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Abstract Defining the molecular mechanisms underlying cardiac resilience is crucial to find effective approaches to protect the heart. A physiologic level of ROS is produced in the heart by fatty acid oxidation, but stressful events can boost ROS and cause mitochondrial dysfunction and cardiac functional impairment. Melusin is a muscle specific chaperone required for myocardial compensatory remodeling during stress. Here we report that Melusin localizes in mitochondria where it binds the mitochondrial trifunctional protein, a key enzyme in fatty acid oxidation, and decreases it activity. Studying both mice and human induced pluripotent stem cell-derived cardiomyocytes, we found that Melusin reduces lipid oxidation in the myocardium and limits ROS generation in steady state and during pressure overload and doxorubicin treatment, preventing mitochondrial dysfunction. Accordingly, the treatment with the lipid oxidation inhibitor Trimetazidine concomitantly with stressful stimuli limits ROS accumulation and prevents long-term heart dysfunction. These findings disclose a physiologic mechanism of metabolic regulation in the heart and demonstrate that a timely restriction of lipid metabolism represents a potential therapeutic strategy to improve cardiac resilience to stress.

Lassa virus (LASV) is a rodent-borne mammarenavirus that causes tens to hundreds of thousands of human infections annually in Western Africa. Approximately 20% of these infections progress to Lassa fever (LF), an acute disease with case–fatality rates from ≈20–70%. Currently, there are no approved vaccines or specific therapeutics to prevent or treat LF. The LASV genome consists of a small (S) segment that has two genes, GP and NP, and a large (L) segment that has two genes, L and Z. In both segments, the two genes are separated by non-coding intergenic regions (IGRs). Recombinant LASVs (rLASVs), in which the L segment IGR was replaced with the S segment IGR or in which the GP gene was codon-deoptimized, lost fitness in vitro, were highly attenuated in vivo, and, when used as vaccines, protected domesticated guinea pigs from otherwise lethal LASV exposure. Here, we report the generation of rLASV/IGR-CD, which includes both determinants of attenuation and further enhances the safety of the vaccine compared with its predecessors. rLASV/IGR-CD grew to high titers in Vero cells, which are approved for human vaccine production, but did not cause signs of disease or pathology in guinea pigs. Importantly, guinea pigs vaccinated with rLASV/IGR-CD were completely protected from disease and death after a typically lethal exposure to wild-type LASV. Our data support the development of rLASV/IGR-CD as a live-attenuated LF vaccine with stringent safety features. [ABSTRACT FROM AUTHOR]

The CARLO (cold ablation robot-guided laser osteotome) is a compact device with integrated multiple sensory, steering and safety checking elements. A multi-center study was performed to evaluate the CARLO device for the linear part of midface osteotomy in 28 patients. Feasibility, success rate, safety, performance and experience of the surgeons were assessed and evaluated. All 28 procedures were completed with CARLO without falling back to the conventional methods, giving a technical success rate of 100%. For 27 (96%) cases, procedural success was achieved with cutting lines deviation less than 2 mm. For 25 procedures, the CARLO-cutting was conducted smoothly. In the other 3 cases, some minor difficulties related to the reference markers were reported. For 18 procedures, no change for the cutting path was necessary. For the other 10 cases, cut path was adapted. Intraoperative re-planning was possible, easy and quick without significant delay of the procedures. No CARLO-related adverse events were recorded. Especially, there was no unexpected and unusual bleeding during the CARLO-conducted osteotomy. The time needed for the registration ranged from 1 to 12 min (median = 4). The CARLO-cutting lasted for 5 to 21 min (median = 7). The present study demonstrated feasibility, simplicity, safety, reliability and accuracy of CARLO for the linear part of midface osteotomy. [ABSTRACT FROM AUTHOR]

Background: Patency capsule (PC) ingestion is commonly used to minimize capsule retention in high-risk patients with Crohn's disease (CD). However, false-positive rates remain high, precluding the use of video capsule endoscopy (VCE). We aimed to compare the efficacy of two preparation protocols in reducing failed PC rates in patients with CD. Methods: This bi-center retrospective case–control study included adult patients with small-bowel CD in clinical remission who underwent PC ingestion. The pro-motility group followed a low-residue diet, then a clear fluid diet, and took bisacodyl after ingestion, while the control group followed only a clear fluid diet. The primary outcome was failed PC, defined as the absence of PC excretion or presence on abdominal X-ray at 30 h post-ingestion. Multivariable logistic regression was used to identify predictors of failed PC. Results: Among 273 patients (83 in the pro-motility group, 190 controls), the pro-motility group was older (median 36 [27–48] vs. 31 [24–43], p = 0.012) and had a lower rate of B2/3 disease phenotype (32.5 vs. 53.1%, p = 0.002) compared to controls. The pro-motility group also had a lower failed PC rate (12.0 vs. 24.7%, p = 0.023). Longer disease duration (adjusted odds ratio (AOR) 1.053, 95% confidence interval (CI) 1.016–1.091, p = 0.005) increased the odds of failed PC, while the pro-motility protocol was protective (AOR 0.438, 95% CI 0.200–0.956, p = 0.038), outweighing the influence of B2/3 disease phenotype (AOR 1.743, 95% CI 0.912–3.332, p = 0.093). Conclusions: The pro-motility preparation protocol could substantially improve the success rates of the small-bowel patency test in patients with CD undergoing PC ingestion, potentially reducing the risk of capsule retention and associated complications. [ABSTRACT FROM AUTHOR]

Oncocytic renal neoplasms are a major source of diagnostic challenge in genitourinary pathology; however, they are typically nonaggressive in general, raising the question of whether distinguishing different subtypes, including emerging entities, is necessary. Emerging entities recently described include eosinophilic solid and cystic renal cell carcinoma (ESC RCC), low-grade oncocytic tumor (LOT), eosinophilic vacuolated tumor (EVT), and papillary renal neoplasm with reverse polarity (PRNRP). A survey was shared among 65 urologic pathologists using SurveyMonkey.com (Survey Monkey, Santa Clara, CA, USA). De-identified and anonymized respondent data were analyzed. Sixty-three participants completed the survey and contributed to the study. Participants were from Asia (n = 21; 35%), North America (n = 31; 52%), Europe (n = 6; 10%), and Australia (n = 2; 3%). Half encounter oncocytic renal neoplasms that are difficult to classify monthly or more frequently. Most (70%) indicated that there is enough evidence to consider ESC RCC as a distinct entity now, whereas there was less certainty for LOT (27%), EVT (29%), and PRNRP (37%). However, when combining the responses for sufficient evidence currently and likely in the future, LOT and EVT yielded > 70% and > 60% for PRNRP. Most (60%) would not render an outright diagnosis of oncocytoma on needle core biopsy. There was a dichotomy in the routine use of immunohistochemistry (IHC) in the evaluation of oncocytoma (yes = 52%; no = 48%). The most utilized IHC markers included keratin 7 and 20, KIT, AMACR, PAX8, CA9, melan A, succinate dehydrogenase (SDH)B, and fumarate hydratase (FH). Genetic techniques used included TSC1/TSC2/MTOR (67%) or TFE3 (74%) genes and pathways; however, the majority reported using these very rarely. Only 40% have encountered low-grade oncocytic renal neoplasms that are deficient for FH. Increasing experience with the spectrum of oncocytic renal neoplasms will likely yield further insights into the most appropriate work-up, classification, and clinical management for these entities. [ABSTRACT FROM AUTHOR]

Photon-counting detector computed tomography (PCD-CT) has emerged as a revolutionary technology in CT imaging. PCD-CT offers significant advancements over conventional energy-integrating detector CT, including increased spatial resolution, artefact reduction and inherent spectral imaging capabilities. In cardiac imaging, PCD-CT can offer a more accurate assessment of coronary artery disease, plaque characterisation and the in-stent lumen. Additionally, it might improve the visualisation of myocardial fibrosis through qualitative late enhancement imaging and quantitative extracellular volume measurements. The use of PCD-CT in cardiac imaging holds significant potential, positioning itself as a valuable modality that could serve as a one-stop-shop by integrating both angiography and tissue characterisation into a single examination. Despite its potential, large-scale clinical trials, standardisation of protocols and cost-effectiveness considerations are required for its broader integration into clinical practice. This narrative review provides an overview of the current literature on PCD-CT regarding the possibilities and limitations of cardiac imaging. [ABSTRACT FROM AUTHOR]

We study complete minimal surfaces in R n with finite total curvature and embedded planar ends. After conformal compactification via inversion, these yield examples of surfaces stationary for the Willmore bending energy W : = 1 4 ∫ | H → | 2 . In codimension one, we prove that the W -Morse index for any inverted minimal sphere or real projective plane with m such ends is exactly m - 3 = W 4 π - 3 . We also consider several geometric properties—for example, the property that all m asymptotic planes meet at a single point—of these minimal surfaces and explore their relation to the W -Morse index of their inverted surfaces. [ABSTRACT FROM AUTHOR]

Copyright of Clinical Epileptology / Zertifizierte Fortbildung is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objectives: Percutaneous vertebroplasty and kyphoplasty are common interventions for osteoporotic vertebral compression fractures. However, there is concern about an increased risk of adjacent-level fractures after treatment. This study aimed to compare the risk of adjacent-level fractures after vertebroplasty and kyphoplasty with the natural history after osteoporotic vertebral compression fractures. Materials and methods: A network meta-analysis of randomized controlled trials (RCTs) was conducted to evaluate the risk of adjacent-level fractures after vertebroplasty and kyphoplasty compared to the natural history after osteoporotic vertebral compression fractures. Frequentist network meta-analysis was conducted using the "netmeta" package, and heterogeneity was assessed using Q statistics. The pooled risk ratio (RR) and 95% confidence intervals (CI) were calculated using random effects. Results: Twenty-three RCTs with a total of 2838 patients were included in the analysis. The network meta-analysis showed comparable risks of adjacent-level fractures between vertebroplasty, kyphoplasty, and natural history after osteoporotic vertebral compression fractures with a mean follow-up of 21.2 (range: 3–49.4 months). The pooled RR for adjacent-level fractures after kyphoplasty compared to natural history was 1.35 (95% CI, 0.78–2.34, p = 0.23) and for vertebroplasty compared to natural history was 1.16 (95% CI, 0.62–2.14) p = 0.51. The risk of bias assessment showed a low to moderate risk of bias among included RCTs. Conclusion: There was no difference in the risk of adjacent-level fractures after vertebroplasty and kyphoplasty compared to natural history after osteoporotic vertebral compression fractures. The inclusion of a large patient number and network meta-analysis of RCTs serve evidence-based clinical practice. Clinical relevance statement: The risk of adjacent-level fracture following percutaneous vertebroplasty or kyphoplasty is similar to that observed in the natural history after osteoporotic vertebral compression fractures. Key Points: RCTs have examined the risk of adjacent-level fracture after intervention for osteoporotic vertebral compression fractures. There was no difference between vertebroplasty and kyphoplasty patients compared to the natural disease history for adjacent compression fractures. This is strong evidence that interventional treatments for these fractures do not increase the risk of adjacent fractures. [ABSTRACT FROM AUTHOR]

Slow waves are a distinguishing feature of non-rapid-eye-movement (NREM) sleep, an evolutionarily conserved process critical for brain function. Non-human studies suggest that the claustrum, a small subcortical nucleus, coordinates slow waves. We show that, in contrast to neurons from other brain regions, claustrum neurons in the human brain increase their spiking activity and track slow waves during NREM sleep, suggesting that the claustrum plays a role in coordinating human sleep architecture. The role of the human claustrum during slow wave sleep is unknown. Here the authors characterize the spiking activity of claustrum neurons in humans and demonstrate that claustrum neurons track slow waves during NREM sleep. [ABSTRACT FROM AUTHOR]

Pertussis is a vaccine-preventable respiratory disease caused by the Gram negative coccobacillus Bordetella pertussis. The licensed acellular pertussis (aP) vaccines protect against disease but do not prevent bacterial colonization and transmission. Here, we developed and tested an intranasal vaccine composed of aP antigens combined with T-vant, a novel adjuvant derived from bacterial outer membrane vesicles, that elicits both mucosal and systemic immune responses. We hypothesized that immunization of mice with aP-T-vant would enhance mucosal immunity and eliminate B. pertussis in the respiratory tract. In contrast to mice immunized intramuscularly with the licensed aP vaccine, intranasal immunization with aP-T-vant eliminated bacteria in both the lung and nasopharynx. Protection was associated with IFN-gamma and IL-17-producing, non-circulating CD4 + T cells in the lung and nasopharynx, and sterilizing immunity in the nasopharynx was dependent on IL-17. Novel mucosal adjuvants, such as T-vant, warrant further investigation to enhance the efficacy of next generation pertussis vaccines. [ABSTRACT FROM AUTHOR]

Purpose of Review: Diabetic neuropathy is a common complication of diabetes mellitus (DM) and can affect up to 50% of DM patients during their lifetime. Patients typically present with numbness, tingling, pain, and loss of sensation in the extremities. Since there is no treatment targeting the underlying mechanism of neuropathy, strategies focus on preventative care and pain management. Recent Findings: Up to 69% of patients with diabetic neuropathy receive pharmacological treatment for neuropathic pain. The United States Food and Drug Administration (FDA) confirmed four drugs for painful diabetic neuropathy (PDN): pregabalin, duloxetine, tapentadol, and the 8% capsaicin patch. Nonpharmacological treatments such as spinal cord stimulation (SCS) and transcutaneous electrical nerve stimulation (TENS) both show promise in reducing pain in DM patients. Summary: Despite the high burden associated with PDN, effective management remains challenging. This update covers the background and management of diabetic neuropathy, including its epidemiology, pathogenesis, preventative care, and current therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: Pharmacy professionals, given their health expertise, can play a role in enhancing health education within their communities and among patients. The potential of the pharmacy workforce to enhance health education among primary school children is underexplored. Aim: This study aimed to investigate the perspectives of pharmacy staff on the provision of education regarding self-care and treatment of minor ailments to primary school-aged children and to identify roles that pharmacists could play in this regard. Method: Qualitative semi-structured interviews were conducted online with frontline pharmacy staff in the UK who had patient facing roles with primary school-aged children and parents. Interviews were audio-recorded and transcribed verbatim. Thematic data analysis was applied to the transcripts. Results: A total of 17 participants were recruited. Participants included 12 pharmacists, two pharmacy technicians and three pharmacy dispensers. All participants worked within community, hospital or primary care facilities. Five themes emerged from the data analysis: sources of health knowledge accessed by children and parents; a perceived lack of knowledge regarding self-care and treatments for minor ailments among children and parents; a perceived positive impact of education on self-care; barriers to health education; and the potential role of pharmacy staff in self-care education in schools. Conclusion: Pharmacy staff recognise the value of integrating health education into primary school curricula. A collaborative approach with educational institutions could bridge the gap in knowledge regarding self-care and treatment of minor ailments, and could empower children and reduce unnecessary use of healthcare resources. [ABSTRACT FROM AUTHOR]

Prudent imaging use is essential for cost reduction and efficient patient triage. Recent efforts have focused on head and neck CTA in patients with emergent concerns for non-focal neurological complaints, but have failed to demonstrate whether increases in utilization have resulted in better care. The objective of this study was to examine trends in head and neck CTA ordering and determine whether a correlation exists between imaging utilization and positivity rates. This is a single-center retrospective observational study at a quaternary referral center. This study includes patients presenting with headache and/or dizziness to the emergency department between January 2017 and December 2021. Patients who received a head and neck CTA were compared to those who did not. The main outcomes included annual head and neck CTA utilization and positivity rates, defined as the percent of scans with attributable acute pathologies. Among 24,892 emergency department visits, 2264 (9.1%) underwent head and neck CTA imaging. The percentage of patients who received a scan over the study period increased from 7.89% (422/5351) in 2017 to 13.24% (662/5001) in 2021, representing a 67.4% increase from baseline (OR, 1.14; 95% CI 1.11–1.18; P <.001). The positivity rate, or the percentage of scans ordered that revealed attributable acute pathology, dropped from 16.8% (71/422) in 2017 to 10.4% (69/662) in 2021 (OR, 0.86; 95% CI 0.79–0.94; P =.001), a 38% reduction in positive examinations. Throughout the study period, there was a 67.4% increase in head and neck CTA ordering with a concomitant 38.1% decrease in positivity rate. [ABSTRACT FROM AUTHOR]

A recurring challenge in quantum science and technology is the precise control of their underlying dynamics that lead to the desired quantum operations, often described by a set of quantum gates. These gates can be subject to application-specific errors, leading to a dependence of their controls on the chosen circuit, the quality measure and the gate-set itself. A natural solution would be to apply quantum optimal control in an application-oriented fashion. In turn, this requires the definition of a meaningful measure of the contextual gate-set performance. Therefore, we explore and compare the applicability of quantum process tomography, linear inversion gate-set tomography, randomized linear gate-set tomography, and randomized benchmarking as measures for closed-loop quantum optimal control experiments, using a macroscopic ensemble of nitrogen-vacancy centers in diamond as a test-bed. Our work demonstrates the relative trade-offs between those measures and how to significantly enhance the gate-set performance, leading to an improvement across all investigated methods. [ABSTRACT FROM AUTHOR]

Purpose: Large language models (LLM) show potential for decision support in breast cancer care. Their use in clinical care is currently prohibited by lack of control over sources used for decision-making, explainability of the decision-making process and health data security issues. Recent development of Small Language Models (SLM) is discussed to address these challenges. This preclinical proof-of-concept study tailors an open-source SLM to the German breast cancer guideline (BC-SLM) to evaluate initial clinical accuracy and technical functionality in a preclinical simulation. Methods: A multidisciplinary tumor board (MTB) is used as the gold-standard to assess the initial clinical accuracy in terms of concordance of the BC-SLM with MTB and comparing it to two publicly available LLM, ChatGPT3.5 and 4. The study includes 20 fictional patient profiles and recommendations for 5 treatment modalities, resulting in 100 binary treatment recommendations (recommended or not recommended). Statistical evaluation includes concordance with MTB in % including Cohen’s Kappa statistic (κ). Technical functionality is assessed qualitatively in terms of local hosting, adherence to the guideline and information retrieval. Results: The overall concordance amounts to 86% for BC-SLM (κ = 0.721, p < 0.001), 90% for ChatGPT4 (κ = 0.820, p < 0.001) and 83% for ChatGPT3.5 (κ = 0.661, p < 0.001). Specific concordance for each treatment modality ranges from 65 to 100% for BC-SLM, 85–100% for ChatGPT4, and 55–95% for ChatGPT3.5. The BC-SLM is locally functional, adheres to the standards of the German breast cancer guideline and provides referenced sections for its decision-making. Conclusion: The tailored BC-SLM shows initial clinical accuracy and technical functionality, with concordance to the MTB that is comparable to publicly-available LLMs like ChatGPT4 and 3.5. This serves as a proof-of-concept for adapting a SLM to an oncological disease and its guideline to address prevailing issues with LLM by ensuring decision transparency, explainability, source control, and data security, which represents a necessary step towards clinical validation and safe use of language models in clinical oncology. [ABSTRACT FROM AUTHOR]

Copyright of Zeitschrift für Rheumatologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Deviations between the determination of bone age (BA) according to Greulich and Pyle (G&P) and chronological age (CA) are common in Caucasians. Assessing these discrepancies in a population over time requires analysis of large samples and low intra-observer variability in BA estimation, both can be achieved with artificial intelligence-based software. The latest software-based reference curve contrasting the BA determined by G&P to the CA of Central European children dates back over two decades. Objective: To examine whether the reference curve from a historical cohort from the Netherlands (Rotterdam cohort) between BA determined by G&P and CA still applies to a current Central European cohort and derive a current reference curve. Materials and methods: This retrospective single-center study included 1,653 children and adolescents (aged 3–17 years) who had received a radiograph of the hand following trauma. The G&P BA estimated using artificial intelligence-based software was contrasted with the CA, and the deviations were compared with the Rotterdam cohort. Results: Among the participants, the mean absolute error between BA and CA was 0.92 years for girls and 0.97 years for boys. For the ages of 8 years (boys) and 11 years (girls) and upward, the mean deviation was significantly greater in the current cohort than in the Rotterdam cohort. The reference curves of both cohorts also differed significantly from each other (P < 0.001 for both boys and girls). Conclusion: The BA of the current Central European population and that of the curve from the Rotterdam cohort from over two decades ago differ. Whether this effect can be attributed to accelerated bone maturation needs further evaluation. [ABSTRACT FROM AUTHOR]

Nanomechanical oscillators are an alternative platform for computation in harsh environments. However, external perturbations arising from such environments may hinder information processing by introducing errors into the computing system. Here, we simulate the dynamics of three coupled Duffing oscillators whose multiple equilibrium states can be used for information processing and storage. Our analysis reveals that, within experimentally relevant parameters, error correcting dynamics can emerge, wherein the system's state is robust against random external impulses. We find that oscillators in this configuration have several surprising and attractive features, including dynamic isolation of resonators exposed to extreme impulses and the ability to correct simultaneous errors. [ABSTRACT FROM AUTHOR]

Understanding the relation between the microstructure and the material's effective behavior is an important aspect in inverse computational materials engineering. Especially in the context of localized, inelastic phenomena like plasticity and crack growth, the microstructure morphology plays a crucial role. Due to the stochastic nature of heterogeneous media, a statistical analysis over multiple simulations is necessary, since even with the same material, the simulated crack paths and effective crack lengths are highly dependent on the specific locations of microstructural features. A relevant factor that limits this type of investigation is the high cost of real microstructure data. This work presents a digital workflow for exploring the fracture properties of materials. Therein, the required statistical analyses are facilitated by an algorithm that reconstructs multiple realization of a material structure given a single example. The reconstructed structures are discretized with a regular non-conforming mesh with a diffuse interface and crack representation. Crack phase-field simulations are conducted in order to analyze the effective response. An in-depth introduction to the required methods is given together with a statistical evaluation of the conducted numerical experiments. It is concluded that the statistical variation of the effective material behavior overshadows morphological trends in the presented case. This confirms the relevance and utility of complementing simulation-based workflows with microstructure reconstruction and statistical analyses. [ABSTRACT FROM AUTHOR]

The shape and function of ethical imperatives may vary if the context is an interaction between strangers, or those who are well acquainted. This idea, taken up from Stephen Toulmin's distinction between an "ethics of strangers" and an "ethics of intimacy", can be applied to encounters in healthcare. There are situations where healthcare personnel (HCP) know their patients (corresponding to an "ethics of intimacy") and situations where HCP do not know their patients (corresponding to "an ethics of strangers"). Does it make a difference for normative imperatives that follow from central concepts and principles in medical ethics whether HCP know their patients or not? In our view, this question has not yet been answered satisfactorily. Once we have clarified what is meant by "knowing the patient", we will show that the distinction is particularly relevant with regard to some thorny questions of autonomy in healthcare (e.g., regarding advance directives or paternalism in the name of autonomy), whereas the differences with regard to imperatives following from the principles of justice and beneficence seem to be smaller. We provide a detailed argument for why knowing the patient is ethically valuable in encounters in healthcare. Consequently, healthcare systems should provide fertile ground for HCP to get to know their patients, and structures that foster therapeutic continuity. For this to succeed, a number of questions still need to be clarified, which is an important task for medical ethics. [ABSTRACT FROM AUTHOR]

Copyright of Die Anaesthesiologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objective: To develop and validate tools for measuring inpatient gastroenterology (GI) consultation quality on oncologic patients. Methods: A total of 145 inpatient GI consults were analyzed using electronic health records in this cross-sectional study. Essential Consult Elements on oncologic-hospitalized patients (EE-COH) and Hospitalized Oncologic Patients Enhanced Quality of Consult Assessment Tool (HOPE-QCAT) were used for grading. Interrater reliability was assessed. Results: Both EE-COH and HOPE-QCAT showed near-perfect interrater reliability across most measures in the validation cohort. On application of these measures for quality assessment, basic evaluation by the requesting hospitalist was partially complete in 24.8%, the request for GI consultation was inappropriate in 18.6%, while the rationale for recommended studies from the GI consultant was provided in 55.7% of cases suggesting key areas for quality improvement. Conclusion: We developed highly reliable quality measures for inpatient GI consults on oncology patients. The EE-COH and HOPE-QCAT tools can be utilized in future studies of inpatient GI consult quality and to form the basis for interventions to improve communication between consultants and hospitalists. Such tools could be adapted for inpatient quality assessment across other specialties and settings. [ABSTRACT FROM AUTHOR]

For Al–Fe–Si foil stock alloys, the recrystallization behavior is one of the key features for the design of the thermo-mechanical process route, which is highly dependent on the content of the elements in solute solution, especially Fe. Consequently, the combined effects of homogenization and hot deformation on the recrystallization behavior are of great interest. The focus of this work is on the resulting recrystallization behavior during hot deformation caused by different homogenization annealings prior to hot deformation. AA8079 samples were homogenized at two different temperatures and then used for uniaxial hot-compression tests at temperatures between 320 °C and 440 °C. The resulting hot deformation and recrystallization behavior were investigated by means of flow curves, optical microscopy, and microhardness measurements. A finite element method (FEM)-based simulation model was used to compute local temperatures and strain rates. The experimental investigation revealed a significant influence of the homogenization treatment on the hot deformation flow stress and subsequent recrystallization behavior. [ABSTRACT FROM AUTHOR]

Purpose of Review: In this manuscript, we aim to review the proposed mechanisms of the pathophysiology of functional heartburn (FH) and functional chest pain (FCP) as well as highlight the different neuromodulatory therapies available to providers and the evidence for each of them. Recent Findings: Understanding the basis for the symptoms that patients are presenting with is essential when evaluating patients with possible esophageal motility disorders or gastroesophageal reflux disease. Objective testing to understand these conditions is a key component to that understanding. Patients undergoing evaluation for heartburn or chest pain, following cardiac evaluation, often require a combination of endoscopy, esophageal manometry, and pH testing. Treatment for FH or FCP often involves some combination of neuromodulatory pharmacologic or behavioral therapies based on their understood pathophysiology. Summary: When a diagnosis of functional heartburn or functional chest pain is reached, it is important for the managing provider to understand the available therapeutic options. Often, treatment requires management with neuromodulation. [ABSTRACT FROM AUTHOR]

Objective: To evaluate obstetric and perinatal outcomes among small for gestational age (SGA) infants born to patients diagnosed with Gestational diabetes mellitus (GDM). Materials and methods: A multicenter retrospective cohort study between 2005 and 2021. The perinatal outcomes of SGA infants born to patients with singleton pregnancy and GDM were compared to SGA infants born to patients without GDM. The primary outcome was a composite adverse neonatal outcome. Infants with known structural/genetic abnormalities or infections were excluded. A univariate analysis was conducted followed by a multivariate analysis (adjusted odds ratio [95% confidence interval]). Results: During the study period, 11,662 patients with SGA infants met the inclusion and exclusion criteria. Of these, 417 (3.6%) SGA infants were born to patients with GDM, while 11,245 (96.4%) were born to patients without GDM. Overall, the composite adverse neonatal outcome was worse in the GDM group (53.7% vs 17.4%, p < 0.01). Specifically, adverse neonatal outcomes such as a 5 min Apgar score < 7, meconium aspiration, seizures, and hypoglycemia were independently associated with GDM among SGA infants. In addition, patients with GDM and SGA infants had higher rates of overall and spontaneous preterm birth, unplanned cesarean, and postpartum hemorrhage. In a multivariate logistic regression assessing the association between GDM and neonatal outcomes, GDM was found to be independently associated with the composite adverse neonatal outcome (aOR 4.26 [3.43–5.3]), 5 min Apgar score < 7 (aOR 2 [1.16–3.47]), meconium aspiration (aOR 4.62 [1.76–12.13]), seizures (aOR 2.85 [1.51–5.37]) and hypoglycemia (aOR 16.16 [12.79–20.41]). Conclusions: Our study demonstrates that GDM is an independent risk factor for adverse neonatal outcomes among SGA infants. This finding underscores the imperative for tailored monitoring and management strategies in those pregnancies. [ABSTRACT FROM AUTHOR]

The role of gut–brain axis functioning gains growing attention in research on the pathophysiology of major depressive disorders. Here, especially consequences of altered microbiota composition on tryptophan metabolism resulting in altered serotonergic neurotransmission in the central nervous system (CNS) have reached a central position. Previous research, however, mainly focused on either microbiota and peripheral serotonin levels or central serotonergic neurotransmission. The present study aimed to combine the analysis of microbiota composition and central serotonergic activity using a valid neurophysiological indicator. We recruited 19 adult patients with type 1 diabetes and depression (D + D; 7 males), 19 patients with type 1 diabetes (D-; 7 male), and 20 healthy participants (HC; 7 males). Next to the analysis of fecal microbiota regarding α- and β-diversity, the loudness dependence of auditory evoked potential (LDAEP) was investigated, a non-invasive measurement of central serotonergic activity. High α-diversity was associated with high LDAEP, i.e., low serotonergic activity, in patients with diabetes and additional depression. Furthermore, relative abundances of bacterial families belonging to Bacteroidetes, Proteobacteria and Firmicutes were shown to have an impact on central serotonergic activity. This finding was supported by a tendency indicating an association of central serotonergic activity with the Bacteroidetes–Firmicutes ratio in both patients' groups. Together, this data suggests that the guts' microbiota composition might play an important role in regulating the central serotonergic activity in the brain. [ABSTRACT FROM AUTHOR]

We prove that 2-dimensional Q-valued maps that are stationary with respect to outer and inner variations of the Dirichlet energy are Hölder continuous and that the dimension of their singular set is at most one. In the course of the proof we establish a strong concentration-compactness theorem for equicontinuous maps that are stationary with respect to outer variations only, and which holds in every dimensions. [ABSTRACT FROM AUTHOR]

This paper addresses the question of how the ups and downs in the development of artificial intelligence (AI) since its inception can be explained. It focuses on the development of artificial intelligence in Germany since the 1970s, and particularly on its current dynamics. An assumption is made that a mere reference to rapid advances in information technologies and the various methods and concepts of artificial intelligence in recent decades cannot adequately explain these dynamics, because from a social science perspective, this is an oversimplified, technology-centred explanation. Drawing on ideas from social scientific innovation research, the hypothesis is rather that artificial intelligence should be understood as a "promising technology". Its various stages of development have always been driven by technological promises about its special powers and capabilities when applied to solving economic and societal challenges. [ABSTRACT FROM AUTHOR]

Plasmodium falciparum is the main causative agent of malaria, a deadly disease that mainly affects children under five years old. Artemisinin-based combination therapies have been pivotal in controlling the disease, but resistance has arisen in various regions, increasing the risk of treatment failure. The non-mevalonate pathway is essential for the isoprenoid synthesis in Plasmodium and provides several under-explored targets to be used in the discovery of new antimalarials. 1-deoxy-D-xylulose-5-phosphate synthase (DXPS) is the first and rate-limiting enzyme of the pathway. Despite its importance, there are no structures available for any Plasmodium spp., due to the complex sequence which contains large regions of high disorder, making crystallisation a difficult task. In this manuscript, we use cryo-electron microscopy to solve the P. falciparum DXPS structure at a final resolution of 2.42 Å. Overall, the structure resembles other DXPS enzymes but includes a distinct N-terminal domain exclusive to the Plasmodium genus. Mutational studies show that destabilization of the cap domain interface negatively impacts protein stability and activity. Additionally, a density for the co-factor thiamine diphosphate is found in the active site. Our work highlights the potential of cryo-EM to obtain structures of P. falciparum proteins that are unfeasible by means of crystallography. DXPS is an important enzyme for isoprenoid synthesis in Plasmodium falciparum. Here, authors elucidate the cryo-EM structure of PfDXPS showing an N-terminal domain only present in this genus. Mutation studies show its importance in DXPS stability and activity. [ABSTRACT FROM AUTHOR]

The modular nature of polyketide assembly lines and the significance of their products make them prime targets for combinatorial engineering. The recently updated module boundary has been successful for engineering short synthases, yet larger synthases constructed using the updated boundary have not been investigated. Here we describe our design and implementation of a BioBricks-like platform to rapidly construct 5 triketide, 25 tetraketide, and 125 pentaketide synthases to test every module combination of the pikromycin synthase. Anticipated products are detected from 60% of the triketide synthases, 32% of the tetraketide synthases, and 6.4% of the pentaketide synthases. We determine ketosynthase gatekeeping and module-skipping are the principal impediments to obtaining functional synthases. The platform is also employed to construct active hybrid synthases by incorporating modules from the erythromycin, spinosyn, and rapamycin assembly lines. The relaxed gatekeeping of a ketosynthase in the rapamycin synthase is especially encouraging in the quest to produce designer polyketides.Engineered polyketide synthases historically have little to no activity. Here, the authors use updated modules from the pikromycin synthase to make 155 synthases, showing that the updated module has a higher success rate, but that ketosynthase gatekeeping and module skipping can prevent function. [ABSTRACT FROM AUTHOR]

Background: Central nervous system (CNS) injury following initiation of veno-venous extracorporeal membrane oxygenation (VV-ECMO) is common. An acute decrease in partial pressure of arterial carbon dioxide (PaCO2) following VV-ECMO initiation has been suggested as an etiological factor, but the challenges of diagnosing CNS injuries has made discerning a relationship between PaCO2 and CNS injury difficult. Methods: We conducted a prospective cohort study of adult patients undergoing VV-ECMO for acute respiratory failure. Arterial blood gas measurements were obtained prior to initiation of VV-ECMO, and at every 2–4 h for the first 24 h. Neuroimaging was conducted within the first 7–14 days in patients who were suspected of having neurological injury or unable to be examined because of sedation. We collected blood biospecimens to measure brain biomarkers [neurofilament light (NF-L); glial fibrillary acidic protein (GFAP); and phosphorylated-tau 181] in the first 7 days following initiation of VV-ECMO. We assessed the relationship between both PaCO2 over the first 24 h and brain biomarkers with CNS injury using mixed methods linear regression. Finally, we explored the effects of absolute change of PaCO2 on serum levels of neurological biomarkers by separate mixed methods linear regression for each biomarker using three PaCO2 exposures hypothesized to result in CNS injury. Results: In our cohort, 12 of 59 (20%) patients had overt CNS injury identified on head computed tomography. The PaCO2 decrease with VV-ECMO initiation was steeper in patients who developed a CNS injury (− 0.32%, 95% confidence interval − 0.25 to − 0.39) compared with those without (− 0.18%, 95% confidence interval − 0.14 to − 0.21, P interaction < 0.001). The mean concentration of NF-L increased over time and was higher in those with a CNS injury (464 [739]) compared with those without (127 [257]; P = 0.001). GFAP was higher in those with a CNS injury (4278 [11,653] pg/ml) compared with those without (116 [108] pg/ml; P < 0.001). The mean NF-L, GFAP, and tau over time in patients stratified by the three thresholds of absolute change of PaCO2 showed no differences and had no significant interaction for time. Conclusions: Although rapid decreases in PaCO2 following initiation of VV-ECMO were slightly greater in patients who had CNS injuries versus those without, data overlap and absence of relationships between PaCO2 and brain biomarkers suggests other pathophysiologic variables are likely at play. [ABSTRACT FROM AUTHOR]

Purpose: The aims of the current study were to describe clinical and biochemical features of patients with Paget disease of bone (PDB) followed at our medical center, and to examine the long-term effectiveness of zoledronate. Methods: Retrospective cohort study included consecutive patients≥18 years with a diagnosis of PDB, followed in the Rabin Medical Center (RMC) Institute of Endocrinology from 1973 to 2023. The cohort comprised two groups: patients treated/not treated with zoledronic acid (ZOL/NZOL). The primary outcome was the percentage of patients who achieved a biochemical therapeutic response. Results: Overall, 101 patients with PDB were included, 68 in the ZOL group and 33 in the NZOL group. The mean age was 65.2 ± 10.0 years, and 47% were female. Notably, 77% exhibited monostotic involvement, and only 3% had experienced fractures attributed to PDB. Mean ALP level at diagnosis was 160 ± 70.6 U/L. The median follow-up duration was 17 years since PDB diagnosis, comparable between the groups. Primary outcome was more prevalent in the ZOL compared to the NZOL group [42 patients (88%) VS 11 patients (52%) respectively, P = 0.004]. At the end of follow-up, mean ALP levels in the NZOL group were significantly higher than the levels in the ZOL group irrespective of the number of infusions received. Conclusion: The majority of patients with PDB experience a mild disease course, marked by monostotic involvement and a low prevalence of fractures. Zoledronic acid effectively manages PDB, providing sustained biochemical response. The necessity for multiple zoledronic acid injections remains questionable, often implemented due to osteoporosis. [ABSTRACT FROM AUTHOR]

The American Diabetes Association (ADA), European Association for the Study of Diabetes (EASD), Joint British Diabetes Societies for Inpatient Care (JBDS), American Association of Clinical Endocrinology (AACE) and Diabetes Technology Society (DTS) convened a panel of internists and diabetologists to update the ADA consensus statement on hyperglycaemic crises in adults with diabetes, published in 2001 and last updated in 2009. The objective of this consensus report is to provide up-to-date knowledge about the epidemiology, pathophysiology, clinical presentation, and recommendations for the diagnosis, treatment and prevention of diabetic ketoacidosis (DKA) and hyperglycaemic hyperosmolar state (HHS) in adults. A systematic examination of publications since 2009 informed new recommendations. The target audience is the full spectrum of diabetes healthcare professionals and individuals with diabetes. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Previous studies have shown that individuals with similar mean glucose levels (MG) or percentage of time in range (TIR) may have different HbA1c values. The aim of this study was to further elucidate how MG and TIR are associated with HbA1c. Methods: Data from the randomised clinical GOLD trial (n=144) and the follow-up SILVER trial (n=98) of adults with type 1 diabetes followed for 2.5 years were analysed. A total of 596 paired HbA1c/continuous glucose monitoring measurements were included. Linear mixed-effects models were used to account for intra-individual correlations in repeated-measures data. Results: In the GOLD trial, the mean age of the participants (± SD) was 44±13 years, 63 (44%) were female, and the mean HbA1c (± SD) was 72±9.8 mmol/mol (8.7±0.9%). When correlating MG with HbA1c, MG explained 63% of the variation in HbA1c (r=0.79, p<0.001). The variation in HbA1c explained by MG increased to 88% (r=0.94, p value for improvement of fit <0.001) when accounting for person-to-person variation in the MG–HbA1c relationship. Time below range (TBR; <3.9 mmol/l), time above range (TAR) level 2 (>13.9 mmol/l) and glycaemic variability had little or no effect on the association. For a given MG and TIR, the HbA1c of 10% of individuals deviated by >8 mmol/mol (0.8%) from their estimated HbA1c based on the overall association between MG and TIR with HbA1c. TBR and TAR level 2 significantly influenced the association between TIR and HbA1c. At a given TIR, each 1% increase in TBR was related to a 0.6 mmol/mol lower HbA1c (95% CI 0.4, 0.9; p<0.001), and each 2% increase in TAR level 2 was related to a 0.4 mmol/mol higher HbA1c (95% CI 0.1, 0.6; p=0.003). However, neither TIR, TBR nor TAR level 2 were significantly associated with HbA1c when accounting for MG. Conclusions/interpretation: Inter-individual variations exist between MG and HbA1c, as well as between TIR and HbA1c, with clinically important deviations in relatively large groups of individuals with type 1 diabetes. These results may provide important information to both healthcare providers and individuals with diabetes in terms of prognosis and when making diabetes management decisions. [ABSTRACT FROM AUTHOR]

Dual-tasks at the memory encoding stage have been shown to decrease recall performance and impair concurrent task performance. In contrast, studies on the effect of dual-tasks at the memory retrieval stage observed mixed results. Which cognitive mechanisms are underlying this dual-task interference is still an unresolved question. In the present study, we investigated the influence of a concurrent reaction-time task on the performance in a long-term memory task in two experiments. In Experiment 1, participants performed an auditory-verbal free recall memory task and a visual-manual spatial Stroop task in a single or dual-task condition, either at the encoding or retrieval stage of the memory task. In Experiment 2, we examined the influence of processing conflicts in a concurrent RT task on memory encoding. Both experiments showed detrimental effects on recall accuracy and concurrent RT task performance in dual-task conditions at the encoding stage. Dual-task conditions at the retrieval stage led to a slowdown in recall latency and impaired concurrent RT task performance, but recall accuracy was maintained. In addition, we observed larger Stroop congruency effects in the dual-task conditions, indicating an increased processing conflict. However, in Experiment 2, we analyzed the effect of the processing conflict in a time-locked manner and could not find a significant influence on success of memory encoding. These findings suggest that processes in both tasks share the same limited capacity and are slowed down due to parallel processing, but we could not find evidence that this is further influenced by task-specific processing conflicts. [ABSTRACT FROM AUTHOR]

When mRNAs have been transcribed and processed in the nucleus, they are exported to the cytoplasm for translation. This export is mediated by the export receptor heterodimer Mex67–Mtr2 in the yeast Saccharomyces cerevisiae (TAP–p15 in humans)1,2. Interestingly, many long non-coding RNAs (lncRNAs) also leave the nucleus but it is currently unclear why they move to the cytoplasm3. Here we show that antisense RNAs (asRNAs) accelerate mRNA export by annealing with their sense counterparts through the helicase Dbp2. These double-stranded RNAs (dsRNAs) dominate export compared with single-stranded RNAs (ssRNAs) because they have a higher capacity and affinity for the export receptor Mex67. In this way, asRNAs boost gene expression, which is beneficial for cells. This is particularly important when the expression program changes. Consequently, the degradation of dsRNA, or the prevention of its formation, is toxic for cells. This mechanism illuminates the general cellular occurrence of asRNAs and explains their nuclear export.Antisense RNAs boost gene expression by accelerating the export of mRNA from the nucleus to the cytoplasm through the Dbp2-mediated formation of double-stranded RNAs, which might explain the prevalence of antisense RNAs. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to evaluate whether a trial of labor after cesarean delivery (TOLAC) in women with a bicornuate uterus is associated with increased maternal and neonatal morbidity compared to women with a non-malformed uterus. Methods: A multicenter retrospective cohort study was conducted at two university-affiliated centers between 2005 and 2021. Parturients with a bicornuate uterus who attempted TOLAC following a single low-segment transverse cesarean delivery (CD) were included and compared to those with a non-malformed uterus. Failed TOLAC rates and the rate of adverse maternal and neonatal outcomes were compared using both univariate and multivariate analyses. Results: Among 20,844 eligible births following CD, 125 (0.6%) were identified as having a bicornuate uterus. The overall successful vaginal delivery rate following CD in the bicornuate uterus group was 77.4%. Failed TOLAC rates were significantly higher in the bicornuate group (22.4% vs. 10.5%, p < 0.01). Uterine rupture rates did not differ between the groups, but rates of placental abruption and retained placenta were significantly higher among parturients with a bicornuate uterus (9.8% vs. 4.4%, p < 0.01, and 9.8% vs. 4.4%, p < 0.01, respectively). Neonatal outcomes following TOLAC were less favorable in the bicornuate group, particularly in terms of neonatal intensive care unit admission and neonatal sepsis. Multivariate analysis revealed an independent association between the bicornuate uterus and failed TOLAC. Conclusions: This study found that parturients with a bicornuate uterus who attempted TOLAC have a relatively high overall rate of vaginal birth after cesarean (VBAC). However, their chances of achieving VBAC are significantly lower compared to those with a non-malformed uterus. Obstetricians should be aware of these findings when providing consultation to patients. [ABSTRACT FROM AUTHOR]

We explore long-lived particle (LLP) searches using non-pointing photons at the LHC as a probe for sterile-to-sterile and active-to-sterile transition magnetic dipole moments of sterile neutrinos. We consider heavy sterile neutrinos with masses ranging from a few GeV to several hundreds of GeV. We discuss transition magnetic dipole moments using the Standard Model effective field theory and low-energy effective field theory extended by sterile neutrinos (NRSMEFT and NRLEFT) and also provide a simplified UV-complete model example. LLP searches at the LHC using non-pointing photons will probe sterile-to-sterile dipole moments two orders of magnitude below the current best constraints from LEP, while an unprecedented sensitivity to sterile neutrino mass of about 700 GeV is expected for active-to-sterile dipole moments. For the UV model example with one-loop transition magnetic moments, the searches for charged lepton flavour violating processes in synergy with LLP searches at the LHC can probe new physics at several TeV mass scales and provide valuable insights into the lepton flavour structure of new physics couplings. [ABSTRACT FROM AUTHOR]

Searches for anomalous neutral triple gauge boson couplings (NTGCs) provide important tests for the gauge structure of the standard model. In SMEFT (“standard model effective field theory”) NTGCs appear only at the level of dimension-8 operators. While the phenomenology of these operators has been discussed extensively in the literature, renormalizable UV models that can generate these operators are scarce. In this work, we study a variety of extensions of the SM with heavy fermions and calculate their matching to d = 8 NTGC operators. We point out that the complete matching of UV models requires four different CP-conserving d = 8 operators and that the single CPC d = 8 operator, most commonly used by the experimental collaborations, does not describe all possible NTGC form factors. Despite stringent experimental constraints on NTGCs, limits on the scale of UV models are relatively weak, because their contributions are doubly suppressed (being d = 8 and 1-loop). We suggest a series of benchmark UV scenarios suitable for interpreting searches for NTGCs in the upcoming LHC runs, obtain their current limits and provide estimates for the expected sensitivity of the high-luminosity LHC. [ABSTRACT FROM AUTHOR]

Prepubertal-type teratomas are uncommon, especially in postpubertal male patients. We document a case of a 28-year-old man with a lifelong history of bilateral testicular masses who presented with scrotal fistulas and no clinical evidence of extratesticular disease. Bilateral radical orchiectomies demonstrated large bilateral solid and cystic masses that contained grossly visible hairs. Microscopically, both tumors consisted of pure teratomas comprising a mixture of mature tissues derived from the three embryonic layers. Germ cell neoplasia in situ was not identified, and fluorescence in situ hybridization studies demonstrated the absence of i(12p), supporting a diagnosis of prepubertal-type teratoma. The absence of metastases in this patient with longstanding tumors highlights the benign nature of prepubertal-type teratomas affecting postpubertal patients. Furthermore, this case illustrates that at least a subset of prepubertal-type teratomas seen in adult men represent a late diagnosis of a largely pediatric entity. Additionally, we performed a comprehensive review of the literature on this topic. [ABSTRACT FROM AUTHOR]

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