Clinical Dilemma Research Articles

Mitophagy in hypertension-mediated organ damage.

Hypertension constitutes a pervasive chronic ailment on a global scale, frequently inflicting damage upon vital organs, such as the heart, blood vessels, kidneys, brain, and others. And this is a complex clinical dilemma that requires immediate attention. The mitochondria assume a crucial function in the generation of energy, and it is of utmost importance to eliminate any malfunctioning or surplus mitochondria to uphold intracellular homeostasis. Mitophagy is considered a classic example of selective autophagy, an important component of mitochondrial quality control, and is closely associated with many physiological and pathological processes. The ubiquitin-dependent pathway, facilitated by PINK1/Parkin, along with the ubiquitin-independent pathway, orchestrated by receptor proteins such as BNIP3, NIX, and FUNDC1, represent the extensively investigated mechanisms underlying mitophagy. In recent years, research has increasingly shown that mitophagy plays an important role in organ damage associated with hypertension. Exploring the molecular mechanisms of mitophagy in hypertension-mediated organ damage could represent a critical avenue for future research in the development of innovative therapeutic modalities. Therefore, this article provides a comprehensive review of the impact of mitophagy on organ damage due to hypertension.

Proteomics profiling reveals lipid metabolism abnormalities during oogenesis in unexplained recurrent pregnancy loss.

Unexplained recurrent pregnancy loss (URPL) is a clinical dilemma in reproductive fields. Its diagnosis is mainly exclusionary after extensive clinical examination, and some of the patients may still face the risk of miscarriage. We analyzed follicular fluid (FF) from in vitro fertilization (IVF) in eight patients with URPL without endocrine abnormalities or verifiable causes of abortion and eight secondary infertility controls with no history of pregnancy loss who had experienced at least one normal pregnancy and delivery by direct data-independent acquisition (dDIA) quantitative proteomics to identify differentially expressed proteins (DEPs). In this study, bioinformatics analysis was performed using online software including g:profiler, String, and ToppGene. Cytoscape was used to construct the protein-protein interaction (PPI) network, and ELISA was used for validation. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that the DEPs are involved in the biological processes (BP) of complement and coagulation cascades. Apolipoproteins (APOs) are key proteins in the PPI network. ELISA confirmed that APOB was low-expressed in both the FF and peripheral blood of URPL patients. Dysregulation of the immune network intersecting coagulation and inflammatory response is an essential feature of URPL, and this disequilibrium exists as early as the oogenesis stage. Therefore, earlier intervention is necessary to prevent the development of URPL. Moreover, aberrant lipoprotein regulation appears to be a key factor contributing to URPL. The mechanism by which these factors are involved in the complement and coagulation cascade pathways remains to be further investigated, which also provides new candidate targets for URPL treatment.

The end of dialysis: the weariness to carry on

Voluntary cessation of hemodialysis is a common cause of death in dialysis patients, often occurring related to an alteration in their quality of life. At the same time, psychiatric disorders such as depression or anxiety are common and often underestimated among these patients, that accentuate the suffering and complicate compliance with dialysis. In this paper some psychopathological conditions will be addressed, as well as the question of the patient's ambivalence towards dialysis and the clinical and ethical dilemma of caregivers: respect the patient's choice to stop treatment or keep them alive at all costs? A multidisciplinary approach, including palliative care, is essential to support the reflection and make balanced decisions while respecting patient autonomy.

Challenging anticoagulation decisions in atrial fibrillation: a narrative review.

Atrial fibrillation (AF) is common and warrants consideration of oral anticoagulant (OAC) medication. Usually, the decision is straightforward, following the pathway outlined in the European Society of Cardiology's guideline; however, certain situations fall outside of this evidence base - such as a diagnosis of subclinical AF made via implanted devices or wearable electrocardiogram monitors, or alternatively diagnosis of 'secondary AF' following a major stressor. Subclinical AF is associated with stroke, though not to the extent of clinical AF, and the benefits of anticoagulation appear to be lower. Longer episodes are more clinically meaningful, and recent randomised controlled trials have demonstrated that some patients derive benefit from OAC. Similarly, when AF is triggered by sepsis or non-cardiac surgery, specific evidence supporting OAC initiation is lacking and clinician behaviour is variable. Observational data demonstrate poorer outcomes in these patients, implying that the perception of a transient, reversible phenomenon may not be correct. Contrastingly, cardiac surgery very frequently induces AF, and the benefits of anticoagulation rarely outweigh the risks of bleeding. Following ischaemic stroke, recent evidence suggests that early (re-)initiation of OAC should be considered as this does not increase the risk of haemorrhagic transformation as previously hypothesised. This narrative review summarises the available literature and outlines, where possible, practical advice for clinicians facing these common clinical dilemmas.

Cancer-Induced Resting Sinus Tachycardia: An Overlooked Clinical Diagnosis.

Elevated resting heart rate is frequently observed in cancer patients, and is associated with increased mortality. Although specific chemotherapeutic agents can induce cardiotoxicity, the presence of sinus tachycardia in chemotherapy-naive patients suggests other factors likely contribute to this clinical presentation. Despite its prevalence, cancer-associated resting sinus tachycardia has not been fully recognized and comprehensively described as a separate clinical entity. Secondary effects of cancer, especially structural cardiac changes, secretory factors (inflammatory cytokines), and thromboembolic disease can cause resting tachycardia. Alternatively, rapid heart rate may reflect compensatory mechanisms responding to increased metabolic demands, raised cardiac output states, and even pain. Hence, cancer-associated tachycardia presents a clinical dilemma; acute life-threatening conditions (such as sepsis, pulmonary embolism, etc.) must be ruled out, but cancer itself can explain resting sinus tachycardia and more conservative management can avoid unnecessary testing, cost and patient stress. Furthermore, identification and management of cardiac conditions associated with cancer may improve survival and the quality of life of cancer patients.

A burning heart: combined therapy of checkpoint-inhibitors and prednisolone in a patient with sarcoidosis

Patients with prior autoimmune diseases such as sarcoidosis require special care when treated with checkpoint inhibitors (CPIs), given the risk for reactivation of inflammation. Here, we address the clinical dilemma of initiating CPIs for recurrent metastatic carcinoma in a patient with extensive sarcoidosis, controlled after prolonged immunosuppressive therapy when the tumor recurrence was detected. To achieve the best possible outcome, the case was discussed by an interdisciplinary team comprising specialists in rheumatology, oncology, and CPI-related myocarditis. Literature on this topic was very limited. Based on the pharmacodynamics of CPIs and the pathophysiology of CPI-related autoimmune diseases, we concluded that initiating CPIs alongside low-dose prednisolone would effectively suppress any reactivation of sarcoidosis without interfering with CPIs in a relevant way.

Therapeutic anticoagulation in patients with acute pancreatitis and splanchnic vein thrombosis: a best evidence topic.

A best evidence topic in general surgery was written according to a structured protocol. The clinical question addressed was: in adult patients with splanchnic vein thrombosis in acute pancreatitis, would administration of therapeutic anticoagulation be advisable considering the rates of vessel recanalization and bleeding complications? Four hundred twenty-four papers were found on Ovid Embase and Medline whilst 222 were found on PubMed using the reported literature search. From these, five articles represented the best evidence to the clinical question. The authors, publication dates, countries, patient groups, study outcomes, and results of these papers were tabulated. There were three systematic reviews with meta-analyses, one systematic review without meta-analysis and one randomized, retrospective study. The authors conclude that among patients with splanchnic vein thrombosis in the context of acute pancreatitis, therapeutic anticoagulation improved the rates of recanalization without increasing the risk of bleeding complications. However, there remains a need for randomized studies to address this clinical dilemma to further increase the quality of available evidence.

Loureirin hydrogel promotes healing of radionuclide-contaminated wounds by regulating angiogenesis and immune cells.

Radionuclide-contaminated wounds face clinical dilemmas such as repeated erosion and ulceration and are difficult to heal. In this work, we aimed to develop a biodegradable hydrogel with a beneficial effect on radionuclide-contaminated wounds and initially investigated the mechanism of action of the hydrogel. The hydrogel was produced through the ring-opening polymerization of polycaprolactone (PCL) triggered by polyethylene glycol (PEG), and its physicochemical properties were characterized by gel permeation chromatography, nuclear magnetic resonance, rheological properties testing, and other techniques. The low critical solution temperatures were 30 °C and 46 °C, which are suitable for the human body to realize the degradable properties of the hydrogel. A radionuclide-contaminated wound model was established, which proved that the biodegradable hydrogel had good healing properties and did not form secondary lesions. The effect was better than clinically used EGF or VB12. Pathological results showed that mature granulation tissue formed on the 7th day after the injury, and by the 10th day after the injury, the scab had completely fallen off, the epithelial coverage had reached over 70% and the wound was essentially completely healed. Additionally, the hydrogel affects immune metabolism, regulates immune cell function, promotes the formation of new blood vessels and granular tissue, and effectively accelerates the healing process of radionuclide-contaminated wounds.

Along came COVID-19: The changing landscape of serious childhood infections

The landscape of acute childhood infections changed dramatically across Europe in the immediate post-COVID-19 period. It was initially characterised by an unprecedented reduction of children with acute infections and reduced circulation of infectious pathogens in the community. With the lifting of non-pharmaceutical interventions (NPI) and return of circulating organisms, we witnessed re-emergence of infectious pathogens. We learned about the impact of NPIs on childhood infections and should learn from this for future outbreaks, balancing immediate need for interrupting population transmission with longer term rebound effects. Outbreaks of monkeypox, severe childhood hepatitis of unclear aetiology, and invasive Group A Streptococcus each presented with unique clinical dilemmas requiring urgent scientific evidence and public health messaging. Implementation of maternal and infant RSV vaccines, as well as other promising vaccine developments, will further impact the landscape of acute childhood infections.

Clinical Dilemma Involving Treatments for Very Low-Birth-Weight Infants and the Potential Risk of Necrotizing Enterocolitis: A Narrative Literature Review.

Necrotizing enterocolitis (NEC) is a critical gastrointestinal emergency with substantial morbidity and mortality risks, especially for very low-birth-weight (VLBW) infants, and unclear multifactorial pathophysiology. Whether common treatments for VLBW infants increase the NEC risk remains controversial. Indomethacin (utilized for patent ductus arteriosus) offers benefits but is concerning because of its vasoconstrictive impact on NEC susceptibility. Similarly, corticosteroids used to treat bronchopulmonary dysplasia may increase vulnerability to NEC by compromising immunity and altering the mesenteric blood flow. Histamine-2 receptor blockers (used to treat gastric bleeding) may inadvertently promote NEC by affecting bacterial colonization and translocation. Doxapram (used to treat apnea) poses a risk of gastrointestinal disturbance via gastric acid hypersecretion and circulatory changes. Glycerin enemas aid meconium evacuation but disrupt microbial equilibrium and trigger stress-related effects associated with the NEC risk. Prolonged antibiotic use may unintentionally increase the NEC risk. Blood transfusions for anemia can promote NEC via interactions between the immune response and ischemia-reperfusion injury. Probiotics for NEC prevention are associated with concerns regarding sepsis and bacteremia. Amid conflicting evidence, this review unveils NEC risk factors related to treatments for VLBW infants, offers a comprehensive overview of the current research, and guides personalized management strategies, thereby elucidating this clinical dilemma.

Contemporary issues in the management of dental trauma.

Contemporary diagnosis and management of traumatic dental injuries requires a multifaceted understanding of the pathological and psychological impact over a patient's lifetime. The legacy of dental trauma injuries can have repercussions for the dentition and supporting tissues, requiring complicated multidisciplinary clinical input. Foresight is required to ensure optimal aesthetic and functional outcomes. Mitigating risks and maximising benefits in patients presenting with polytrauma can be challenging, but if optimally managed at the acute presentation, the long-term burden to the patient and the clinician is reduced. This paper aims to discuss the contemporary clinical dilemmas, challenges and controversies related to the management of dental trauma.

NEWCORONAVIRUS INFECTIONANDPULMONARYTUBERCULOSIS: CLINICAL CASES

At the end of 2019, an outbreak of a new coronavirus infection, SARS-CoV-2, emerged in the People’s Republic of China with the epicenter in the city of Wuhan, Hubei Province. On February 11, 2020, the World Health Organization determined the official name of the disease caused by the new coronavirus – COVID-19, and on March 11, 2020, announced the beginning of a pandemic caused by the SARS-CoV-2 infection. COVID-19 is a “young disease”, which determines the importance of studying the influence of chronic comorbid pathology on the risk of infection with SARS-CoV-2, the severity of the course and the likelihood of developing an unfavorable outcome of the disease. Accumulated data identify several risk groups for severe COVID-19. First of all, this applies to patients with concomitant chronic pathologies: diabetes, cardiovascular diseases, obesity, and others [5, 15]. Coinfections affecting the respiratory tract pose clinical dilemmas as well as diagnostic and therapeutic challenges. This article presents clinical cases of the course of a combination of COVID-19 infection and pulmonary tuberculosis. The new coronavirus infection was more severe in a female patient with newly diagnosed tuberculosis than in a female patient with a chronic tuberculosis process, which confirms a different influence of the pathological processes on each other.

10098-MPC-10 HOW SHOULD WE RESPOND TO REPEATED WHO REVISIONS? IN-HOUSE MOLECULAR DIAGNOSIS SYSTEM BY ADVANCED MEDICAL SYSTEM

Abstract BACKGROUND Since the WHO2016 revision, required molecular markers has been increasing, placing a burden on clinical practice of diffuse gliomas. We established an in-house molecular diagnostic platform by Senshin-Iryo (meaning advanced medical care system) and have since been partially modifying the analysis method in accordance with the WHO2021 revision. We review our achievements in total 5 years. METHODS Analyses of IDH, BRAF, and H3 point mutations, loss of heterozygosity on 1p19q and chromosomes 10 and 17, and MGMT methylation were combined into a set and submitted as a Senshin-Iryo "Drug resistance gene testing for anticancer chemotherapy" and approved in August 2018. Subsequently, in October 2021, Sanger sequencing for TERT promotor mutation was added to the set and the LOH analysis was replaced to MLPA, in order to analyze 1p19q codeletion and newly required genetic markers; EGFR, PTEN, CDKN2A, etc. in WHO2021. RESULTS The cumulative number of cases has reached over 200. Among them, 54 cases were analyzed after WHO2021 revision. The laboratory has maintained the diagnostic platform in which molecular diagnoses are steadily confirmed generally within two weeks. The initial expenditure was exceeded the income obtained from the patient co-payment, however, it has gradually been reduced to running costs alone, then is approaching profitability. After WHO2021 revision, diagnoses could be confirmed by molecular markers obtained from Senshin-Iryo in 38 of 54 cases (70.1%). Among the remaining 16, only 4 (7.4%) cases remained diagnosed as diffuse glioma, NEC, exclusionary after 12 cases in which glioblastoma was confirmed by histopathological diagnosis. CONCLUSIONS Our Senshin-Iryo trial has functioned as a salvage system to overcome the current transition period in which the continuing revision of WHO classification causing a clinical dilemma of healthcare system.

Telepsychiatry – few clinical and ethical dilemmas

Telepsychiatry – few clinical and ethical dilemmas

Metastatic pancreatic cancer mimicking medication related osteonecrosis of the jaw—A rare clinical presentation

AbstractPancreatic cancer is a highly aggressive malignancy with a poor prognosis owing to its rapid progression, high mortality rate, and alarming 5‐year survival rate of 5%. Skeletal metastases represent an understated site of metastasis in patients with pancreatic cancer, occurring in about 5%–20% of these patients. The clinical presentation of metastasis to the jaws and osteonecrosis of jaw can exhibit similarities, which may lead to an erroneous diagnosis or create a diagnostic dilemma. We present a case of a 62‐year‐old male patient diagnosed with pancreatic adenocarcinoma and a prior history of bisphosphonate administration who displayed symptoms such as jaw pain, numbness, reduced mouth opening, and an extra‐oral swelling involving a recent tooth extraction site, likely due to medication‐related osteonecrosis of the jaw (ONJ). Despite initial conservative treatment, the patient's symptoms persisted, prompting further investigation. Depending on the specific context and clinical scenario, it is crucial to employ a comprehensive approach such as clinical examination, radiographic imaging, histopathological examination and monitoring the progression of symptoms over time for accurate diagnosis and timely management. This article presents a rare case of metastatic pancreatic cancer mimicking medication related ONJ, highlighting the clinical dilemma and challenges encountered when presenting symptoms and signs are ambiguous. While the prognosis for such cases is generally poor, dentists and healthcare providers should remain vigilant regarding potential sites of metastasis in cases of pancreatic adenocarcinoma.

Understanding barriers, recommended solutions, and future prospects for the diagnosis and management of Pythium insidiosum keratitis.

Pythium insidiosum keratitis (PIK) is a devastating corneal infection resulting in blindness in a large number of cases. Clinically and morphologically, it closely mimics fungal keratitis, and hence is also labeled as "parafungus." Although many clinical studies have documented evidence regarding the virulence of microorganism, and anatomical and functional outcomes, it remains a clinical challenge and diagnostic dilemma for most clinicians. Till today, PIK is being diagnosed and treated with certainty at only limited centers across the globe. But the question is why this is so? Taking this as the research question, this section on current ophthalmology aims to highlight the understanding of barriers to diagnosing and treating PIK, the suggestions to improve diagnosis and treatment, and the future prospects.

IMMU-05. CD8 IMMUNOPET IMAGING IS ABLE TO MONITOR THE IMMUNE RESPONSE SENSITIVELY AND SPECIFICALLY IN GBM PATIENTS FOLLOWING NEOADJUVANT CHECKPOINT BLOCKADE IMMUNOTHERAPY

Abstract The sensitive and specific evaluation of treatment response in glioblastoma (GBM) patients following immunotherapy is a clinical dilemma. Traditional MRI assessments to visualize and quantify intracranial tumor burden following immunotherapy cannot reliably differentiate tumor progression and pseudo progression remains a complicating factor. In this study, we provide an early report on the use of an investigational new functional imaging PET tracer (CD8 ImmunoPET, 89Zr-crefmirlimab berdoxam, ImaginAb) prior to and immediately following neoadjuvant checkpoint blockade immunotherapy in five patients with recurrent GBM. Tumor samples were collected from each patient at surgery following a two-week neoadjuvant checkpoint blockade to assess gene expression changes and TIL density. We then evaluated how such tumor measurements correlated with PET metrics obtained at baseline and within 2 weeks after treatment initiation which included standardized uptake values (SUVmax, SUVpeak, and SUVmean), and two proposed new metrics indicating the Volume of Immunometabolism (VIM), and the Total Lesion or Lymph nodes’ T cells called TLTc (TLTc = VI x SUVmean) in the tumor bed and lymph node basins (neck, axillae, and inguinal regions). CD8 ImmunoPET demonstrated tracer uptake in the intracranial tumor at both time points, as well as specific physiologic uptake in lymph node basins, spleen, liver, and bone marrow. Neoadjuvant checkpoint blockade with PD-1 +/- CTLA-4 mAb (Nivolumab, Ipilimumab, BMS) at 2 weeks induced variable changes in SUV, but in four of the five initial patients studied in this clinical trial, an increase in VI and TLTc was observed within the tumor bed. Tracer uptake was associated with elevated T cell infiltration into the tumor bed and gene expression changes indicative of interferon signaling and immune cells in these same patients. Our early findings identify a noninvasive functional imaging platform to evaluate the immunometabolism secondary to T cell infiltration and/or activation changes following immunotherapy in GBM patients.

Intraoperative bioprinting of human adipose-derived stem cells and extra-cellular matrix induces hair follicle-like downgrowths and adipose tissue formation during full-thickness craniomaxillofacial skin reconstruction

Craniomaxillofacial (CMF) reconstruction is a challenging clinical dilemma. It often necessitates skin replacement in the form of autologous graft or flap surgery, which differ from one another based on hypodermal/dermal content. Unfortunately, both approaches are plagued by scarring, poor cosmesis, inadequate restoration of native anatomy and hair, alopecia, donor site morbidity, and potential for failure. Therefore, new reconstructive approaches are warranted, and tissue engineered skin represents an exciting alternative. In this study, we demonstrated the reconstruction of CMF full-thickness skin defects using intraoperative bioprinting (IOB), which enabled the repair of defects via direct bioprinting of multiple layers of skin on immunodeficient rats in a surgical setting. Using a newly formulated patient-sourced allogenic bioink consisting of both human adipose-derived extracellular matrix (adECM) and stem cells (ADSCs), skin loss was reconstructed by precise deposition of the hypodermal and dermal components under three different sets of animal studies. adECM, even at a very low concentration such as 2 % or less, has shown to be bioprintable via droplet-based bioprinting and exhibited de novo adipogenic capabilities both in vitro and in vivo. Our findings demonstrate that the combinatorial delivery of adECM and ADSCs facilitated the reconstruction of three full-thickness skin defects, accomplishing near-complete wound closure within two weeks. More importantly, both hypodermal adipogenesis and downgrowth of hair follicle-like structures were achieved in this two-week time frame. Our approach illustrates the translational potential of using human-derived materials and IOB technologies for full-thickness skin loss.

A Comparative Efficacy of Antidepressants in the Treatment of Major Depressive Disorder: A Systematic Review and Meta-Analysis

Major Depressive Disorder (MDD) affects about 280, 000, 000 people globally, with a higher incidence among females than males. The increasing incidence implicates health burdens and clinical dilemmas regarding the low efficacy of the existing antidepressants. A literature search was performed on electronic databases, PubMed, the Cochrane Library of Randomized Trials, Scopus, and ProQuest, for studies reporting the efficacy of an SNRI (Desvenlafaxine 50 mg/d), a serotonin modulator (Vortioxetine 10-20 mg/d), and an aminoketone antidepressant (Bupropion). Study selection focused on randomized controlled trials (RCTs) and observational studies. All statistical analyses and visualization were performed using the Review Manager (RevMan) software and Python programming. The random effects model, ANOVA test, and Cohen’s d were used for statistical analyses. The present meta-analysis involved 17 studies, including 11, 533 participants. The results aligned with previous studies and accounts provided by literature regarding the efficacy of antidepressants used to manage MDD. Five studies, including 2, 377 MDD patients, reported a statistically significant outcome, that Desvenlafaxine 50 mg/d reduced MDD’s severity than placebo (OR: 0.52, 95% CI [0.44, 0.62], P < 0.00001, I2 = 0%). Three studies involving 742 MDD patients reported the efficacy of dextromethorphan-bupropion (AXS-50). The reduction of MADRS scores in the treatment group was statistically insignificant, with high variability, favouring the placebo (OR of 1.85 [95% CI: 0.93, 3.70], p = 0.08, I2 = 79%). Additionally, Vortioxetine 10-20 mg/d produced adverse effects, headache, vomiting, nausea, diarrhea, dizziness, nasopharyngitis, somnolence, and suicidal ideation among 6, 669 MDD patients reported by the 9 studies. The finding was statistically significant but with a high variability OR: 15.25, 95% CI [12.55, 18.52], P < 0.00001, I2 = 98%). A preliminary analysis of evidence collected following Desvenlafaxine, AXS-50, and Vortioxetine administration yielded compelling evidence on the efficacy of antidepressants in MDD treatment. Desvenlafaxine and AXS-50 reported reduced severity and symptomatology in MDD, respectively. On the other hand, Vortioxetine implicated adverse effects, which are common with most antidepressants. Despite adverse effects like headache, vomiting, nausea, diarrhea, dizziness, nasopharyngitis, somnolence, and suicidal ideation, antidepressants used to treat MDD yield clinically satisfying outcomes like decreased severity of depression and relief from symptoms. Clinicians should monitor patients to take care of any adverse effects resulting from the treatments. Keywords: Antidepressant efficacy, adverse effects, major depressive disorder, MDD symptomatology, severity, improved outcomes.

A Diagnostic and Therapeutic Dilemma Concerning Exostosin 1/Exostosin 2-associated Lupus-like Membranous Nephropathy with Positive Antinuclear Antibody in an Elderly Man with Various Immune Abnormalities.

Exostosin 1 (EXT1) and exostosin 2 (EXT2)-associated membranous nephropathy (MN) may be associated with active autoimmune disease. We encountered an elderly man who presented with EXT1/EXT2-associated lupus-like MN with full house immune deposits, monoclonal gammopathy of uncertain significance and Sjögren's syndrome. The patient exhibited various other immune abnormalities. Although he did not fulfill the criteria of clinical systemic lupus erythematosus (SLE), he met a stand-alone renal criterion of the Systemic Lupus International Collaborating Clinics (SLICC) 2012. Whether or not a stand-alone renal criterion with EXT1/EXT2 positivity, as in the present patient, can efficiently guide decisions regarding the diagnosis and treatment of SLE remains a clinical dilemma.