The unmet promise of trustworthy AI in healthcare: why we fail at clinical translation.

Artificial intelligence (AI) has the potential to revolutionize healthcare, for example via decision support systems, computer vision approaches, or AI-based prevention tools. Initial results from AI applications in healthcare show promise but are rarely translated into clinical practice successfully and ethically. This occurs despite an abundance of "Trustworthy AI" guidelines. How can we explain the translational gaps of AI in healthcare? This paper offers a fresh perspective on this problem, showing that failing translation of healthcare AI markedly arises from a lack of an operational definition of "trust" and "trustworthiness". This leads to (a) unintentional misuse concerning what trust (worthiness) is and (b) the risk of intentional abuse by industry stakeholders engaging in ethics washing. By pointing out these issues, we aim to highlight the obstacles that hinder translation of Trustworthy medical AI to practice and prevent it from fulfilling its unmet promises.

Differential expression of small bowel TGFß1 and TGFß3 characterizes intestinal strictures in patients with fibrostenotic Crohn's disease.

Small bowel strictures remain a debilitating consequence of Crohn's disease and contribute to poor outcomes for patients. Recently, TGFß has been identified as an important driver of intestinal fibrosis. We studied the localization of TGFß isoforms in ileal strictures of patients with Crohn's disease using in situ hybridization to understand TGFß's role in stricture formation. The mucosa of strictures was characterized by higher TGFß1 while the stricture submucosa showed higher TGFß3 compared to normal ileum from patients without Crohn's disease (p = 0.02 and p = 0.044, respectively). We correlated these findings with single-cell transcriptomics which demonstrated that TGFß3 transcripts overall are very rare, which may partially explain why its role in intestinal fibrosis has remained unclear to date. There were no significant differences in fibroblast or B cell TGFß1 and/or TGFß3 expression in inflamed vs. noninflamed ileum. We discuss the implications of these findings for therapeutic development strategies to treat patients with fibrostenotic Crohn's disease.

Isometric Exercise Training and Arterial Hypertension: An Updated Review.

Hypertension is recognised as a leading attributable risk factor for cardiovascular disease and premature mortality. Global initiatives towards the prevention and treatment of arterial hypertension are centred around non-pharmacological lifestyle modification. Exercise recommendations differ between professional and scientific organisations, but are generally unanimous on the primary role of traditional aerobic and dynamic resistance exercise. In recent years, isometric exercise training (IET) has emerged as an effective novel exercise intervention with consistent evidence of reductions in blood pressure (BP) superior to that reported from traditional guideline-recommended exercise modes. Despite a wealth of emerging new data and endorsement by select governing bodies, IET remains underutilised and is not widely prescribed in clinical practice. This expert-informed review critically examines the role of IET as a potential adjuvant tool in the future clinical management of BP. We explore the efficacy, prescription protocols, evidence quality and certainty, acute cardiovascular stimulus, and physiological mechanisms underpinning its anti-hypertensive effects. We end the review with take-home suggestions regarding the direction of future IET research.

Production study of Fr, Ra and Ac radioactive ion beams at ISOLDE, CERN.

The presented paper discusses the production of radioactive ion beams of francium, radium, and actinium from thick uranium carbide (UC x ) targets at ISOLDE, CERN. This study focuses on the release curves and extractable yields of francium, radium and actinium isotopes. The ion source temperature was varied in order to study the relative contributions of surface and laser ionization to the production of the actinium ion beams. The experimental results are presented in the form of release parameters. Representative extractable yields per µ C are presented for 222 - 231 Ac, several Ra and Fr isotopes in the mass ranges 214 ≤ A ≤ 233 and 205 ≤ A ≤ 231 respectively. The release efficiency for several isotopes of each of the studied elements was calculated by comparing their yields to the estimated in-target production rates modeled by CERN-FLUKA. The maximal extraction efficiency of actinium was calculated to be 2.1(6)% for a combination of surface ionization using a Ta ion source and resonant laser ionization using the two-step 438.58 nm, and 424.69 nm scheme.

Effect of Human Head Shape on the Risk of Traumatic Brain Injury: A Gaussian Process Regression-based Machine Learning Approach.

INTRODUCTION: Computational head injury models are promising tools for understanding and predicting traumatic brain injuries. However, most available head injury models are "average" models that employ a single set of head geometry (e.g., 50th-percentile U.S. male) without considering variability in these parameters across the human population. A significant variability of head shapes exists in U.S. Army soldiers, evident from the Anthropometric Survey of U.S. Army Personnel (ANSUR II). The objective of this study is to elucidate the effects of head shape on the predicted risk of traumatic brain injury from computational head injury models. MATERIALS AND METHODS: Magnetic resonance imaging scans of 25 human subjects are collected. These images are registered to the standard MNI152 brain atlas, and the resulting transformation matrix components (called head shape parameters) are used to quantify head shapes of the subjects. A generative machine learning model is used to generate 25 additional head shape parameter datasets to augment our database. Head injury models are developed for these head shapes, and a rapid injurious head rotation event is simulated to obtain several brain injury predictor variables (BIPVs): Peak cumulative maximum principal strain (CMPS), average CMPS, and the volume fraction of brain exceeding an injurious CMPS threshold. A Gaussian process regression model is trained between head shape parameters and BIPVs, which is then used to study the relative sensitivity of the various BIPVs on individual head shape parameters. We distinguish head shape parameters into 2 types: Scaling components ${T_{xx}}$, ${T_{yy}}$, and ${T_{zz}}$ that capture the breadth, length, and height of the head, respectively, and shearing components (${T_{xy}},{T_{xz}},{T_{yx}},{T_{yz}},{T_{zx}}$, and ${T_{zy}}$) that capture the relative skewness of the head shape. RESULTS: An overall positive correlation is evident between scaling components and BIPVs. Notably, a very high, positive correlation is seen between the BIPVs and the head volume. As an example, a 57% increase in peak CMPS was noted between the smallest and the largest investigated head volume parameters. The variation in shearing components ${T_{xy}},{T_{xz}},{T_{yx}},{T_{yz}},{T_{zx}}$, and ${T_{zy}}$ on average does not cause notable changes in the BIPVs. From the Gaussian process regression model, all 3 BIPVs showed an increasing trend with each of the 3 scaling components, but the BIPVs are found to be most sensitive to the height dimension of the head. From the Sobol sensitivity analysis, the ${T_{zz}}$ scaling parameter contributes nearly 60% to the total variance in peak and average CMPS; ${T_{yy}}$ contributes approximately 20%, whereas ${T_{xx}}$ contributes less than 5%. The remaining contribution is from the 6 shearing components. Unlike peak and average CMPS, the VF-CMPS BIPV is associated with relatively evenly distributed Sobol indices across the 3 scaling parameters. Furthermore, the contribution of shearing components on the total variance in this case is negligible. CONCLUSIONS: Head shape has a considerable influence on the injury predictions of computational head injury models. Available "average" head injury models based on a 50th-percentile U.S. male are likely associated with considerable uncertainty. In general, larger head sizes correspond to greater BIPV magnitudes, which point to potentially a greater injury risk under rapid neck rotation for people with larger heads.

The effect of image category and incidental arousal on boundary restriction.

People's memory for scenes has consequences, including for eyewitness testimony. Negative scenes may lead to a particular memory error, where narrowed scene boundaries lead people to recall being closer to a scene than they were. But boundary restriction-including attenuation of the opposite phenomenon boundary extension-has been difficult to replicate, perhaps because heightened arousal accompanying negative scenes, rather than negative valence itself, drives the effect. Indeed, in Green et al. (2019) arousal alone, conditioned to a particular neutral image category, increased boundary restriction for images in that category. But systematic differences between image categories may have driven these results, irrespective of arousal. Here, we clarify whether boundary restriction stems from the external arousal stimulus or image category differences. Presenting one image category (everyday-objects), half accompanied by arousal (Experiment 1), and presenting both neutral image categories (everyday-objects, nature), without arousal (Experiment 2), resulted in no difference in boundary judgement errors. These findings suggest that image features-including inherent valence, arousal, and complexity-are not sufficient to induce boundary restriction or reduce boundary extension for neutral images, perhaps explaining why boundary restriction is inconsistently demonstrated in the lab.

Myeloid AMPK signaling restricts fibrosis but is not required for metformin improvements during CDAHFD-induced NASH in mice.

Metabolic programming underpins inflammatory processes of immune cells. In the context of chronic liver disease, liver macrophage activation and response to hepatocellular damage is dependent on profound metabolic changes. Here, we sought to identify the role of an important metabolic regulator, AMP-activated protein kinase (AMPK), specifically within myeloid cells during the progression of non-alcoholic steatohepatitis (NASH) and whether treatment with metformin, a first line therapy for diabetes and activator of AMPK could stem disease progression. Male and female Prkaa1fl/fl/Prkaa2fl/fl (Flox) control and Flox-LysM-Cre+ (MacKO) mice were fed a low-fat control or a choline-deficient, amino acid defined 45% Kcal high fat diet (CDAHFD) for 8 weeks, where metformin was introduced in the drinking water (50 or 250 mg/kg/day) for the last 4 weeks. Hepatic steatosis and fibrosis were dramatically increased in response to CDAHFD-feeding compared to low-fat control. While myeloid AMPK signaling had no effect on markers of hepatic steatosis or circulating markers, fibrosis as measured by total liver collagen was significantly elevated in livers from MacKO mice, independent of sex. Although treatment with 50 mg/kg/day metformin had no effect on any parameter, intervention with 250 mg/kg/day metformin completely ameliorated hepatic steatosis and fibrosis in both male and female mice. While the protective effect of metformin was associated with lower final body weight, decrease expression of lipogenic and Col1a1 transcripts, it was independent of myeloid AMPK signaling. These results suggest that endogenous AMPK signaling in myeloid cells, both liver-resident and infiltrating, acts to restrict fibrogenesis during CDAHFD-induced NASH progression but is not the mechanism by which metformin improves markers of NASH.

Comparison of the Prognostic Accuracy of Full Outline of Unresponsiveness (FOUR) Score with Glasgow Coma Scale (GCS) Score among Patients with Traumatic Brain Injury in a Tertiary Care Center.

Objectives The Glasgow Coma Scale (GCS) is widely used and considered the gold standard in assessing the consciousness of patients with traumatic brain injury. However, some significant limitations, like the considerable variations in interobserver reliability and predictive validity, were the reason for developing the Full Outline of Unresponsiveness (FOUR) score. The current study aims to compare the prognostic accuracy of the FOUR score with the GCS score for in-hospital mortality and morbidity among patients with traumatic brain injury. Materials and Methods A prospective cohort study was conducted, where 237 participants were selected by consecutive sampling from a tertiary care center. These patients were assessed with the help of GCS and FOUR scores within 6 hours of admission, and other clinical parameters were also noted. The level of consciousness was checked every day with the help of GCS and FOUR scores until their last hospitalization day. Glasgow Outcome Scale was used to assess their outcome on the last day of hospitalization. The GCS and FOUR scores were compared, and data were analyzed by descriptive and inferential statistics. The chi-square test, independent Student's t -test, and receiver operating characteristic analysis were used for inferential analysis. Results The area under the curve (AUC) for the GCS score at the 6th hour for predicting mortality was 0.865 with a cutoff value of 5.5, and it yields a sensitivity of 87% and a specificity of 64%. The AUC for FOUR scores at the 6th hour for predicting the mortality was 0.893, with a cutoff value of 5.5, and it yields a sensitivity of 87% and a specificity of 73%. Conclusion The current study shows that, as per the AUC of GCS and FOUR scores, their sensitivity was equal, but specificity was higher in the FOUR score. So, the FOUR score has higher accuracy than the GCS score in the prediction of mortality among traumatic brain injury patients.

Right heart catheterization in idiopathic pulmonary hypertension: An all-inclusive necessity.

The gold standard for diagnosis of pulmonary hypertension is right heart catheterization. This procedure requires considerable expertise and has its own procedure related complications. If not done properly, it can lead to misinterpretations of its findings. We have highlighted the procedural technique and major pitfalls in the diagnosis of pulmonary hypertension.

Neutrophil lymphocyte ratio and heart type fatty acid binding protein as a prognostic marker in Myocardial infarction within 48 h of admission.

BACKGROUND: The neutrophil to lymphocyte ratio (NLR) is a measure of systemic inflammation, whereas Heart type fatty acid protein (HFABP) is a cytosolic protein released early after acute coronary syndrome (ACS). The aim of this research study is to determine whether NLR and H-FAB are useful in predicting the prognosis in patients with ST segment elevation myocardial infarction (STEMI) 48 h after admission. This is a prospective observational study conducted on 97 patients who had been admitted to emergency room with ST-elevation myocardial infarction in their ECG in a tertiary care centre of south India. The neutrophil-lymphocyte ratio was measured at the time of admission, 24th hour and 48th hour, and then compared with the outcome. To determine their significance in the MI episode, troponin-I and H-FABP were also measured. RESULTS: A significant correlation was found in the final outcomes of patients and the NLR at the time of admission and at 48 h (p = 0.01). Additionally, a substantial correlation between NLR and various degrees of LV dysfunction was also observed (p = 0.01). H-FABP was found to be positive in all 97 of the patients examined, whereas Troponin-I was only found to be positive in 56.7%. CONCLUSION: The study's findings, indicated strong correlations between NLR and LVEF, indicated that NLR might serve as an early predictor of cardiac events which could be either poor prognosis or higher mortality. This research found that H-FABP may serve as an early MI diagnostic marker.

Level of Vitamin D and Its Relation with Incident Hypertension among Bangladeshi Adults.

Effect of vitamin D level on incident hypertension was not elucidated in our country perspective. The objective of the study was to report the level of vitamin D and its relation with incident hypertension among the Bangladeshi adults. This cross-sectional assessment was conducted in Bangabandhu Sheikh Mujib Medical University (BSMMU), Bangladesh for a period of one year (1st January 2019 to 31st December 2019). A total of 187 participants who had no known history of hypertension and comorbidities were included. Vitamin D assay and risk factors assessment for hypertension were performed for each patient. Data collection was done using a structured questionnaire and the study was conducted in compliance with current declaration of Helsinki. Analysis was conducted with SPSS 26.0. Out of 187 participants 33(17.6%) was newly diagnosed with hypertension. Predominant age group was 31-40 years (30.5%) and the average of incidence ±SD was 36.76±12.14 years. Sufficient, insufficient and deficient vitamin D was present in 11.8%, 32.6% and 55.6% cases, respectively. Mean±SD SBP and DBP were 117.41±12.84 and 76.87±9.46 mm of Hg. Hypertension was significantly more common in male than female (p=0.047), but there was no association of vitamin D with hypertension (p=0.262). Both hypertensive and normotensive patients shared similar risk factor profile in terms of age, gender, BMI, unhealthy food habit, extra salt intake, tobacco use, caffeine consumption, hormonal contraceptive of female (p>0.05 for all). Nearly one-fifth participants had newly diagnosed hypertension and more than fifty percent had vitamin D deficiency. However, vitamin D level didn't have any statistically significant association with incident hypertension.

Characteristics of coexisting attractors and ghost orbiting in an optomechanical microresonator.

We explore the nonlinear interactions of an optomechanical microresonator driven by two external optical signals. Optical whispering-gallery waves are coupled to acoustic surface waves of a fused silica medium in the equatorial plane of a generic microresonator. The system exhibits coexisting attractors whose behaviors include limit cycles, steady states, tori, quasi-chaos, and fully developed chaos with ghost orbits of a known attractor. Bifurcation diagrams demonstrate the existence of self-similarity, periodic windows, and coexisting attractors and show high-density lines within chaos that suggests a potential ghost orbit. In addition, the Lyapunov spectral components as a function of control parameter illuminate the dynamic nature of attractors and periodic windows with symmetric and asymmetric formations, their domains of existence, their bifurcations, and other nonlinear effects. We show that the power-shift method can access accurately and efficiently attractors in the optomechanical system as it does in other nonlinear systems. To test whether the ghost orbit is the link between two attractors interrupted by chaos, we examine the elements of the bifurcation diagrams as a function of control parameter. We also use detuning as a second control parameter to avoid the chaotic region and clarify that the two attractors are one.

Two doses of subcutaneous methadone for postoperative analgesia in dogs undergoing tibial plateau levelling osteotomies.

OBJECTIVES: To evaluate analgesia, sedation and adverse effects of two doses of subcutaneous methadone in dogs undergoing tibial plateau levelling osteotomy. MATERIALS AND METHODS: Seventeen client-owned dogs undergoing unilateral tibial plateau levelling osteotomy were randomly allocated to receive either 0.25 mg/kg methadone (eight dogs) or 0.5 mg/kg methadone (nine dogs). All dogs were premedicated with methadone and 2 to 6 mcg/kg dexmedetomidine subcutaneously. They were induced and maintained on a standard protocol. All animals received a second dose of methadone subcutaneously 4 hours after premedication and a 4.4 mg/kg dose of carprofen subcutaneously at 8 hours after premedication. During surgery, blood pressure, heart rate and temperature were assessed every 5 minutes. Postoperatively, sedation scores, temperature, heart rate and Glasgow composite modified pain score - short form were assessed for 12 hours postoperatively. RESULTS: One of 17 (5.9%) dogs had intraoperative hypotension, nine of 17 dogs had intra-operative bradyarrhythmias and 17 of 17 dogs had intra-operative hypothermia. No dogs required intra-operative rescue. Composite modified pain score - short form scores were below the threshold for intervention in 16 of 17 (94.1%) animals. Only one of 17 (5.9%) dogs required rescue analgesia. Median sedation score was 0 by the T8 time point. Adverse events were rare in both groups with only vocalisation and hypothermia reported commonly postoperatively. CLINICAL SIGNIFICANCE: Two doses of methadone at either 0.25 or 0.5 mg/kg administered via subcutaneous injections pre-operatively and 4 hours later, along with 4.4 mg/kg carprofen subcutaneously 8 hours after the first methadone dose appear to provide sufficient pain control for up to 12 hours in dogs undergoing tibial plateau levelling osteotomy.

The neutralizing effect of heparin on blood-derived antimicrobial compounds: impact on antibacterial activity and inflammatory response.

Acting through a combination of direct and indirect pathogen clearance mechanisms, blood-derived antimicrobial compounds (AMCs) play a pivotal role in innate immunity, safeguarding the host against invading microorganisms. Besides their antimicrobial activity, some AMCs can neutralize endotoxins, preventing their interaction with immune cells and avoiding an excessive inflammatory response. In this study, we aimed to investigate the influence of unfractionated heparin, a polyanionic drug clinically used as anticoagulant, on the endotoxin-neutralizing and antibacterial activity of blood-derived AMCs. Serum samples from healthy donors were pre-incubated with increasing concentrations of heparin for different time periods and tested against pathogenic bacteria (Acinetobacter baumannii, Enterococcus faecium, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus) and endotoxins from E. coli, K. pneumoniae, and P. aeruginosa. Heparin dose-dependently decreased the activity of blood-derived AMCs. Consequently, pre-incubation with heparin led to increased activity of LPS and higher values of the pro-inflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6). Accordingly, higher concentrations of A. baumannii, E. coli, K. pneumoniae, and P. aeruginosa were observed as well. These findings underscore the neutralizing effect of unfractionated heparin on blood-derived AMCs in vitro and may lead to alternative affinity techniques for isolating and characterizing novel AMCs with the potential for clinical translation.

The gut microbiome associates with phenotypic manifestations of post-acute COVID-19 syndrome.

The mechanisms underlying the many phenotypic manifestations of post-acute COVID-19 syndrome (PACS) are poorly understood. Herein, we characterized the gut microbiome in heterogeneous cohorts of subjects with PACS and developed a multi-label machine learning model for using the microbiome to predict specific symptoms. Our processed data covered 585 bacterial species and 500 microbial pathways, explaining 12.7% of the inter-individual variability in PACS. Three gut-microbiome-based enterotypes were identified in subjects with PACS and associated with different phenotypic manifestations. The trained model showed an accuracy of 0.89 in predicting individual symptoms of PACS in the test set and maintained a sensitivity of 86% and a specificity of 82% in predicting upcoming symptoms in an independent longitudinal cohort of subjects before they developed PACS. This study demonstrates that the gut microbiome is associated with phenotypic manifestations of PACS, which has potential clinical utility for the prediction and diagnosis of PACS.

An integrative approach for management of post-traumatic dorsal foot wounds - A case report.

Crush injuries to the foot have become increasingly prevalent in contemporary settings, primarily arising from incidents such as the impact of large objects falling onto the foot or involvement in traffic accidents. The complexity of treating these injuries is compounded by the intricate anatomy of the foot. In specific scenarios, the implementation of an integrated management approach could prove advantageous. In this report, we depict the case of a 23-year-old male who visited the Shalya OPD with a wound on his left foot caused by trauma. The wound covered the medial portion of the foot, involving the dorsal area, and measured roughly 20 cm by 9 cm and was unable to walk. We successfully managed the case by adopting an integrative approach. The Ayurvedic treatment included Panchavalkala kashaya for wound irrigation, as well as oral administration of Amalaki rasayana, Triphala guggulu, Shatavari churna and Ashwagandha churna. Jatyadi taila was topically applied. For the first seven days, in addition to these ayurvedic medications, we also employed analgesics and antibiotics to treat infection and pain. To accomplish early closure, we employed a split-thickness skin graft after sufficient granulation tissue had appeared. The wound was completely healed within three months and the patient was able to walk freely without any support. The combined approach yielded a promising result in this case.

Genetic background and sex influence somatosensory sensitivity and oxycodone analgesia in the Hybrid Rat Diversity Panel.

Opioid use disorder (OUD) is an ongoing public health concern in the United States, and relatively little work has addressed how genetic background contributes to OUD. Understanding the genetic contributions to oxycodone-induced analgesia could provide insight into the early stages of OUD development. Here, we present findings from a behavioral phenotyping protocol using several inbred strains from the Hybrid Rat Diversity Panel. Our behavioral protocol included a modified "up-down" von Frey procedure to measure inherent strain differences in the sensitivity to a mechanical stimulus on the hindpaw. We also performed the tail immersion assay, which measures the latency to display tail withdrawal in response to a hot water bath. Initial withdrawal thresholds were taken in drug-naïve animals to record baseline thermal sensitivity across the strains. Oxycodone-induced analgesia was measured after administration of oxycodone over the course of 2 h. Both mechanical and thermal sensitivity are shaped by genetic factors and display moderate heritability (h2 = 0.23-0.40). All strains displayed oxycodone-induced analgesia that peaked at 15-30 min and returned to baseline by 2 h. There were significant differences between the strains in the magnitude and duration of their analgesic response to oxycodone, although the heritability estimates were quite modest (h2 = 0.10-0.15). These data demonstrate that genetic background confers differences in mechanical sensitivity, thermal sensitivity, and oxycodone-induced analgesia.

Race, Ethnicity, and Other Barriers to Access Dental Care During Pregnancy.

BACKGROUND: Historically, women of color showed poorer oral health and lower dental service utilization in the USA. These barriers to dental care during pregnancy included dental coverage, primary language, dental provider availability, safety concerns, affordability of dental care, and perceived oral health benefits during pregnancy. METHODS: The purpose of this study is to examine whether race/ethnicity modified the associations between barriers to accessing dental care and dental service utilization during pregnancy. This cross-sectional study sample included 62,189 women aged 20 and older with a recent birth history in 21 states from the Pregnancy Risk Assessment Monitoring System (PRAMS) data from 2016 to 2019. We introduced a race/ethnicity by barrier interaction term to our multiple logistic regression models. RESULTS: After adjusting for other confounders, dental insurance during pregnancy and perceived oral health benefits were associated with 4.0- and 5.6-fold higher odds, respectively, of dental service utilization during pregnancy. Statistically significant effect modification by race/ethnicity was observed in crude and adjusted analyses of the relationship between dental service utilization for all barriers included in the interaction analyses with all adjusted p-values < 0.001. CONCLUSION: The interaction analysis found that racial/ethnic disparity in visiting dentists during pregnancy was significant among women who reported these dental barriers. In contrast, such racial/ethnic disparity was substantially attenuated among women who did not report such barriers. PRACTICAL IMPLICATIONS: The observed racial/ethnic disparities could be mitigated by such supporting mechanisms: dental coverage, provider availability and willingness to treat pregnant women, oral health education on the safety of dental care during pregnancy, and affordable dental care costs.