OBJECTIVE: Can certain characteristics identify as solvable some undiagnosed patients who seek extensive evaluation and thorough record review, like by the Undiagnosed Diseases Network (UDN)?
METHODS: The UDN is a national research resource to solve medical mysteries through team science. Applicants provide informed consent to access to their medical records. After review, expert panels assess if applicants meet inclusion and exclusion criteria to select participants. When not accepting applicants, UDN experts may offer suggestions for diagnostic efforts. Using minimal information from initial applications, we compare features in applicants not accepted with those accepted and either solved or still not solved by the UDN. The diagnostic suggestions offered to non-accepted applicants and their clinicians were tallied.
RESULTS: Non-accepted applicants were more often female, older at first symptoms and application, and longer in review than accepted applicants. The accepted and successfully diagnosed applicants were younger in ages, shorter in review time, more often non-white, of Hispanic ethnicity, and presenting with nervous system features. Half of non-accepted applicants were given suggestions for further local diagnostic evaluation. A few seemed to have two major diagnoses or a provocative environmental exposure history.
CONCLUSIONS: Comprehensive UDN record review generates possibly helpful advice.

Background The clinical diagnosis of acute appendicitis (AA) can be challenging. This study aimed to evaluate the significance of this diagnosis amidst technological progress. It compared clinical diagnosis to radiology-aided diagnostic outcomes and negative appendicectomy rates (NAR). Methodology This study conducted a single-center retrospective and prospective cohort observational study on all adult patients presenting with suspected AA in 2018 at a major tertiary teaching hospital in Perth, Western Australia. Key demographics, clinicopathological, radiology, and operative reports were reviewed. Data were analyzed using SPSS v.27. Results Of 418 patients with suspected AA, 234 (56%) were in the retrospective group. The median age was 35 (IQR=26), and 224 (54%) were female. The overall NAR was 18.6% (95% CI (14.8-22.4)) and 20.8% for clinical diagnosis. Notably, the NAR for ultrasound (USS)-reported AA (false positive) was 17.6% (95% CI (10.6-27.4)). Three-quarters of the patients, 298 (71.3%), had radiological imaging. The most common modality was CT 176 (59.1%), and 33 (7.9%) had both CT and USS imaging performed. Compared with final histopathology, no significant difference was found in the accuracy of clinically diagnosed and USS-diagnosed cases, with rates of 83.5% and 82.5%, respectively (p=0.230). CT had the best positive predictive value at 82.1%. Single-modality imaging did not cause a significant surgical delay (p=0.914), but multi-modal imaging showed a non-significant trend toward delay (p=0.065). When surgeons assessed an appendix as normal, 54 (12.9%), the histopathological assessment revealed pathology in 28 (51.9%). The inter-observer agreement was only fair to moderate, Kappa=0.46 (95% CI (0.33-0.58); p<0.001). The intraoperative identification of a normal appendix inversely correlated to the grade of the primary surgeon, which was likely related to the number of surgical personnel in the theater (p<0.001). Conclusion This study showed that clinical diagnosis matches the diagnostic accuracy of imaging technologies. Utilizing diagnostic imaging methods promptly and appropriately did not lead to considerable delays in surgery. Surgeons\' capability to diagnose appendicitis during surgery is moderately accurate. Most patients underwent imaging, with CT scans being the most common. Moving forward, practitioners must minimize excessive reliance on imaging techniques as this can be resource-intensive, especially in developing countries. Future clinical practice should balance embracing technological advancements and preserving essential clinical diagnostic expertise, for medicine is both a science and an art.

The proposed expert opinion aimed to address the current knowledge on conceptual, clinical, and therapeutic aspects of diabetic peripheral neuropathy (DPN) and to provide a guidance document to assist clinicians for the best practice in DPN care. The participating experts consider the suspicion of the disease by clinicians as a key factor in early recognition and diagnosis, emphasizing an improved awareness of the disease by the first-admission or referring physicians. The proposed \"screening and diagnostic\" algorithm involves the consideration of DPN in a patient with prediabetes or diabetes who presents with neuropathic symptoms and/or signs of neuropathy in the presence of DPN risk factors, with careful consideration of laboratory testing to rule out other causes of distal symmetric peripheral neuropathy and referral for a detailed neurological work-up for a confirmative test of either small or large nerve fiber dysfunction in atypical cases. Although, the first-line interventions for DPN are currently represented by optimized glycemic control (mainly for type 1 diabetes) and multifactorial intervention (mainly for type 2 diabetes), there is a need for individualized pathogenesis-directed treatment approaches for DPN. Alpha-lipoic acid (ALA) seems to be an important first-line pathogenesis-directed agent, given that it is a direct and indirect antioxidant that works with a strategy targeted directly against reactive oxygen species and indirectly in favor of endogenous antioxidant capacity for improving DPN conditions. There is still a gap in existing research in the field, necessitating well-designed, robust, multicenter clinical trials with sensitive endpoints and standardized protocols to facilitate the diagnosis of DPN via a simple and effective algorithm and to track progression of disease and treatment response. Identification of biomarkers/predictors that would allow an individualized approach from a potentially disease-modifying perspective may provide opportunities for novel treatments that would be efficacious in early stages of DPN, and may modify the natural course of the disease. This expert opinion document is expected to increase awareness among physicians about conceptual, clinical, and therapeutic aspects of DPN and to assist them in timely recognition of DPN and translating this information into their clinical practice for best practice in the management of patients with DPN.

Abnormal aggregation and accumulation of pathological amyloid proteins such as amyloid-β, Tau, and α-synuclein play key pathological roles and serve as histological hallmarks in different neurodegenerative diseases (NDs) such as Alzheimer\'s disease (AD) and Parkinson\'s disease (PD). In addition, various post-translational modifications (PTMs) have been identified on pathological amyloid proteins and are subjected to change during disease progression. Given the central role of amyloid proteins in NDs, tremendous efforts have been made to develop amyloid-targeting strategies for clinical diagnosis and molecular classification of NDs. In this review, we summarize two major strategies for targeting amyloid aggregates, with a focus on the trials in AD diagnosis. The first strategy is a positron emission tomography (PET) scan of protein aggregation in the brain. We mainly focus on introducing the development of small-molecule PET tracers for specifically recognizing pathological amyloid fibrils. The second strategy is the detection of PTM biomarkers on amyloid proteins in cerebrospinal fluid and plasma. We discuss the pathological roles of different PTMs in diseases and how we can use the PTM profile of amyloid proteins for clinical diagnosis. Finally, we point out the potential technical challenges of these two strategies, and outline other potential strategies, as well as a combination of multiple strategies, for molecular diagnosis of NDs.

Purpose of Review: This review aims to provide a comprehensive overview of the diagnosis of brain death/death by neurologic criteria (BD/DNC) by emphasizing the clinical criteria established by the American Academy of Neurology (AAN) in light of their updated guidelines released in 2023. In this review, we will focus on the current implementation of ancillary tests including the catheter cerebral angiogram, nuclear scintigraphy, and transcranial Doppler, which provide support in diagnoses when clinical examination and apnea tests are inconclusive. Finally, we will also provide examples to discuss the implementation of certain imaging studies in the context of diagnosing BD/DNC. Recent Findings: Recent developments in the field of neurology have emphasized the importance of clinical criteria for diagnosing BD/DNC, with the AAN providing clear updated guidelines that include coma, apnea, and the absence of brainstem reflexes. Current ancillary tests, including the catheter cerebral angiogram, nuclear scintigraphy, and transcranial Doppler play a crucial role in confirming BD/DNC when the clinical assessment is limited. The role of commonly used imaging studies including computed tomography and magnetic resonance angiographies of the brain as well as CT/MR perfusion studies will also be discussed in the context of these new guidelines. Summary: BD/DNC represents the permanent cessation of brain functions, including the brainstem. This review article provides the historical context, clinical criteria, and pathophysiology that goes into making this diagnosis. Additionally, it explores the various ancillary tests and selected imaging studies that are currently used to diagnose BD/DNC under the newly updated AAN guidelines. Understanding the evolution of how to effectively use these diagnostic tools is crucial for healthcare professionals who encounter these BD/DNC cases in their practice.

Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized by the accumulation of 4R-tau protein aggregates in various brain regions. PSP leads to neuronal loss, gliosis, and tau-positive inclusions, such as neurofibrillary tangles, tufted astrocytes, and coiled bodies. These pathological changes mainly affect the brainstem and the basal ganglia, resulting in distinctive MRI features, such as the hummingbird and morning glory signs. PSP shows clinical heterogeneity and presents as different phenotypes, the most classical of which is Richardson\'s syndrome (PSP-RS). The region of involvement and the mode of atrophy spread can further distinguish subtypes of PSP. PSP patients can experience various signs and symptoms, such as postural instability, supranuclear ophthalmoplegia, low amplitude fast finger tapping, and irregular sleep patterns. The most common symptoms of PSP are postural instability, falls, vertical gaze palsy, bradykinesia, and cognitive impairment. These features often overlap with those of Parkinson\'s disease (PD) and other Parkinsonian syndromes, making the diagnosis challenging. PSP is an essential clinical topic to research because it is a devastating and incurable disease. However, there are still many gaps in knowledge about its pathophysiology, diagnosis, and treatment. Several clinical trials are underway to test noveltherapies that target tau in various ways, such as modulating its post-translational modifications, stabilizing its interaction with microtubules, or enhancing its clearance by immunotherapy. These approaches may offer new hope for slowing down the progression of PSP. In this review, we aim to provide an overview of the current knowledge on PSP, from its pathogenesis to its management. We also discuss the latest advances and future directions in PSP research.

Pancreatic masses are commonly encountered in clinical practice, with concern for the possibility of cancer. Tissue sampling or outright surgical resection may be offered in this setting. However, surgery has been unnecessarily performed in patients with pancreatic masses that proved to be benign. Less invasive options for pancreatic masses that may be benign like tuberculosis should thus be explored. Three adult Filipino patients less than 60 years old presented with symptomatic pancreatic masses suspected of cancer on abdominal imaging studies. Two were smokers without a history of prior tuberculosis. Without any tissue sampling, anti-tuberculosis treatment was eventually given to all three patients due to concomitant diagnoses of extrapancreatic tuberculosis. Endoscopic ultrasound documentation of post-treatment resolution of pancreatic masses was noted in all cases. In endemic regions, although clinical diagnosis of tuberculosis may be possible for pancreatic masses, empiric treatment should still be a last-line option in cases where tissue sampling cannot be done.

Infertility represents a significant global health challenge impacting millions of couples worldwide. Approximately half of all infertile couples exhibit compromised semen quality, indicative of diminished male fertility. While the diagnosis of male infertility traditionally relies on semen analysis, its limitations in providing a comprehensive assessment of male reproductive health have spurred efforts to identify novel biomarkers. Seminal plasma, a complex fluid containing proteins, lipids, and metabolites, has emerged as a rich source of such indicators. Reproduction depends heavily on seminal plasma, the primary transporter of chemicals from male reproductive glands. It provides a non-invasive sample for urogenital diagnostics and has demonstrated potential in the identification of biomarkers linked to illnesses of the male reproductive system. The abundance of seminal proteins has enabled a deeper understanding of their biological functions, origins, and differential expression in various conditions associated with male infertility, including azoospermia, asthenozoospermia, oligozoospermia, teratozoospermia, among others. The true prevalence of male infertility is understated due to the limitations of the current diagnostic techniques. This review critically evaluates the current landscape of seminal plasma biomarkers and their utility in assessing male infertility. Βy bridging the gap between research and clinical practice, the integrative assessment of seminal plasma biomarkers offers a multimodal approach to comprehensively evaluate male infertility.

NUT Carcinoma（NC） is a rare malignant tumor of unknown origin, which is highly aggressive. It is characterized by chromosome rearrangement accompanied by NUTM1 gene. The pathological manifestations were sudden and focal squamous in poorly differentiated or undifferentiated carcinoma. NUTM1gene rearrangement can be used to diagnose NC. The prognosis of NUT cancer is poor. Clinically, there is no established treatment plan. treatment options mainly comprise surgery, radiotherapy and chemotherapy. A 74-year-old patient with NC of the nasal cavity and sinuses was reported. Her clinical presentation was right nasal congestion with facial swelling. Sinus CT and MRI showed soft tissue density in the right nasal cavity and maxillary sinus with bone destruction. After admission, the patient underwent nasal endoscopic biopsy, and the postoperative pathological FISH staining showed BRD4/NUT fusion t（15, 19）. The tumor was significantly reduced after two courses of sequential chemoradiotherapy. Two months later, the patient underwent a partial maxillary resection due to the rapid regrowth of sinusoidal mass, invading the hard palate. The patient died 2 months after surgery due to multiple organ failure resulted from tumor metastasis, with a survival time of 11 months. The clinical characteristics, diagnosis and treatment of this case were reported and related literature was reviewed.
摘要: NUT癌（NUT Carcinoma）是一种罕见的起源不明的具有高度侵袭性的恶性肿瘤，其以伴有NUTM1基因染色体重排为主要特点，病理表现为具有突然和局灶性鳞状分化低分化或未分化癌，FISH检测见NUTM1基因重排可明确诊断，NUT癌预后较差，临床上并未明确治疗方案，治疗方式多为手术、放疗及化疗。本文报道1例74岁鼻腔鼻窦NUT癌患者，临床表现为右侧鼻塞伴面部肿胀，鼻窦CT及MRI示右侧鼻腔及上颌窦软组织密度影伴骨质破坏，入院后行鼻窦肿物活检术，术后病理FISH染色结果示BRD4/NUT融合t（15，19），予序贯同步放化疗2个疗程后肿物显著减小，2个月后肿物再次迅速增长侵及硬腭影响进食，行上颌骨部分切除术，术后2个月患者因肿瘤转移累及全身脏器衰竭死亡，生存期11个月，现对本病例的临床特征和诊疗经过进行报告及相关文献复习。.

BACKGROUND: Focal liver lesions (FLLs) are a common form of liver disease, and identifying accurate pathological types is required to guide treatment and evaluate prognosis.
OBJECTIVE: To compare and analyze the application effect of contrast-enhanced ultrasound (CEUS) and conventional ultrasound (US) in the clinical diagnosis of focal liver lesions.
METHODS: A retrospective analysis was performed on 682 patients with space-occupying liver lesions admitted to our hospital between December 2015 and August 2021. Of these, 280 underwent CEUS-guided biopsies and 402 underwent conventional US biopsies, with the results of each biopsy subsequently compared between the two groups. The success rate and accuracy of the biopsies and their relationship with different pathological features were also analyzed.
RESULTS: The success rate, sensitivity, diagnostic accuracy, positive predictive value, and negative predictive value of the CEUS group were significantly higher than those of the US group (P < 0.05). Lesion size accuracy in the CEUS group was significantly higher than that in the US group (89.29% vs. 40.55%; P < 0.05). Lesion type accuracy in the CEUS group was significantly higher than that in the US group (86.49% vs. 43.59%), and the difference between the two groups was statistically significant (P < 0.05). The logistic regression analysis indicated that malignant lesions, lesions ≥5 cm, and lesions ≤1 cm were independent factors affecting the success rate of the puncture procedure (P < 0.05).
CONCLUSIONS: The sensitivity, specificity, and diagnostic accuracy of lesion size and type in the CEUS group were higher than those in the US group.