Miracle-dz/UniFAR-FTUs huggingface dataset:
Recommendations for the design and implementation of an Early Feasibility Studies program for medical devices in the European Union

ABSTRACT Introduction Early Feasibility Studies (EFS) are among the pre-market clinical investigations allowed by the International Standard for Clinical investigation of medical devices (MD) for human subjects. The Food and Drug Administration (FDA) introduced an EFS program in the US in 2013. The European Union (EU) MD Regulation, that entered into force in May 2021, opened the possibility of EFS in the EU. However, European countries at present have no standardized procedural framework for EFS. In this paper, we address the desirability of a European EFS program. Areas covered Characteristics of EFS conducted so far are reviewed, and perceptions of an expert, multidisciplinary panel of key stakeholders are explored regarding desirability and feasibility of a European EFS program and critical factors favoring or hampering its implementation. Expert opinion Implementing an EFS program in the EU would contribute to creating a favorable environment for early-stage clinical investigations, with positive effects on the quality and timeliness of clinical evidence for novel MDs, and attractiveness of the European system for pre- and post-market clinical research. Based on discussion with experts, also leveraging on the US experience, three dimensions should be considered for effective design and implementation: process, resources, and ethical issues.
Additional parameters to improve the prognostic value of the 8th edition of the UICC classification for human papillomavirus‐related oropharyngeal tumors

The prognostic reliability of the UICC's TNM classification (8th edition) for human papillomavirus (HPV)‐positive tonsillar squamous cell carcinomas (TSCCs) compared to the 7th edition was explored, and its improvement by using additional anatomical and nonanatomical parameters.
Leelamine Exerts Antineoplastic Effects in Association with Modulating Mitogen‑Activated Protein Kinase Signaling Cascade

Abstract Mitogen‑activated protein kinase (MAPK) pathway is a prominent signaling cascade that modulates cell proliferation, apoptosis, stress response, drug resistance, immune response, and cell motility. Activation of MAPK by various small molecules/natural compounds has been demonstrated to induce apoptosis in cancer cells. Herein, the effect of leelamine (LEE, a triterpene derived from bark of pine trees) on the activation of MAPK in hepatocellular carcinoma (HCC) and breast cancer (BC) cells was investigated. LEE induced potent cytotoxicity of HCC (HepG2 and HCCLM3) and BC (MDA-MB-231 and MCF7) cells over normal counterparts (MCF10A). LEE significantly enhanced the phosphorylation of p38 and JNK MAPKs in a dose-dependent fashion and it did not affect the phosphorylation of ERK in HCC and BC cells. The apoptosis-driving effect of LEE was further demonstrated by cleavage of procaspase-3/Bid and suppression of prosurvival proteins (Bcl-xL and XIAP). Furthermore, LEE also reduced the SDF1-induced-migration and -invasion of HCC and BC cells. Taken together, the data demonstrated that LEE promotes apoptosis and induces an anti-motility effect by activating p38 and JNK MAPKs in HCC and BC cells.
Folate intake and risk of colorectal cancer: a systematic review and up-to-date meta-analysis of prospective studies

Purpose Colorectal cancer is one of the most commonly diagnosed and deadly cancers worldwide. Epidemiological studies on the relationship between folate intake and the risk of colorectal cancer have reported inconsistent findings since folate fortification in the USA. For this situation, we conducted a large number of data analyses to study the relationship between folate intake and colorectal cancer risk. Methods PubMed and EMBASE databases were used to search the literature systematically. Eligible studies were reviewed and meta-analyzed to assess the relationship. Results A total of 24 cohort studies involving 37 280 patients and 6 165 894 individuals were included. The results showed that high folate intake was associated with a reduced risk of colorectal cancer. The combined relative risk (RR) for the highest intake compared with the lowest was 0.88 [95% confidence interval (CI), 0.83–0.92, P = 10−4). Further studies indicated that the increase of folate intake may decrease the risk of colorectal cancer in people with medium or high alcohol consumption (RR = 0.97, 95% CI: 0.96–0.99, P = 0.008; RR = 0.95, 95% CI: 0.92–0.98, P = 0.003), but not in non-drinkers (RR = 1.00, 95% CI: 0.98–1.02, P = 0.827). Next, high folate intake may decrease the risk of colon cancer (RR = 0.86, 95% CI: 0.81–0.92, P = 10−4) but not rectal cancer (RR = 0.92, 95% CI: 0.84–1.02, P = 0.112). Additionally, the result that high folate intake may decrease the risk of colorectal cancer was observed in the USA and Europe but not in other regions. Conclusion High folate intake may be protective against colon cancer, particularly in people with middle or high alcohol consumption, but it still needs to be further confirmed.
Episodic boundary cells in human medial temporal lobe during the free recall task

A necessary condition for forming episodic memories is the construction of specific episodes demarcated from other episodes in space and time. Evidence from studies of episodic memory formation using rodent models suggest that the medial temporal lobe (MTL) supports the representation of boundary information. Building on recent work using human microelectrode recordings as well, we hypothesized of human MTL neurons with firing rates sensitive to episodic boundary information. We identified 27 episodic boundary neurons out of 736 single neurons recorded across 27 subjects. Firing of these neurons increased at the beginning and end of mnemonically relevant episodes in the free recall task. We distinguish episodic boundary neurons from a population of ramping neurons (n = 58), which are time‐sensitive neurons whose activity provides complementary information during episodic representation. Episodic boundary neurons exhibited a U‐shaped activity pattern demonstrating increased activity after both beginning and end boundaries of encoding and retrieval epochs. We also describe evidence that the firing of boundary neurons within episodic boundaries is organized by hippocampal theta oscillations, using spike‐field coherence metrics.
Effects of COVID-19-related worry and rumination on mental health and loneliness during the pandemic: longitudinal analyses of adults in the UK COVID-19 mental health & wellbeing study

Abstract Background The lasting effects of the coronavirus disease 2019 pandemic are likely to be significant. Aims This study tracked worry and rumination levels during the pandemic and investigated whether periods with higher COVID-related worry and rumination were associated with more negative mental health and loneliness. Methods A quota survey design and a sampling frame that permitted recruitment of a national sample were employed. Findings for waves 1 (March 2020) to 6 (November 2020) are reported (N = 1943). Results Covid-related worry and rumination levels were highest at the beginning of the first lockdown, then declined but increased when the UK returned to lockdown. Worry levels were higher than rumination levels throughout. High levels of COVID-related worry and rumination were associated with a five- and ten-fold increase in clinically meaningful rates of depression and anxiety (respectively) together with lower well-being and higher loneliness. The effects of COVID-related worry on depression and anxiety levels were most marked and clinically meaningful in individuals living with a pre-existing mental health condition. Conclusions Psychological interventions should include components that specifically target COVID-related worry and rumination. Individuals with pre-existing mental health conditions should be prioritised as we emerge from the current pandemic and in any future public health crises.
Load measurement and health monitoring in cable stays via guided wave magnetostrictive ultrasonics

Loaded cables made of wires, strands or bars are employed in civil structures as load carrying members in cable stayed and suspension bridges. Steel strands are also employed in prestressed structures for the pretensioning or posttensioning of concrete. Accurate and real time knowledge of the force acting on these stressing systems can contribute immensely to ensuring the safety of a bridge structure. Monitoring cable loads in service can also allow for detection of excessive wind and traffic overloads or, in the worst scenario, problems such as accidental broken wires and corrosion. The overall objective of this paper is to further the understanding of an ultrasonic method that is able to monitor live loads in multiwire steel strands as well as detect possible discontinuities such as indentations and broken wires. The characterization of wave propagation in steel strands is achieved through a broadband, laser ultrasonic setup and time frequency wavelet transform processing. Those vibrating frequencies propagating with minimal losses are identified as they are suitable for long range testing of the strands. In addition, the wave transmission spectra are found to be sensitive to the load level. Sensors based on the magnetostrictive effect are used for the wave generation and detection. The acoustoelastic effect is also considered for live load monitoring. Signal processing based on the discrete wavelet transform is used to enhance the discontinuity detection sensitivity and acquisition speed.
Integrating the effects of sucrose intake on the brain and white adipose tissue: Could autophagy be a possible link?

Excess dietary sucrose is associated with obesity and metabolic diseases. This relationship is driven by the malfunction of several cell types and tissues critical for the regulation of energy balance, including hypothalamic neurons and white adipose tissue (WAT). However, the mechanisms behind these effects of dietary sucrose are still unclear and might be independent of increased adiposity. Accumulating evidence has indicated that dysregulation of autophagy, a fundamental process for maintenance of cellular homeostasis, alters energy metabolism in hypothalamic neurons and WAT, but whether autophagy could mediate the detrimental effects of dietary sucrose on hypothalamic neurons and WAT that contribute to weight gain is a matter of debate. In this review, we examine the hypothesis that dysregulated autophagy in hypothalamic neurons and WAT is an adiposity‐independent effect of sucrose that contributes to increased body weight gain. We propose that excess dietary sucrose leads to autophagy unbalance in hypothalamic neurons and WAT, which increases caloric intake and body weight, favoring the emergence of obesity and metabolic diseases.
Corrosion monitoring of high-level waste storage Tank 8-D2 at the West Valley Demonstration Project

From 1966 to 1972, nearly 600,000 gallons of highly radioactive liquid waste were generated at the site of the only commercial nuclear fuel reprocessing facility to have operated in the United States, located in West Valley, New York. This waste has been held in underground storage tanks since reprocessing operations ceased in 1972. Premature failure of tank walls represents a significant safety risk at West Valley. For this reason, application of conventional methods of probe insertion and data acquisition are impractical. Because a satisfactory corrosion monitoring system must allow for remote monitoring, as well as decontamination of any probe or coupon that comes into contact with the liquid high-level waste (HLW) held in the tanks, a fully automated Integrated Corrosion Monitoring System has been implemented at West Valley. This system allows for remote continuous monitoring of corrosion effects by linear polarization and electrical resistance probes. Real time corrosion data that indicates metal loss versus time and corrosion rate for electrical resistance probes, as well as corrosion rate and pitting tendencies for linear polarization resistance probes is depicted on a electroluminescent display. Because corrosion rates are being continuously checked, this system is ideal for monitoring the corrosive conditions that will affectmore » the life of the containment HLW storage vessels. The probes in the system also permits the simultaneous use of coupons for determining specific types of corrosion occurring, and the average corrosion rate for the entire exposure period. This paper describes the design parameters, installation procedures, and the results of data collected from the Integrated Corrosion Monitoring System installed at West Valley. « less
Twenty-Year Experience and Outcomes in a National Pediatric Pulmonary Hypertension Service

Rationale Pediatric pulmonary hypertension is an important cause of childhood morbidity and mortality, but there are limited data on the range of associated diseases, contributions of different pulmonary hypertension subtypes, therapeutic strategies, and clinical outcomes in children. Objectives To report the 20-year experience of a large UK National Pediatric Pulmonary Hypertension Service focusing on epidemiology and clinical outcomes. Methods Consecutive patients presenting between 2001 and 2021 were included, and survival analysis was performed for incident patients. Measurements and Main Results Of 1,353 patients assessed, a pulmonary hypertension diagnosis was made in 1,101 (81.4%) patients (51% female, median age, 2.6 [interquartile range, 0.8–8.2] years). The most common form was pulmonary arterial hypertension in 48%, followed by 32.3% with pulmonary hypertension due to lung disease. Multiple contributory causes of pulmonary hypertension were common, with 16.9% displaying features of more than one diagnostic group. The annual incidence of childhood pulmonary hypertension was 3.5 (95% confidence interval [CI], 3.3–3.8) per 1 million children, and the prevalence was 18.1 (95% CI, 15.8–20.4) per 1 million. The incidence was highest for pulmonary hypertension due to lung disease in infancy (15.0 [95% CI, 12.7–17.2] per 1 million per year). Overall, 82.4% patients received pulmonary arterial hypertension therapy, and escalation to triple therapy during follow-up was required in 13.1%. In 970 (88.1%) incident patients, transplant-free survival was 86.7% (95% CI, 84.5–89%) at 1 and 68.6% (95% CI, 64.7–72.6%) at 10 years. Pulmonary hypertension due to left heart disease had the lowest survival (hazard ratio, 2.0; 95% CI, 1.36–2.94; P < 0.001). Conclusions Clinical phenotypes of pediatric pulmonary hypertension are heterogeneous and overlapping, with clinical phenotypes that evolve throughout childhood. Despite widespread use of pulmonary arterial hypertension therapy, the prognosis remains poor.
Evaluation of a tryptase depletion index for better pathologic identification of mast cell activation syndrome

Abstract Background Laboratory evidence supporting diagnosis of the prevalent condition of mast cell activation syndrome (MCAS) currently includes elevated levels in blood or urine of mediators relatively specific to mast cells (MCs) and/or increased numbers of MCs in luminal gastrointestinal (GI) tract tissues. However, identification of elevated mediators is technically challenging and expensive, and controversy persists regarding the normal ranges of numbers/counts of MCs in various GI tract segments, let alone challenges in determining how many of the visualized MCs are activated. To aid diagnosis of MCAS, we developed a potential new approach for the pathologist to identify the extent of GI tract MC activation easily and inexpensively. Participants and Methods Visualization of MCs in gastrointestinal biopsies from 251 patients vs. 95 controls using antibodies against CD117 and tryptase; MC counting per mm 2 ; calculation of the difference between the CD117-positive MCs (identifying all MCs) vs. tryptase-positive MCs (identifying non-activated tryptase-containing MCs), which we define as the tryptase depletion index (TDI). Results Mean total MC counts did not differ significantly between patients and controls, but mean TDIs differed significantly. Non-overlapping confidence intervals at the 99.9% level identified cut-offs of TDIs between patients vs. controls of 26, 45 and 32 MCs/mm 2 in gastric antrum, duodenum, and colon, respectively. Conclusions The TDI may discriminate between MCAS patients vs. controls. If this preliminary work can be independently confirmed, the TDI may become a useful additional minor diagnostic criterion for MCAS.
Efficacy of tofacitinib in patients with rheumatoid arthritis stratified by baseline body mass index: an analysis of pooled data from phase 3 studies

Objective Tofacitinib is an oral Janus kinase for the treatment of rheumatoid arthritis (RA). This post hoc analysis assessed whether baseline body mass index (BMI) impacts tofacitinib efficacy in patients with RA. Methods Pooled data from six phase 3 studies in patients receiving tofacitinib 5 mg (N=1589) or 10 mg (N=1611) twice daily or placebo (advancing to active treatment at months 3 or 6; N=680), ±conventional synthetic disease-modifying antirheumatic drugs, were stratified by baseline BMI (<25, 25 to <30, ≥30 kg/m2). Endpoints (through to month 6) were assessed descriptively: American College of Rheumatology 20/50/70 response rates; changes from baseline (∆) in Disease Activity Score in 28 joints, erythrocyte sedimentation rate (DAS28-4(ESR)), DAS28-4(C-reactive protein), Clinical Disease Activity Index (CDAI), Health Assessment Questionnaire-Disability Index (HAQ-DI) and pain; and proportions of patients achieving DAS28-4(ESR) ≥1.2 and HAQ-DI ≥0.22 decreases from baseline, low disease activity (DAS28-4(ESR) ≤3.2 or CDAI ≤10) and radiographic non-progression (Δmodified Total Sharp Score ≤0.5; months 12 and 24). Estimates were adjusted using multivariable models for selected outcomes. Univariate/multivariable regression analyses determined predictors of month 6 outcomes. Results Of 3880 patients included, 1690 (43.6%), 1173 (30.2%) and 1017 (26.2%) had baseline BMI <25, 25 to <30 and ≥30 kg/m2, respectively. Tofacitinib showed greater efficacy improvements versus placebo in each BMI category. Differences in efficacy outcomes (adjusted and unadjusted) were generally not clinically meaningful across BMI categories within treatment groups. In regression analyses, BMI was not consistently associated with selected outcomes. Conclusions Baseline BMI did not consistently affect tofacitinib response suggesting that tofacitinib is an effective oral treatment option for adults with moderate to severe RA regardless of baseline BMI, including patients with BMI ≥30 kg/m2. Trial registration numbers NCT00814307, NCT01039688; NCT00960440; NCT00847613; NCT00856544; NCT00853385.
A Holistic Approach For Student Assessment In Project Based Multidisciplinary Engineering Capstone Design

A capstone design course involves multiple complexities which make its teaching conspicuously challenging; e.g., sponsors’ requirements, team dynamics, and available resources, as well as the usual engineering educational goals. At the core of the challenge is assessment – giving each student a fair final grade. In this paper we describe a holistic approach to developing a fair and accurate evaluation for individual students in multidisciplinary teams. The approach includes assessment of communication, team participation, design process, and project results, with input from students and sponsors to calibrate the evaluations of the instructor teams. In addition, we adopted a new team teaching approach that facilitates multidisciplinary participation; and also made grading processes more objective by separating roles associated with instructor coaching and judging. Furthermore, implementation of a communication intensive requirement provided greater insight into individual student contributions. The holistic approach allows greater consistency in the grading process, yet is flexible enough to handle a wide variety of multidisciplinary design projects. We submit that the basic structure of the assessment (i.e., blending objectives with procedural justice and evaluation from multiple sources) is consistent with practices in industry that students will face after their graduation.
Adolescents With Non-Suicidal Self-Harm—Who Among Them Has Attempted Suicide?

Abstract We aimed to determine differences between adolescents with non-suicidal self-harm with and without a history of suicide attempt (SA). Sixty-eight adolescents with a mean age of 15.6 years (SD = 1.5) attending child and adolescent psychiatric outpatient clinics for repeated self-harm in Oslo, Norway, were included. A battery of instruments was used to assess sociodemographic information and psychopathology such as Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnoses, emotional and behavioral problems, borderline symptoms, depression, hopelessness, suicidal ideation, and history of SA. Twenty-six participants (38.2%) reported a lifetime history of SA. Compared to the participants without a history of SA, those with an SA history had used a higher number of methods of self-harm and methods with higher lethality and had higher degrees of emotional and behavioral problems. They also scored higher in depressive symptoms, borderline pathology, emotional dysregulation, hopelessness, and suicidal ideation. History of SA was independently associated with perceived moderate to high risk of death on the most severe episode of self-harm (adjusted odds ratio [aOR], 15.93; 95% confidence interval [CI], 1.96–129.66), a longer duration (months) since self-harm debut (aOR, 1.07; 95% CI, 1.01–1.13), and suicidal ideation severity (aOR, 1.05; 95% CI, 1.01–1.11). Parental report of behavioral problems associated with SA suggested a strong association with externalizing problems. A combination of having a high level of psychopathology, externalizing problems, an extended history of self-harm behavior and use of more lethal self-harm methods seems to entail a significantly increased risk for making SAs among adolescents with non-suicidal self-harm. HIGHLIGHTS Non-suicidal self-harm (NSSH) with suicide attempt may be distinctive from NSSH without suicide attempt. Adolescents with NSSH with suicide attempt had relatively greater psychopathology. Protracted/lethal self-harm methods and externalizing problems indicate comorbidity.
Global developments in social prescribing

Social prescribing is an approach that aims to improve health and well-being. It connects individuals to non-clinical services and supports that address social needs, such as those related to loneliness, housing instability and mental health. At the person level, social prescribing can give individuals the knowledge, skills, motivation and confidence to manage their own health and well-being. At the society level, it can facilitate greater collaboration across health, social, and community sectors to promote integrated care and move beyond the traditional biomedical model of health. While the term social prescribing was first popularised in the UK, this practice has become more prevalent and widely publicised internationally over the last decade. This paper aims to illuminate the ways social prescribing has been conceptualised and implemented across 17 countries in Europe, Asia, Australia and North America. We draw from the ‘Beyond the Building Blocks’ framework to describe the essential inputs for adopting social prescribing into policy and practice, related to service delivery; social determinants and household production of health; workforce; leadership and governance; financing, community organisations and societal partnerships; health technology; and information, learning and accountability. Cross-cutting lessons can inform country and regional efforts to tailor social prescribing models to best support local needs.