Clinical Phase Research Articles

Clinical trials are becoming more complex: a machine learning analysis of data from over 16,000 trials

The past decade has seen substantial innovation in clinical trials, including new trial formats, endpoints, and others. Also there have been regulatory changes, increasing competitive pressures and other external factors which impact clinical trials. In parallel, trial timelines have increased and success rates remain stubbornly low. This has led many observers to question whether clinical trials have become overly complex and if this complexity is always needed. Here we present a large-scale analysis of protocols and other data from over 16,000 trials. Using a machine learning algorithm, we automatically assessed key features of these trials, such as number of endpoints, number of inclusion–exclusion criteria and others. Using a regression analysis we combined these features into a new metric, the Trial Complexity Score, which correlates with overall clinical trial duration. Looking at this score across different clinical phases and therapeutic areas we see substantial increases over time, suggesting that clinical trials are indeed becoming more complex. We discuss drivers of increasing trial complexity, necessary or helpful (‘good’) complexity versus unnecessary (‘bad’) complexity, and we explore mechanisms of how sponsors of clinical trials can reduce trial complexity where appropriate.

The Double-Edged Sword of Third-Party Resources: Examining Use and Financial Burden of Extracurricular Tools in Medical Students

Background Since before the COVID-19 pandemic, use of third-party resources (or educational tools separate from the in-house medical curriculum) has been steadily increasing. The transition to virtual learning in 2020 fostered a greater reliance on these mostly online resources during medical training, yet their contributions have rarely been evaluated. Thus, we aimed to review third-party resources and their implications for medical education, particularly their financial burden on students. Methods We examined 31 peer-reviewed articles that discuss third-party resources for medical students and relevant studies related to their equitable access. Results Studies suggest third-party resources are used in a task-dependent manner with a supplemental role to the in-house lectures during the preclinical phase and a primary role for USMLE preparation during the clinical phase. Medical students ubiquitously access these resources out of a perceived necessity to use them to perform well on board exams, prompted by studies demonstrating their efficacy in increasing USMLE Step 1 scores. Though certain resources have been more frequently cited for improving board performance (e.g.,First Aid and UWorld), students may combine multiple third-party resources to best serve their exam preparation. Findings also show the subscription-pricing model of most third-party resources and 12-month access prices range from $100 to $479, suggesting that third-party resource use contributes to an increase financial strain on students. This, coupled with overwhelming medical student debt, may exacerbate existing socioeconomic disparities in medical education. Conclusion Institutions should evaluate third-party resource use among their medical students and consider provisions to increase access to these co-curricular tools.

A Comprehensive Review on Biomarker and Its Role in Diseases

Biomarkers are essential to clinical practice. Understanding the organized definition, types, and roles of biomarkers in various clinical phases and diseases is crucial for understanding the significance of biomarkers in healthcare and medical research. This data highlights the significance of biomarkers in prognosis prediction, therapeutic decision guidance, and the advancement of personalized medicine, in addition to their role in illness diagnosis.
 The division of biomarkers into molecular, cellular, and imaging types offers a thorough summary of the various modalities that are employed in biomarker research. In addition, the segmentation according to clinical phases, which differentiates between prognostic, therapeutic, and diagnostic biomarkers, deepens the conversation by emphasizing the diverse functions that biomarkers fulfill in patient treatment.
 In the diagnosis, prognosis and treatment of a wide range of diseases, biomarkers are a component of a relatively new and perfect clinical instrument. Using biomarkers to research different aspects of diseases, develop new drugs, and track possible therapeutic intervention results has many advantages. They contribute to drug development, personalized medicine, and therapeutic interventions. The aim is to develop biomarkers with higher sensitivity and specificity to enhance decision-making and simplify the drug development process, add depth to the discussion, emphasizing the varied roles of biomarkers in patient care.

Novel Therapies for Lipoprotein(a): Update in Cardiovascular Risk Estimation and Treatment.

Lipoprotein(a) is an important causal risk factor for cardiovascular disease but currently no available medication effectively reduces lipoprotein(a). This review discusses recent findings regarding lipoprotein(a) as a causal risk factor and therapeutic target in cardiovascular disease, it reviews current clinical recommendations, and summarizes new lipoprotein(a) lowering drugs. Epidemiological and genetic studies have established lipoprotein(a) as a causal risk factor for cardiovascular disease and mortality. Guidelines worldwide now recommend lipoprotein(a) to be measured once in a lifetime, to offer patients with high lipoprotein(a) lifestyle advise and initiate other cardiovascular medications. Clinical trials including antisense oligonucleotides, small interfering RNAs, and an oral lipoprotein(a) inhibitor have shown great effect on lowering lipoprotein(a) with reductions up to 106%, without any major adverse effects. Recent clinical phase 1 and 2 trials show encouraging results and ongoing phase 3 trials will hopefully result in the introduction of specific lipoprotein(a) lowering drugs to lower the risk of cardiovascular disease.

Oral administration of DNA alginate nanovaccine induced immune-protection against Helicobacter pylori in Balb/C mice

BackgroundHelicobacter pylori (H. Pylori), is an established causative factor for the development of gastric cancer and the induction of persistent stomach infections that may lead to peptic ulcers. In recent decades, several endeavours have been undertaken to develop a vaccine for H. pylori, although none have advanced to the clinical phase. The development of a successful H. pylori vaccine is hindered by particular challenges, such as the absence of secure mucosal vaccines to enhance local immune responses, the absence of identified antigens that are effective in vaccinations, and the absence of recognized indicators of protection.MethodsThe DNA vaccine was chemically cloned, and the cloning was verified using PCR and restriction enzyme digestion. The efficacy of the vaccination was investigated. The immunogenicity and immune-protective efficacy of the vaccination were assessed in BALB/c mice. This study demonstrated that administering a preventive Alginate/pCI-neo-UreH Nanovaccine directly into the stomach effectively triggered a robust immune response to protect against H. pylori infection in mice.ResultsThe level of immune protection achieved with this nano vaccine was similar to that observed when using the widely accepted formalin-killed H. pylori Hel 305 as a positive control. The Alginate/pCI-neo-UreH Nanovaccine composition elicited significant mucosal and systemic antigen-specific antibody responses and strong intestinal and systemic Th1 responses. Moreover, the activation of IL-17R signaling is necessary for the defensive Th1 immune responses in the intestines triggered by Alginate/pCI-neo-UreH.ConclusionAlginate/pCI-neo-UreH is a potential Nanovaccine for use in an oral vaccine versus H. pylori infection, according to our findings.

Assessment of Mobility Trajectories Using Wearable Inertial Sensors During Autologous Hematopoietic Cell Transplant

ObjectiveThis study aimed to characterize mobility patterns using wearable inertial sensors and serial assessment across autologous hematopoietic cell transplant (autoHCT) and investigate the relation between mobility and perceived function in patients with hematologic cancer. DesignProspective longitudinal study. SettingHospital adult transplant clinic followed by discharge. Participants78 patients with hematological cancer receiving autoHCT. Main Outcome MeasuresMobility was measured across 3 clinical phases (pretransplant, pre-engraftment, and post-engraftment) in using inertial sensors worn during prescribed performance tests in the hospital. Perceived function was assessed using validated provider-reported (Eastern Cooperative Oncology Group [ECOG] Performance Status Scale) and patient-reported [European Organization for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ-C30]) measures. Trajectories of 5 selected mobility characteristics (turn duration, gait speed, stride time variability, double support time, and heel strike angle) across the clinical phases were also evaluated using piecewise linear mixed-effects models. ResultsUsing Principal Components Analysis, 4 mobility patterns were identified pretransplant: Gait Limitation, Sagittal Sway, Coronal Sway, and Balance Control. Gait Limitation measured pretransplant was significantly inversely associated with perceived function reported by the provider- (β = -0.11; 95% CI: -0.19, -0.02) and patient- (β = -4.85; 95% CI: -7.72, -1.99) post-engraftment in age-adjusted linear regression models. Mobility characteristics demonstrated immediate declines early pre-engraftment with stabilization by late pre-engraftment. ConclusionPatients with hematological cancer experiencing gait limitations pretransplant are likely to have worse perceived function post-engraftment. Mobility declines in early phases post-transplant and may not fully recover, indicating an opportunity for timely rehabilitation referrals. Wearable inertial sensors can be used to identify early mobility problems and patients who may be at risk for future functional decline who may be candidates for early physical rehabilitation.

Radiographic Diagnostic Choices of Palestinian Dentists for Implant Therapy

ABSTRACT Aim: To report the radiographic preferences during dental implant therapy in Palestine. Materials and Methods: Fourteen multiple-choice questions were delivered in electronic and hardcopy formats questionnaires during the Sixth International Implantology Conference (Palestine). The questions investigated the radiographic techniques that are mostly used based on various clinical scenarios and treatment phases. Results: One hundred and thirty-seven responses were captured. The majority of the participants were general dentists with implant experience (79.6%). Less than a third of the participants (27.2%) were members of the Palestinian Association of Dental Implantology. The majority (85.9%) of them have their practice in a city zone. Panoramic radiograph (PAN) combined with cone beam computed tomography (CBCT) was the most preferred radiographic technique during the planning stage. Conclusion: PAN and CBCT was the preferred choice during the planning stages. A PAN was preferred postoperatively and if no complications were associated. In the case of symptomatic patients, CBCT was the radiograph of choice.

Does gene therapies clinical research in rare diseases reflects the competitivity of the country: Example of France

Rare diseases are chronic, serious and generally genetic conditions affecting a small number of people, and their therapeutic management is a real challenge. They represent a considerable burden for patients, caregivers and society alike. Compared with existing symptomatic treatments, gene therapies represent a promising new approach aimed at treating these diseases by replacing a defective gene, or by abolishing or reviving a gene-derived function. France is considered one of the leading countries in the research and development of drugs for rare diseases, yet the position of French public and private stakeholders in the research and development of gene therapies for rare diseases at global and European level remains unclear. To answer this question, we used the GENOTRIAL FR database developed by OrphanDev to clarify France's involvement and competitiveness in this field. The results show that France is actively involved in gene therapy clinical trials, with a dense international collaboration network and solid expertise. However, the French medical infrastructure is mainly involved in clinical research on gene therapy candidates sponsored by several foreign countries. To a lesser extent, French public and private entities are also developing their own gene therapy candidates for various rare diseases, some of which have already reached advanced clinical phases. In conclusion, a number of technical and financial challenges need to be overcome if France is to maintain its position as a European and world leader and increase its contribution to reducing the economic and social burden of rare diseases by developing revolutionary and effective new therapies.

Assessment of performance and confidence level of simulation based clinical examination of respiratory system in undergraduate medical students of a medical college: a comparative cross-sectional study

Introduction: Students in the preclinical phase have adequate clinical exposure to normal physiological findings of clinical examinations performed in healthy peers but do not have exposure to pathological findings other than theoretical knowledge, which is challenging for students during the clinical phase of curricula in examining actual patients. Simulation based medical education (SBME) has recently emerged to address this gap. This study aimed to assess performance and confidence level of simulation based clinical examination of respiratory system in preclinical undergraduate medical students of a medical college. Methods: A comparative cross-sectional study was conducted in the Department of Human Physiology of Medical College. All second year medical students using purposive sampling were taken. Students were divided into three groups and subdivided into six subgroups and each subgroup carried out examination in either healthy subjects or both healthy subjects and manikin. Predesigned proforma was used for assessment of students and the clinical examination process was invigilated by certified physiologists. Results: Students who received both simulation and conventional tutoring methods were able to accurately identify all lung sounds better as compared to those with conventional tutoring with the percentage difference being maximum in identifying vesicular (29 vs 6), stridor (28 vs 6), and bronchial (25 vs 6) breath sounds and least in identifying coarse crackles (3 vs 2). Majority (39 out of 41) of the students receiving SBME of respiratory system were satisfied with the simulation based practice and 34 of those students were even confident on clinical examination. Conclusion: SBME increases performance status and confidence level in medical students. A practical curriculum can be planned to incorporate simulation based clinical examination in preclinical medical students in practical sessions.

BacPROTACs targeting Clp protease: a promising strategy for anti-mycobacterial drug discovery.

Tuberculosis (TB) has claimed more lives over the course of two millennia than any other infectious disease worldwide. In 2021, the World Health Organization (WHO) estimated that 10.6 million people were diagnosed with TB, resulting in the deaths of 1.4 million HIV-negative individuals. The emergence of multidrug-resistant TB (MDR-TB), defined as resistance to at least rifampicin (RIF) and isoniazid (INH), and extensively drug-resistant TB (XDR-TB), poses the primary challenge to overcome in the coming years. We have recently conducted an extensive analysis of investments and research endeavours in the field, with the overarching objective of achieving the established milestone of TB eradication by the year 2030. Over the past several years, there has been notable progress in advancing a multitude of promising compounds, each possessing distinct mechanisms of action, into clinical phases of development. However, it is worth noting that strains of mycobacteria resistant to current antitubercular drugs have already emerged for some of these compounds The exploration of the innovative Proteolytic Target Chimeras (PROTACs) protein degradation approach has emerged as a viable avenue for the discovery of novel antimicrobials. While the ubiquitin system is exclusive to eukaryotic cells, certain bacteria use a similar degradation system that relies on the recognition of phosphorylated arginine residues (pArg) by the ClpC:ClpP (ClpCP) protease, thereby leading to protein degradation. In this opinion article, we have described and analized the advances in the use of PROTACs that leverage bacterial proteolytic machinery (BacPROTACs) to design new antitubercular agents. Scope Statement. The development of novel pharmaceuticals for tuberculosis treatment is deemed urgently necessary due to the emergence of resistant strains. In this context, the introduction of new technologies capable of alleviating the disease and attaining the objectives outlined by the World Health Organization is imperative. Among the innovative strategies, the degradation of proteins that are crucial for the survival of the bacillus holds promise for generating new medications, particularly those that are effective at treating latent (non-replicating) Mycobacterium tuberculosis. Within this perspective, we present the advancements and obstacles encountered in the exploration of new BacPROTAC compounds, with the intention of encouraging research and illuminating challenges associated with the implementation of BacPROTACs to address to the global tuberculosis crisis.

P300 An Expert Delphi Consensus: Early Identification of Patients at Risk of Crohn's Disease in Perianal Fistulas and Abscesses (PREFAB) and Identification and Management of Isolated Perianal Crohn's Disease (ipCD) - Part A, PREFAB

Abstract Background In ± 10% of all Crohn’s disease (CD) patients a perianal abscess (PAA) or fistula (PAF) is the manifesting symptom. The delay in diagnosis of CD, from fistula or abscess onset, is very long and associated with worse outcomes. The aim of this Delphi study was to reach consensus on a clinical decision tool to help select patients with raised suspicion of CD in PAA/PAF patients, to identify underlying CD earlier and reduce the diagnostic delay. Methods A panel of international experts in the field of proctology and/or Inflammatory Bowel Disease (IBD), consisting of surgeons, gastroenterologists and radiologists were invited to participate in the PREFAB part of this Delphi study. The first round was an electronic survey and the second round a virtual consensus meeting. In the first round, participants were asked to anonymously provide their opinion probing 1) the relevance and use of clinical characteristics (“Red Flags”) suggestive of underlying CD, 2) the use of faecal calprotectin (FCP) as an adjunct for screening for CD and 3) on the diagnostic work-up for IBD in PAA/PAF patients with raised clinical suspicion. In the second round, statements were paired/revised based on the feedback from the first round and presented in a final set of statements. Consensus was predefined as ≥70% agreement. Results A total of 30 experts participated in the first round and 25 in the second round (83.3%). Final consensus was reached for 29% of all statements in the first Delphi round and, after adjustments/merging, for all 11 statements (100%) in the second round. Ninety-seven percent of participants agreed that shortening of the delay in diagnosis by using a clinical decision tool could improve outcomes in patients with perianal disease as a first symptom. Consensus was reached on the red flags to be included in the clinical decision tool, on screening of all patients with any perianal fistula (regardless of the complexity, biological behaviour and co-existent perianal symptoms) to identify CD in an early (sub)clinical phase, on referral criteria and on the diagnostic workup and follow up of patients with raised suspicion. Conclusion A clinical decision tool for early identification of CD in patients with PAA/PAF as a first symptom could shorten delay in diagnosis and improve outcomes. Global consensus for this tool, including a practical and relevant algorithm for finding or excluding CD in patients with PAA/PAF as a manifesting sign, was reached within two rounds. This clinical decision tool will be validated in 2024 in a large, prospective multicenter study.

P687 Ozanimod as a once-daily oral therapy for Japanese patients with ulcerative colitis: results from the induction period of a Phase 2/3 study (J-True North)

Abstract Background Ozanimod is an oral, small molecule sphingosine 1-phosphate (S1P) receptor modulator that selectively targets the S1P1 and S1P5 receptor subtypes. Ozanimod is approved in multiple countries outside Japan for the treatment of moderately to severely active ulcerative colitis (UC) and/or relapsing forms of multiple sclerosis. We herein report the efficacy and safety results during the induction period of J-True North, a multi-centre, randomised, double-blind, placebo-controlled clinical Phase 2/3 study consisting of a 12-week induction period, followed by a 40-week maintenance period and an open-label extension period in Japanese patients with moderately to severely active UC. Methods Japanese male and female UC patients aged 18 to 75 years with moderately to severely active UC (defined as Mayo score of 6 to 12, with endoscopic subscore ≥2, rectal bleeding score (RBS) ≥1, and stool frequency score ≥1) were randomised in a 1:1:1 ratio to receive either 0.46 mg or 0.92 mg ozanimod, or placebo capsules orally once daily. All patients had received prior treatment with aminosalicylates or corticosteroids. The primary endpoint was clinical response at Week 12 (defined as a reduction from baseline in the complete Mayo score of ≥ 3 points and ≥ 30%, and a reduction from baseline in the RBS of ≥ 1 point or an absolute RBS of ≤ 1 point), and key secondary endpoints were clinical remission, clinical response, endoscopic improvement, mucosal healing and safety at Week 12 and 52. Results Patients were randomised to the ozanimod 0.46 mg group (n=68), 0.92 mg group (n=65), and the placebo group (n=65). At baseline, 36.4% of patients were female, mean age was 42.6 y and mean complete Mayo score was 8.4. The clinical response rate at Week 12 was 52.9%, 61.5%, and 32.3% in the ozanimod 0.46 mg, 0.92 mg, and placebo groups, respectively, demonstrating a statistically significant improvement of ozanimod vs placebo (Figure 1). Similarly, higher improvement rates were observed in all key secondary clinical and endoscopic endpoints in the ozanimod groups compared with the placebo group at Week 12. Frequent adverse events (AEs) observed in the induction period were nasopharyngitis, headache, et.al. (Table 1). AEs observed in the study were similar to those in the global phase 3 True North study with 0.92 mg ozanimod, and there were no new safety signals with ozanimod in the J-True North study. Conclusion Ozanimod as a once-daily oral therapy was effective as induction therapy for Japanese patients with moderately to severely active UC, and the safety profile was consistent with the results of previous studies. Figure 1 Table 1

Crystal structure of human serum albumin in complex with megabody reveals unique human and murine cross-reactive binding site.

The pharmacokinetic properties of small biotherapeutics can be enhanced via conjugation to cross-reactive albumin-binding ligands in a process that improves their safety and accelerates testing through multiple pre-clinical animal models. In this context, the small and stable heavy-chain-only nanobody NbAlb1, capable of binding both human and murine albumin, has recently been successfully applied to improve the stability and prolong the in vivo plasma residence time of multiple small therapeutic candidates. Despite its clinical efficacy, the mechanism of cross-reactivity of NbAlb1 between human and murine serum albumins has not yet been investigated. To unveil the molecular basis of such an interaction, we solved the crystal structure of human serum albumin (hSA) in complex with NbAlb1. The structure was obtained by harnessing the unique features of a megabody chimeric protein, comprising NbAlb1 grafted onto a modified version of the circularly permutated and bacterial-derived protein HopQ. This structure showed that NbAlb1 contacts a yet unexplored binding site located in the peripheral region of domain II that is conserved in both human and mouse serum albumin proteins. Furthermore, we show that the binding of NbAlb1 to both serum albumin proteins is retained even at acidic pH levels, thus explaining its extended in vivo half-life. The elucidation of the molecular basis of NbAlb1 cross-reactivity to human and murine albumins might guide the design of novel nanobodies with broader reactivity toward a larger panel of serum albumins, thus facilitating the pre-clinical and clinical phases in humans.

Lipoprotein(a): from Causality to Treatment.

This paper reviews the evidence why lipoprotein(a) (Lp(a)) is a causal risk factor for cardiovascular disease and how high Lp(a) concentrations should be managed now and with an outlook to the future. No optimal and widely available animal models exist to study the causality of the association between Lp(a) and cardiovascular disease. This has been a major handicap for the entire field. However, genetic studies turned the page. Already in the early 1990s, the principle of Mendelian randomization studies was applied for the first time ever (even if they were not named so at that time). Genetic variants of the LPA gene such as the apolipoprotein(a) isoform size, the number and sum of kringle IV repeats and later single nucleotide polymorphisms are strongly associated with life-long exposure to high Lp(a) concentrations as well as cardiovascular outcomes. This evidence provided a basis for the development of specific Lp(a)-lowering drugs that are currently in clinical testing phase. Lp(a) is one of the most important genetically determined risk factors for cardiovascular disease. With the specific Lp(a)-lowering therapies, we might get tools to fight this common risk factor in case the outcome trials will be positive.

Exploring workplace-based learning in distributed healthcare settings: a qualitative study

BackgroundDistributed healthcare settings such as district hospitals, primary care, and public health facilities are becoming the real-life settings for workplace-based learning required to educate the future healthcare workforce. Therefore, a major focus should be on designing and developing workplace-based learning in these learning environments. Healthcare professionals and educational policymakers play a significant role in these settings as role models in workplace-based learning, and as leaders in integrating learning into their work environments. It is relevant to explore their beliefs, attitudes, and behaviors towards workplace-based learning in their own settings, in order to provide context-relevant recommendations that can assist in shaping workplace-based learning environments.MethodsWe used individual interviews to understand professionals’ experiences with workplace-based learning in distributed healthcare settings. We - three clinicians, an educationalist, and a philosopher - thematically analyzed transcripts of 13 interviews with healthcare professionals and educational policymakers from different healthcare settings who were involved in the clinical phase of undergraduate medical education.ResultsClustering and categorizing of the data led to the construction of five overarching themes: Identification with and attitude towards medical education, Sense of ownership, Perceived time and space, Mutual preconceptions and relations, and Curriculum for a changing profession.ConclusionsThese themes accentuate aspects relevant to the development of workplace-based learning in distributed healthcare settings on the individual, team, or organizational level. We highlight the significance of individual professionals in the development of workplace-based learning and emphasize the need for recognition and support for those occupying the ‘broker’ role at the intersection of education and practice. For future research and educational practice, we recommend prioritizing initiatives that build on good-practices in workplace-based learning and involve dedicated individuals in distributed healthcare settings.

Peto's "Paradox" and Six Degrees of Cancer Prevalence.

Peto's paradox and the epidemiologic observation of the average six degrees of tumor prevalence are studied and hypothetically solved. A simple consideration, Petho's paradox challenges our intuitive understanding of cancer risk and prevalence. Our simple consideration is that the more a cell divides, the higher the chance of acquiring cancerous mutations, and so the larger or longer-lived organisms have more cells and undergo more cell divisions over their lifetime, expecting to have a higher risk of developing cancer. Paradoxically, it is not supported by the observations. The allometric scaling of species could answer the Peto paradox. Another paradoxical human epidemiology observation in six average mutations is necessary for cancer prevalence, despite the random expectations of the tumor causes. To solve this challenge, game theory could be applied. The inherited and random DNA mutations in the replication process nonlinearly drive cancer development. The statistical variance concept does not reasonably describe tumor development. Instead, the Darwinian natural selection principle is applied. The mutations in the healthy organism's cellular population can serve the species' evolutionary adaptation by the selective pressure of the circumstances. Still, some cells collect multiple uncorrected mutations, adapt to the extreme stress in the stromal environment, and develop subclinical phases of cancer in the individual. This process needs extensive subsequent DNA replications to heritage and collect additional mutations, which are only marginal alone. Still, together, they are preparing for the first stage of the precancerous condition. In the second stage, when one of the caretaker genes is accidentally mutated, the caused genetic instability prepares the cell to fight for its survival and avoid apoptosis. This can be described as a competitive game. In the third stage, the precancerous cell develops uncontrolled proliferation with the damaged gatekeeper gene and forces the new game strategy with binary cooperation with stromal cells for alimentation. In the fourth stage, the starving conditions cause a game change again, starting a cooperative game, where the malignant cells cooperate and force the cooperation of the stromal host, too. In the fifth stage, the resetting of homeostasis finishes the subclinical stage, and in the fifth stage, the clinical phase starts. The prevention of the development of mutated cells is more complex than averting exposure to mutagens from the environment throughout the organism's lifetime. Mutagenic exposure can increase the otherwise random imperfect DNA reproduction, increasing the likelihood of cancer development, but mutations exist. Toxic exposure is more challenging; it may select the tolerant cells on this particular toxic stress, so these mutations have more facility to avoid apoptosis in otherwise collected random mutational states.

Discovery of Repurposable Drugs in the Combination Therapy of Breast Cancer: A Virtual Drug Screening Study

Cathepsin D (Cat D) is a lysosomal aspartic acid protease encoded by CTSD gene and has significant biological roles such as degradation of extracellular and intracellular proteins, regulation of apoptosis, hormone processing, antigen processing etc. Furthermore, it is overexpressed by breast cancer cells and it acts a role in many processes affecting the cancer prognosis such as metastasis, angiogenesis, invasion, and drug resistance through regulation of the metabolic pathways and digesting the extracellular matrix (ECM) proteins. Due to that there is no drug targeting Cat D in clinical trial phases, a virtual drug screening in order to reveal possible drugs with high Cat D inhibitory activity from a library composed of 12,111 ligands is carried out with this study. Results have demonstrated that ZINC000003922429 (Adozelesin), ZINC000012358610 (Phthalocyanine), ZINC000051951669 (Bemcentinib), ZINC000003786250 (YM022), and ZINC000150338819 (Ledipasvir) have high binding affinity to Cat D. Among these chemical ligands, YM022 from Drugs in Clinical Trials dataset has been evaluated as most promising one that might be repurposed in the treatment of breast cancer due to its high affinity, convenient ADME and Toxicity properties, and highest bioactivity profiles. However, the possible activity of YM022 should be analyzed with further molecular dynamics (MD) simulations, in vitro and in vivo studies.

Wall permeability on magnetic resonance imaging is associated with intracranial aneurysm symptoms and wall enhancement.

Wall remodeling and inflammation accompany symptomatic unruptured intracranial aneurysms (UIAs). The volume transfer constant (Ktrans) of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) reflects UIA wall permeability. Aneurysmal wall enhancement (AWE) on vessel wall MRI (VWI) is associated with inflammation. We hypothesized that Ktrans is related to symptomatic UIAs and AWE. Consecutive patients with UIAs were prospectively recruited for 3-T DCE-MRI and VWI from January 2018 to March 2023. UIAs were classified as asymptomatic and symptomatic if associated with sentinel headache or oculomotor nerve palsy. Ktrans and AWE were assessed on DCE-MRI and VWI, respectively. AWE was evaluated using the AWE pattern and wall enhancement index (WEI). Spearman's correlation coefficient and univariate and multivariate analyses were used to assess correlations between parameters. We enrolled 82 patients with 100 UIAs (28 symptomatic and 72 asymptomatic). The median Ktrans (2.1 versus 0.4min-1; p < 0.001) and WEI (1.5 versus 0.4; p < 0.001) were higher for symptomatic aneurysms than for asymptomatic aneurysms. Ktrans (odds ratio [OR]: 1.60, 95% confidence interval [95% CI]: 1.01-2.52; p = 0.04) and WEI (OR: 3.31, 95% CI: 1.05-10.42; p = 0.04) were independent risk factors for symptomatic aneurysms. Ktrans was positively correlated with WEI (Spearman's coefficient of rank correlation (rs) = 0.41, p < 0.001). The combination of Ktrans and WEI achieved an area under the curve of 0.81 for differentiating symptomatic from asymptomatic aneurysms. Ktrans may be correlated with symptomatic aneurysms and AWE. Ktrans and WEI may provide an additional value than the PHASES score for risk stratification of UIAs. The volume transfer constant (Ktrans) from DCE-MRI perfusion is associated with symptomatic aneurysms and provides additional value above the clinical PHASES score for risk stratification of intracranial aneurysms. • The volume transfer constant is correlated with intracranial aneurysm symptoms and aneurysmal wall enhancement. • Dynamic contrast-enhanced and vessel wall MRI facilitates understanding of the pathophysiological characteristics of intracranial aneurysm walls. • The volume transfer constant and wall enhancement index perform better than the traditional PHASES score in differentiating symptomatic aneurysms.

Functional magnetic resonance imaging in schizophrenia: current evidence, methodological advances, limitations and future directions.

Functional neuroimaging emerged with great promise and has provided fundamental insights into the neurobiology of schizophrenia. However, it has faced challenges and criticisms, most notably a lack of clinical translation. This paper provides a comprehensive review and critical summary of the literature on functional neuroimaging, in particular functional magnetic resonance imaging (fMRI), in schizophrenia. We begin by reviewing research on fMRI biomarkers in schizophrenia and the clinical high risk phase through a historical lens, moving from case-control regional brain activation to global connectivity and advanced analytical approaches, and more recent machine learning algorithms to identify predictive neuroimaging features. Findings from fMRI studies of negative symptoms as well as of neurocognitive and social cognitive deficits are then reviewed. Functional neural markers of these symptoms and deficits may represent promising treatment targets in schizophrenia. Next, we summarize fMRI research related to antipsychotic medication, psychotherapy and psychosocial interventions, and neurostimulation, including treatment response and resistance, therapeutic mechanisms, and treatment targeting. We also review the utility of fMRI and data-driven approaches to dissect the heterogeneity of schizophrenia, moving beyond case-control comparisons, as well as methodological considerations and advances, including consortia and precision fMRI. Lastly, limitations and future directions of research in the field are discussed. Our comprehensive review suggests that, in order for fMRI to be clinically useful in the care of patients with schizophrenia, research should address potentially actionable clinical decisions that are routine in schizophrenia treatment, such as which antipsychotic should be prescribed or whether a given patient is likely to have persistent functional impairment. The potential clinical utility of fMRI is influenced by and must be weighed against cost and accessibility factors. Future evaluations of the utility of fMRI in prognostic and treatment response studies may consider including a health economics analysis.

Clinical insights: Anxiety levels and sleep quality among Hang Tuah Faculty of Medicine's class of 2017-2022 pre-clinical and clinical Students

Anxiety is a global psychiatric phenomenon, while poor sleep quality remains a pressing public health issue. The arduous medical education journey exposes students to prolonged stress, potentially exacerbating anxiety and sleep disturbances. This study investigates the correlation between anxiety and sleep quality in Hang Tuah Faculty of Medicine students, bridging the pre-clinical and clinical phases. Employing an analytical observational approach with a cross-sectional design, this study enrolled students from pre-clinical (batches 2020, 2021, 2022) and clinical years (batches DM45, DM46, DM47). Among the 409 approached participants, 296 met the inclusion criteria after excluding 113 samples. Data collection utilized online questionnaires with acquired informed consent. Sleep quality was evaluated via the Pittsburgh Sleep Quality Index, generating scores from 0 to 21. This study showed significantly robust evidence of an association between anxiety and sleep quality (p-value: 0.0001; r: 0.342) across both pre-clinical and clinical students. This study underscores a direct relationship: elevated anxiety levels correspond to diminished sleep quality. Such findings resonate with the prevailing challenges in medical education and their impact on students' mental and physical well-being. Implementing targeted interventions is crucial to address these concerns. In conclusion, this study underscores the undeniable link between anxiety and sleep quality among Hang Tuah Faculty of Medicine students, encompassing the years 2017 to 2022. The implications are far-reaching, emphasizing the necessity of interventions that enhance both psychological well-being and sleep quality. By recognizing and addressing these challenges, medical institutions can foster healthier academic environments and better equip students for their medical careers.