Clinical Context Research Articles

A Review on Novel Applications of Nanotechnology in the Management of Prostate Cancer.

Prostate cancer continues to be a serious danger to men's health, despite advances in the field of cancer nanotechnology. Although different types of cancer have been studied using nanomaterials and theranostic systems derived from nanomaterials, they have not yet reached their full potential for prostate cancer due to issues with in vivo biologic compatibility, immune reaction responses, accurate targetability, as well as a therapeutic outcome related to the nano-structured mechanism. The ultimate motive of this article is to understand the theranostic nanotechnology-based scheme for treating prostate cancer. The categorization of diverse nanomaterials in accordance with biofunctionalization tactics and biomolecule sources has been emphasized in this review so that they might potentially be used in clinical contexts and future advances. These opportunities can enhance the direct visualization of prostate tumors, early identification of prostate cancer-associated biomarkers at extremely low detection limits, and finally, the therapy for prostate cancer. In December 2022, a thorough examination of the scientific literature was carried out utilizing the Web of Science, PubMed, and Medline databases. The goal was to analyze novel applications of nanotechnology in the treatment of prostate cancer, together with their structural layouts and functionalities. The various treatments and the reported revolutionary nanotechnology-based systems appear to be precise, safe, and generally successful; as a result, this might open up a new avenue for the detection and eradication of prostate cancer.

Artificial intelligence-enabled electrocardiogram for mortality and cardiovascular risk estimation: a model development and validation study

Artificial intelligence (AI)-enabled electrocardiography (ECG) can be used to predict risk of future disease and mortality but has not yet been adopted into clinical practice. Existing model predictions do not have actionability at an individual patient level, explainability, or biological plausibi. We sought to address these limitations of previous AI-ECG approaches by developing the AI-ECG risk estimator (AIRE) platform. The AIRE platform was developed in a secondary care dataset (Beth Israel Deaconess Medical Center [BIDMC]) of 1 163 401 ECGs from 189 539 patients with deep learning and a discrete-time survival model to create a patient-specific survival curve with a single ECG. Therefore, AIRE predicts not only risk of mortality, but also time-to-mortality. AIRE was validated in five diverse, transnational cohorts from the USA, Brazil, and the UK (UK Biobank [UKB]), including volunteers, primary care patients, and secondary care patients. AIRE accurately predicts risk of all-cause mortality (BIDMC C-index 0·775, 95% CI 0·773-0·776; C-indices on external validation datasets 0·638-0·773), future ventricular arrhythmia (BIDMC C-index 0·760, 95% CI 0·756-0·763; UKB C-index 0·719, 95% CI 0·635-0·803), future atherosclerotic cardiovascular disease (0·696, 0·694-0·698; 0·643, 0·624-0·662), and future heart failure (0·787, 0·785-0·789; 0·768, 0·733-0·802). Through phenome-wide and genome-wide association studies, we identified candidate biological pathways for the prediction of increased risk, including changes in cardiac structure and function, and genes associated with cardiac structure, biological ageing, and metabolic syndrome. AIRE is an actionable, explainable, and biologically plausible AI-ECG risk estimation platform that has the potential for use worldwide across a wide range of clinical contexts for short-term and long-term risk estimation. British Heart Foundation, National Institute for Health and Care Research, and Medical Research Council.

Types of Genetic Determinism in Direct-to-Consumer Genetic Testing for Health

Prior research has challenged genetic determinism by highlighting the complex ways lay people engage with genetics. However, most of these critiques took place prior to the availability of direct-to-consumer (DTC) genetic health testing and were based on reactions to genetic testing administered in a clinical context due to either symptoms or family history. Today, many lay people interact with genetic health information outside of medicine, and often without pre-existing symptoms or family history. This suggests the need to revisit genetic determinism in the context of this new mode of public engagement with genetic information about health. In this paper we examine how a sample of 39 people who had previously taken a DTC genetic test for health make sense of their results. We find genetic determinism is prominent, but takes on several distinct forms, including protective determinism, motivating determinism, and absolute determinism. Considering this, we argue that genetic determinism should not be treated as a singular or fixed concept and cannot be dismissed as insignificant, given its continued salience for DTC genetic test-takers. Our analysis also pays particular attention to how test-takers interpret negative results (i.e., no elevated risks detected), as this is a common outcome of DTC genetic tests but has not been a focus of prior research.

Family physicians have greater ambiguity tolerance in the clinical context: A nationwide cross‐sectional study

AbstractBackgroundAmbiguity tolerance in the clinical context is increasingly recognized as essential for physicians to work as professionals. However, the relationship between specialty and ambiguity tolerance in the clinical context has been understudied. Here, we investigated the association between specialty and ambiguity tolerance in the clinical context, focusing on differences between family physicians (FPs) and non‐FPs.MethodsWe performed a nationwide cross‐sectional study in Japan. We asked FPs from 14 family medicine residency programs across Japan and non‐FPs from monitors of an internet survey company in Japan to participate in the study. We assessed their tolerance for ambiguity using the Japanese version of the Tolerance for Ambiguity in Medical Students and Doctors (J‐TAMSAD) scale.ResultsIn total, 388 physicians (178 FPs and 210 non‐FPs) completed our anonymous online survey and were included in the analysis. After adjustment for possible confounders (gender and postgraduate years), FPs had higher J‐TAMSAD scale scores than internists/pediatricians, surgeons, and physicians with other specialties, meaning that FPs had greater ambiguity tolerance.ConclusionsThis study reveals that FPs had greater tolerance for ambiguity in the clinical context than non‐FPs. Our findings suggest that there may be a need to increase non‐FP's tolerance for ambiguity specific to the clinical context through educational interventions, since ambiguity is inherent and growing in medicine today. FPs and non‐FPs should work together to complement each other's strengths, rather than simply improving the training of non‐FPs.

Baseline C-reactive protein as a predictor of non-ischemic LGE in myocarditis

Abstract Background Identifying reliable early indicators of myocardial injury in myocarditis is a pressing concern in cardiology. Despite their established role in detecting myocardial necrosis, traditional markers like high-sensitivity cardiac troponin (hs-cTn) may not fully capture the extent of myocardial damage identified by non-ischemic late gadolinium enhancement (LGE) on cardiovascular magnetic resonance (CMR) Purpose To identify early admission biomarkers associated with non-ischemic LGE in patients with myocarditis, offering the potential for improved risk stratification and therapeutic targeting. Methods In this retrospective study, we analyzed 59 myocarditis patients admitted to a high-volume medical center from 2017 to 2023, who underwent CMR to evaluate LGE. 41 patients (69.5%) exhibited non-ischemic LGE and 18 (30.5%) did not. We assessed baseline laboratory and echocardiographic parameters, employing Pearson correlation, logistic regression, and ROC curve analyses to elucidate the potential association of baseline biomarkers with non-ischemic LGE, while also discerning subepicardial from midwall patterns. Results Baseline C-reactive Protein (CRP) levels were significantly correlated with non-ischemic LGE (Pearson's r=0.301, p<0.05). Logistic regression analysis substantiated CRP as a predictor of non-ischemic LGE (OR=1.41, p<0.05), corroborated by a multivariate approach even after accounting for age and sex (OR=1.33; p<0.05). Among non-ischemic patterns, subepicardial LGE exhibited the strongest correlation with CRP (Pearson's r=0.321, p<0.05). In contrast, hs-cTn levels showed no significant association with non-ischemic LGE. The ROC analysis revealed that while both CRP and hs-cTn provide valid predictive values for non-ischemic LGE, with AUCs of 0.7333 and 0.6898 respectively, CRP demonstrated a higher discriminative performance, indicating that CRP may offer a more reliable assessment in this clinical context. Additionally, diabetic status emerged as the most significant condition associated with increased CRP levels, with diabetic patients presenting a substantial elevation in baseline CRP compared to non-diabetic patients (8.75 mg/dl vs 3.21 mg/dl; p<0.05). Conclusion CRP appears as a key early biomarker for non-ischemic LGE in myocarditis, with its predictive value being particularly evident in the subepicardial pattern and notably more pronounced among diabetic patients who demonstrate an increased inflammatory burden. These findings suggest a critical role for CRP in risk stratification right from the point of hospital admission and underline the potential for tailored therapeutic approaches that warrant further investigations. Figure 1: ROC curves comparison for CRP and hs-cTn in predicting non-ischemic LGE in myocarditis patients. Figure 2: Patients with diabetes (DM) exhibit significantly higher CRP levels (mean 8.75 mg/dl, SE = 5.54 mg/dl) than those without DM (mean 3.21 mg/dl, SE = 0.49 mg/dl).ROC curves comparisonCPR in patients with and without DM

Development of a systematic referral model to primary care health interventions for patients with atrial fibrillation. a delphi study

Abstract Background The European Society of Cardiology (ESC) guidelines for the management of atrial fibrillation (AF) recommend integrated care in AF, combining medical treatment with lifestyle modifications and psychosocial management in a multi-disciplinary set-up. Research show that patients with AF can benefit from lifestyle interventions and psychosocial management, like patient education. According to World Health Organization recommendations, these health interventions are moving from hospitals to primary healthcare settings. Therefore, patients with AF should be systematically referred to these interventions. Yet, an evidence-based referral model that can support this transition is lacking. Purpose The purpose is to develop a systematic referral model for primary care health interventions for patients with AF. Methods We used the Delphi-technique with three rounds of questionnaires (figure 1). International and national clinical experts in AF across disciplines and health sectors were invited to participate. In the first round, the expert panel evaluated items that could be part of a referral model on relevance, improvability and self-reporting. In the second round, the expert panel evaluated each item as either an inclusion or exclusion criteria, important knowledge to have, or not relevant. In the third round, the expert panel evaluated the items according to data source and outcome status. A final model was drawn based on items reaching consensus. The study was reported according to the guidance on conducting and reporting Delphi studies (CREDES). Results In total, 69 of 139 invited experts accepted to participate (50%). These were mostly academics or clinicians (90%), stemming from primary sector (16%), secondary sector (35%) and research (32%). Most were medical doctors (36%) and nurses (35%). However physiotherapist, psychologists, dieticians, and other disciplines along with six patients with AF were also represented. The expert panel (60% females) had a mean age of 50 years, and 65% were from Denmark. For the final referral model (figure 2), AF symptom burden and impaired health-related quality of life, anxiety and poor medicine compliance combined with a risk factor profile were the main inclusion criteria. Furthermore, it was important to know about the patients’ mental well-being, self-management abilities and comorbidities. Conclusion Consensus was reached for a generic referral model, which can be further adjusted in the appropriate clinical context. The model includes inclusion criteria which closely correlate with guidelines for AF management focusing on reducing the patients’ symptom and risk factor burden. The referral model is expected to increase the number of patients with AF referred to primary care health interventions, which could lead to better quality of life, fewer hospital admissions and lowered health care costs in AF.

Digital-twin co-simulation framework to support informed decision in healthcare planning and management

This manuscript aims to show the proof-of-concept for the integration of digital twin (DT) and discrete event co-simulation through its application to forward simulation of physical activities of care providers and robots in an intensive care unit (ICU). Co-simulation focuses on modular integration of heterogeneous simulation components to capture the complexity inherent in systems. Advancing this conception, the proposed co-simulation attempted to narrow gaps with real-world systems by using DT while simultaneously leveraging the forward simulation capacity of discrete event simulation (DES). In particular, we created a co-simulation for human–robot interactions in a simulated ICU facility, which modeled the hospital layout including the facility, robot, avatars for healthcare professionals, equipment, patient bed, and vital signs, which comprise physical twin (PT). In addition, specific patient-care scenarios were defined to drive PT for which the states of interest were represented in the DT, and then used for a dynamic input to the discrete event co-simulation. At the onset of the co-simulation, the parameters needed to run DES were manually configured to align the parameters with those of the DT. For internal validation, this DES was replicated under different work-system policies, and the co-simulation outcomes were interpreted in clinical context. Our co-simulation approach has potential for application to a broader class of problems in healthcare planning and management by supporting informed decision-making. Methodologically, timely information exchanges of PT with DT, and ensuing model updates in the Discrete Event System Specification (DEVS) is a promising approach for co-simulation, to maintain robustness against perturbations to real-world systems.

1.N. Scientific session: Child injuries monitoring and reporting: Challenges and technological developments

Abstract Globally, more than 1,600 children and adolescents below the age of 19-years die every day from preventable injuries. Road traffic injuries, drowning and self-harm represent leading causes of death and injury among children and adolescents (WHO 2021; WHO Regional Office for Europe, 2021; Unicef, 2021). Most unintentional injuries in early childhood occur at home and children from less advantaged backgrounds are exposed to more hazardous home environments due to overcrowding or unsafe structures over which parents often have limited control (WHO, 2020). According to the IDB data analysis approximately 15% of home injuries could have been prevented by improved product safety and parental education. The COVID-19 pandemic and the conflict in Ukraine have created a complex and challenging situation for children and adolescents in the region, increasing their vulnerability and compromising their well-being. To efficiently prevent child injuries, one must account for a complex interplay between human factors as well as physical and socio-cultural environments. Multiple determinants of child injury cannot be addressed by the health sector alone, this is why a whole-of-government and a whole-of-society approaches are required. Schools have a crucial role to play for promoting the well-being of children and serve as a platform to increase access to health services. However, EU countries are still missing intersectoral collaboration and strong information systems to enable efficient response to the problem. Data on child injuries are still inconsistently collected in Europe due to substantial differences in coding systems, variation between injury mechanisms, different general policies pertaining to the admission of patients, and legal policies on reporting requirements. EU-wide networks such as the Eurosafe study (IDB network) collecting information on child injuries, are scarce. Likewise, access to healthcare services and support systems are unevenly distributed, particularly in underserved communities. Building country capacity in collecting, analysing and increasing the use of child injury data for decision making at global, regional, and national levels, is critical. Adequate epidemiological data on the burden of child injuries are necessary to allow governments prioritize areas for intervention and maximize the impact of their resources. Utilizing evidence-based tools and procedures and promoting intersectoral collaboration is vital. The workshop aims to discuss trends and inequalities of injury burden and present efficient measures and latest developments in monitoring and reporting child injuries across EU countries. The workshop will further discuss the methodological challenges in collecting and analysing data on child injuries. Evidence-informed tools for sharing health information and improved measurements of injury burden that are feasible and usable in both research and clinical contexts will be presented and success stories will be presented. Key messages • There is an EU-wide need for epidemiological data on the burden of child injuries. • Validated tools, well-designed injury data management systems and standard data collection procedures are missing.

Advancing Pain Understanding and Drug Discovery: Insights from Preclinical Models and Recent Research Findings

Despite major advancements in our understanding of its fundamental causes, pain—both acute and chronic—remains a serious health concern. Various preclinical investigations utilizing diverse animal, cellular, and alternative models are required and frequently demanded by regulatory approval bodies to bridge the gap between the lab and the clinic. Investigating naturally occurring painful disorders can speed up medication development at the preclinical and clinical levels by illuminating molecular pathways. A wide range of animal models related to pain have been developed to elucidate pathophysiological mechanisms and aid in identifying novel targets for treatment. Pain sometimes drugs fail clinically, causing high translational costs due to poor selection and the use of preclinical tools and reporting. To improve the study of pain in a clinical context, researchers have been creating innovative models over the past few decades that better represent pathological pain conditions. In this paper, we provide a summary of traditional animal models, including rodents, cellular models, human volunteers, and alternative models, as well as the specific characteristics of pain diseases they model. However, a more rigorous approach to preclinical research and cutting-edge analgesic technologies may be necessary to successfully create novel analgesics. The research highlights from this review emphasize new opportunities to develop research that includes animals and non-animals using proven methods pertinent to comprehending and treating human suffering. This review highlights the value of using a variety of modern pain models in animals before human trials. These models can help us understand the different mechanisms behind various pain types. This will ultimately lead to the development of more effective pain medications.

Prediction of mortality, future arrhythmia and cardiovascular disease: an artificial intelligence-enhanced electrocardiography platform

Abstract Background Artificial intelligence-enhanced electrocardiography (AI-ECG) can be used to identify existing disease, but could additionally be used to predict occurrence of future disease and death. Purpose We developed an AI-ECG platform that predicts mortality and a wide spectrum of future arrhythmia and cardiovascular disease. Methods The AI-ECG risk estimation platform (AIRE) was developed in a dataset of 1,163,401 ECGs from 189,539 patients from a secondary care setting in the USA. Uniquely, AIRE uses deep learning with a residual convolutional neural network with a discrete-time survival loss function to output subject-specific survival curves (Fig 1A). AIRE was fine-tuned to additionally predict the endpoints described below. Results AIRE accurately predicts risk of all-cause mortality (C-index 0.775 (0.773-0.776) and can differentiate prognosis in high- and low-risk subjects, even when only cardiologist-defined normal ECGs are considered (Fig 2B). Additionally, in Cox regression analyses, AIRE was superior to conventional risk factors (Fig 1B). AIRE accurately predicted future ventricular arrhythmia (c-index 0.760 (0.756-0.763)), future complete heart block (CHB) (0.809 (0.805-0.814), future atrial fibrillation (0.753 (0.751-0.756), future atherosclerotic cardiovascular disease (0.696 (0.694-0.698)) and future heart failure (0.787 (0.785-0.789)) . AIRE was superior to left ventricular ejection fraction (LVEF) in predicting risk of future ventricular arrhythmias in subjects with LVEF <50% (C-index 0.649 (0.638 – 0.660) vs 0.615 (0.603 – 0.626) p < 0.0001 ). For CHB prediction, AIRE was able to further risk stratify subjects with bifascicular block and syncope into low (1.9% 5 year CHB), intermediate (8.8%), and high risk (20.7%) groups, and could guide treatment decisions. We externally validated our findings in four diverse, transnational cohorts from Brazil and the UK, including volunteers, primary care subjects and patients with Chagas disease, and found AIRE accurately predicted all-cause mortality in all four external cohorts (Fig 2). Non-mortality endpoints were successful externally validated in the UKB. In explainability analyses, we found features of QRS morphology, low QRS voltage, poor precordial R wave progression, inverted and biphasic T waves and ST segment changes were the most significant morphological features associated with high predicted mortality (Fig 1D). Through phenome- and genome-wide association studies (GWAS), we identified candidate biological pathways including changes in cardiac structure (LV mass, LV trabeculation and left atrial size). GWAS identified variants adjacent to VGLL2, KCNQ1, CCDC91 and TBX3 which have been described in association with QT interval, biological aging and metabolic syndrome (Fig 1E). Conclusion AIRE could be used worldwide across a range of clinical contexts for risk estimation of not only mortality but a wide spectrum of future arrhythmia and cardiovascular diseases.Figure 1Figure 2

Sexual Dysfunctions and Gynecomastia in Male Rheumatological Patients Treated with Methotrexate: A Systematic Review

Objectives: The aim of the current review was to elucidate the clinical context and presentation of sexual dysfunction (SD) and gynecomastia in rheumatological patients undergoing methotrexate treatment. Moreover, we aimed also to make physicians aware of the occurrence of these side effects, to adequately inform the patient before starting treatment. Methods: Systematic review (PROSPERO id: CRD42022358275) was performed according to preferred reporting items for systematic reviews and meta-analyses. Studies (1 January 1995 to 31 May 2022) were identified by highly sensitive searches of electronic databases (Medline, Embase, Cochrane Library databases). Key terms included: ((“sexual dysfunction” OR “erectile dysfunction” OR “impotence”) AND (“methotrexate” OR “MTX”)) and ((“gynecomastia” OR “male breast”) AND (“methotrexate” OR “MTX”)). Results: A total of seven papers (seven case reports), involving a total of eleven patients (min one, max three), were included in the final analysis. The age of the patients ranged from 19 to 68 years (median: 50.9 years). Rheumatoid arthritis (RA) was the most frequent rheumatic disease reported (n = 8, 72.7%). No patients reported erectile dysfunction (ED) and/or gynecomastia before using MTX. Time to onset of SD and gynecomastia after MTX ranged from 2 to 104 weeks (median: 22.7 weeks). ED (n = 5, 45.4%) and gynecomastia (n = 3, 27.2%) were the most common forms of presentation. Conclusions: Future prospective controlled studies with a large sample size and long follow-up as well as randomized controlled trials are needed to confirm this association, investigate its pathophysiological basis, assess the safest dosages, evaluate the most appropriate management, and provide clear recommendations.

Personalized, performance-specific speech intervention in children with a cleft palate: A systematic review protocol.

The provision of speech intervention in children requires personalized, child-tailored approaches. Different speech-intervention approaches exist to eliminate cleft-related speech errors in children with a cleft palate. However, it is unclear what approach works best for the subtypes of cleft-related speech errors. To describe a protocol for a systematic review that provides speech-language pathologists with the current literature concerning more individualized speech intervention in children with a cleft palate. A systematic literature review was performed following the preferred reporting items for systematic reviews and meta-analyses. Two speech-language pathologists with clinical and scientific experience in cleft speech searched different electronic databases for relevant studies. No limit regarding publication date was set. Specific eligibility criteria were defined and used to include or exclude the studies. All included studies were evaluated with a risk-of-bias assessment tool and levels of evidence. Relevant data were extracted from the studies (study design, study population characteristics, intervention characteristics and outcome characteristics) and a narrative synthesis was performed. The findings of this systematic review will significantly contribute to the evidence on personalized speech intervention in children with a cleft palate. The study will inform speech-language pathologists on the possibilities to tailor treatment plans more to the specific subtype of cleft-related speech errors. The planned systematic review also makes recommendations for further cleft speech intervention research. What is already known on this subject At present, there is growing evidence for different speech therapy approaches in children with a cleft palate. Despite the recognized need for personalized, child-tailored therapy, there is no consensus on the best speech therapy approach per different subtype of compensatory cleft speech characteristic. What this study adds to the existing knowledge This paper provides a protocol for a systematic literature review of this topic. Specifically, it searches the literature for the use of personalized speech therapy approaches in children with different subtypes of compensatory cleft speech characteristics. What are the practical and clinical implications of this work? The systematic literature review provides speech-language pathologists with the current literature concerning personalized, performance-specific speech intervention in children with a cleft palate. Besides, the results will support therapy decision-making in children with a cleft palate in different speech-related clinical contexts.

A Wearable, Steerable, Transcranial Low-Intensity Focused Ultrasound System.

Transcranial low-intensity focused ultrasound (LIFU) offers unique opportunities for precisely neuromodulating small and/or deep targets within the human brain, which may be useful for treating psychiatric and neurological disorders. This article presents a novel ultrasound system that delivers focused ultrasound through the forehead to anterior brain targets and evaluates its safety and usability in a volunteer study. The ultrasound system and workflow are described, including neuronavigation, LIFU planning, and ultrasound delivery components. Its capabilities are analyzed through simulations and experiments in water to establish its safe steering range. A cohort of 20 healthy volunteers received a LIFU protocol aimed at the anterior medial prefrontal cortex (amPFC), using imaging and questionnaires to screen for adverse effects. Additional development after the study also analyzes the effect of the skull and sinus cavities on delivered ultrasound energy. Simulations and hydrophone readings agreed with <5% error, and the safe steering range was found to encompass a 1.8 cm × 2.5 cm × 2 cm volume centered at a depth 5 cm from the surface of the skin. There were no adverse effects evident on qualitative assessments, nor any signs of damage in susceptibility-weighted imaging scans. All participants tolerated the treatment well. The interface effectively enabled the users to complete the workflow with all participants. In particular, the amPFC of every participant was within the steering limits of the system. A post hoc analysis showed that "virtual fitting" could aid in steering the beams around subjects' sinuses. The presented system safely delivered LIFU through the forehead while targeting the amPFC in all volunteers, and was well-tolerated. With the capabilities validated here and positive results of the study, this technology appears well-suited to explore LIFU's efficacy in clinical neuromodulation contexts.

Advancing Children’s Participation Rights in Healthcare Through Play

Abstract Within the vulnerable clinical context, children’s participation rights are easily compromised in relation to their protection and service provision. Unfortunately, failure to engage children in medical conversations can make this stressful context even more acute. In response to this problem, this Article presents the legal, philosophical and evidence-based arguments for incorporating play as a child-friendly intervention to engage young patients in meaningful participation in clinical settings. Play as the natural language of children can make them receive and assimilate medical information without fear. Play is also a well-recognised mechanism of child agency and their most natural form of participation, and as such can become a springboard for engaging and empowering children in healthcare.

Impact of gestational age on the management of acute appendicitis during pregnancy: A nationwide observational study.

To compare conservative management and appendectomy for acute appendicitis during pregnancy by trimester. This retrospective cohort study used data from a national inpatient database from July 2010 to March 2022. Pregnant women diagnosed with acute appendicitis were included. Multivariable analysis using generalized estimating equations was performed to compare outcomes between conservative management and appendectomy across trimesters. The main outcomes were preterm labor, preterm delivery, or abortion; antepartum hemorrhage; duration of hospitalization; and duration of antibiotic use. A total of 3158 individuals from 632 acute-care hospitals were eligible. The proportion of conservative management versus appendectomy by trimester were 507 (49.1%) versus 525 (50.9%) in the first, 690 (44.6%) versus 856 (55.4%) in the second, and 337 (58.1%) versus 243 (41.9%) in the third. In the second trimester, appendectomy was associated with a higher rate of preterm delivery, preterm labor, or abortion (odds ratio [OR], 2.91 [95% confidence interval (CI), 1.62-5.25]). Antepartum hemorrhage occurred more frequently for appendectomy in the first (OR, 2.12 [95% CI, 1.31-3.43]) and third (OR, 2.43 [95% CI, 1.79-3.31]) trimesters. Appendectomy was associated with a longer duration of hospitalization in the second (2.15 days; 95% CI, 1.14-3.17 days) and third (3.97 days; 95% CI, 2.22-5.71 days) trimesters. Antibiotic use duration was shorter for appendectomy in the first (-1.20 days [95% CI -1.51 to -0.90 days]) and second (-0.61 days [95% CI -0.90 to -0.32 days]) trimesters. Clinical outcomes of acute appendicitis during pregnancy vary by trimester. Considering the appendectomy risks, conservative management may be viable depending on the clinical context and trimester.

A Methodology to Quantify the Effective Vertical Thickness of Prephonatory Vocal Fold Medial Surface

ObjectiveThe shape of the vocal fold medial surface, particularly its vertical thickness, has been shown in computational and physical modeling studies to be highly influential in regulating glottal closure during phonation. However, because of the difficulty to quantify the vertical thickness in real vocal folds, this influence has often been overlooked in clinical contexts. Therefore, the goal of this study is to present a method to calculate an effective vertical thickness of the medial surface that is predictive of the glottal closure pattern during phonation. MethodsAn effective vertical thickness of the medial surface is calculated as a weighted integral of the medial surface contour along the vertical dimension. The weight is one for the part of the medial surface within a fixed threshold distance from the most medial point, and decays exponentially otherwise. The influence of the threshold distance value on the effective thickness value is investigated. Additionally, the sensitivity of the calculated effective thickness to slight misidentification of the vertical glottal midline is also studied. The methodology is validated on the vocal fold medial surface data from a canine hemilarynx at different levels of thyroarytenoid muscle activation. ResultsFor most threshold distances, the thickness follows an expected sigmoid-like trend with respect to the thyroarytenoid muscle activation level. A threshold distance of 0.05 mm appears optimal as it produced thickness changes in a range comparable to previous computational and experimental studies. The methodology is relatively robust to slight misidentification of the vertical glottal midline. ConclusionsA methodology to estimate the effective vocal fold vertical thickness from medial surface contours is proposed. The methodology can be applied in future studies to correlate medial surface shape to relevant parameters characterizing vocal fold vibration as well as clinical evaluation of treatment effectiveness.

Confirmatory validation of a brief patient-reported outcome measure assessing psychological distress in caregivers of malignant mesothelioma patients: the Mesothelioma Psychological Distress Tool–Caregivers

ObjectiveThe diagnosis of malignant mesothelioma (MM) can be devastating for both patients and caregivers, who may experience intense suffering from a physical, psychological, and interpersonal perspective. Despite the extensive literature on caregiver distress, there is a lack of validated measures to provide evidence of psychological distress of caregivers of MM patients. Therefore, in a previous study we developed the Mesothelioma Psychological Distress Tool–Caregivers (MPDT-C) to evaluate the specific profile of psychological distress in this population. This paper describes the item selection, factor analysis, and psychometric evaluation of the revised MPDT-C.MethodsThe analyses of this work first aimed to confirm the previous factorial structure. In the case of nonfit, it aimed to find an alternative structure and causes of nonfit in the model. Examination of the fit of the factorial model was conducted using a Bayesian approach.ResultsThe final version of the MPDT-C is a 7-item self-report questionnaire consisting of one factor (Burden for the caregiver).ConclusionHaving a short self-report questionnaire to assess the psychological distress experienced by caregivers of MM patients has several advantages. First, it is suited to epidemiological studies where multiple variables and measures are involved. Second, it is easy to administer and does not take much time to complete. Therefore, the MPDT-C can also be administered in clinical contexts, perhaps when MM patients attend follow-up medical evaluation. Lastly, short measures are less affected by cognitive fatigue, which is very common in a long battery of tests and could affect response reliability.

Low SMARCD3 expression is associated with poor prognosis in patients with prostate cancer.

SWI/SNF complexes represent a family of multi-subunit chromatin remodelers that are affected by alterations in >20% of human tumors. While mutations of SWI/SNF genes are relatively uncommon in prostate cancer (PCa), the literature suggests that deregulation of various subunits plays a role in prostate tumorigenesis. To assess SWI/SNF functions in a clinical context, we studied the mutually exclusive, paralogue accessory subunits SMARCD1, SMARCD2, and SMARCD3 that are included in every known complex and are sought to confer specificity. Performing immunohistochemistry (IHC), the protein levels of the SMARCD family members were measured using a tissue microarray (TMA) comprising malignant samples and matching healthy tissue of non-metastatic PCa patients (n = 168). Moreover, IHC was performed in castration-resistant tumors (n = 9) and lymph node metastases (n = 22). To assess their potential role as molecular biomarkers, SMARCD1 and SMARCD3 protein levels were correlated with clinical parameters such as T stage, Gleason score, biochemical recurrence, and progression-free survival. SMARCD1 protein levels in non-metastatic primary tumors, lymph node metastases, and castration-resistant samples were significantly higher than in benign tissues. Likewise, SMARCD3 protein expression was elevated in tumor tissue and especially lymph node metastases compared to benign samples. While SMARCD1 levels in primary tumors did not exhibit significant associations with any of the tested clinical parameters, SMARCD3 exhibited an inverse correlation with pre-operative PSA levels. Moreover, low SMARCD3 expression was associated with progression to metastasis. In congruence with previous literature, our results implicate that both SMARCD1 and SMARCD3 may exhibit relevant functions in the context of prostate tumorigenesis. Moreover, our approach suggests a potential role of SMARCD3 as a novel prognostic marker in clinically non-metastatic PCa.

The Immunomodulatory Mechanisms of BTK Inhibition in CLL and Beyond

Bruton’s tyrosine kinase (BTK), a cytoplasmic tyrosine kinase, plays a pivotal role in B cell biology and function. As an essential component of the B cell receptor (BCR) signaling pathway, BTK is expressed not only in B cells but also in myeloid cells, including monocytes/macrophages, dendritic cells, neutrophils, and mast cells. BTK inhibitors (BTKis) have revolutionized the treatment of chronic lymphocytic leukemia (CLL) and other B cell malignancies. Besides their well-characterized role in inhibiting BCR signaling, BTKis also exert significant immunological influences outside the tumor cell that extend their therapeutic potential and impact on the immune system in different ways. This work elucidates the immunomodulatory mechanisms associated with BTK inhibition, focusing on CLL and other clinical contexts. We discuss how BTK inhibition affects various immune cells, including B cells, T cells, and macrophages. The effects of BTKis on the profiles of cytokines, also fundamental parts of the tumor microenvironment (TME), are summarized here as well. This review also appraises the implications of these immunomodulatory actions in the management of autoimmune diseases and infections. Summarizing the dual role of BTK inhibition in modulating malignant lymphocyte and immune cell functions, this paper highlights the broader potential clinical use of compounds targeting BTK.

Why do dentists refrain from intervention in cases of persistent asymptomatic apical periodontitis in root canal filled teeth? An interview study among general dental practitioners.

To explore the context in which general dental practitioners (GDPs) decide to refrain from further treatment, that is, ortho- or retrograde retreatment or extraction of a root canal filled tooth with persistent asymptomatic apical periodontitis (PAAP). Fifteen GDPs were strategically selected for in-depth interviews. The informants were encouraged to describe in their own words and in as much detail as possible, the three most recent patient cases of PAAP of a root canal filled tooth, in which they decided to refrain from further treatment. The interviews were recorded digitally and transcribed verbatim. The collected material was analysed according to Qualitative Content Analysis with an inductive approach. A pattern of varying degrees of uncertainty associated with the decision process was identified. The motives to refrain intervention had great diversity. The result from analysis of the qualitative data was formulated in an overall theme 'Between doubt and certainty in a complex clinical context' covering the latent content. The first main category covering the manifest content was 'The continuum of confidence' with three subcategories 'Experienced uncertainty', 'Reluctant approval' and 'At ease with refraining' illustrating the feelings and attitudes experienced by the informants. The second category was 'In support of acceptance' with three subcategories 'Patient's autonomy, risks and cost-benefits', 'Emotional aspects' and 'Relieving measures' representing the reasons for refraining from intervention. The decision to refrain from further treatment, that is, ortho- or retrograde retreatment or extraction of a root canal filled tooth with PAAP was made with some measure of confidence, combined with compensatory strategies to support the decision, taking into account not only values beneficial to the patient and awareness of limited external resources, but also factors related to the informants' personal preferences, convenience, concerns, ambition and emotions.