Clinical Dilemma Research Articles

Siamese deep learning video flow cytometry for automatic and label-free clinical cervical cancer cell analysis.

Automatic and label-free screening methods may help to reduce cervical cancer mortality rates, especially in developing regions. The latest advances of deep learning in the biomedical optics field provide a more automatic approach to solving clinical dilemmas. However, existing deep learning methods face challenges, such as the requirement of manually annotated training sets for clinical sample analysis. Here, we develop Siamese deep learning video flow cytometry for the analysis of clinical cervical cancer cell samples in a smear-free manner. High-content light scattering images of label-free single cells are obtained via the video flow cytometer. Siamese deep learning, a self-supervised method, is built to introduce cell lineage cells into an analysis of clinical cells, which utilizes generated similarity metrics as label annotations for clinical cells. Compared with other deep learning methods, Siamese deep learning achieves a higher accuracy of up to 87.11%, with about 5.62% improvement for label-free clinical cervical cancer cell classification. The Siamese deep learning video flow cytometry demonstrated here is promising for automatic, label-free analysis of many types of cells from clinical samples without cell smears.

Diagnosing Polyomavirus Nephropathy without a Biopsy: Validation of the Urinary PyV-Haufen-Test in a Proof-of-Concept Study including Uromodulin Knock-out-Mice.

Polyomavirus nephropathy (PyVN) leads to kidney transplant dysfunction and loss. Since a definitive diagnosis requires an invasive kidney biopsy, a timely diagnosis is often hampered. In this clinical dilemma the PyV-haufen-test, centering around the detection of three-dimensional PyV aggregates in the urine, might provide crucial diagnostic information. A multistep experimental design. Hypothesis: PyV-haufen form within the kidneys under high concentrations of uromodulin, a kidney specific protein; PyV-haufen are kidney-specific-disease-markers. Investigative step A showed colocalization of uromodulin with aggregated PyV (i) in ten kidneys with PyVN by immunohistochemistry, (ii) in urine samples containing PyV-haufen by electron microscopy/immunogold labeling (n = 3), and (iii) in urine samples containing PyV-haufen by immunoprecipitation assays (n = 4). Investigative step B: In in-vitro experiments only high uromodulin concentrations of ≥ 1.25 mg/mL aggregated PyV, as is expected to occur within injured nephrons. In contrast, in voided urine samples (n = 59) uromodulin concentrations were below aggregation concentrations (1.2 -19.6 µg/mL). Investigative step C: 0/11 (0%) uromodulin KO-/- mice with histologic signs of PyVN showed urinary PyV-haufen shedding compared to 10/14 (71%) WT+/+ mice. PyV-haufen form within kidneys under high uromodulin concentrations. Thus, PyV-haufen detected in the urine are specific biomarkers for intra-renal disease, i.e. definitive PyVN.

Current Clinical Concepts: Nonoperative Management of Shoulder Instability.

Non-operative management following a shoulder dislocation or subluxation remains a challenging and complex task. Accurate diagnosis of the condition, and shared decision-making regarding operative and non-operative management, as well as timing of return to play is required. This clinical concept paper introduces a shoulder instability framework that addresses these fundamental clinical dilemmas. Valid clinical prognostic tools which can predict recurrent shoulder instability are reviewed. The process of shared decision-making within the realm of shoulder instability is also presented. Finally, a framework for progressive rehabilitation that addresses deficits in motor control, strength, and endurance in scapula and shoulder musculature is presented to guide patients from an initial instability event, through to return to play.

Consensus statement on the management of hyperkalaemia-An Asia-Pacific perspective.

Hyperkalaemia is an electrolyte imbalance that impairs muscle function and myocardial excitability, and can potentially lead to fatal arrhythmias and sudden cardiac death. The prevalence of hyperkalaemia is estimated to be 6%-7% worldwide and 7%-10% in Asia. Hyperkalaemia frequently affects patients with chronic kidney disease, heart failure, and diabetes mellitus, particularly those receiving treatment with renin-angiotensin-aldosterone system (RAAS) inhibitors. Both hyperkalaemia and interruption of RAAS inhibitor therapy are associated with increased risks for cardiovascular events, hospitalisations, and death, highlighting a clinical dilemma in high-risk patients. Conventional potassium-binding resins are widely used for the treatment of hyperkalaemia; however, caveats such as the unpalatable taste and the risk of gastrointestinal side effects limit their chronic use. Recent evidence suggests that, with a rapid onset of action and improved gastrointestinal tolerability, novel oral potassium binders (e.g., patiromer and sodium zirconium cyclosilicate) are alternative treatment options for both acute and chronic hyperkalaemia. To optimise the care for patients with hyperkalaemia in the Asia-Pacific region, a multidisciplinary expert panel was convened to review published literature, share clinical experiences, and ultimately formulate 25 consensus statements, covering three clinical areas: (i) risk factors of hyperkalaemia and risk stratification in susceptible patients; (ii) prevention of hyperkalaemia for at-risk individuals; and (iii) correction of hyperkalaemia for at-risk individuals with cardiorenal disease. These statements were expected to serve as useful guidance in the management of hyperkalaemia for health care providers in the region.

How should respiratory depression and loss of airway patency be handled during initiation of palliative sedation?

Loss of airway patency has been reported during initiation of palliative sedation. In present guidelines the loss of airway patency during initiation of palliative sedation is not addressed. Airway patency can be restored by jaw thrust/chin lift or placing the patient in the recovery position. A structured ethical analysis of how respiratory depression and loss of airway patency during initiation of palliative sedation should be handled. The essence of the dilemma is whether it is appropriate to apply simple non-invasive methods to restore airway patency in order to avoid the patient's immediate death. A structured analysis based on the four principles of healthcare ethics and stakeholders' interests. Beneficence and autonomy support a decision not to regain airway patency whereas non-maleficence lends weight to a decision to restore airway patency. Whether the proportionality criterion of the principle of double effect is met depends on the features of the individual case. The ethical problem appears to be a genuine dilemma where important values and arguments point to different conclusions. Whether to restore airway patency when the airway is obstructed during initiation of palliative sedation will ultimately be based on clinical judgment taking into account both any known patient preferences and relevant clinical information. There are strong arguments favoring both options in this clinical and ethical dilemma. The fact that a clear and universal recommendation cannot be made does not imply indifference regarding what is the clinically and ethically best option for each individual patient.

Characterizing acute and postsurgical pain management in patients receiving buprenorphine or buprenorphine/naloxone

BackgroundThere is currently a clinical dilemma in treating acute pain in patients receiving long-term buprenorphine products. MethodsThis is a retrospective cohort review involving patients receiving long-term buprenorphine therapy who either underwent a surgical procedure or presented to an emergency department (ED) for acute pain between January 1, 2012 and January 1, 2022. Patients were excluded if opioids were prescribed 30 days before the index date. Chart reviews were conducted to characterize buprenorphine treatment strategies and the addition of new pain medications. Chart review revealed (1) incidence of opioid use disorder (OUD) relapse, (2) hospital re-presentation for pain or OUD, (3) fatal and non-fatal overdose, and (4) all-cause mortality and suicidality. Descriptive statistics were used to analyze results. ResultsA total of 70 of 259 screened patients met inclusion criteria. The mean (±SD) age was 50.3 ± 13 years, 92.9% male, 64.3% White, and 78.6% had an OUD diagnosis. While 84.3% presented to the ED, 15.7% underwent surgical procedures. For the primary endpoint, the total daily dose of buprenorphine or buprenorphine/naloxone from index date to discharge was continued in 90.0%, increased in 2.9%, decreased in 1.4%, and discontinued in 5.7% of cases. At discharge, 46.2% were prescribed an additional pain medication. A total of 7.1% re-presented for pain or OUD relapse, 15.7% experienced an OUD relapse, 1.4% experienced new-onset suicidality, and 1.4% experience all-cause mortality within 90 days of the index date. No fatal or non-fatal opioid overdoses were observed. ConclusionThe most commonly observed practice was continuing buprenorphine doses in patients with acute or postsurgical pain, which was effective and safe. Although further data is necessary to fully elucidate these findings, the data herein may suggest that clinicians can safely continue buprenorphine doses in the acute pain setting in patients receiving these products chronically.

Achilles' Heel of currently approved immune checkpoint inhibitors: immune related adverse events.

Immunotherapy has revolutionized the cancer treatment landscape by opening up novel avenues for intervention. As the use of immune checkpoint inhibitors (ICIs) has exponentially increased, so have immune-related adverse events (irAEs). The mechanism of irAEs may involve the direct damage caused by monoclonal antibodies and a sequence of immune responses triggered by T cell activation. Common side effects include dermatologic toxicity, endocrine toxicity, gastrointestinal toxicity, and hepatic toxicity. While relatively rare, neurotoxicity, cardiotoxicity, and pulmonary toxicity can be fatal. These toxicities pose a clinical dilemma regarding treatment discontinuation since they can result in severe complications and necessitate frequent hospitalization. Vigilant monitoring of irAEs is vital in clinical practice, and the principal therapeutic strategy entails the administration of oral or intravenous glucocorticoids (GSCs). It may be necessary to temporarily or permanently discontinue the use of ICIs in severe cases. Given that irAEs can impact multiple organs and require diverse treatment approaches, the involvement of a multidisciplinary team of experts is imperative. This review aims to comprehensively examine the pathogenesis, clinical manifestations, incidence, and treatment options for various irAEs.

Adrenal Cysts: To Operate or Not to Operate?

Adrenal cysts are uncommon and usually asymptomatic, and therefore are usually incidentally discovered adrenal lesions. They have a broad pathohistological spectrum that includes pseudocysts and endothelial (vascular), parasitic, and epithelial (mesothelial) cysts. Although most adrenal cysts are benign and hormonally non-functional lesions, some can have ambiguous imaging appearances and mimic malignant adrenal neoplasms. On the other hand, the actual malignant neoplasms could undergo cystic transformation. Additionally, immune cell infiltrations, thrombosis, or haemorrhage seen in sepsis can frequently cause adrenal cyst development, raising a question about the possible connection between severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and adrenal cystic lesions. Due to the disease’s rarity, the likelihood of malignancy, and the lack of specific guidelines, the management of adrenal cysts is always challenging especially in a young person. This review discusses the important diagnostic and the current treatment possibilities for adrenal cystic lesions. Aiming to emphasize clinical dilemmas and help clinicians navigate the challenges when encountering a patient with an adrenal cyst in everyday practice, we based our review on a practical question–answer framework centred around the case of a young woman with an incidentally discovered large adrenal cyst.

Insights into the management of Lewy body dementia: a scoping review.

Lewy body dementia (LBD) is situated at the convergence of neurodegenerative disorders, posing an intricate and diverse clinical dilemma. The accumulation of abnormal protein in the brain, namely, the Lewy body causes disturbances in typical neural functioning, leading to a range of cognitive, motor, and mental symptoms that have a substantial influence on the overall well-being and quality of life of affected individuals. There is no definitive cure for the disease; however, several nonpharmacological and pharmacological modalities have been tried with questionable efficacies. The aim of this study is to figure out the role of different interventional strategies in the disease. Donepezil, rivastigmine, memantine, and galantamine were the commonly used drugs for LBD. Together with that, levodopa, antipsychotics, armodafinil, piracetam, and traditional medications like yokukansan were also used, when indicated. Talking about nonpharmacological measures, exercise, physical therapy, multicomponent therapy, occupational therapy, psychobehavioral modification, transcranial stimulation, and deep brain stimulation have been used with variable efficacies. Talking about recent advances in the treatment of LBD, various disease-modifying therapies like ambroxol, neflamapimod, irsenontrine, nilotinib, bosutinib, vodobatinib, clenbuterol, terazosin, elayta, fosgonimeton, and anle138b are emerging out. However, there drugs are still in the different phases of clinical trials and are not commonly used in clinical practice. With the different pharmacological and nonpharmacological modalities we have for treatment of LBD, all of them offer symptomatic relief only. Being a degenerative disease, definite cure of the disease can only be possible with regenerative measures.

Role of TGF-β3 in modulating inflammatory responses and wound healing processes in ischemic ulcers in atherosclerotic patients.

Ischemic ulcers pose a multifaceted clinical dilemma for patients with atherosclerosis, frequently compounded by suboptimal wound healing mechanisms. The dual function of Transforming Growth Factor Beta 3 (TGF-β3) in ischemic ulcer healing is not fully comprehended, despite its involvement in modulating inflammatory responses and tissue regeneration. The main aim of this investigation was to clarify the functions and mechanisms by which TGF-β3 regulates inflammatory responses and promotes wound healing in patients with ischemic ulcers who have atherosclerosis. Between August 2022 and November 2023, this cross-sectional investigation was conducted on 428 patients diagnosed with atherosclerotic ischemic ulcers in Haikou, China. The expression and function of TGF-β3 were examined throughout the different stages of wound healing, including inflammation, proliferation and remodelling. In addition to documenting patient demographics and ulcer characteristics, an analysis was conducted on biopsy samples to determine the expression of TGF-β3, pro-inflammatory and anti-inflammatory markers. A subset of patients were administered topical TGF-β3 in order to evaluate its therapeutic effects. The expression pattern of TGF-β3 was found to be stage-dependent and significant, exhibiting increased levels during the phase of inflammation and reduced activity in subsequent phases. TGF-β3 levels were found to be greater in ulcers that were larger and deeper, especially in inflammatory phase. TGF-β3 applied topically induced discernible enhancement in ulcer healing parameters, such as reduction in ulcer depth and size. The therapeutic significance of TGF-β3 was emphasised due to its twofold function of regulating the inflammatory environment and facilitating the regeneration of damaged tissues. Ischemic ulcer lesion healing is significantly influenced by TGF-β3, which functions as an anti-inflammatory and pro-inflammatory mediator. Its correlation with ulcer characteristics and stages of healing suggests that it may have utility as a targeted therapeutic agent.

Interpretation of Impedance Data on High-resolution Impedance Manometry Studies-A Worldwide Survey.

Esophageal manometry is the gold standard for esophageal motility evaluation. High-resolution esophageal manometry with impedance (HRIM) allows concurrent assessment of bolus transit and manometry. Inconsistencies between concomitant impedance and manometry data pose a clinical dilemma and has not yet been addressed. We aim to assess interpretation trends of HRIM data among gastroenterologists worldwide. A cross-sectional study using an anonymous survey was conducted among gastroenterologists worldwide. Statistical analysis was performed to compare responses between providers. We received responses from 107 gastroenterologists (26 countries). Most were adult providers (69, 64.5%), and most (77, 72.0%) had > 5 years of experience. Impedance was found to be helpful by 83 (77.6%) participants, but over 30% reported inconsistencies between impedance and manometry data. With incomplete bolus clearance and normal manometry 41 (38.7%) recommended observation, 41 (38.7%) recommended 24-hours pH-impedance, and 16 (15.1%) recommended prokinetics. With abnormal manometry and complete bolus clearance, 60 (57.1%) recommended observation while 18 (17.1%) recommended 24-hours pH impedance and 15 (14.3%) recommended prokinetics. A significant difference was found between providers from different continents in treating cases with discrepancy between impedance and manometry findings (P < 0.001). No significant differences were seen in responses between adult versus pediatric providers and between providers with different years of experience. There is no consensus on interpreting HRIM data. Providers' approaches to studies with inconsistencies between manometry and impedance data vary. There is an unmet need for guidelines on interpreting impedance data in HRIM studies.

Primate Model Carrying LMNA Mutation Develops Dilated Cardiomyopathy

To solve the clinical transformation dilemma of lamin A/C (LMNA)-mutated dilated cardiomyopathy (LMD), we developed an LMNA-mutated primate model based on the similarity between the phenotype of primates and humans. We screened out patients with LMD and compared the clinical data of LMD with TTN-mutated and mutation-free dilated cardiomyopathy to obtain the unique phenotype. After establishment of the LMNA c.357-2A>G primate model, primates were continuously observed for 48months, and echocardiographic, electrophysiological, histologic, and transcriptional data were recorded. The LMD primate model was found to highly simulate the phenotype of clinical LMD. In addition, the LMD primate model shared a similar natural history with humans.

Consent-GPT: is it ethical to delegate procedural consent to conversational AI?

Obtaining informed consent from patients prior to a medical or surgical procedure is a fundamental part of safe and ethical clinical practice. Currently, it is routine for a significant part...

Hierarchically Assembled Nanofiber Scaffold Guides Long Bone Regeneration by Promoting Osteogenic/Chondrogenic Differentiation of Endogenous Mesenchymal Stem Cells.

Critical-sized segmental long bone defects represent a challenging clinical dilemma in the management of battlefield and trauma-related injuries. The residual bone marrow cavity of damaged long bones contains many bone marrow mesenchymal stem cells (BMSCs), which provide a substantial source of cells for bone repair. Thus, a three-dimensional (3D) vertically aligned nanofiber scaffold (VAS) is developed with long channels and large pore size. The pore of VAS toward the bone marrow cavity after transplantation, enables the scaffolds to recruit BMSCs from the bone marrow cavity to the defect area. In vivo, it is found that VAS can significantly shorten gap distance and promote new bone formation compared to the control and collagen groups after 4 and 8 weeks of implantation. The single-cell sequencing results discovered that the 3D nanotopography of VAS can promote BMSCs differentiation to chondrocytes and osteoblasts, and up-regulate related gene expression, resulting in enhancing the activities of bone regeneration, endochondral ossification, bone trabecula formation, bone mineralization, maturation, and remodeling. The Alcian blue and bone morphogenetic protein 2(BMP-2) immunohistochemical staining verified significant cartilage formation and bone formation in the VAS group, corresponding to the single-cell sequencing results. The study can inspire the design of next-generation scaffolds for effective long-bone regeneration is expected by the authors.

Unraveling the complex interplay between anti-tumor immune response and autoimmunity mediated by B cells and autoantibodies in the era of anti-checkpoint monoclonal antibody therapies.

The intricate relationship between anti-tumor immunity and autoimmunity is a complex yet crucial aspect of cancer biology. Tumor microenvironment often exhibits autoimmune features, a phenomenon that involves natural autoimmunity and the induction of humoral responses against self-antigens during tumorigenesis. This induction is facilitated by the orchestration of anti-tumor immunity, particularly within organized structures like tertiary lymphoid structures (TLS). Paradoxically, a significant number of cancer patients do not manifest autoimmune features during the course of their illness, with rare instances of paraneoplastic syndromes. This discrepancy can be attributed to various immune-mediated locks, including regulatory or suppressive immune cells, anergic autoreactive lymphocytes, or induction of effector cells exhaustion due to chronic stimulation. Overcoming these locks holds the risk to induce autoimmune mechanisms during cancer progression, a phenomenon notably observed with anti-immune checkpoint therapies, in contrast to more conventional treatments like chemotherapy or radiotherapy. Therefore, the challenge arises in managing immune-related adverse events (irAEs) induced by immune checkpoint inhibitors treatment, as decoupling them from the anti-tumor activity poses a significant clinical dilemma. This review summarizes recent advances in understanding the link between B-cell driven anti-tumor responses and autoimmune reactions in cancer patients, and discusses the clinical implications of this relationship.

Alliance A022101: A pragmatic randomized phase III trial evaluating total ablative therapy for patients with limited metastatic colorectal cancer—Evaluating radiation, ablation, and surgery (ERASur).

TPS236 Background: For patients with oligometastatic colorectal cancer (CRC), aggressive local therapy of isolated metastases, particularly in the liver, has been associated with long-term progression-free survival and overall survival (OS) primarily based on retrospective evidence. However, in patients with limited metastatic CRC that is deemed inoperable or those with additional disease outside of the liver or lungs, the role of local ablative therapies, including microwave ablation (MWA) and stereotactic body radiation therapy (SBRT), to render patients disease free is less clear. Further, despite the long history of treating oligometastatic CRC with local therapy, which is provider biased and not evidence based, questions remain regarding the benefit of extending the paradigm of metastatic directed therapy to patients with more extensive disease. This trial seeks to use a pragmatic multimodality approach that mirrors the current clinical dilemma. This study is designed to evaluate the safety and efficacy of adding total ablative therapy (TAT) of all sites of disease to standard of care systemic treatment in those with limited metastatic CRC. Methods: A022101 is a National Clinical Trials Network randomized phase III study planned to enroll 364 patients with newly diagnosed metastatic CRC (BRAF wild-type, microsatellite stable) with ≤4 sites of metastatic disease on baseline imaging. Liver-only metastatic disease is not permitted, and lesions must be amenable to any combination of surgical resection, MWA, and/or SBRT with SBRT required for at least one lesion. Patients receive first-line systemic therapy for 4-6 months and are then randomized 1:1, stratified by number of metastatic organ sites (1-2 vs. 3-4), timing of metastatic disease diagnosis (de novo vs. secondary), and presence of metastatic disease outside the liver and lungs in at least one site. Patients in Arm 1 will receive TAT which consists of treatment of all metastatic sites with SBRT ± MWA ± surgical resection followed by standard of care systemic therapy. Patients in Arm 2 will continue with standard of care systemic therapy alone. The primary endpoint is OS. Secondary endpoints include event-free survival, treatment-related toxicities, and local recurrence with exploratory biomarker analyses. The study needs 346 evaluable patients combined in the 2 arms to demonstrate an improvement in OS with a hazard ratio of 0.7 to provide 80% power with a one-sided alpha of 5%. The trial utilizes a group sequential design with two interim analyses (25% and 50% of events) for futility. The trial activated in January 2023 and recruitment is ongoing. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org. U10CA180820 (ECOG-ACRIN); U10CA180868 (NRG); U10CA180888 (SWOG). Clinical trial information: NCT05673148 .

Multidimensional Transcriptomics Unveils RNF34 as a Prognostic Biomarker and Potential Indicator of Chemotherapy Sensitivity in Wilms' Tumour.

Nephroblastoma, colloquially known as Wilms' tumour (WT), is the predominant malignant renal neoplasm arising in the paediatric population. Modern therapeutic approaches for WT incorporate a synergistic combination of surgical intervention, radiotherapy, and chemotherapy, which substantially ameliorate the overall patient survival rate. Despite this, the optimal sequence of chemotherapy and surgical intervention remains a matter of contention, with each strategy presenting its own strengths and weaknesses that could influence clinical decision-making. To make some headway on this clinical dilemma, we deployed a multidimensional transcriptomics integration approach by analysing bulk RNA sequencing data with 136 samples, as well as single-nucleus RNA sequencing (snRNA-seq) and paired spatial transcriptome sequencing (stRNA) data from 32 WT specimens. Our findings identified a distinct elevation of RNF34 expression within WT samples, which correlated with unfavourable prognostic outcomes. Leveraging the Genomics of Drug Sensitivity in Cancer (GDSC), we simultaneously revealed that patients with high expression of RNF34 have higher sensitivity to commonly used chemotherapy drugs for WT. Furthermore, our analysis of snRNA and stRNA data unveiled a reduced proportion of RNF34 expression in neoplastic cells after chemotherapy. Moreover, stRNA data delineated a significant association between a higher proportion of RNF34 expression in cancer cells and adverse features such as anaplastic histology and tumour recurrence. Intriguingly, we also observed a close association between elevated RNF34 expression and a characteristic exhausted tumour immune microenvironment. Collectively, our findings underscore the pivotal role of RNF34 in the prognostic prediction potential and treatment sensitivity of WT. This comprehensive analysis can potentially inform and refine clinical decision-making for WT patients and guide future studies towards the development of optimized, rational therapeutic strategies.

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.