6 Complex Localization Factor 2 (SLF2) as a regulator of the DDR and biomarker for a B‐cell lymphoma (BCL) patient subgroup with an adverse prognosis. SLF2‐deficiency leads to loss of DDR factors including Claspin (CLSPN) and consequently impairs CHK1 activation. In line with this mechanism, genetic deletion of Slf2 drives lymphomagenesis in vivo. Tumor cells lacking SLF2 are characterized by a high level of DNA damage, which leads to alterations of the post‐translational SUMOylation pathway as a safeguard. The resulting co‐dependency confers synthetic lethality to a clinically applicable SUMOylation inhibitor (SUMOi), and inhibitors of the DDR pathway act highly synergistic with SUMOi. Together, our results identify SLF2 as a DDR regulator and reveal co‐targeting of the DDR and SUMOylation as a promising strategy for treating aggressive lymphoma.

Abstract ABCC9‐related intellectual disability and myopathy syndrome (AIMS) arises from loss‐of‐function (LoF) mutations in the ABCC9 gene, which encodes the SUR2 subunit of ATP‐sensitive potassium (KATP) channels. KATP channels are found throughout the cardiovascular system and skeletal muscle and couple cellular metabolism to excitability. AIMS individuals show fatigability, muscle spasms, and cardiac dysfunction. We found reduced exercise performance in mouse models of AIMS harboring premature stop codons in ABCC9. Given the roles of KATP channels in all muscles, we sought to determine how myopathy arises using tissue‐selective suppression of KATP and found that LoF in skeletal muscle, specifically, underlies myopathy. In isolated muscle, SUR2 LoF results in abnormal generation of unstimulated forces, potentially explaining painful spasms in AIMS. We sought to determine whether excessive Ca2+ influx through CaV1.1 channels was responsible for myopathology but found that the Ca2+ channel blocker verapamil unexpectedly resulted in premature death of AIMS mice and that rendering CaV1.1 channels nonpermeable by mutation failed to reverse pathology; results which caution against the use of calcium channel blockers in AIMS.

Obesity impairs tissue insulin sensitivity and signaling, promoting type-2 diabetes. Although improving insulin signaling is key to reversing diabetes, the multi-organ mechanisms regulating this process are poorly defined. Here, we screen the secretome and receptome in Drosophila to identify the hormonal crosstalk affecting diet-induced insulin resistance and obesity. We discover a complex interplay between muscle, neuronal, and adipose tissues, mediated by Bone Morphogenetic Protein (BMP) signaling and the hormone Bursicon, that enhances insulin signaling and sugar tolerance. Muscle-derived BMP signaling, induced by sugar, governs neuronal Bursicon signaling. Bursicon, through its receptor Rickets, a Leucine-rich-repeat-containing G-protein coupled receptor (LGR), improves insulin secretion and insulin sensitivity in adipose tissue, mitigating hyperglycemia. In mouse adipocytes, loss of the Rickets ortholog LGR4 blunts insulin responses, showing an essential role of LGR4 in adipocyte insulin sensitivity. Our findings reveal a muscle-neuronal-fat-tissue axis driving metabolic adaptation to high-sugar conditions, identifying LGR4 as a critical mediator in this regulatory network. Obesity induces insulin resistance and impairs insulin signaling, causing diabetes. Here, the authors show that BMP and LGR signaling mediate communication between muscle, neuronal, and adipose tissues to enhance insulin signaling, identifying LGR as key in protecting against insulin resistance. [ABSTRACT FROM AUTHOR]

Background: Recently the peroneus longus tendon (PLT) gained popularity in anterior cruciate ligament (ACL) reconstruction and has been utilized with satisfactory outcomes. However, there are concerns regarding donor site morbidity. This study aims to compare the functional outcome of ACL reconstruction using hamstring (HT) and PLT autografts and evaluate the donor site morbidity. Methods: Patients who underwent ACL reconstruction were allocated to two groups (HT and PLT). Graft diameter was measured intraoperatively. Knee functional outcome was evaluated with IKDC and Tegner-Lysholm scores preoperatively, and postoperatively after 3 months, 6 months, and 1 year. Donor site morbidities were assessed with thigh circumference measurements, subjective evaluation of sensory disturbances, and ankle scoring with AOFAS and FADI scores. Results: At 1-year follow-up, the PLT group showed comparable IKDC (p = 0.925) and Tegner-Lysholm (p = 0.600) scores with those of the HT group. The mean graft diameter in the PLT group (7.93 ± 0.52 mm) was larger compared with the HT group (7.43 ± 0.50 mm) (p < 0.001). The incidence of thigh atrophy (HT-16.7%, PLT-10%) and sensory disturbances (HT-73.3%, PLT-10%) was greater in the HT group. There was no significant ankle donor site morbidity in the PLT group (AOFAS-98.67 ± 3.45, FADI-99.23 ± 1.69). Conclusion: ACL reconstruction with PLT had comparable functional outcome with that of HT at 1 year. However, PLT demonstrated larger graft diameter, less donor site morbidity, and enhanced muscle recovery without significantly affecting the ankle function. PLT can be safely used as an acceptable alternative graft choice harvested from outside the knee for ACL reconstruction. [ABSTRACT FROM AUTHOR]

This study examines whether retail ownership of a firm is associated with the likelihood that the firm is subject to monitoring and enforcement by the two largest divisions of the SEC. Monitoring is a form of ex ante or preventative regulatory oversight, while enforcement is a form of ex post or punitive oversight. We find a negative association between retail ownership and SEC monitoring. In contrast, we find a positive association between retail ownership and SEC enforcement. These results suggest that the SEC is less likely to monitor firms with high retail ownership, potentially leaving current retail investors more vulnerable to unresolved financial reporting issues. Additionally, the SEC is more likely to issue enforcement actions against firms with high retail ownership, imposing costs on current retail investors when the firm is accused of egregious cases of perceived financial misreporting. [ABSTRACT FROM AUTHOR]

Background: Human epidermal growth factor-2 (HER2) overexpression is an oncogenic driver in many solid tumors, including urothelial bladder cancer (UBC). In addition, activating mutations in the ERBB2 gene have been shown to play an oncogenic role similar to ERBB2 amplification. Objective: To describe and compare the frequency and nature of genomic alterations (GA) of ERBB2-altered (mutations, amplification) and ERBB2 wild-type UBC. Patients and Methods: Using a hybrid capture-based comprehensive profiling assay, 9518 UBC cases were grouped by ERBB2 alteration and evaluated for all classes of genomic alterations (GA), tumor mutational burden (TMB), microsatellite instability (MSI), genome-wide loss of heterozygosity (gLOH), and genomic mutational signature. PD-L1 expression was measured by immunohistochemistry (Dako 22C3). Categorical statistical comparisons were performed using Fisher's exact tests. Results: A total of 602 (6.3%) UBC cases featured ERBB2 extracellular domain short variant (SV) GA (ECDmut+), 253 (2.7%) cases featured ERBB2 kinase domain SV GA (KDmut+), 866 (9.1%) cases had ERBB2 amplification (amp+), and 7797 (81.9%) cases were ERBB2 wild-type (wt). European genetic ancestry of ECDmut+ was higher than ERBB2wt. Numerous significant associations were observed when comparing GA by group. Notably among these, CDKN2A/MTAP loss were more frequent in ERBB2wt versus ECDmut+ and amp+. ERBB3 GA were more frequent in ECDmut+ and KDmut+ than ERBB2wt. TERT GA were more frequent in ECDmut+, KDmut+, and amp+ versus ERBB2wt. TOP2A amplification was significantly more common in ECDmut+ and amp+ versus ERBB2wt, and TP53 SV GA were significantly higher in ERBB2 amp+ versus ERBB2wt. Mean TMB levels were significantly higher in ECDmut+, KDmut+, and amp+ than in ERBB2wt. Apolipoprotein B mRNA-editing enzyme, catalytic polypeptides (APOBEC) signature was more frequent in ECDmut+, KDmut+, and amp+ versus ERBB2wt. No significant differences were observed in PD-L1 status between groups, while gLOH-high status was more common in amp+ versus ERBB2wt. MSI-high status was more frequent in KDmut+ versus ERBB2wt, and in ERBB2wt than in amp+. Conclusions: We noted important differences in co-occurring GA in ERBB2-altered (ECDmut+, KDmut+, amp+) versus ERBB2wt UBC, as well as higher mean TMB and higher APOBEC mutational signature in the ERBB2-altered groups. Our results can help refine future clinical trial designs and elucidate possible response and resistance mechanisms for ERBB2-altered UBC. [ABSTRACT FROM AUTHOR]

Abstract The major social and economic impacts of international migration have led to a strong interest in better understanding the drivers of cross-border movement. Quantitative models have sought to explain global migration patterns in terms of economic, social, climatic, and other variables, and future projections of these variables are increasingly being used to forecast international migration flows. An important implicit assumption in the most widely used class of these approaches, so-called gravity models, is that their parameterisation based on panel data enables them to describe the effects of predictor variables on migration flows across both space and time, i.e., that they explain flow variation both across country pairs at a given time and across time for a given country pair. Here we show that this assumption does not hold. Whilst gravity models describe spatial patterns of international migration very well, they fail to capture even basic temporal dynamics, indeed, often worse than even the time-invariant average of the historical flows. We show that standard validation techniques have been unable to detect this important limitation of gravity models due to the different orders of magnitude of migration flows across spatial corridors, on the one hand, and over time, on the other hand. Our analysis suggests that gravity-model-based inferences about the effects that certain variables have had, or will have, on international migration over time may in reality represent statistical artefacts rather than true mechanisms. We argue that future predictions based on gravity models lack statistical support and that, in its current form, this class of models is not suited for informing policy makers about migration trajectories in the coming years and decades.

Wrist function is a top priority for transradial amputees. However, the combined functional, biomechanical, and cognitive impact of using a powered prosthetic wrist is unclear. Here, we quantify task performance, compensatory movements, and cognitive load while three transradial amputees performed a modified Clothespin Relocation Task using two myoelectric prostheses with and without the wrists. The two myoelectric prostheses include a commercial prosthesis with a built-in powered wrist, and a newly developed inexpensive prosthetic wrist for research purposes, called the "Utah wrist", that can be adapted to work with various sockets and prostheses. For these three participants, task failure rate decreased significantly from 66% ± 12% without the wrist to 39% ± 9% with the Utah wrist. Compensatory forward leaning movements also decreased significantly, from 24.2° ± 2.5 without the wrist to 12.6° ± 1.0 with the Utah wrist, and from 23.6° ± 7.6 to 15.3° ± 7.2 with the commercial prosthesis with an integrated wrist. Compensatory leftward bending movements also significantly decreased, from 20.8° ± 8.6 to 12.3° ± 5.3, for the commercial with an integrated wrist. Importantly, simultaneous myoelectric control of either prosthetic wrist had no significant impact on cognitive load, as assessed by the NASA Task Load Index survey and a secondary detection response task. This work suggests that functional prosthetic wrists can improve dexterity and reduce compensation without significantly increasing cognitive effort. These results, and the introduction of a new inexpensive prosthetic wrist for research purposes, can aid future research and development and guide the prescription of upper-limb prostheses. [ABSTRACT FROM AUTHOR]

Out-of-hospital cardiac arrest (OHCA) is a global health problem affecting approximately 4.4 million individuals yearly. OHCA has a poor survival rate, specifically when unwitnessed (accounting for up to 75% of cases). Rapid recognition can significantly improve OHCA survival, and consumer wearables with continuous cardiopulmonary monitoring capabilities hold potential to "witness" cardiac arrest and activate emergency services. In this study, we used an arterial occlusion model to simulate cardiac arrest and investigated the ability of infrared photoplethysmogram (PPG) sensors, often utilized in consumer wearable devices, to differentiate normal cardiac pulsation, pulseless cardiac (i.e., resembling a cardiac arrest), and non-physiologic (i.e., off-body) states. Across the classification models trained and evaluated on three anatomical locations, higher classification performances were observed on the finger (macro average F1-score of 0.964 on the fingertip and 0.954 on the finger base) compared to the wrist (macro average F1-score of 0.837). The wrist-based classification model, which was trained and evaluated using all PPG measurements, including both high- and low-quality recordings, achieved a macro average precision and recall of 0.922 and 0.800, respectively. This wrist-based model, which represents the most common form factor in consumer wearables, could only capture about 43.8% of pulseless events. However, models trained and tested exclusively on high-quality recordings achieved higher classification outcomes (macro average F1-score of 0.975 on the fingertip, 0.973 on the finger base, and 0.934 on the wrist). The fingertip model had the highest performance to differentiate arterial occlusion pulselessness from normal cardiac pulsation and off-body measurements with macro average precision and recall of 0.978 and 0.972, respectively. This model was able to identify 93.7% of pulseless states (i.e., resembling a cardiac arrest event), with a 0.4% false positive rate. All classification models relied on a combination of time-, power spectral density (PSD)-, and frequency-domain features to differentiate normal cardiac pulsation, pulseless cardiac, and off-body PPG recordings. However, our best model represented an idealized detection condition, relying on ensuring high-quality PPG data for training and evaluation of machine learning algorithms. While 90.7% of our PPG recordings from the fingertip were considered of high quality, only 53.2% of the measurements from the wrist passed the quality criteria. Our findings have implications for adapting consumer wearables to provide OHCA detection, involving advancements in hardware and software to ensure high-quality measurements in real-world settings, as well as development of wearables with form factors that enable high-quality PPG data acquisition more consistently. Given these improvements, we demonstrate that OHCA detection can feasibly be made available to anyone using PPG-based consumer wearables. [ABSTRACT FROM AUTHOR]

Introduction: The debate continues as to whether laparoscopic total Nissen (LNF) versus partial posterior Toupet fundoplication (LTF) leads to better outcomes in the surgical treatment of axial hiatal hernia with gastroesophageal reflux disease. In the most recent meta-analysis including 13 RCTs with 1564 patients, no significant difference was found between the two procedures in terms of perioperative complications and recurrent reflux rates. Further comparative analyses are urgently needed. Methods: This retrospective analysis of prospectively recorded data from the Herniamed Registry compared the perioperative and 1-year follow-up outcomes after total Nissen versus partial Toupet fundoplication. Propensity score matching was chosen as the statistical method. Matching was performed for n = 2290 pairs. Results: No systematic discrepancy was found between the Nissen and Toupet fundoplication for any of the outcome parameters (intraoperative complications LNF 2.10% vs LTF 1.48%, general complications 2.27% vs 2.88%, postoperative complications 1.44% vs 1.18%, complication-related reoperation 1.00% vs 0.91%, recurrence on 1-year follow-up 6.55% vs 5.33%, pain on exertion on 1-year follow-up 12.49% vs 9.52%, pain at rest on 1-year follow-up 10.44 vs 9.52% and pain requiring treatment on 1-year follow-up 9.61% vs 8.17%). Also the postoperative dysphagia rate showed with 5.34% after LNF and with 4.64% after LTF no significant difference. Conclusion: The findings presented here did not show any significant difference up to 1 year after Nissen or Toupet fundoplication. This is in concordance with the findings of the meta-analyses. However, the perioperative and 1-year follow-up outcomes demonstrate that both operation techniques should be carried out by experienced surgeons. [ABSTRACT FROM AUTHOR]

Recent artificial intelligence advances, especially those of large language models (LLMs), have increasingly shown glimpses of human-like intelligence. This has led to bold claims that these systems are no longer a mere "it" but now a "who," a kind of person deserving respect. In this paper, I argue that this view depends on a Cartesian account of personhood, on which identifying someone as a person is based on their cognitive sophistication and ability to address common-sense reasoning problems. I contrast this with a different account of personhood, one where an agent is a person if they are autonomous, responsive to norms, and culpable for their actions. On this latter account, I show that LLMs are not person-like, as evidenced by their propensity for dishonesty, inconsistency, and offensiveness. Moreover, I argue current LLMs, given the way they are designed and trained, cannot be persons—either social or Cartesian. The upshot is that contemporary LLMs are not, and never will be, persons. [ABSTRACT FROM AUTHOR]

Introduction: The prefrontal cortex (PFC), crucial for cognition and memory, occupies a third of the cerebral cortex. This study investigated the protective effects of aqueous extract of Colocasia esculenta leaf (AECEL) against lipopolysaccharide (LPS)-induced PFC damage in mice. Methods: 42 male Swiss albino mice (18–22 g) were divided into six groups. Group A: healthy controls. Groups B-F received daily intraperitoneal LPS injections (0.5 mg/kg) for seven days. Group B: received distilled water, (2 ml) subsequently. Groups C-E: AECEL at 400, 600, and 800 mg/kg, respectively. Group F: donepezil (DPZ, 2.5 mg/kg) by oral gavage. All treatments continued for 28 days. Results: LPS exposure significantly increased brain oxidative stress markers and reduced antioxidant enzymes compared to controls (p < 0.05). AECEL and DPZ administration significantly reduced brain oxidative stress markers and reduced antioxidant enzymes, as well as tumor necrosis factor-α and interleukin-6 levels (p < 0.05) compared to LPS ONLY group. Y-maze testing revealed decreased alternation (%) in the LPS group compared to controls (p < 0.05). Based on Y-maze performance, AECEL at 400 mg/kg emerged as the most effective dose, significantly improving alternation (%) compared to both LPS and LPS + DPZ groups (p < 0.05). Bielschowsky staining showed senile plaques and neurofibrillary tangles in the LPS group. Conclusion: LPS induced PFC damage. Among the tested doses, AECEL at 600 mg/kg demonstrated the most effective improvement in cognitive function, memory, and anxiety-like behaviors as measured by the Y-maze test.Article Highlights: Intraperitoneal administration of Lipopolysaccharide induced damages to the Prefrontal Cortex of mouse Aqueous extract of Colocasia esculenta leaf exhibited antioxidant property Aqueous extract of Colocasia esculenta leaf ameliorated pathological changes in the Prefrontal cortex. Aqueous extract of Colocasia esculenta leaf has therapeutic potential of mitigating Alzheimer’s disease-like pathology and preserving brain morphology. Aqueous extract of Colocasia esculenta leaf improved cognitive function. [ABSTRACT FROM AUTHOR]

Dyslipidaemia describes the condition of abnormal lipid levels in a person's bloodstream. Since the 1980s, statin medications have been used to treat dyslipidaemia and other comorbidities, such as stroke risk and atherosclerosis. Statin medications were initially synthesised from fungal metabolites, but many synthetic statin drugs have been manufactured since then. Statin medication is quite effective in reducing total cholesterol levels in the bloodstream, but it has limitations. Due to their poor water solubility, statin drugs possess poor oral bioavailability, which hinders their therapeutic efficacy. Nanoparticle drug delivery technology has been shown to improve the pharmacokinetic profiles of many drug classes, and statins have great potential to benefit from this. This paper reviewed the currently available literature on nanoparticle statin medication and evaluated the possible improvements that can be made to the pharmacokinetic profile and efficacy of conventional statin medication. It was found that the oral bioavailability of nanoparticle medication consistently outperformed conventional medication by up to 400% in some cases. Substantial improvements in time to peak plasma concentration and plasma concentration peaks were also found, and increased periods in circulation before excretion were shown. It was concluded that nanoparticle technology has the potential to completely replace conventional statin medication as it offers more significant benefits with minimal drawbacks. Upon further study and development, the manufacture of nanoparticle statin medication should become feasible enough for large-scale application, which will significantly benefit patients and unburden healthcare systems. [ABSTRACT FROM AUTHOR]

Purpose: In light of the reported association between REM-related obstructive sleep apnoea (OSA) and heightened cardiovascular risk, this study aims to compare cardiac autonomic function in patients with REM-OSA and OSA independent of sleep stage. We hypothesized that REM-OSA patients would exhibit higher sympathetic cardiac modulation based on heart rate variability (HRV) profiles. Methods: HRV was compared between the OSA group (AHI ≥ 5 events/h, n = 252) and the REM-OSA group (AHI ≥ 5 events/h, AHIREM:AHINREM ≥ 2, n = 137). Time- and frequency-domain measures of HRV were analysed during N2 and REM sleep. Results: Clinical characteristics between the two test groups differed significantly, 45% of REM-OSA patients were female, with mild OSA (median, interquartile range (IQR)) AHI of 10 (7) events/h. Only 26% of the OSA cohort were female with moderate OSA (AHI = 17 (20) events/h, p < 0.001). Compared with the OSA group, the low frequency to high frequency ratio (LF:HF) and LF power were lower and HF power was higher in the REM-OSA group during N2 (LF:HF, p = 0.012; LF; p = 0.013; HF, p = 0.007) and in REM sleep (LF:HF, p = 0.002; LF, p = 0.004; HF, p < 0.001). Patient sex and OSA severity had a significant combined effect on average N to N interval, LF power, and LF:HF ratio during N2 and REM sleep (all p < 0.001). Conclusion: Contrary to our hypothesis, REM-OSA patients demonstrated consistently higher cardiac vagal modulation, reflecting better cardiac autonomic adaptation. These results were attributed to differences in OSA severity and sex in these two groups, both independently affecting HRV. This study emphasises the need for future research into the underlying pathophysiology of REM-OSA and the potential implications of sex and OSA severity on cardiovascular risk. [ABSTRACT FROM AUTHOR]

Materials with hierarchical architectures that combine soft and hard material domains with coalesced interfaces possess superior properties compared with their homogeneous counterparts1–4. These architectures in synthetic materials have been achieved through deterministic manufacturing strategies such as 3D printing, which require an a priori design and active intervention throughout the process to achieve architectures spanning multiple length scales5–9. Here we harness frontal polymerization spin mode dynamics to autonomously fabricate patterned crystalline domains in poly(cyclooctadiene) with multiscale organization. This rapid, dissipative processing method leads to the formation of amorphous and semi-crystalline domains emerging from the internal interfaces generated between the solid polymer and the propagating cure front. The size, spacing and arrangement of the domains are controlled by the interplay between the reaction kinetics, thermochemistry and boundary conditions. Small perturbations in the fabrication conditions reproducibly lead to remarkable changes in the patterned microstructure and the resulting strength, elastic modulus and toughness of the polymer. This ability to control mechanical properties and performance solely through the initial conditions and the mode of front propagation represents a marked advancement in the design and manufacturing of advanced multiscale materials.Frontal polymerization spin mode dynamics is used to autonomously fabricate patterned crystalline domains in poly(cyclooctadiene) with multiscale organization. [ABSTRACT FROM AUTHOR]

The oral bioavailability of sildenafil citrate is approximately 43%, primarily limited by the low aqueous solubility and first-pass effect. Considering the drug properties and biopharmaceutical considerations, this study aimed to develop an immediate release, taste masked orodispersible film (ODF) of sildenafil citrate for the efficient management of pulmonary arterial hypertension (PAH). The optimization was done by applying 32 full-factorial design. The drug-loaded film was prepared and evaluated for the physical and mechanical parameters like; thickness, disintegration time, tensile strength, elongation, swelling index, content uniformity, disintegration and in vitro drug release in pH 6.2 stimulated salivary fluid. The FTIR and DSC data proved excellent compatibility between the drug and polymers used. The time taken for disintegration by the optimized film was about 62.66 s, while the drug release was observed ~ 96% in 10 min. Pharmacokinetic studies exhibited better sildenafil plasma level (p < 0.05) and Cmax (p < 0.001) of orally disintegrating film which is significantly higher than the oral drug solution. The AUC0–8 (24874.425 ± 1234.45 ng. h/mL) in the oromucosal application was 1.2-fold more (p < 0.0001) than the control. The presence of sweetening and flavoring agents in the formulation masked the drug bitterness, resulting in a higher intake of the formulation in rats compared to the unmasked drug solution, as observed with in vivo taste masking studies. The importance of ODF as a feasible, effective, and optimal approach for delivering sildenafil citrate via oromucosal administration for the treatment of PAH was successfully highlighted by these results. [ABSTRACT FROM AUTHOR]

Unmodeled displacements in GNSS times series, induced by instrumental artifacts or geophysical events, create significant biases in station trajectory parameters that can propagate into the reference frame itself. While non-tectonic ‘jumps’, such as equipment changes, affect only a specific GNSS station, seismically-induced displacements can affect large numbers of sites, severely threatening the frame’s stability. Manually reviewing individual GNSS time series for such effects is highly impractical because there can be thousands of GNSS stations in a frame, and the total number of earthquakes Mw ≥ 6.0 since GPS became fully operational is + 5100. To avoid this time-consuming task, automated methods rely on empirical power-law functions to determine which earthquake-station pairs require coseismic displacement parameters. Still, ‘conservative’ power-law functions tend to add coseismic offsets to stations that do not need them, which can also threaten the stability of the frame. In this work, we present an empirical formulation that was obtained using 809 global seismic events to fit power-law parameters that do not overestimate the region of influence of earthquakes. Our method is based on a two-level selection process: level 1 is isotropic and only considers the epicentral distance between the stations and the earthquake, and level 2 uses the geophysical parameters of the earthquake to predict a ‘tighter’ displacement pattern to select which stations require coseismic trajectory parameters. We applied our level 2 method to a database of ~ 4700 event-station pairs and showed that it removed ~ 55% of the total pairs, all of which had been falsely selected by level 1. [ABSTRACT FROM AUTHOR]

Present work was conducted to prepare amidoximated based nanocomposites (A-PAMM) could be applied as novel nanoadsorbents for the removal of Cu(II) from aqueous environments. The nanoadsorbents were synthesized via chemical grafting of polyacrylonitrile (PAN) onto surface of ethylenediamine-functionalized montmorillonite (EDA-MMT). The as-synthesized nanoadsorbents were analyzed using Fourier transform infrared spectrometry (FTIR), transmission electron microscopy (TEM), X-ray diffraction (XRD), and Brunauer–Emmett–Teller (BET). The polymerization of monomer was carried out using 2 wt0% initiator benzoyl peroxide (BPO, C14H10O4). The prepared A-PAMM nanoadsorbents were further modified with hydroxylamine hydrochloride. The amidoximation process enhances the adsorption capacity of nanocomposites by introducing amidoxime functional groups, which facilitate stronger interactions with Cu(II) through chelation and electrostatic attraction, leading to improved adsorption efficiency. The effects of pH, contact time at different temperature and adsorbent dosage on rate of Cu (II) adsorption was evaluated and the maximum adsorption was obtained with pH 5.4 and contact time of 180 min at 40°C with A-PAMM 5%. The kinetic analysis indicated a pseudo-second-order model for adsorption, with amidoxime-modified samples exhibiting higher rates due to additional amine sites. The Freundlich model best described the adsorption data, particularly for A-PAMM 5%, which had a greater affinity for Cu(II) than EDA-MMT. These findings highlight the effectiveness of amidoxime-modified nanocomposites for Cu(II) removal in wastewater treatment. [ABSTRACT FROM AUTHOR]

Although it is unanimous among scientists and researchers that the food production chain is a substantial contributor to environmental challenges, so far, no food ingredient has been evaluated for its environmental performance relative to planetary boundaries. Given this, this study conducts an analysis oriented to food key ingredients considered essential in human nutrition, namely: proteins, β-carotene as a precursor of vitamin A, and polyunsaturated fatty acids (docosahexaenoic and eicosapentaenoic acids), using life cycle assessment (LCA) linked to the planetary boundary structure, under nine indices: climate change, biosphere integrity, global biogeochemical fluxes, stratospheric ozone depletion, ocean acidification, global freshwater use, land use change, chemical pollution, and atmospheric aerosol loading. Protein sources from animals such as beef, pork, and poultry, β-carotene from palm oil and synthetic routes, and fatty acids from fish oil were also compared to alternative sources from microalgae-based ingredients. The results show that protein ingredients of animal origin and alternatives have largely contributed to the disruption of planetary boundaries. However, the worst environmental performance for protein ingredients studied was attributed to bovine protein, matching three risk indices (climate change, ecotoxicity, and photochemical ozone formation) out of the nine evaluated. On the other hand, among fine chemical food ingredients, only vitamin A from palm oil, which is mostly found in a risk and uncertainty zone, when compared to conventional synthetic processes and microalgae-based; these, in turn, operate fully within safe limits. In contrast, only one planetary index is assigned to the uncertainty zone for polyunsaturated fatty acids from fish oil, the others operate in safe zones equally for microalgae-based processes. Therefore, the conclusions highlight major challenges the food production chain faces to achieve safe and sustainable food. These results guide critical food groups and environmental indicators to prioritize in future efforts to reduce environmental impact. [ABSTRACT FROM AUTHOR]

Calorie restriction has many beneficial effects on healthspan and lifespan in a variety of species. However, how late in life application of caloric restriction can extend fly life is not clear. Here we show that late-life calorie restriction increases lifespan in female Drosophila melanogaster aged on a high-calorie diet. This shift results in rapid decrease in mortality rate and extends fly lifespan. In contrast, shifting female flies from a low- to a high-calorie diet leads to a rapid increase in mortality and shorter lifespan. These changes are mediated by immediate metabolic and physiological adaptations. One of such adaptation is rapid adjustment in egg production, with flies directing excess energy towards egg production when shifted to a high diet, or away from reproduction in females shifted to low-caloric diet. However, lifelong female fecundity reveals no associated fitness cost due to CR when flies are shifted to a high-calorie diet. In view of high conservation of the beneficial effects of CR on physiology and lifespan in a wide variety of organisms, including humans, our findings could provide valuable insight into CR applications that could provide health benefits later in life. [ABSTRACT FROM AUTHOR]

Despite the universal impact of sarcopenia on compromised health and quality of life in the elderly, promising pharmaceutical approaches that can effectively mitigate loss of muscle and function during aging have been limited. Our group and others have reported impairments in peripheral motor neurons and loss of muscle innervation as initiating factors in sarcopenia, contributing to mitochondrial dysfunction and elevated oxidative stress in muscle. We recently reported a reduction in α motor neuron loss in aging mice in response to the compound OKN-007, a proposed antioxidant and anti-inflammatory agent. In the current study, we asked whether OKN-007 treatment in wildtype male mice for 8–9 months beginning at 16 months of age can also protect muscle mass and function. At 25 months of age, we observed a reduction in the loss of whole-body lean mass, a reduced loss of innervation at the neuromuscular junction and well-preserved neuromuscular junction morphology in OKN-007 treated mice versus age matched wildtype untreated mice. The loss in muscle force generation in aging mice (~ 25%) is significantly improved with OKN-007 treatment. In contrast, OKN-007 treatment provided no protection in loss of muscle mass in aging mice. Mitochondrial function was improved by OKN-007 treatment, consistent with its potential antioxidative properties. Together, these exciting findings are the first to demonstrate that interventions through neuroprotection can be an effective therapy to counter aging-related muscle dysfunction. [ABSTRACT FROM AUTHOR]

Localizing security-relevant hard blocks on modern System-on-Chips for physical attacks, such as side-channel analysis and fault attacks, has become increasingly time-consuming due to ever-increasing chip-area and -complexity. While this development increases the effort and reverse engineering cost, it is not sufficient to withstand resolute attackers. This paper explores the application of camera-based lock-in thermography, a nondestructive testing method, for identifying and localizing security hard blocks on integrated circuits. We use a synchronous signal to periodically activate security-related functions in the firmware, which causes periodic temperature changes in the activated die areas that we detect and localize via an infrared camera. Using this method, we demonstrate the precise detection and localization of security-related hard blocks at the die level on a modern SoC. [ABSTRACT FROM AUTHOR]

Summary: Patients who sustain fragility fractures prior to total shoulder arthroplasty have significantly higher risk for bone health-related complications within 8 years of procedure. Identification of these high-risk patients with an emphasis on preoperative, intraoperative, and postoperative bone health optimization may help minimize these preventable complications. Purpose: As the population ages, more patients with osteoporosis are undergoing total shoulder arthroplasty (TSA), including those who have sustained a prior fragility fracture. Sustaining a fragility fracture before TSA has been associated with increased risk of short-term revision rates, periprosthetic fracture (PPF), and secondary fragility fractures but long-term implant survivorship in this patient population is unknown. Therefore, the purpose of this study was to characterize the association of prior fragility fractures with 8-year risks of revision TSA, periprosthetic fracture, and secondary fragility fracture. Methods: Patients aged 50 years and older who underwent TSA were identified in a large national database. Patients were stratified based on whether they sustained a fragility fracture within 3 years prior to TSA. Patients who had a prior fragility fracture (7631) were matched 1:1 to patients who did not based on age, gender, Charlson Comorbidity Index (CCI), smoking, obesity, diabetes mellitus, and alcohol use. Kaplan–Meier and Cox Proportional Hazards analyses were used to observe the cumulative incidences of all-cause revision, periprosthetic fracture, and secondary fragility fracture within 8 years of index surgery. Results: The 8-year cumulative incidence of revision TSA (5.7% vs. 4.1%), periprosthetic fracture (3.8% vs. 1.4%), and secondary fragility fracture (46.5% vs. 10.1%) were significantly higher for those who had a prior fragility fracture when compared to those who did not. On multivariable analysis, a prior fragility fracture was associated with higher risks of revision (hazard ratio [HR], 1.48; 95% confidence interval [CI], 1.24–1.74; p < 0.001), periprosthetic fracture (HR, 2.98; 95% CI, 2.18–4.07; p < 0.001) and secondary fragility fracture (HR, 8.39; 95% CI, 7.62–9.24; p < 0.001). Conclusions: Prior fragility fracture was a significant risk factor for revision, periprosthetic fracture, and secondary fragility fracture within 8 years of primary TSA. Identification of these high-risk patients with an emphasis on preoperative and postoperative bone health optimization may help minimize these complications. Level of Evidence: III. [ABSTRACT FROM AUTHOR]

Mild traumatic brain injury (mTBI) and occupational blast exposure in military Service Members may lead to impaired brain waste clearance which increases neurological disease risk. Perivascular spaces (PVS) are a key part of the glymphatic system which supports brain waste clearance, preferentially during sleep. Visible PVS on clinical magnetic resonance imaging have been previously observed in patients with neurodegenerative diseases and animal neurotrauma models. The purpose of this study was to determine associations between PVS morphological characteristics, military career stage, and mTBI history in Special Operations Forces (SOF) Soldiers. Participants underwent T2-weighed neuroimaging to capture three-dimensional whole brain volumes. Segmentation was performed using a previously validated, multi-scale deep convolutional encoder-decoder neural network. Only PVS clusters within the white matter mask were quantified for analyses. Due to non-normal PVS metric distribution, non-parametric Mann–Whitney U tests were used to determine group differences in PVS outcomes. In total, 223 healthy SOF combat Soldiers (age = 33.1 ± 4.3yrs) were included, 217 reported career stage. Soldiers with mTBI history had greater PVS number (z = 2.51, P = 0.013) and PVS volume (z = 2.42, P = 0.016). In-career SOF combat Soldiers had greater PVS number (z = 2.56, P = 0.01) and PVS volume (z = 2.28, P = 0.02) compared to a baseline cohort. Mild TBI history is associated with increased PVS burden in SOF combat Soldiers that are clinically recovered from mTBI. This may indicate ongoing physiological changes that could lead to impaired waste clearance via the glymphatic system. Future studies should determine if PVS number and volume are meaningful neurobiological outcomes for neurodegenerative disease risk and if clinical interventions such as improving sleep can reduce PVS burden. [ABSTRACT FROM AUTHOR]

Ayapana triplinervis (M.Vahl) R.M.King & H.Rob. (Asteraceae), popularly known as japana, is a tropical, aromatic subshrub widely used as tea to combat some diseases. The essential oil was obtained from the leaves by hydrodistillation (3 h), and the chemical composition was analyzed by gas chromatography coupled to mass spectrometry. For in vivo assays, Mus musculus/Swiss mice were used to evaluate oral acute toxicological (at dose of 2000 mg/kg); peripheral and central analgesic for abdominal contortion (doses of 6.25, 12.5, 25, 50 and 100 mg/kg), hot plate test (12.5, 25, 50, and 100 mg/kg) and formalin (25, 50 and 100 mg/kg); open field test (100 mg/kg); and anti-inflammatory by ear swelling induced by xylene (6.25,12.5, 25, 50, and 100 mg/kg). The yield of A. triplinervis essential oil (AtEO) was 4.6%, and the oxygenated monoterpene 2,5-dimethoxy-p-cymene was the major compound in this study (63.6%). AtEO at a dose of 2,000 mg/kg orally did not change the behavior patterns or mortality of the animals; liver and kidney biochemical levels were similar to the control group, indicating no liver and kidney toxicity. Moreover, AtEO, at doses of 6.25, 12.5, 25, 50, and 100 mg/kg, reduced abdominal contortions by 21%, 54%, 91%, 58%, and 55%, respectively. In the hot plate test, AtEO showed a significant increase in latency time in the 60-min interval at doses of 25 mg/kg (11.3 ± 3.3 s) and 100 mg/kg (11.9 ± 0.9 s). In the first phase of the formalin test, AtEO decreased paw licking time at doses of 25, 50, and 100 mg/kg, with inhibition of 22%, 38%, and 83%; in the second phase, the same doses, decreased licking time with inhibition of 24%, 34%, and 76%. AtEO did not present a significant change in the spontaneous locomotor activity of the animals. Doses of 6.25, 12.5, 25, 50, and 100 mg/kg significantly reduced ear edema induced by topical application of xylene with percentages of 40%, 39%, 54%, 45%, and 45%, respectively. So, AtEO demonstrated low acute oral toxicity and exhibited significant antinociceptive and anti-inflammatory actions, consistent with the use of A. triplinervis in traditional medicine. [ABSTRACT FROM AUTHOR]

Purpose of review: Adolescent wrestlers undergo intense physical combat. While guidelines are effective in keeping the sport safer, concerns specific to the adolescent wrestler may be missed at primary care visits without knowledge of the unique challenges faced by these athletes. The following review highlights important characteristics of the adolescent wrestler which are of interest to primary care providers. Recent findings: Recommendations for concussion management are evolving to gradual return-to-sport after physician clearance rather than total sport removal. Prolonged skin-to-skin contact also places athletes at greater risk of dermatologic infections, which often require removal from competition, treatment, and/or coverage. Finally, adolescent nutritional literature recommends limiting pre-match weight loss to 3–5% body weight due to noted kidney damage that may result from larger deficits. Summary: Adolescent wrestlers are more prone to acute injuries than chronic overuse injuries, with most injuries occurring above the trunk. Primary care providers should consider obtaining imaging to rule out severe injuries or referring to specialist providers. Current guidelines for skin infections require frequent pre-match skin checks and mandatory waiting periods when certain infections are identified. However, the primary care provider is well-equipped for more in-depth skin examination, discussion of skin hygiene, and appropriate treatment of skin infections. Athletes attempting to meet lower weight classes may put themselves at risk of acute kidney damage, under-fueling, and eating disorders. Current guidelines attempt to mitigate excessive weight changes in the adolescent wrestler during competition season, but primary care providers should emphasize healthier methods of weight fluctuation and look for indicators of physiological or psychological effects. [ABSTRACT FROM AUTHOR]

Purpose: The current diagnostic methods for leptospirosis diagnosis are technically complex and expensive, with limited applicability to specialized laboratories. Furthermore, they lack diagnostic accuracy in the acute stage of the disease, which coincides with a period when antibiotics are highly effective. New simple and accurate tests are mandatory to decentralize and improve diagnosis. Here, we introduced a new lateral flow immunoassay (Lepto-LF) for human leptospirosis. Methods: We conducted a double-blinded assay using 104 serum samples from patients with confirmed or discarded diagnosis for leptospirosis. The diagnostic performance of Lepto-LF was estimated across different ranges of days from onset of symptoms (dpo), considering the diagnostic algorithm as reference standard. Additionally, it was compared with the screening methods enzyme-linked immunosorbent assay (IgM-ELISA) and the slide agglutination test using temperature-resistant antigen (SATR). Results: Lepto-LF exhibited perfect diagnostic performance with a Youden´s index J = 1 from 6 dpo in the acute phase. IgM-ELISA gave slightly lower accuracy with J = 0.91 and 95.5% of both sensitivity and specificity; while SATR showed a markedly inferior yield (J = 0.41, sensitivity = 95.5%, specificity = 45.5%). The performances remained consistent in the convalescence phase of the disease (> 10 dpo). Conclusion: Lepto-LF was found to be a reliable test for simple, rapid and early diagnosis of leptospirosis, resulting a promising tool for decentralizing leptospirosis diagnosis and enabling timely treatment of patients. In addition, Lepto-LF may be employed as confirmatory test, especially in remote areas and vulnerable contexts where the standard MAT is not available. [ABSTRACT FROM AUTHOR]

When calculating cardiac index (C.I.) by the Fick method, oxygen consumption (VO2) is often unknown, so assumed values are typically used. This practice introduces a known source of inaccuracy into the calculation. Using a measured VO2 (mVO2) from the CARESCAPE E-sCAiOVX module provides an alternative that may improve accuracy of C.I. calculations. Our aim is to validate this measurement in a general pediatric catheterization population and compare its accuracy with assumed VO2 (aVO2). mVO2 was recorded for all patients undergoing cardiac catheterization with general anesthesia and controlled ventilation during the study period. mVO2 was compared to the reference VO2 (refVO2) determined by the reverse Fick method using cardiac MRI (cMRI) or thermodilution (TD) as a reference standard for measurement of C.I. when available. 193 VO2 measurements were obtained, including 71 with a corresponding cMRI or TD measure of cardiac index for validation. mVO2 demonstrated satisfactory concordance and correlation with the TD- or cMRI-derived refVO2 (ρc = 0.73, r2 = 0.63) with a mean bias of − 3.2% (SD ± 17.3%). Assumed VO2 demonstrated much weaker concordance and correlation with refVO2 (ρc = 0.28, r2 = 0.31) with a mean bias of + 27.5% (SD ± 30.0%). Subgroup analysis of patients < 36 months of age demonstrated that error in mVO2 was not significantly different from that observed in older patients. Many previously reported prediction models for assuming VO2 performed poorly in this younger age range. Measured oxygen consumption using the E-sCAiOVX module is significantly more accurate than assumed VO2 when compared to TD- or cMRI-derived VO2 in a pediatric catheterization lab. [ABSTRACT FROM AUTHOR]

Palm kernel oil (PKO) is a non-edible oil which is enriched with saturated fatty acids that can be used as a raw material for many industrial applications. Indian PKO (IPKO) was chosen in this study which has been explored sporadically in industries. IPKO was characterized and utilized for the synthesis of fatty acid alkyl esters through transesterification (solvolysis) using methanol and ethanol solvents coupled with alkali catalysts such as sodium hydroxide (NaOH) and potassium hydroxide (KOH). Upon comparison, methanol and NaOH resulted in the maximum biodiesel (esters) yield of 67.77% as compared to ethanol-based solvolysis. Compositional analysis of fatty acid methyl esters (FAMEs) through GC–MS elucidated the presence of long chain (C12:0 to C18:1) esters, which can be utilized as biodiesel. Therefore, IPKO FAME has been tested as diesel blend in engines without any modification, where, B5 (5% v/v) blend showed at-par fuel characteristics and engine efficiency as compared to non-blended diesel with minimal emissions. To induct a waste circular reprocessing startegy, crude glycerol resulted from transesterification of IPKO was supplemented to Candida tropicalis NCIM3118 for xylitol (a sweetener) synthesis. The results indicated that upon supplemention of IPKO crude glycerol as co-substrate, enhancement in xylitol production of about 0.93 gxylitol/gtotal organic carbon as compared to only xylose as 'C' source (0.81 gxylitol/gtotal organic carbon) was observed with efficiency improvement in overall growth kinetic behavior. This study demonstrates the circular economy approach in which that the IPKO can be utilized for biodiesel production, while, the by-product (crude glycerol) generated could be deployed for xylitol production. [ABSTRACT FROM AUTHOR]

Subaerial biofilms (SAB) are intricate microbial communities living on terrestrial surfaces, of interest in a variety of contexts including cultural heritage preservation, microbial ecology, biogeochemical cycling, and biotechnology. Here we propose a mathematical model aimed at better understanding the interplay between cyanobacteria and heterotrophic bacteria, common microbial SAB constituents, and their mutual dependence on local environmental conditions. SABs are modeled as thin mixed biofilm-liquid water layers sitting on stone. A system of ordinary differential equations regulates the dynamics of key SAB components: cyanobacteria, heterotrophs, polysaccharides and decayed biomass, as well as cellular levels of organic carbon, nitrogen and energy. These components are interconnected through a network of energetically dominant metabolic pathways, modeled with limitation terms reflecting the impact of biotic and abiotic factors. Daily cylces of temperature, humidity, and light intensity are considered as input model variables that regulate microbial activity by influencing water availability and metabolic kinetics. Relevant physico-chemical processes, including pH regulation, further contribute to a description of the SAB ecology. Numerical simulations explore the dynamics of SABs in a real-world context, revealing distinct daily activity periods shaped by water activity and light availability, as well as longer time scale survivability conditions. Results also suggest that heterotrophs could play a substantial role in decomposing non-volatile carbon compounds and regulating pH, thus influencing the overall composition and stability of the biofilm. [ABSTRACT FROM AUTHOR]

Background: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and glomerulonephritis is uncommon in children. We sought to characterize the histological and clinical features of the disease and report on risk factors for adverse outcomes in a pediatric cohort. Methods: Retrospective single-center cohort of all pediatric (< 20 years) patients diagnosed with ANCA-associated glomerulonephritis (AAGN) by kidney biopsy between 2002 and 2022 at Johns Hopkins University. Histological and clinical features were extracted from the medical record. Clinical, laboratory, and histological findings were analyzed to determine the association with kidney failure (KF) and/or death. Results: A total of 17 patients were identified (GPA n = 7, MPA = 10) with a median age of 15 years (IQR 12–17) at presentation, a slight female predominance (59%), with seven patients reaching the composite outcome of death (n = 1) or kidney failure (n = 6). There was no difference in presenting clinical symptoms or extra-renal manifestations between the two groups. Univariable Cox regression identified several factors associated with an increased hazard of endpoint including the degree of global or segmental sclerosis, interstitial fibrosis and tubular atrophy (IFTA), C3 and C1q staining, presence of subendothelial deposits, and proteinuria. Multivariable regression was not performed due to the small sample size. We saw a trend towards increased utilization of plasma exchange and a decrease in cyclophosphamide utilization in the more recent era. There was no association between treatment modality and outcome. Conclusions: Pediatric AAGN is a rare disease associated with significant morbidity. We identified glomerulosclerosis and IFTA on histology, and proteinuria on initial presentation as risk factors for KF/death. [ABSTRACT FROM AUTHOR]

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Long Acting Injectable (LAI) therapy to treat HIV is an alternative to daily oral medications. The success of early roll-out of LAI to eligible patients requires a better understanding of patients' awareness and interest in this novel therapy. We administered an electronic survey to patients attending an urban HIV clinic in the US South. Eligible participants were 18 + years old with a most recent HIV-1 viral load < 200 copies/ml, without any evidence of genotypic resistance to LAI components or chronic hepatitis B. Survey recipients were asked about current treatment, engagement in care, and knowledge of LAI. Between January-April 2023, 480 patients were screened; 319 were eligible, and 155 (49%) completed the survey. The majority (119, 77%) were aware of, and 87 (56%) were interested in LAI. In regression analysis, only age was associated with interest in LAI (OR 0.95, 95% CI 0.92,0.99). Among proposed benefits of injectables, ease of travel without pills, lack of daily pill-taking, and fewer medication interactions were most appealing. Among proposed concerns with injectables, higher cost and insurance coverage of the new medicine were most worrisome. A large majority of people with HIV (PWH) are aware of the newest treatment available, and just over half of our sample expressed interest in LAI. Older age was associated with lower interest in LAI. LAI is appealing for its convenience, privacy, and avoidance of drug interactions, while the increased costs associated with LAI need to be addressed. [ABSTRACT FROM AUTHOR]

Common Reed Phragmites australis, globally one of the mostly widely distributed wetland plants, is important for biodiversity and for humans. However, like most wetland plant communities, reedbed has rarely been mapped at large geographical scales, restricting the information available to study reed’s range dynamics or inform its management. Using Sentinel-2 data and machine learning, we aimed to produce the first published remotely-sensed reedbed map of Britain; however, accuracy as assessed by field validation was relatively low (AUC = 0.671), with many false positives (commission error of 93.4%). A similar workflow carried out in Google Earth Engine, using nearly an order of magnitude more images, gave a lower commission error but a disproportionately higher omission error. Using the known commission and omission error, we estimate that in 2015–2017 ~ 7800 ha of Britain was reedbed. Our study highlights the enduring barriers to accurate land cover classification at large spatial scales. Even with a ‘big data’ approach, reflectance error and ecological factors such as confusion land cover types and geographical variation in temporal reflectance function will probably continue to limit the size of area for which land cover can be classified accurately, therefore limiting the utility of remote sensing for ecologists. [ABSTRACT FROM AUTHOR]

Replicating the architecture of extracellular matrices (ECM) is crucial in tissue engineering to support tissues’ natural structure and functionality. The ECM’s structure plays a significant role in directing cell alignment. Electrospinning is an effective technique for fabricating nanofibrous substrates that mimic the architecture of extracellular matrices (ECM). This study aims to evaluate the efficacy of resin 3D-printed scaffolds made from a low-conductivity material (i.e., a resin composed of methacrylated oligomers, monomers, and photoinitiators) in directing the alignment of electrospun polycaprolactone (PCL) nanofibers. Six 3D-printed scaffolds were fabricated using stereolithography (SLA) technology and strategically positioned on an aluminum foil collector plate during electrospinning. The structured geometry of the scaffolds, rather than the local electric field distribution, is hypothesized to guide nanofiber alignment. Images acquired through the scanning electron microscopy (SEM) were used to analyze and statistically quantify the nanofibrous scaffolds to evaluate the alignment of nanofibers over the scaffolds compared to a set of randomly deposited control nanofiber samples in the absence of the 3D printed scaffolds. SEM images also showed significant alignment of nanofibers within the pores of scaffolds, using histograms as a means for indicating the distribution of orientation angles. Statistical analysis revealed that this distribution deviates from normality due to the deviations in the tails and the existence of relatively smaller peaks at angles relative to 0°, particularly within a range of ± 50° and ± 40°. It is further found that the average peak orientation angle relative to 0° had a maximum probability of 0.014. Furthermore, the statistical analysis confirmed the distribution and significant differences in orientation between test samples with 3D-printed scaffolds and control samples. These findings demonstrate the effectiveness of resin 3D-printed scaffolds, particularly their geometric filtering effect, leading to controlled nanofiber alignment, which is proposed to be beneficial for enhancing cell adhesion, proliferation, and cell migration in tissue engineering applications. [ABSTRACT FROM AUTHOR]

People often display ingroup bias in punishment, punishing outgroup members more harshly than ingroup members. However, the impact of group membership may be less pronounced when people are choosing whether to stop interacting with someone (i.e., partner rejection). In two studies (N = 1667), we investigate the impact of group membership on both response types. Participants were assigned to groups based on a “minimal” groups paradigm (Study 1) or their self-reported political positions (Study 2) and played an incentivized economic game with other players. In this game, participants (Responders) responded to other players (Deciders). In the Punishment condition, participants could decrease the Decider’s bonus pay. In the Partner Rejection condition, participants could reject future interactions with the Decider. Participants played once with an ingroup member and once with an outgroup member. To control for the effects of intent and outcome, scenarios also differed based on the Decider’s Intent (selfish versus fair) and the Outcome (equal versus unequal distribution of resources). Participants punished outgroup members more than ingroup members, however group membership did not influence decisions to reject partners. These results highlight partner rejection as a boundary condition for the impact of group on responses to transgressions. [ABSTRACT FROM AUTHOR]

Folates are B-group vitamins that function in one-carbon metabolism. Here we show that a specific folate can activate serotonergic neurons in C. elegans to modulate behavior through a pathway that requires the folate receptor FOLR-1 and the GON-2 calcium channel. FOLR-1 and GON-2 physically interact in a heterologous system, and both are expressed in the HSN and NSM serotonergic neurons. Both the folate 10-formyl-THF and a non-metabolic pteroate induce increases in the number of Ca2+ transients in the HSN neurons and egg laying in an FOLR-1- and GON-2-dependent manner. FOLR-1 and GON-2 are required for the activation of the NSM neurons in response to 10-formyl-THF, and for full NSM-mediated stoppage of movement when starved animals encounter bacteria. Our results demonstrate that FOLR-1 acts independently of one-carbon metabolism and suggest that 10-formyl-THF acts as a dietary signal that activates serotonergic neurons to impact behavior through a pathway that involves calcium entry. Folates are B vitamins that are known to be important for embryonic development and other important processes. Here, the authors show that a specific folate acts as a signal to activate serotonergic neurons to control behavior in C. elegans via a metabolism-independent pathway that requires the folate receptor and a calcium channel. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is one of the deadliest brain cancers with a median survival of only 15 months. This poor prognosis has prompted exploration of novel therapeutic targets for GBM patients. Human cytomegalovirus (HCMV) has been implicated in GBM; however, its impact remains poorly defined, and there is conflicting data over the presence of HCMV in tumors. Nonetheless, clinical trials targeting HCMV have shown promising initial data, and evidence suggests that HCMV may negatively impact GBM patient survival by multiple mechanisms including changes in GBM cell behavior and the tumor microenvironment (TME) that potentiate tumor progression as well as therapy-induced virus reactivation. Moreover, HCMV has many effects on host immunity that could impact tumor behavior by altering the TME, which are largely unexplored. The goal of this review is to describe these potential interactions between HCMV and GBM. Better understanding of these processes may allow the development of new therapeutic modalities to improve GBM patient outcomes. [ABSTRACT FROM AUTHOR]

CDK1 has been known to be the sole cyclin-dependent kinase (CDK) partner of cyclin B1 to drive mitotic progression1. Here we demonstrate that CDK5 is active during mitosis and is necessary for maintaining mitotic fidelity. CDK5 is an atypical CDK owing to its high expression in post-mitotic neurons and activation by non-cyclin proteins p35 and p392. Here, using independent chemical genetic approaches, we specifically abrogated CDK5 activity during mitosis, and observed mitotic defects, nuclear atypia and substantial alterations in the mitotic phosphoproteome. Notably, cyclin B1 is a mitotic co-factor of CDK5. Computational modelling, comparison with experimentally derived structures of CDK–cyclin complexes and validation with mutational analysis indicate that CDK5–cyclin B1 can form a functional complex. Disruption of the CDK5–cyclin B1 complex phenocopies CDK5 abrogation in mitosis. Together, our results demonstrate that cyclin B1 partners with both CDK5 and CDK1, and CDK5–cyclin B1 functions as a canonical CDK–cyclin complex to ensure mitotic fidelity.Cyclin B1 is a mitotic co-factor of CDK5. [ABSTRACT FROM AUTHOR]