Clinical Importance Research Articles

Update of newly-recognized salivary gland neoplasms: molecular and immunohistochemical findings and clinical importance.

With the advancement of molecular testing and the routine use of immunohistochemical stains, salivary gland tumours previously categorized as adenoma or adenocarcinoma, not otherwise specified, are being reclassified with distinct diagnoses. Newly recognized benign entities include: sclerosing polycystic adenoma, keratocystoma, intercalated duct hyperplasia and adenoma, and striated duct adenoma. Newly recognized malignant salivary gland tumours include: microsecretory adenocarcinoma, sclerosing microcytic adenocarcinoma, and mucinous adenocarcinoma. Additionally, rare subtypes of mucoepidermoid carcinoma have been described, including Warthin-like and oncocytic. Understanding of intraductal carcinoma continues to evolve. Correctly distinguishing these lesions from mimickers can be crucial for appropriate patient care and prognostication, as well as future conceptualization of salivary disease.

A Machine Learning Model for Risk Stratification of Postdiagnosis Diabetic Ketoacidosis Hospitalization in Pediatric Type 1 Diabetes: Retrospective Study.

Diabetic ketoacidosis (DKA) is the leading cause of morbidity and mortality in pediatric type 1 diabetes (T1D), occurring in approximately 20% of patients, with an economic cost of $5.1 billion/year in the United States. Despite multiple risk factors for postdiagnosis DKA, there is still a need for explainable, clinic-ready models that accurately predict DKA hospitalization in established patients with pediatric T1D. We aimed to develop an interpretable machine learning model to predict the risk of postdiagnosis DKA hospitalization in children with T1D using routinely collected time-series of electronic health record (EHR) data. We conducted a retrospective case-control study using EHR data from 1787 patients from among 3794 patients with T1D treated at a large tertiary care US pediatric health system from January 2010 to June 2018. We trained a state-of-the-art; explainable, gradient-boosted ensemble (XGBoost) of decision trees with 44 regularly collected EHR features to predict postdiagnosis DKA. We measured the model's predictive performance using the area under the receiver operating characteristic curve-weighted F1-score, weighted precision, and recall, in a 5-fold cross-validation setting. We analyzed Shapley values to interpret the learned model and gain insight into its predictions. Our model distinguished the cohort that develops DKA postdiagnosis from the one that does not (P<.001). It predicted postdiagnosis DKA risk with an area under the receiver operating characteristic curve of 0.80 (SD 0.04), a weighted F1-score of 0.78 (SD 0.04), and a weighted precision and recall of 0.83 (SD 0.03) and 0.76 (SD 0.05) respectively, using a relatively short history of data from routine clinic follow-ups post diagnosis. On analyzing Shapley values of the model output, we identified key risk factors predicting postdiagnosis DKA both at the cohort and individual levels. We observed sharp changes in postdiagnosis DKA risk with respect to 2 key features (diabetes age and glycated hemoglobin at 12 months), yielding time intervals and glycated hemoglobin cutoffs for potential intervention. By clustering model-generated Shapley values, we automatically stratified the cohort into 3 groups with 5%, 20%, and 48% risk of postdiagnosis DKA. We have built an explainable, predictive, machine learning model with potential for integration into clinical workflow. The model risk-stratifies patients with pediatric T1D and identifies patients with the highest postdiagnosis DKA risk using limited follow-up data starting from the time of diagnosis. The model identifies key time points and risk factors to direct clinical interventions at both the individual and cohort levels. Further research with data from multiple hospital systems can help us assess how well our model generalizes to other populations. The clinical importance of our work is that the model can predict patients most at risk for postdiagnosis DKA and identify preventive interventions based on mitigation of individualized risk factors.

Impact of p53-associated acute myeloid leukemia hallmarks on metabolism and the immune environment

Acute myeloid leukemia (AML), an aggressive malignancy of hematopoietic stem cells, is characterized by the blockade of cell differentiation, uncontrolled proliferation, and cell expansion that impairs healthy hematopoiesis and results in pancytopenia and susceptibility to infections. Several genetic and chromosomal aberrations play a role in AML and influence patient outcomes. TP53 is a key tumor suppressor gene involved in a variety of cell features, such as cell-cycle regulation, genome stability, proliferation, differentiation, stem-cell homeostasis, apoptosis, metabolism, senescence, and the repair of DNA damage in response to cellular stress. In AML, TP53 alterations occur in 5%–12% of de novo AML cases. These mutations form an important molecular subgroup, and patients with these mutations have the worst prognosis and shortest overall survival among patients with AML, even when treated with aggressive chemotherapy and allogeneic stem cell transplant. The frequency of TP53-mutations increases in relapsed and recurrent AML and is associated with chemoresistance. Progress in AML genetics and biology has brought the novel therapies, however, the clinical benefit of these agents for patients whose disease is driven by TP53 mutations remains largely unexplored. This review focuses on the molecular characteristics of TP53-mutated disease; the impact of TP53 on selected hallmarks of leukemia, particularly metabolic rewiring and immune evasion, the clinical importance of TP53 mutations; and the current progress in the development of preclinical and clinical therapeutic strategies to treat TP53-mutated disease.

Quality of life among borderline ovarian tumor survivors: A comparison with survivors of early-stage ovarian cancer and a cancer-free population: A cross-sectional population-based PROFILES study

ObjectiveThis study assessed the health-related quality of life (HRQo) of women surviving a borderline ovarian tumor (BOT) in comparison with early-stage ovarian cancer survivors treated surgically alone and with a matched cancer-free population. MethodsSurvivors of BOT and ovarian cancer were invited in two Dutch cross-sectional, population-based studies. Ovarian cancer survivors with tumor stage I who were treated surgically only were included. A random sample from the cancer-free population was matched on sex, age and education to the sample of BOT survivors. The EORTC QLQ-C30 (version 3.0) and the EORTC QLQ-OV28 were completed by the cancer-free population and the BOT and ovarian cancer survivors in study 1 and 2. The Hospital Anxiety and Depression Scale (HADS) was only completed by the cancer-free population and the survivors of BOT and ovarian cancer in study 1. BOT survivors were compared to early-stage ovarian cancer survivors and the general population using linear regression analyses and effect sizes regarding clinical importance. Results83 BOT (42%), 88 early-stage ovarian cancer survivors (52%), and 82 women from the general population were included. In most HRQoL domains, BOT survivors were not significantly different from early-stage ovarian cancer survivors and the cancer-free population, except that BOT survivors reported significantly less insomnia than early-stage ovarian cancer survivors and more dyspnea than the cancer-free population (small clinical difference). ConclusionIn general, BOT survivors' HRQoL lies between the HRQoL of early-stage ovarian cancer survivors and of the cancer-free population, but clinical effect sizes between the groups were mostly only trivial.

Use of Minimal Important Difference for Patient-Reported Outcome Measures in Plastic Surgery: A Systematic Review.

The minimal important difference (MID) is vital to consider when interpreting the clinical importance of observed changes from surgical interventions assessed by patient-reported outcome measures (PROMs). There is no gold-standard for how to calculate MIDs, and uptake in plastic surgery literature is currently unknown, leading to methodological and interpretation issues. Medline and Embase were searched to identify all plastic surgery randomized controlled trials (RCTs) employing PROMs as outcomes, and MID estimation studies for PROMs used by RCTs. Included studies were assessed for uptake and application of MIDs, and MID estimation methodology and values were categorized. A total of 554 RCTs employing PROMs as outcomes were identified. Of these, 419 RCTs had the possibility of incorporating a previously published MID. Uptake rate of MIDs was 11.5% (n=48/419). The most common ways MIDs were applied was to calculate sample size (37.5%) or to determine whether results were clinically important (35.4%). A total of 99 studies estimating MID values for the most common PROMs in plastic surgery, based on our review, were analyzed. The most common estimation methodologies were receiver-operator curve analysis (49%), change difference (31%), and standard deviation (25%). Our review highlights limited uptake and application of MIDs in plastic surgery. We propose four major barriers: 1) there existed no repository of published MIDs for PROMs used in plastic surgery; 2) available MIDs are not specific to plastic surgery populations; 3) high heterogeneity in MID estimation methodology; 4) wide ranges in MID values with no superior choice.

Deciphering the Role of Peroxisome Proliferator-activated Receptor α and Phosphodiesterase Type 5 Targets in Alzheimer's Disease.

The most prevalent cause of dementia is Alzheimer's disease (AD). Although the global AD rate is on a constant rise, medical research is yet to find a cure for this neurological condition. Current available therapeutic drugs for AD treatment only provide symptomatic alleviation. Therefore, it is essential to establish effective AD treatment strategies in addressing clinical needs. The development of disease-modifying treatments for use in the disease's early stages and the advancement of symptomatic drugs principally used in the disease's later stages are priorities in AD research. Given that the etiology of AD is difficult to comprehend, using a multimodal therapy intervention that targets molecular targets of AD-related degenerative processes is a practical strategy to change the course of AD progression. The current review article discussed PPAR-α (Peroxisome proliferator-activated receptor-α) and PDE5 (Phosphodiesterase type 5) targets with evidence for their preclinical and clinical importance. Furthermore, we support the targets with AD-related processes, functions, and remedial measures. A unique synergistic method for treating AD may involve the beneficial combinatorial targeting of these two receptors. Furthermore, we reviewed different PDE chemical families in this research and identified PDE5 inhibitors as one of the promising AD-related experimental and clinical disease-modifying medications. Lastly, we suggest jointly targeting these two pathways would be more beneficial than monotherapy in AD treatments.

Intelligent skin lesion segmentation using deformable attention Transformer U-Net with bidirectional attention mechanism in skin cancer images.

In recent years, the increasing prevalence of skin cancers, particularly malignant melanoma, has become a major concern for public health. The development of accurate automated segmentation techniques for skin lesions holds immense potential in alleviating the burden on medical professionals. It is of substantial clinical importance for the early identification and intervention of skin cancer. Nevertheless, the irregular shape, uneven color, and noise interference of the skin lesions have presented significant challenges to the precise segmentation. Therefore, it is crucial to develop a high-precision and intelligent skin lesion segmentation framework for clinical treatment. A precision-driven segmentation model for skin cancer images is proposed based on the Transformer U-Net, called BiADATU-Net, which integrates the deformable attention Transformer and bidirectional attention blocks into the U-Net. The encoder part utilizes deformable attention Transformer with dual attention block, allowing adaptive learning of global and local features. The decoder part incorporates specifically tailored scSE attention modules within skip connection layers to capture image-specific context information for strong feature fusion. Additionally, deformable convolution is aggregated into two different attention blocks to learn irregular lesion features for high-precision prediction. A series of experiments are conducted on four skin cancer image datasets (i.e., ISIC2016, ISIC2017, ISIC2018, and PH2). The findings show that our model exhibits satisfactory segmentation performance, all achieving an accuracy rate of over 96%. Our experiment results validate the proposed BiADATU-Net achieves competitive performance supremacy compared to some state-of-the-art methods. It is potential and valuable in the field of skin lesion segmentation.

Comparison of the Application Value of Transthoracic Echocardiography in Diagnosing Patent Foramen Ovale Under Different States of Stimulation: A Retrospective Study.

This study aims to evaluate the application value of contrast-enhanced transthoracic echocardiography (cTEE) in the diagnosis of patent foramen ovale (PFO) under different states of stimulation, with the goal of enhancing the accuracy and efficiency of PFO diagnosis. This research consecutively enrolled patients suspected of having PFO from October 2022 to February 2024, presenting primary clinical symptoms such as unexplained syncope, headache, dizziness, and stroke. Patients underwent standard transthoracic echocardiography (TTE) and cTEE under three different states of stimulation (resting state, coughing, and Valsalva maneuver). Based on the presence of microbubbles in the left heart and their initial appearance time, patients were classified into PFO and control groups, with further diagnostic confirmation via transesophageal echocardiography (TEE) or foramen ovale closure procedures. The study results revealed significant differences between the PFO and control groups regarding age (p = 0.034) and headache symptoms (p = 0.001). In the PFO group, TTE showed a higher positivity rate both at rest and during coughing, highlighting the association between PFO and specific clinical symptoms. The number of microbubbles observed during TTE increased significantly under various stimulation states, particularly during the Valsalva maneuver (p < 0.05). This increase became more pronounced as the duration of the maneuver was extended, underscoring the differential response of PFO patients under varied physiological testing conditions, especially during prolonged Valsalva maneuvers. The study confirms the significant value of cTEE in diagnosing PFO under different stimulation states, particularly emphasizing the application of the Valsalva maneuver to significantly improve the sensitivity and specificity of PFO detection. Thus, incorporating cTEE examinations under various stimulation states holds significant clinical importance for enhancing the accuracy and efficiency of PFO diagnosis.

A bio-behavioral model of systemic inflammation at breast cancer diagnosis and fatigue of clinical importance two years later

We aimed to generate a model of cancer-related fatigue (CRF) of clinical importance two years after diagnosis of breast cancer building on clinical and behavioral factors and integrating pre-treatment markers of systemic inflammation. Women with stage I-III HR+/HER2- breast cancer were included from the multimodal, prospective CANTO cohort (NCT01993498). The primary outcome was global CRF of clinical importance (EORTC QLQ-C30≥40/100) two years after diagnosis (year-2). Secondary outcomes included physical, emotional, and cognitive CRF (EORTC QLQ-FA12). All pre-treatment candidate variables were assessed at diagnosis, including inflammatory markers (interleukin [IL]-1a, IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, interferon gamma, IL-1 receptor antagonist, TNF-α, and C-reactive protein), and were tested in multivariable logistic regression models implementing multiple imputation and validation by 100-fold bootstrap resampling. Among 1208 patients, 415 (34.4%) reported global CRF of clinical importance at year-2. High pre-treatment levels of IL-6 (Quartile 4 vs.1) were associated with global CRF at year-2 (adjusted Odds Ratio [aOR]: 2.06 [95% Confidence Interval 1.40-3.03]; p=0.0002; AUC=0.74). Patients with high pre-treatment IL-6 had unhealthier behaviors, including being frequently either overweight or obese (62.4%; mean BMI 28.0 [SD 6.3] Kg/m2) and physically inactive (53.5% did not meet WHO recommendations). Clinical and behavioral associations with CRF at year-2 included pre-treatment CRF (aOR vs no: 3.99 [2.81-5.66]), younger age (per 1-year decrement: 1.02 [1.01-1.03]), current smoking (vs never: 1.81 [1.26-2.58]), and worse insomnia or pain (per 10-unit increment: 1.08 [1.04-1.13], and 1.12 [1.04-1.21], respectively). Secondary analyses indicated additional associations of IL-2 (aOR per log-unit increment:1.32 [CI 1.03-1.70]) and IL-10 (0.73 [0.57-0.93]) with global CRF and of C-reactive protein (1.42 [1.13-1.78]) with cognitive CRF at year-2. Emotional distress was consistently associated with physical, emotional, and cognitive CRF. This study proposes a bio-behavioral framework linking pre-treatment systemic inflammation with CRF of clinical importance two years later among a large prospective sample of survivors of breast cancer.

Diagnostic significance of LncRNA MIAT in periodontitis and the molecular mechanisms influencing periodontal ligament fibroblasts via the miR-204-5p/DKK1 axis

ObjectiveThis study investigated the clinical importance of long noncoding RNA myocardial infarction-associated transcript (MIAT) in periodontitis and its impact on the functional regulation of human periodontal ligament fibroblasts (hPDLFs). MethodsNinety-eight periodontitis patients and 74 healthy controls were enrolled. In vitro cellular models were created using Porphyromonas gingivalis lipopolysaccharide (Pg-LPS) to stimulate hPDLFs Real-time quantitative polymerase chain reaction was used to measure mRNA levels of MIAT and osteogenic factors. Inflammation factor concentration was assessed using an enzyme-linked immunosorbent assay. Cell viability and apoptosis were examined by cell counting kit -8 and flow cytometry assay. The targeting relationship was verified by the dual-luciferase reporter and RNA Immunoprecipitation assay. ResultsHighly expressed MIAT and Dicckopf-1 (DDK1), and lowly expressed miR-204-5p were found in the gingival crevicular fluid of periodontitis patients and Pg-LPS induced hPDLFs. MIAT has a sensitivity of 76.53% and a specificity of 86.49% for identifying patients with periodontitis among healthy individuals. MIAT acts as a sponge for miR-204-5p and upregulates DDK1 mRNA expression. Silencing of MIAT diminished the promotion of apoptosis and inflammation in hPDLFs by Pg-LPS and enhanced osteogenic differentiation. However, a miR-204-5p inhibitor significantly reversed the effect of silenced MIAT. ConclusionsMIAT may act as a promising biomarker for periodontitis. It modulates apoptosis, inflammation, and osteogenic differentiation of PDLFs by focusing on the miR-204-5p/DKK1 axis, indicating its potential as a new therapeutic target for treating periodontitis.

Drug Shortages: A Scoring System to Evaluate and Prioritize the Clinical Importance of Drugs in Canada

Drug shortages are an ongoing global health issue and pose significant challenges to policy-makers and health care providers. They may result from various factors (e.g., supply chain disruptions and recalls) and have a negative impact on patient outcomes and health care expenditures. The ability to accurately predict drugs at risk of a shortage would be a vital aspect in the effective management of drug shortages and help ensure proactive measures for consistent drug supply and optimized patient care; however, these drugs must also be prioritized in a meaningful way to identify high priority targets among the large number of drugs in the market and help ensure resources are allocated to the most important at-risk drugs. The purpose of this Environmental Scan aimed to identify a systematic method of objectively evaluating and ranking the value of drugs based on important clinical criteria and adapt the selected tool to prioritize the clinical importance of drugs in Canada. A total of 5 potential scoring systems were considered, and 1 scoring system was selected and adapted (based on expert panel member feedback). Finally, an assessment of 9 clinical criteria was made across 5 broad categories. The criteria include an evaluation of disease severity, size of the population, clinical guidelines, comparator interventions limitations (unmet needs), improvement of efficacy or effectiveness, improvement of safety and tolerability, improvement of patient-reported outcomes (PRO), type of medical service (e.g., symptom relief, prolonging life, cure), and public health interest. The proposed tool can be used in situations where decision-making requires an objective and systematic evaluation of drugs' clinical importance. Additionally, it will help inform a drug shortage risk framework in Canada, which will consider both the clinical importance and supply chain risks of drugs as part of the Health Canada Drug Shortages Task Force.

Prevalence of Multiple Sclerosis in Vitiligo Patients and Their First-Degree Relatives: Two Diseases with Similarities in Pathogenesis and Treatment

Introduction: Vitiligo is a common pigmentation disorder manifested by white macules and patches. It is accompanied by some autoimmune and neurological diseases. Recently, it has been suggested that multiple sclerosis (MS) is more common in vitiligo patients and that they have a higher risk of developing MS during their lifetime. Objectives: In this study, we aimed to determine the prevalence of MS in patients with vitiligo and their first-degree relatives and compare it with the prevalence in the population. Methods: In this cross-sectional study, data were consecutively collected from patients referred to Razi Hospital from March 2020 to December 2021. Results: 709 patients with vitiligo participated in this study, and 15 reported a history of MS (2.12%, 95% CI: 1.06-3.17%). This rate was significantly higher than the prevalence of MS in the average population of Tehran (p &lt; 0.001). Of the 2886 first-degree relatives of the patients, 10 had MS (0.35%, 95% CI: 0.13-0.56%), which was higher than the prevalence of MS, yet not statistically significant. Conclusions: A significant association between vitiligo and MS was observed, which should be of clinical and therapeutic importance. However, the prevalence of MS in first-degree relatives of vitiligo patients was higher than the average rate, yet not statistically significant.

CDK12 is a promising therapeutic target for the transcription cycle and DNA damage response in metastatic osteosarcoma.

Osteosarcoma (OS) is a bone malignant tumor affecting children, adolescents and young adults. Currently, osteosarcoma is treated with chemotherapy regimens established over 40 years ago. The investigation of novel therapeutic strategies for the treatment of osteosarcoma remains an important clinical need. Cyclin-dependent kinases (CDKs) have been considered promising molecular targets in cancer therapy. Among these, CDK12 has been shown to play a crucial role in the pathogenesis of malignancies, but its clinical significance and biological mechanisms in osteosarcoma remain unclear. In the present study, we aim to determine the expression and function of CDK12, and evaluate its prognostic and therapeutic value in metastatic osteosarcoma. We found that overexpression of CDK12 was associated with high tumor grade, tumor progression and reduced patient survival. Underlying mechanism revealed that knockdown of CDK12 expression with siRNA or functional inhibition with the CDK12-targeting agent THZ531 effectively exhibited time- and dose-dependent cytotoxicity. Downregulation of CDK12 paused transcription by reducing RNAP II phosphorylation, interfered with DNA damage repair with increased γH2AX, and decreased cell proliferation through the PI3K-AKT pathway. This was accompanied by the promotion of apoptosis, as evidenced by enhanced Bax expression and reduced Bcl-xL expression. Furthermore, the CDK12 selective inhibitor THZ531 also hindered ex vivo 3D spheroid formation, growth of in vitro 2D cell colony, and prevented cell mobility. Our findings highlight the clinical importance of CDK12 as a potentially valuable prognostic biomarker and therapeutic target in metastatic osteosarcoma.

The Biochemistry and Clinical Importance of Ribonucleic Acid (RNA): A Review Article

The Biochemistry and Clinical Importance of Ribonucleic Acid (RNA): A Review Article

A Systematic and Critical Review on the Anatomy of the Ethmoidal Foramina.

The osteologic anatomy of the orbit is still a field of intense research, particularly as far as vascular channels are concerned. Among them, ethmoidal foraminas (EFs) are certainly those that have more clinical importance and indeed have been deeply investigated. Unfortunately, the vast production of articles, far from clarifying their anatomy, generated a certain degree of confusion. A search on Pubmed and Scopus databases updated up to December 31, 2023, has been carried out with the keyword "ethmoidal foramen" yielding a list of 357 items. With a careful screening process, 31 articles were enlisted to be included in the present review. A critical review process confirmed that many results published over the years appear inconsistent, particularly as far as EFs topography is concerned. The possible reasons for this lack of consistency can be traced back to inter-ethnical differences, uncertainty on the anterior bony landmarks employed in the investigations, and lack of a general consensus over EFs classification. A novel approach, based on the normalization of the distance of the anterior landmarks relative to the length of the orbit (relative depth index), should overcome some of the major problems encountered so far. Novel and clear guidelines to classify EFs and to locate them on the medial wall are required. Determining the relative depth index of EFs may be an interesting approach to solve the matter. Other methods can be also devised. However, direct measurements from bony landmarks, without any further analysis seem inadequate and possibly misleading.

Lysosomal-Associated Protein Transmembrane 5, Tubular Senescence, and Progression of CKD.

Tubular senescence is a major determinant of chronic kidney disease (CKD) and identification of potential therapeutic targets involved in senescent tubular epithelial cells has clinical importance. Lysosomal-associated protein transmembrane 5 (LAPTM5) is a key molecule related to T and B cell receptor expression and inflammation. However, the expression pattern of LAPTM5 in the kidney and the contribution of LAPTM5 to the development of CKD keep unknown. LAPTM5-/- mice and tubule specific-LAPTM5 knockout mice were used to examine the role of LAPTM5 in tubular senescence by establishing different experimental mouse CKD models. LAPTM5 expression was significantly induced in the kidney, especially in proximal tubules and distal convoluted tubules, from mice with aristolochic acid nephropathy, bilateral ischemia/reperfusion injury (IRI)-induced CKD or unilateral ureter obstruction (UUO). Tubule-specific deletion of LAPTM5 inhibited senescence of tubular epithelial cells and alleviated tubulointerstitial fibrosis in aged mice. Moreover, LAPTM5 deficiency ameliorated kidney injury and tubular senescence in mice with CKD. Mechanistically, LAPTM5 inhibited ubiquitination of NICD1 by mediating WWP2 lysosomal degradation, then leading to cellular senescence in tubular epithelial cells. Notably, we also observed a higher expression of LAPTM5 in tubules from individuals with CKD and the level of LAPTM5 was correlated with kidney fibrosis and tubular senescence in people with CKD. LAPTM5 contributed to tubular senescence by regulating WWP2/NICD1 signaling pathway and exacerbated kidney injury during the progression of CKD.

In vitro synergistic antiviral activity of repurposed drugs against enterovirus 71.

Enteroviruses cause viral diseases that are harmful to children. Hand, foot, and mouth disease (HFMD) with neurological complications is mainly caused by enterovirus 71 (EV71). Despite its clinical importance, there is no effective antiviral drug against EV71. However, several repurposed drugs have been shown to have antiviral activity against related viruses. Treatments with single drugs and two-drug combinations were performed in vitro to assess anti-EV71 activity. Three repurposed drug candidates with broad-spectrum antiviral activity were found to demonstrate potent anti-EV71 activity: prochlorperazine, niclosamide, and itraconazole. To improve antiviral activity, combinations of two drugs were tested. Niclosamide and itraconazole showed synergistic antiviral activity in Vero cells, whereas combinations of niclosamide-prochlorperazine and itraconazole-prochlorperazine showed only additive effects. Furthermore, the combination of itraconazole and prochlorperazine showed an additive effect in neuroblastoma cells. Itraconazole and prochlorperazine exert their antiviral activities by inhibiting Akt phosphorylation. Repurposing of drugs can provide a treatment solution for HFMD, and our data suggest that combining these drugs can enhance that efficacy.

Modifiable lifestyle factors and the risk of post-COVID-19 multisystem sequelae, hospitalization, and death

Effective prevention strategies for post-COVID complications are crucial for patients, clinicians, and policy makers to mitigate their cumulative burden. This study evaluated the association of modifiable lifestyle factors (smoking, alcohol intake, BMI, physical activity, sedentary time, sleep duration, and dietary habits) with COVID-19 multisystem sequelae, death, and hospitalization in the UK Biobank cohort (n = 68,896). A favorable lifestyle (6-10 healthy factors; 46.4%) was associated with a 36% lower risk of multisystem sequelae (HR, 0.64; 95% CI, 0.58-0.69; ARR at 210 days, 7.08%; 95% CI, 5.98-8.09) compared to an unfavorable lifestyle (0-4 factors; 12.3%). Risk reductions spanned all 10 organ systems, including cardiovascular, coagulation, metabolic, gastrointestinal, kidney, mental health, musculoskeletal, respiratory disorders, and fatigue. This beneficial effect was largely attributable to direct lifestyle impacts independent of corresponding pre-infection comorbidities (71% for any sequelae). A favorable lifestyle was also related to the risk of post-COVID death (HR 0.59, 0.52-0.66) and hospitalization (HR 0.78, 0.73-0.84). These associations persisted across acute and post-acute infection phases, irrespective of hospitalization status, vaccination, or SARS-CoV-2 variant. These findings underscore the clinical and public health importance of adhering to a healthy lifestyle in mitigating long-term COVID-19 adverse impacts and enhancing future pandemic preparedness.

Ferroptosis-based advanced therapies as treatment approaches for metabolic and cardiovascular diseases.

Ferroptosis has attracted attention throughout the last decade because of its tremendous clinical importance. Here, we review the rapidly growing body of literature on how inhibition of ferroptosis may be harnessed for the treatment of common diseases, and we focus on metabolic and cardiovascular unmet medical needs. We introduce four classes of preclinically established ferroptosis inhibitors (ferrostatins) such as iron chelators, radical trapping agents that function in the cytoplasmic compartment, lipophilic radical trapping antioxidants and ninjurin-1 (NINJ1) specific monoclonal antibodies. In contrast to ferroptosis inducers that cause serious untoward effects such as acute kidney tubular necrosis, the side effect profile of ferrostatins appears to be limited. We also consider ferroptosis as a potential side effect itself when several advanced therapies harnessing small-interfering RNA (siRNA)-based treatment approaches are tested. Importantly, clinical trial design is impeded by the lack of an appropriate biomarker for ferroptosis detection in serum samples or tissue biopsies. However, we discuss favorable clinical scenarios suited for the design of anti-ferroptosis clinical trials to test such first-in-class compounds. We conclude that targeting ferroptosis exhibits outstanding treatment options for metabolic and cardiovascular diseases, but we have only begun to translate this knowledge into clinically relevant applications.

Morphometric MRI Study of Third Ventricle of Brain among Bangladeshi Adults

Background: The third ventricle of the brain is a small median cleft located in the diencephalon between right and left thalamus; anteriorly it communicates to the lateral ventricles by foramen of Monro, posteriorly connects to the fourth ventricle through the cerebral aqueduct. Morphometry and accurate measurements of the brain ventricles have clinical importance because various diseases affect the size and morphology of the ventricles. Objective: This study was aimed to determine the morphometry of third ventricle of brain by magnetic resonance imaging (MRI) scan. Methods: This cross-sectional study was conducted at Department of Anatomy, Dhaka Medical College, Dhaka, Bangladesh from January 2020 to December 2020. Patients referred by Department of Medicine, Dhaka Medical College Hospital (DMCH) for MRI were enrolled as study subjects. Total 100 adult Bangladeshi subjects (50 male and 50 female) were selected following selection criteria. Their MRI of brain was done by MAGNETOM VIDA (3T Tesla) SIEMENS MRI machine following standard procedure. The MRI scans were evaluated by registered radiologists. All parameters were measured from the soft copy of MRI scans using RadiAnt DICOM Viewer. Results: The mean (±SD) maximum height of the third ventricle was 23.69 ± 1.13 mm in male and 22.38 ± 0.72 mm in female, that was significantly larger in male (p&lt;0.001). The mean (±SD) anterior-posterior length of third ventricle was 27.17 ± 0.67 mm and 26.16 ± 0.58 mm in male and female respectively, which was significantly higher in male than female (p&lt;0.001). However, no significant difference was observed in mean (±SD) anterior-posterior commissural distance between male and female (26.47 ± 1.6 mm and 26.06 ± 1.00 mm, p= 0.129). The mean (±SD) maximum width of third ventricle was found significantly higher in male than female (4.33 ± 0.41 mm versus 3.68 ± 0.68 mm, p&lt;0.001). Conclusion: The maximum height, anterior to posterior length and maximum width of third ventricle ........