Introduction: Primary central nervous system vasculitis (PCNSV) is a rare, heterogenous and polymorphic disorder affecting the blood vessels of the CNS. It is a diagnosis of exclusion with no disease specific clinical features, serological or imaging findings. Historically, the presence of hemorrhages was considered rare in PCNSV. However, with the advent of susceptibility weighted imaging (SWI) sequences of MRI, the presence of microhemorrhages has been found to be common despite macrohemorrhages being uncommon. Hypothesis: The presence of microhemorrhages in the cerebellar tonsils on SWI sequences of MRI brain in a patient with an unexplained neurological deficit are indicative of PCNSV. Methods: We retrospectively evaluated our biopsy proven PCNSV patients and patients with hypertensive cerebellar hemorrhage who underwent an MRI (1.5T or 3T) between 2020-2024. All clinic-radiological and histopathological details of these patients were entered into a predesigned proforma. A senior neuroradiologist evaluated the MRI scans for the presence of tonsillar microhemorrhages. Results: Twenty-nine patients of PCNSV (15- granulomatous vasculitis; 14 – lymphocytic vasculitis) and 44 patients with hypertensive cerebellar ICH fulfilled the study criteria. The clinical characteristics of the patients are mentioned in table 1. All PCNSV patients (100%) were found to have tonsillar microhemorrhages along with supratentorial and infratentorial lesions (T2/ FLAIR/ SWI) and 27/29 (93.1%) revealed punctate or linear enhancement of these tonsillar lesions (Figure 1). There was no difference in the microhemorrhage pattern between granulomatous and lymphocytic vasculitis subtypes of PCNSV. In comparison, only 9/44 (20.4%) patients with cerebellar hemorrhage had tonsillar microhemorrhages. Amongst them, all of them had pontine microhemorrhages while 6/9 (66.7%) and 5/9 (55.5%) had concomitant midbrain and medullary microhemorrhages respectively. Most patients with concomitant pontine microhemorrhages had no cerebellar tonsil involvement. Conclusions: Cerebellar tonsillar microhemorrhages in PCNSV may be a marker of its intrinsic microangiopathy. The presence of cerebellar tonsillar microhemorrhages in patients with an unexplained neurological deficit may be an imaging marker for diagnosing PCNSV.

Fasciitis-like primary breast pyoderma gangrenosum: A rare case report

Limited availability of live CBA for AQP4-IgG testing and its consequences for the diagnosis and treatment of NMOSD in Latin American countries.

Immune gene correlation networks differentiate both chronic lung allograft dysfunction and survival.

Drug treatment of hydatid cysts is usually carried out using benzimidazole compounds such as albendazole and mebendazole. However, limited efficacy, the need for long-term use, and side effects such as liver damage and gastrointestinal problems have made the use of these drugs challenging. The present study aimed to evaluate the antiparasitic effects of Baicalein (BC) on Echinococcus granulosus protoscoleces (PTS) and its inhibitory effects on the expression level of antioxidant genes. The antiparasitic effects of BC on PTS was evaluated using eosin exclusion test. The effects of BC on the expression level of antioxidant genes glutathione glutathione S-transferase (GST), thioredoxin (Trx), and thioredoxin peroxidase (TPx) in PTS was performed using Real-time PCR. For cytotoxicological tests, two human cell lines including normal liver cells (THLE-2) and liver cancer cells (HepG2) were used for MTT assay. The findings demonstrated that both the lethality and subsequent mortality of E. granulosus PTS increased significantly with rising concentrations of BC and prolonged exposure time (p < 0.001). Among the concentrations evaluated, BC exhibited the most pronounced antiparasitic activity against PTS at 64 and 128 µM/mL, achieving complete protoscolicidal effects after 30 and 20min, respectively. Furthermore, the calculated CC50 values were 161.3 µM/mL for THLE-2 cells and 75.6 µM/mL for HepG2 cells. Treatment of PTS with the BC dose-dependently reduced the relative expression level of the GST, TRx, and TPx genes (P < 0.001); while significantly increased the reactive oxygen species in the PTS. The results of the study showed that BC had a significant protoscolicicidal effect on E. granulosus PTS, which increased parasite death by reducing the expression of antioxidant genes, indicating a direct effect on their defense system and metabolic pathways. Also, BC had a favorable selective effect on HepG2 cancer cells and showed less toxicity than normal THLE-2 cells, which confirms its high selectivity index. Future studies can focus on developing novel drug delivery formulations and investigating signaling pathways related to oxidative stress and apoptosis in parasites to optimize the antiparasitic and anticancer effects of BC.

Background: Physical activity is important for prevention of some of the most common diseases worldwide: cardiovascular disease, type 2 diabetes mellitus, and certain types of cancers. However, extremely strenuous exercise performed over a prolonged period can lead to Overtraining Syndrome (OTS), especially in athletes competing at elite levels. This is characterized by psychological, neuroendocrine and immunological disturbance, and a prolonged decrease in exercise tolerability. Although many theories have emerged about the etiology of this condition, the pathophysiology is still unknown. That makes it difficult to diagnose OTS, as the resulting symptoms, including fatigue and diminished exercise performance, are common in athletes and largely nonspecific. Aim: The goal of this study was to synthesize current evidence on possible hormonal biomarkers that may assist in the diagnosis of OTS. Materials and methods: The search was conducted via PubMed, Science Direct, NCBI, and Google Scholar databases for articles with a focus on human studies. The keywords included “overtraining syndrome”, “OTS”, “overreaching syndrome”, “hormonal biomarkers”, “testosterone cortisol ratio”, “testosterone estradiol ratio”, “hypothalamic pituitary axis”, “hypothalamic dysfunction”, “EROS-HPA axis”. Results: Certain studies suggest that basal and dynamic hormone measurements may aid in the diagnosis of OTS. The Cadegiani and Kater EROS studies (2017-2020) [9, 10, 11] have proposed diagnostic tools composed of clinical and biological markers that, in the tested cohort, showed 100% diagnostic accuracy in distinguishing between OTS and non-OTS athletes. However, without an established pathophysiological pathway, many researchers remain sceptical. Conclusions: There is a definite need for validation of proposed diagnostic tools and reaching a consensus on the diagnostic process of OTS, instead of having it be a diagnosis of exclusion.

Adverse Childhood Experiences (ACEs) and Positive Childhood Experiences (PCEs) are each independently associated with a range of adult outcomes, including mental health, substance use, and criminal justice involvement. However, few studies have examined how the balance between these experiences influences outcomes. This study explores the predictive utility of a PCE:ACE ratio. Unlike previous measures of resiliency and risk protection scales that treat risk and protective factors as parallel dimensions, the ratio is population-level heuristic intended to capture the relative balance of positive versus adverse experiences using a single relational metric. Using data from a representative sample of 1,203 adults in Northern Ireland, participants completed validated measures of 13 ACEs and 10 positive childhood experiences (PCEs) A weighted PCE:ACE ratio was calculated, and participants were categorised into high, moderate, or low ratio groups. Findings showed that a higher ratio was significantly associated with reduced odds of arrest, incarceration, school exclusion, substance use, and mental health diagnosis, even after adjusting for age, gender, and deprivation. Those in the low-ratio group had the highest rates of adverse outcomes. While the ratio offers an intuitive and accessible framework for understanding developmental balance, limitations include the potential for oversimplification of distinct ACE-PCE profiles. These findings support the feasibility of a ratio-based approach that standardises balance rather than the independent accumulation of risks and strengths, and suggests that a stronger balance of protective experiences may buffer the impact of adversity. Further research is needed to explore threshold effects and interaction dynamics. However, the ratio provides a useful metric and sound basis for capturing population health and the extent to which public investment is tipped in favour of positive or less positive outcomes.

Bone pain is a frequent yet challenging complaint encountered in paediatric practice. While most cases are benign and attributable to growing pains, a significant minority may represent serious underlying conditions such as infection, inflammatory disease, metabolic disorders, or malignancy. Growing pains remain a diagnosis of exclusion, and inappropriate reassurance without adequate clinical assessment may lead to delayed diagnosis of life-threatening disorders. Conversely, indiscriminate investigations contribute to parental anxiety and unnecessary healthcare expenditure. This review provides a comprehensive and evidence-based overview of growing pains and bone pain in children, emphasizing epidemiology, pathophysiology, clinical features, red-flag signs, differential diagnoses, rational investigative strategies, and management principles. The aim is to guide paediatricians toward a structured, safe, and cost-effective approach while ensuring early recognition of pathological causes.

Arthrofibrosis after total knee arthroplasty (TKA) is the result of excessive scar formation because of the inflammatory insult of surgery. This formation can lead to significant loss of range of motion, pain, and functional deficits requiring further treatment. Although much has been researched on arthrofibrosis, it continues to lack definitive diagnostic testing. This has led to an array of approaches and treatments to relieve patients of this complication. In response to the inflammatory insult caused by TKA, arthrofibrosis occurs because of an overactivation and proliferation of myofibroblasts. This leads to an abundant deposition of type I collagen and scar tissue formation. This general cascade has been found to be associated with multiple signaling pathways involving primarily transforming growth factor-beta. Additionally, there is a multifactorial component of risk factors and comorbidities, which contribute to the formation of arthrofibrosis. Arthrofibrosis is diagnosed as both a clinical diagnosis and a diagnosis of exclusion. Using the patient's history, clinical examination, and diagnostic testing to rule out other etiologies, one can obtain the diagnosis of arthrofibrosis. While stiffness is an umbrella term that is commonly used interchangeably with arthrofibrosis, it is imperative to use the diagnostic testing to systematically rule out other causes of stiffness. There is no definitive imaging, biopsy, or biomarker test specific for arthrofibrosis currently, which makes obtaining a definitive diagnosis difficult. Nonoperative and operative treatment options are available for the treatment of arthrofibrosis. Most conservative approaches begin with physical therapy, appropriate pain management, and oral anti-inflammatory medication. Treatment options rise in invasiveness with manipulation under anesthesia, arthroscopic lysis of adhesions, open lysis of adhesions, and ultimately revision TKA. This review will focus on the role of manipulation under anesthesia in the setting of arthrofibrosis.

More than just shoulder pain - uncovering neuralgic amyotrophy Neuralgic amyotrophy (NA), also known as Parsonage-Turner syndrome, is a collective term for a group of (multi)focal peripheral nerve lesions caused by an immune-mediated inflammatory process. The classic presentation involves sudden, severe shoulder pain, rapidly followed by paresis and muscle atrophy in the upper limb. However, the clinical spectrum is highly variable. Improved understanding of the disease may help clinicians to consider NA from the outset in the differential diagnosis. This would allow for a more targeted use of technical investigations, preventing NA from remaining merely a diagnosis of exclusion, as is often the case now. NA is characterized by inflammation-induced (multi)focal axonal nerve injury, potentially accompanied by focal neural deformities, so-called ‘hourglass constrictions’. This inflammatory process is frequently preceded by physical or immunological stressors. The axonal damage, including its sometimes characteristic distribution, can be demonstrated through targeted electromyographic studies. Advanced imaging modalities may further help in identifying focal neural deformities. An early onset and positive family history should raise suspicion for a hereditary form, which is clinically relevant due to its higher recurrence risk. Long-term spontaneous recovery is generally favorable, making functional rehabilitation and pain management the primary therapeutic goals. Although various other treatment strategies have been reported, most are supported only by anecdotal evidence. This article presents two clinical cases to underscore the underdiagnosed nature of NA and highlight its diverse clinical manifestations.

Cryptogenic cirrhosis is a diagnosis of exclusion with heterogeneous and often overlapping etiologies, making systematic investigation challenging in routine clinical practice. We propose a unified statistical and epidemiological framework that integrates classical study designs (case–control and cohort with survival analysis), evidence synthesis (meta-analysis), exploratory genetics (genome-wide association studies), and modern machine learning to examine potential contributors such as long-term analgesic exposure and metabolic comorbidities. A motivating clinical vignette is used solely to illustrate the clinical context in which such analyses may arise. All quantitative results presented in this study are derived from fully simulated datasets constructed to demonstrate the behavior and interpretability of the proposed workflow rather than to establish real-world causal effects. Within these illustrative simulations, analgesic exposure is specified to act as a risk factor, leading to elevated association measures in case–control analyses, separation of survival curves in cohort analyses, and high feature importance in predictive models, while exploratory GWAS simulations yield no genome-wide significant signals, underscoring the need for adequately powered real studies. The proposed workflow is transparent, reproducible, and deployable in prospective registries, with the primary goal of generating testable etiologic hypotheses rather than confirming definitive clinical associations.

Introduction Pyoderma gangrenosum (PG), often considered a diagnosis of exclusion, can be challenging to diagnose. A new deep convolutional neural network (CNN) outperformed dermatologists (sensitivity 97% vs. 73%, respectively) in diagnosing PG versus venous ulcer (VU) using 422 clinical wound photographs in a training setting. Our purpose was to test its performance using real-world photographs. Methods Clinical photos from 58 cases of suspected PG at our institution were obtained retrospectively, with 51 having confirmed PG diagnoses by board-certified dermatologists. The CNN predicted the probability of PG for each photo using 50% as the decision threshold. For patients with more than one photo, probabilities were averaged to generate one per patient. Results The CNN correctly identified 31 of 51 PG cases and 5 of 7 non-PG cases, yielding a sensitivity and specificity of 60.8% and 71.4%, respectively. Discussion Delayed or missed diagnoses of PG can lead to poor patient outcomes due to distinct treatment pathways for PG versus other causes of ulceration. Therefore, a reliable and prompt diagnostic tool is needed. Based on data from our prior retrospective study evaluating PG rating tools, the CNN outperforms the Delphi and Su methods but not PARACELSUS (sensitivities 12%, 25%, and 100%, respectively). Limitations of this study include a lack of standardized image quality, and the CNN’s ability to distinguish only between PG and VU. The CNN may hold value in validating practitioners’ diagnoses but further refinement and training using diverse, real-world datasets are necessary to enhance its diagnostic, clinical utility.

Pyoderma gangrenosum (PG) is a rare skin condition characterized by chronic, painful ulcerations. It is considered a diagnosis of exclusion, often resulting in diagnostic delay. Histological results in PG, even when biopsied despite a risk of pathergy, are nonspecific. To examine retrospectively the utility of biopsies in the diagnosis of 58 patients treated for PG. Medical records were reviewed to compare biopsy results versus the efficacy of diagnostic rating systems (Delphi, Su, PARACELSUS). Among 58 patients, 26 (45%) underwent biopsies, with only 10 (38%) contributing to a PG diagnosis. As a single-centre and retrospective study, documentation style and sample size limit generalizability. Given risk of pathergy, nonspecific histopathological findings and low sensitivity, in our opinion, based on this small sample size, biopsies have limited diagnostic value for PG.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic inflammatory condition characterized by bladder pain and lower urinary tract symptoms. As a diagnosis of exclusion, IC/BPS shares overlapping features with bladder tumors, which may lead to misdiagnosis or delayed diagnosis. Clinical evidence regarding the relationship between IC/BPS and bladder tumors remains limited. In this single-center retrospective study, 863 patients initially diagnosed with IC/BPS who underwent cystoscopic hydrodistension with random multi-site bladder biopsies between January 2015 and June 2025 were reviewed. Twenty-five patients who were subsequently diagnosed with bladder cancer or nephrogenic adenoma based on initial or repeated biopsies were included. Clinical, imaging, cystoscopic, pathological, treatment, and follow-up data were analyzed. The cohort included 15 males and 10 females, with a median age of 56years. The most common initial symptoms were urinary frequency, urgency, and dysuria. Hematuria developed in eight patients during disease progression. Imaging frequently showed bladder wall thickening without definite mass lesions. Cystoscopic findings were heterogeneous, ranging from diffuse inflammatory changes to tumor-like lesions. Fourteen patients were diagnosed at initial biopsy, while others were diagnosed after repeated biopsies. Twelve patients underwent radical cystectomy. During a median follow-up of 48months, recurrence and metastasis rates were low. Oncologic outcomes should be interpreted cautiously because follow-up was incomplete and heterogeneous. A subset of patients initially diagnosed with IC/BPS may harbor or develop bladder tumors. Close surveillance and repeated cystoscopic multi-site biopsies are recommended, particularly in high-risk patients such as males and those with hematuria, to improve early detection and outcomes.

When did "I don't know" become a diagnosis? A conceptual review on diagnoses of exclusion.

PurposeCyclic vomiting syndrome (CVS), is a diagnosis of exclusion within the disorders of the gut-brain interaction, consisting of recurrent vomiting episodes unexplained by another medical condition or its triggers. When a patient presents with a recurrent vomiting episode, a broad differential is considered. The aim of this systematic review is to provide a hierarchal differential diagnostic approach to children with known or possible recurrent vomiting.MethodsThis study followed the Preferred Reporting Items in Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, EMBASE and Scopus databases were searched using the following criteria: (1) Subjects aged 18 or under with vomiting spells classified as cyclic vomiting syndrome according to Rome IV criteria or equivalents for older publications and; (2) experimental, observational, or cross-sectional studies of 10 or more patients. A comprehensive literature search was performed with specific search criteria that included the diagnosis of cyclic vomiting syndrome. The results were analyzed using a Bayesian methodology to determine the rate estimates and 95% credible intervals for each disease.ResultsSeventeen studies (1,375 patients and 1,415 events) were recovered. 80.4% of the differential included: psychological stress (26.2%; 95% credible intervals [CredI], 24–28.5), infection (22%; 95% CredI, 19.9–24.2), motion sickness (19.3%; 95% CredI, 17.3–21.4) and migraine (12.9%; 95% CredI, 11.2–14.7). Surgical causes (4.8%; 95% CredI, 3.6–6.2) and mitochondrial diseases (0.4%; 95% CredI, 0.1–0.8) were uncommon.ConclusionMany triggers and diagnoses are associated with recurrent vomiting and CVS: psychological stress, infection, motion sickness, and migraine accounted for most cases. Serious surgical or metabolic diseases were less common.

Tolosa–Hunt syndrome (THS) is caused by idiopathic granulomatous inflammation of the cavernous sinus, superior orbital fissure, or orbit, presenting with painful ophthalmoplegia due to palsy of one or more ocular motor nerves. It may be associated with autoimmune and systemic inflammatory conditions such as lupus, sarcoidosis, and Wegener’s granulomatosis. The diagnosis is based on the clinical presentation, neuroimaging with a magnetic resonance imaging of the brain with contrast, which shows cavernous sinus thickening, isointense tissue on T1, hypo- or isointense on T2, contrast enhancement, and lateral convexity of the cavernous sinus, with possible extension into the orbital apex; and a rapid response to steroids. As a diagnosis of exclusion, blood and cerebrospinal fluid studies are performed to rule out other causes of painful ophthalmoplegia when THS is suspected. We are reporting a challenging and intriguing case of THS successfully managed with a multidisciplinary approach.

A 79-year-old female presented with progressive dyspnea. A bone marrow biopsy revealed hypoplastic marrow with abnormal lymphoid cells. A genetic analysis revealed a MYD88 p.V204F mutation, supporting the diagnosis of lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia (LPL/WM). Additional evaluations established a concomitant diagnosis of aplastic anemia (AA). Treatment prioritized AA with cyclosporine and eltrombopag. Subsequently, the LPL/WM was treated with rituximab monotherapy. This sequential treatment resulted in a symptomatic improvement. Although AA is a diagnosis of exclusion, its coexistence with lymphoma is rare. This case highlights the diagnostic and therapeutic complexity of AA and LPL/WM overlap and suggests that prioritizing the treatment of AA may lead to better outcomes.

Routinely collected administrative data provide insights into health care utilization and outcomes but lack detailed clinical information, such as the specific site and intent of radiation therapy (RT). This study aimed to validate claims-based algorithms to accurately identify thoracic RT (TRT) and curative-intent RT in administrative databases. Patients at our institution with lung cancer and any RT Current Procedural Terminology (CPT) code from October 2015 to January 2024 were analyzed. RT claims were organized by treatment episode, and RT details were manually abstracted from the electronic health record to classify episodes as TRT or non-TRT and curative or noncurative. A priori algorithms were defined as the presence of respiratory motion management codes, >14 treatment codes (except for stereotactic body RT [SBRT] courses), with or without exclusive thoracic malignancy diagnosis codes. Positive predictive value (PPV) was computed for each episode, stratified by modality (three-dimensional conformal RT [3DCRT], intensity-modulated RT [IMRT], and SBRT). Algorithms were considered acceptable if the lower bound of the Clopper-Pearson 95% CI for PPV exceeded 70%. A total of 3,846 RT episodes were analyzed. The primary a priori TRT algorithm achieved a PPV of 97% (95% CI, 96 to 98) for IMRT, 99% (95% CI, 97 to 99) for SBRT, and 87% (95% CI, 81 to 92) for 3DCRT. Performance declined when exclusive thoracic malignancy diagnosis codes were excluded. For curative-intent RT, PPVs were 87% for IMRT, 90% for SBRT, and 55% for 3DCRT. Clinically informed algorithms can accurately identify TRT in claims data, achieving high PPVs particularly for IMRT and SBRT courses. These algorithms can be applied in claims databases to assess RT toxicity and effectiveness. External validation across diverse data sets will be important to confirm generalizability.

A Novel Exclusive Group Testing Strategy Towards Large-Scale Electromagnetic Susceptibility Testing with Improved Efficiency