Systematic Diagnostic Approach Research Articles

Challenges in the assessment and management of pain in non-verbal autistic children: a case report of an osteochondroma revealed by self-aggressive behavior

Introduction: To highlight the challenges of identifying and managing pain in non-verbal autistic children through a case of osteochondroma revealed by self-aggressive behavior and to propose a structured diagnostic approach for these complex situations. Case description: We report the case of a 14-year-old girl with severe non-verbal autism spectrum disorder who developed a progressive increase in self-aggressive behavior over 20 months. The evaluation required an in-depth functional behavioral analysis and an adapted clinical examination, complemented by a radiological work-up. Behavioral analysis revealed that the function of the behavioral problems pointed towards an organic origin: an increase in behavior when moving around, a protective limping when dodging with an exacerbation in the evening. The assessment identified a femoral osteochondroma. The introduction of an alternative communication system with analgesic treatment led to an 80% reduction in self-aggressive behavior. Our observation highlights the difficulties in identifying pain in non-verbal ASD patients and the importance of a structured diagnostic approach. The development of alternative communication appears to be a key element in the assessment and management of pain. Conclusion: Pain management in non-verbal ASD patients requires particular vigilance and a systematic diagnostic approach. Early implementation of alternative communication tools is essential to optimize their assessment and treatment.

Pediatric Diffuse Lung Disease in Infants: Imaging Findings and Histopathologic Correlation.

Childhood interstitial lung disease (chILD) encompasses a diverse group of genetic, infectious, and inflammatory conditions affecting infants and children. The recognition and understanding of these entities have highlighted the necessity for more accurate classification. This group of rare heterogeneous diseases comprises more than 200 different conditions and has a combined estimated prevalence of less than one patient per 100 000 children. Hence, a systematic diagnostic approach is crucial. This article describes a diagnostic approach for pediatric diffuse lung diseases in infancy, including an analysis of clinical presentations and imaging and histologic features to effectively distinguish among various chILD entities. Although they often have overlapping and nonspecific radiologic features, some chILD entities may exhibit typical imaging findings, resulting in a CT diagnosis or aiding in narrowing the differential diagnosis, thus guiding the clinician to the appropriate genetic tests, potentially limiting unnecessary biopsies. This approach aims to enhance the understanding and diagnosis of chILD in infants, thereby facilitating improved patient care.

Spectrum of liver affection in children with sickle cell disease: case series

BackgroundSickle cell hepatopathy (SCH) is a relatively uncommon complication of sickle cell disease (SCD), yet it does not accommodate variations in presentation, outcome, or severity according to age.AimTo present SCH characteristics and assess the effect of implementation of a high-suspicion systematic diagnostic approach and early intervention plan of management.MethodsThis case series presented the characteristics of five children with SCD with variable hepatic manifestation and implemented a diagnostic approach that included testing the transaminases and bilirubin in any patient with any suspicion of liver affection.ResultsThe five patients had a complicated SCD history. They all presented with fever, abdominal pain, and deepening of jaundice. The final diagnosis was reached with a more individualized approach; two had significant coagulopathy and were diagnosed with sickle cell intrahepatic cholestasis, while one had normal synthetic functions of the liver with rising transaminases and bilirubin levels, as well as high titer of Epstein–Barr virus diagnosed as acute viral hepatitis complicated with sickle cell hepatic crisis. One other patient had markedly elevated bilirubin with mild elevation of transaminases, and magnetic resonance cholangiopancreatography showed acute extrahepatic biliary dilatation treated by endoscopic removal of the stone. The fifth patient proved to have portal vein thrombosis by portal duplex causing portal hypertension and decompensated liver. The management plan included early exchange transfusion to keep their hemoglobin S (HbS) below 15% which was performed in three of the patients, in addition to aggressive supportive measures for correction of coagulopathy with full recovery and normalization of their liver functions.ConclusionDespite the diagnostic challenges, the lack of standard diagnostic criteria, and the overlapping clinical presentation of SCH, the management and outcomes improved by following a systematic diagnostic approach.

Noninvasive Assessment in Takotsubo Syndrome: A Diagnostic Challenge.

Takotsubo syndrome (TTS) is a clinical syndrome characterized by a transient left ventricular dysfunction whose diagnosis can be challenging due to its resemblance to acute myocardial infarction (AMI). Despite the growing recognition of TTS, acute complications and long-term mortality rates are comparable to those observed in AMI patients. In this context, a systematic diagnostic approach is imperative for an accurate patient assessment, with due consideration of the distinctive characteristics and optimal timing of each imaging modality. Coronary angiography with ventriculography may be reserved for cases presenting with ST-segment elevation, whereas in all other cases, the use of multimodality noninvasive imaging allows for a comprehensive evaluation of typical diagnostic features and detection of acute complications while also providing prognostic insights. The aim of this review is to evaluate the current research on non-invasive modalities and to propose a diagnostic algorithm that will facilitate the identification and management of TTS.

Pulmonary hypertension associated with lung diseases.

Pulmonary hypertension (PH) associated with chronic lung disease (CLD) is both common and underrecognised. The presence of PH in the setting of lung disease has been consistently shown to be associated with worse outcomes. Recent epidemiological studies have advanced understanding of the heterogeneity of this patient population and shown that defining both the specific type of CLD as well as the severity of PH (i.e. deeper phenotyping) is necessary to inform natural history and prognosis. A systematic diagnostic approach to screening and confirmation of suspected PH in CLD is recommended. Numerous uncontrolled studies and one phase 3 randomised, controlled trial have suggested a benefit in treating PH in some patients with CLD, specifically those with fibrotic interstitial lung disease (ILD). However, other studies in diseases such as COPD-PH showed adverse outcomes with some therapies. Given the expanding list of approved pharmacological treatments for pulmonary arterial hypertension, developing a treatment algorithm for specific phenotypes of CLD-PH is required. This article will summarise existing data in COPD, ILD and other chronic lung diseases, and provide recommendations for classification of CLD-PH and approach to the diagnosis and management of these challenging patients.

Le gradient reste élevé après mon TAVI, que faire?

Over the past two decades, transcatheter aortic valve implantation (TAVI) has become a safe and effective therapeutic option for symptomatic and severe aortic stenosis, regardless of the surgical risk spectrum. With the expansion of TAVI indications to low-risk and younger patients, it is crucial to ensure satisfactory and durable hemodynamic outcomes to guarantee transcatheter heart valve (THV) longevity. However, secondary THV dysfunction may occur, often manifested by an increased transvalvular gradient. According to VARC-3 criteria, these dysfunctions can be attributed to four main mechanisms: 1) structural valve deterioration; 2) non-structural valve dysfunction; 3) thrombosis; 4) and endocarditis. Each mechanism leads to specific abnormalities, requiring a systematic diagnostic approach and appropriate treatment. This article illustrates, through two clinical cases, the diagnosis and management of secondary transvalvular gradient elevation after TAVI.

Diagnostic Insights for Optimal Avanza/Xenia AC Performance

This study investigates the AC system of Avanza/Xenia vehicles through diagnostic procedures aimed at identifying potential issues and ensuring adherence to maintenance standards. The air conditioning (AC) system in vehicles plays a pivotal role in ensuring driver and passenger comfort, necessitating regular monitoring and maintenance. Utilizing measuring tools such as compressors and multimeters, the main components including the magnetic clutch and evaporator were assessed. Results indicate that measured values, including magnetic clutch coil resistance (3.9 ohms), magnetic clutch gap (0.5 mm), and blower system resistance (ranging from 0 to 2.6 ohms), fall within acceptable service limits outlined in the Avanza/Xenia manual. Consequently, no repair procedures were deemed necessary, affirming the normal condition and suitability for use of the AC system. This research fills a knowledge gap by providing a systematic diagnostic approach for evaluating vehicle AC systems, offering implications for maintenance practices in ensuring optimal performance and longevity. Highlights: Routine maintenance prolongs AC system lifespan. Accurate diagnosis prevents potential issues. Component inspection ensures system health. Keywords: PMCB, Vehicle Air Conditioning System, Maintenance, Repair, Troubleshooting

Multiparametric ultrasound-based assessment of overt hyperthyroid diffuse thyroid disease.

Hyperthyroidismis a prevalent condition affecting global populations, with an overall prevalence of 1.2%. Our research aimed to establish a systematic diagnostic approach using multiparametric ultrasound (MPUS) to diagnose hyperthyroid diffuse thyroid disease (DTD). We conducted a retrospective study from June 2021 to June 2023 at a specialized endocrinology center in Timisoara, Romania, enrolling subjects presenting with clinical hyperthyroidism. Using the Mach 30 Aixplorer ultrasound equipment, evaluations were performed initially in B-mode US, followed by Color Doppler and Spectral Doppler measurements, and finally, 2D Shear wave elastography (SWE). From the 218 patients analyzed, the diagnosis of DTD with hyperthyroidism was confirmed through biochemical assessment, subgrouping various pathologies such as subacute thyroiditis, Graves' disease, painless thyroiditis, Hashimoto's thyroiditis, iatrogenic, as well as healthy controls. In the first step, B-mode hypoechogenicity had an AUC of 0.951 for DTD detection. In the second step, the peak systolic velocity differentiated Graves' disease with a median of 42.4 cm/s and an AUC of 1. Lastly, the third step consisted of SWE evaluation, revealing a mean elasticity index in the SAT subgroup significantly higher from other subgroups (p<0.001) with an AUC of 1. Our study offers a step-by-step evaluation algorithm for DTD diagnosis, with a very good overall diagnostic performance (AUC of 0.946).

Diagnostic Puzzles and Cause-Targeted Treatment Strategies in Myocardial Infarction with Non-Obstructive Coronary Arteries: An Updated Review.

Myocardial infarction with nonobstructive coronary arteries (MINOCA) is a distinct subtype of myocardial infarction (MI), occurring in about 8-10% of spontaneous MI cases referred for coronary angiography. Unlike MI with obstructive coronary artery disease, MINOCA's pathogenesis is more intricate and heterogeneous, involving mechanisms such as coronary thromboembolism, coronary vasospasm, microvascular dysfunction, dissection, or plaque rupture. Diagnosing MINOCA presents challenges and includes invasive and non-invasive strategies aiming to differentiate it from alternative diagnoses and confirm the criteria of elevated cardiac biomarkers, non-obstructive coronary arteries, and the absence of alternate explanations for the acute presentation. Tailored management strategies for MINOCA hinge on identifying the underlying cause of the infarction, necessitating systematic diagnostic approaches. Furthermore, determining the optimal post-MINOCA medication regimen remains uncertain. This review aims to comprehensively address the current state of knowledge, encompassing diagnostic and therapeutic approaches, in the context of MINOCA while also highlighting the evolving landscape and future directions for advancing our understanding and management of this intricate myocardial infarction subtype.

Curriculum Innovations: A Social Media-Based Educational Curriculum Improves Knowledge for Trainees in Neurocritical Care: Results of a Stratified Randomized Study.

The Neurocritical Care (NCC) Society Resident and Fellow Task Force's NEURON study concluded that learners had significant concerns regarding the need for educational improvement in NCC. To address these shortcomings, we identified the lack of an educational curriculum for trainees in NCC and developed a Twitter-based educational curriculum for trainees to improve knowledge in NCC. The objectives of this study were to describe the pathophysiology, delineate a systematic diagnostic approach, and apply evidence-based strategies in the management of diseases in NCC. Ten trainees developed a Tweetorial (educational content available on Twitter)-based curriculum, with individual review by at least 2 NCC faculty. Learners were recruited through Twitter and randomized to 1 of 2 groups in a wait-list control prospective study. Group 1 completed the curriculum in the first 6 months of the 2021-2022 academic year, and group 2 completed the curriculum in the second half. Tweetorials were posted weekly on a private Twitter account only available to the active learner group. Learners were assessed by a multiple-choice format test (written by the trainees and reviewed by faculty) at 3 time points: before the first Tweetorial was released (preeducational curriculum assessment), after group 1 completed all tutorials and before group 2 started the curriculum (assessment 1), and after both groups finished (assessment 2). The primary outcome was the mean score on the second and third assessments. One hundred forty-six learners were assigned to group 1 or 2 using stratified block randomization including 99 (68%) Neurology residents, 81 (55%) US-based. Each group was composed of 73 participants. A total of 20 Tweetorials were published on a private Twitter account (@NeurocriticalE). Completed assessments were obtained from 100, 32, and 18 learners for the pre-educational curriculum assessment, assessment 1, and assessment 2, respectively. Group 1 and group 2 performed similarly in the pre-educational curriculum assessment. A potential for knowledge improvement was observed in group 1 at assessments 1 and 2 when compared with the learner group 2. Group 1 had more impressions, engagements, likes, URL clicks, and media views. Although there was some learner attrition, our study demonstrates that social media can effectively deliver educational content and engage a diverse group of trainees around the globe.

Approach to the Patient With Parathyroid Carcinoma.

Parathyroid carcinoma (PC) is usually associated with severe symptomatic primary hyperparathyroidism (PHPT) and accounts for less than 1% of all cases of PHPT and approximately 0.005% of all cancers. PC most commonly occurs as a sporadic disease and somatic CDC73 mutations can be detected in up to 80% of cases. Approximately 30% of patients harbor a germline mutation of the CDC73 gene. Preoperative diagnosis of PC is difficult because no disease-specific markers are available, and PC should be suspected in patients with severe hypercalcemia and end-organ complications. The diagnosis is based on the evidence of invasive tumor growth at histology and/or metastases. En bloc resection of the tumor, together with the ipsilateral thyroid lobe and adjacent structures, should be performed by an experienced surgeon when PC is suspected. This surgical approach reduces the risk of recurrence and metastasis and offers the highest chance of cure. Nonetheless, PC has a recurrence rate of 40% to 60% and, if feasible, multiple surgical procedures should be performed. When surgery is no longer an option, medical treatment is aimed to reduce hypercalcemia and target organ complications. Targeted agents have been effectively used in a few cases. We describe herein a patient with severe PHPT due to PC and provide a systematic diagnostic and treatment approach. A thorough review of the medical history, a typical clinical and biochemical phenotype and, in some cases, the revision of the histological examination provide the clues for the diagnosis of PC.

Severe Pulmonary Hypertension Secondary to Concomitant Mitral Stenosis with Veno-occlusive Disease in the Context of Systemic Sclerosis: Importance of Careful and Comprehensive Assessment

Pulmonary Arterial Hypertension (PAH) is a clinical syndrome consisting of physiologic/ hemodynamic criteria that are a consequence of several etiologies. Confirmation of pulmonary hypertension is based on right heart catheterization.&#x0D; Pulmonary hypertension is a devastating condition that can lead to considerable morbidity and premature mortality. In the last few decades, significant advancement in the pharmacotherapy of pulmonary hypertension has resulted from better understanding of the complex pathogenesis and pathophysiology of this dreaded disease. Despite these accomplishments, pharmacotherapy of pulmonary hypertension is still far from perfect, and the mortality in this modern treatment era is still unacceptably high.&#x0D; We report a complex clinical presentation characterized by severe pulmonary hypertension secondary to concomitant mitral stenosis with veno-occlusive disease in the context of systemic sclerosis.&#x0D; Our case highlights the importance of a systematic and comprehensive diagnostic approach to avoid missing an underlying pathology.

A stepwise diagnostic approach for undiagnosed Anemia in children: A model for low-middle income country

BackgroundReaching a precise diagnosis in rare inherited anemia is extremely difficult and challenging, especially in areas with limited use of genetic studies, which makes undiagnosed anemia a unique clinical entity in tertiary hematology centers. In this study, we aim at plotting a stepwise diagnostic approach in children with undiagnosed anemia while identifying indications for genetic testing. Patients and methodsA one-year cross-sectional study involved 44 children and adolescents with undiagnosed anemia after undergoing an initial routine panel of investigations. They were classified based on mean corpuscular volume (MCV) into 3 groups: microcytic (n = 19), normocytic (n = 14) and macrocytic (n = 11). An algorithm that included four levels of investigations was devised for each category. ResultsAfter applying a systematic diagnostic approach, 33 patients (75 %) were diagnosed of whom 7 (15 %) had combined diagnoses, while 11 (25 %) patients remained undiagnosed. Based on the first, second, third and fourth levels of investigations, patients were diagnosed, respectively, as follows: of the 11 patients, 7 were microcytic, 3 normocytic and 1 macrocytic; of the 7 patients, 2 were microcytic, 2 normocytic, and 3 macrocytic; of 10 patients, 5 were microcytic, 4 normocytic and 1 macrocytic; finally, of the 16 patients, 8 were microcytic, 6 normocytic and 2 macrocytic. Numbers recorded appear higher than the actual number of the patients because some of them were diagnosed by more than one level of investigation. The diagnoses obtained in the microcytic group showed hemoglobinopathies, iron refractory iron deficiency anemia (IRIDA), membrane defects, sideroblastic anemia, hypo-transferrinemia, a combined diagnosis of sickle cell trait and pyropoikilocytosis. The diagnoses also showed a combined diagnosis of hereditary spherocytosis (HS) and alpha thalassemia minor, and a combined diagnosis of iron deficiency anemia and beta thalassemia minor, while 15 % remained undiagnosed. In the normocytic group, the diagnosis revealed autosomal recessive (AR) HS, vitamin B12 deficiency, pyruvate kinase deficiency (PKD), congenital dyserythropoietic anemia (CDA) type I, Diamond Blackfan anemia and beta thalassemia major. In addition, it showed a combined diagnosis of AR HS and CDA type II, a combined diagnosis of AR HS and PKD, and a combined diagnosis of dehydrated stomatocytosis (DHS) and G6PD carrier, meanwhile 20 % remained undiagnosed. Finally, the macrocytic group was diagnosed by vitamin B12 deficiency, sideroblastic anemia, PKD, a combined diagnosis of PKD and G6PD deficiency carrier, while 45 % remained undiagnosed. ConclusionConducting a stepwise approach with different levels of investigations may help reach the diagnosis of difficult anemia without having to resort to unnecessary investigations. Combined diagnosis is an important cause of undiagnosed anemia, especially in countries with high frequency of consanguinity. The remaining 25 % of the patients continued to be undiagnosed, requiring more sophisticated investigations.

Reported neurological symptoms after severe acute respiratory syndrome coronavirus type 2 (SARS CoV-2) infection: a systematic diagnostic approach.

Following increasing demands of patients with suspected neurological symptoms after infection with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the Department of Neurology at the Medical University of Vienna established a new outpatient clinic to systematically assess, diagnose and document neurological complaints potentially associated with a prior SARS-CoV-2 infection. The data presented here include prospectively collected 156 outpatients from May 2021 to April 2022. Patients underwent semi-standardized interviewing about symptoms with reported onset after SARS CoV-2 infection, neurological examination, and comprehensive diagnostic workup. Reported new-onset symptoms after infection included fatigue (77.6%), subjective cognitive impairment (72.4%), headache (47.7%), loss of smell and/or taste (43.2%), and sleep disturbances (42.2%). Most patients had a mild coronavirus disease (COVID-19) disease course (84%) and reported comorbidities (71%), thereof the most frequent were psychiatric disorders (34%). Frequency of symptoms was not associated with age, sex, or severity of COVID-19 course. A comprehensive diagnostic workup revealed no neurological abnormalities in the clinical examination, electrophysiological, or imaging assessments in the majority of patients (n=143, 91.7%). Neuropsychological assessment of a subgroup of patients (n = 28, 17.9%) showed that cognitive impairments in executive functions and attention, anxiety, depression, and somatization symptoms were highly common. In this systematic registry we identified fatigue, cognitive impairment, and headache as the most frequently reported persisting complaints after SARS-CoV-2 infection. Structural neurological findings were rare. We suspect a link between the growing burden of the COVID pandemic on personal lives and the increase in reported neurological and psychiatric complaints.

A comprehensive diagnostic approach in suspected neurosarcoidosis

Neurosarcoidosis presents a diagnostic challenge in clinical settings, as it has no pathognomonic symptoms or signs and a wide range of differential diagnoses. The aim of this report is to present the pathological features of our group of patients, obtained through a systematic diagnostic approach. This retrospective cohort study enrolled all adult patients primarily diagnosed with neurosarcoidosis at the neurology department of a tertiary center in Sweden over a period of 30 years, from 1990 to 2021. We identified 90 patients, 54 with possible neurosarcoidosis and 36 with probable neurosarcoidosis. CNS biopsy revealed an alternative diagnosis for 24 patients, who were then excluded. The collected data from medical records included demographic and clinical characteristics, systemic and/or neurological isolated involvement, various laboratory tests, including cerebrospinal fluid (CSF), serum analysis, imaging studies (MRI, FDG-PET/CT, and HRCT), nerve conduction studies, electromyography, and pathology reports of central nervous system (CNS), and extra-neural tissue biopsies. Sixty-six patients were included in our cohort. The median age at onset of symptoms was 49 years, with a similar sex distribution. Cranial neuropathies (38%), motor deficit (32%), headache (16%), and pituitary dysfunction (12%) were the most common presenting features. CSF studies were abnormal in 77% of the patients, who showed lymphocytosis (57%), elevated protein (44%), oligoclonal bands (40%), elevated ACE (28%), and raised T lymphocyte CD4+/CD8+ ratios (13%). Strikingly, MRI showed that 17% of the patients presented with isolated pituitary gland lesions. FDG-PET/CT was performed in 22 patients (33%) and confirmed systemic sarcoidosis in 11. Despite our extensive workup, the final classification for our patients only allowed for a definite diagnosis in 14 patients; the remainder were classified as probable (32) or possible (20) neurosarcoidosis. Since 2007, the employment of a structured laboratory and imaging approach and the increasing number of CNS biopsies have facilitated and improved the process of correct attribution in patients with presumptive neurosarcoidosis, especially in patients with isolated neurological lesions. We highlight a higher frequency of pituitary lesions due to neurosarcoidosis than has been classically described. A detailed laboratory diagnostic workup is included.

High yield on aetiology using a systematic diagnostic approach to paediatric acute liver failure, analysis of a nationwide cohort.

Paediatric acute liver failure (P-ALF) is a rare and devastating condition that leads to death or liver transplantation (LTx) in 40%-60% of cases. Determining the aetiology can enable disease-specific treatment, aid in prognostication for hepatic recovery and guide the decision-making for liver transplantation. This study aimed to retrospectively evaluate a systematic diagnostic approach to P-ALF in Denmark and to collect epidemiological nationwide data. All Danish children aged 0-16 years with P-ALF diagnosed between 2005 and 2018, and who were evaluated using a standardised diagnostic assessment programme, were eligible for retrospective analysis of clinical data. A total of 102 children with P-ALF were included (presentation at 0 days to 16.6 years of age, 57 females). Aetiological diagnosis was established in 82% of cases, the remainder were indeterminate. Fifty percent of children with P-ALF of indeterminate aetiology died or underwent LTx within 6 months after their P-ALF diagnosis, compared to 24% of children with an aetiological diagnosis, p= 0.04. Following a systematic diagnostic evaluation programme, made it possible to identify the aetiology of P-ALF in 82% of cases which is associated with improved outcomes. The diagnostic workup should never be considered complete but rather adapt to ongoing diagnostic advances.

A practical approach to weight loss in adult horses

Common causes of weight loss in horses include inadequate dietary intake, dental problems and endoparasites. However, once these common causes are ruled out, the spectrum of weight loss causes can be ample and in some cases, may indicate the presence of severe illness. Given the clinical relevance of weight loss, the equine clinician is faced with important questions that need to be answered. A systematic diagnostic approach to weight loss should be followed.

The European guideline on management of major bleeding and coagulopathy following trauma: sixth edition

BackgroundSevere trauma represents a major global public health burden and the management of post-traumatic bleeding continues to challenge healthcare systems around the world. Post-traumatic bleeding and associated traumatic coagulopathy remain leading causes of potentially preventable multiorgan failure and death if not diagnosed and managed in an appropriate and timely manner. This sixth edition of the European guideline on the management of major bleeding and coagulopathy following traumatic injury aims to advise clinicians who care for the bleeding trauma patient during the initial diagnostic and therapeutic phases of patient management.MethodsThe pan-European, multidisciplinary Task Force for Advanced Bleeding Care in Trauma included representatives from six European professional societies and convened to assess and update the previous version of this guideline using a structured, evidence-based consensus approach. Structured literature searches covered the period since the last edition of the guideline, but considered evidence cited previously. The format of this edition has been adjusted to reflect the trend towards concise guideline documents that cite only the highest-quality studies and most relevant literature rather than attempting to provide a comprehensive literature review to accompany each recommendation.ResultsThis guideline comprises 39 clinical practice recommendations that follow an approximate temporal path for management of the bleeding trauma patient, with recommendations grouped behind key decision points. While approximately one-third of patients who have experienced severe trauma arrive in hospital in a coagulopathic state, a systematic diagnostic and therapeutic approach has been shown to reduce the number of preventable deaths attributable to traumatic injury.ConclusionA multidisciplinary approach and adherence to evidence-based guidelines are pillars of best practice in the management of severely injured trauma patients. Further improvement in outcomes will be achieved by optimising and standardising trauma care in line with the available evidence across Europe and beyond.

Post-Inflammatory Hypopigmentation: Review of the Etiology, Clinical Manifestations, and Treatment Options.

Post-inflammatory hypopigmentation is a common acquired pigmentary disorder that is more prominent in skin of color, leading to great cosmetic and psychosocial implications. Often, a diagnosis with a pigmentary disorder can negatively impact an individual's health-related quality of life and may result in stigma. Although most cases of post-inflammatory hypopigmentation resolve spontaneously over time, a systematic diagnostic approach can help with identifying the underlying etiology and informing treatment strategies. It can be due to cutaneous inflammation, sequelae of inflammatory or infectious dermatoses, or dermatologic procedures. Therefore, a thorough understanding of the epidemiology, patient history, physical exam findings, and clinical features of post-inflammatory hypopigmentation phenomenon can explain the primary cause to providers and allow for patient education. It is also important to understand the various therapeutic approaches available and the efficacy of these options, which will inform providers to choose the appropriate therapy for patients. Although algorithms exist for classifying acquired disorders of hypopigmentation, there are no established algorithms for the diagnosis and treatment of post-inflammatory hypopigmentation, which warrants further exploration and discourse.

A Multi-Cohort Gene Expression Classifier (ALLCatchR) Identifies B-Precursor ALL Subtypes and Their Developmental Trajectories across Age Groups

The molecular landscape of B cell precursor acute lymphoblastic leukemia (BCP-ALL) describes >20 disease subtypes defined by initiating genomic alterations and corresponding gene expression signatures. Some subtypes represent phenocopies with shared gene expression signatures but distinct or absent genomic drivers. The majority of BCP-ALL subtypes have been acknowledged as diagnostic entities by the currently revised classifications of hematologic malignancies (WHO-HAEM5 / International Consensus Classification). Thus, unified diagnostic approaches are needed to systematically identify subtypes in individual BCP-ALL cases in clinical routine. Gene expression signatures represent the shared functional equivalent of heterogeneous genomic driver alterations. Therefore, we established a gene expression-based classifier to identify BCP-ALL subtypes and related clinical and biological phenotypes. We analyzed a total of n=3477 BCP-ALL gene expression profiles obtained from transcriptome sequencing of adult (n=1253) and pediatric patients (n=2224) including publicly available (n=2074; Gu Z et al. Nat. Genet. 2019; Schmidt B. et al. Blood Adv. 2022) and own data sets (n=1403) from adult and pediatric European study groups (GMALL, AIEOP-BFM, CELL). Raw read counts from 6 cohorts representing heterogeneous library preps (i.e., stranded/unstranded; mRNA/total RNA), sequencing platforms/depths, and gene count quantifications were included. All samples had been previously allocated to molecular BCP-ALL subtypes based on integration of independent genomic profiling, gene fusion calling and gene expression. For classification, data with defined subgroup allocation were randomly split into training (n=1831; 70%) and testing sets (n=785; 30%) and two hold-out studies (n=305). To define gene expression signatures of 21 BCP-ALL subtypes, we used training set samples and extracted specific gene sets employing different feature selection algorithms as well as ranking of genes in individual subtypes. Based on these definitions we established a BCP-ALL subtype classifier (ALLCatchR), which integrates machine learning models (support vector machines) and nearest-neighbors associations of single sample gene set enrichment analyses (Fig. A). ALLCatchR performed molecular subtype allocation for the testing set at high sensitivity (0.934±0.165) and specificity (0.997±0.005) on average across subtypes. A similar performance was achieved in the two hold-out cohorts despite completely independent data structures which have not been shown to the classifier (sensitivity: 0.946±0.097 / specificity: 0.996±0.007). Overall accuracies of 0.952 and 0.92 for testing and hold-out-data sets indicate that ALLCatchR reliably identifies molecular BCP-ALL subtypes in mixed adult / pediatric cohorts based on gene expression profiles alone (Fig. A, below). Among n=44/1090 (4%) samples of the combined hold-out/testing set with ambiguous subtype allocation (deemed 'unclassified'), ALLCatchR provides candidate subtype allocations (sensitivity: 0.671±0.393 / specificity: 0.978±0.036) for confirmation based on genomic driver alterations. In addition, we modified our classifier to predict baseline variables such as patient's sex (accuracy: 0.991), immunophenotype (accuracy: 0.935) or blast count (R=0.633). To define the corresponding B cell differentiation stage of origin, we compared BCP-ALL subtypes to differentiation stage-specific gene sets extracted from 7 FACS-sorted lymphopoietic subsets from healthy bone marrow donors (n=4). We observed defined BCP-ALL subtype-specific enrichment patterns which can be grouped along 4 major differentiation stages (Pro-B to Pre-B-II-Large, Fig. 1B) with a high degree of similarity in independent adult and pediatric cohorts. Thus, B cell developmental trajectories underlying BCP-ALL subtypes are dissected at high resolution by gene expression profiling and differentiation stages may favor the selection of specific leukemogenic drivers. ALLCatchR is a gene expression classifier for 21 established BCP-ALL molecular subtypes, which performs at independently validated cohorts with an accuracy of >90% and allows imputation of clinical baseline variables as well as underlying B cell developmental trajectories. It provides a reliable basis for systematic diagnostic approaches in pediatric and adult BCP-ALL patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal