INTRODUCTION: The use of signal dogs for cancer detection is not yet routinely performed,but dogs and their powerful olfactory system have proven to be a unique and valuable tool for many lineages and are beginning to be incorporated into medical practice. This method has great advantages; the dog can detect a tumour in the human body already in preclinical stages, when the patient has no symptoms yet. The identification of cancer biomarkers to enable early diagnosis is a need for many types of cancer, whose prognosis is strongly dependent on the stage of the disease. However, this method also has its various pitfalls that must be taken into account. AIM: The aim of the study was to identify and highlight the factors that affect the level of detection accuracy, but also the conditions associated with olfactometric diagnosis. METHODS: The study included 48 dogs and 48 handlers, that were part of the training between 2016 and 2023.All those who started olfactometry training and remained in training for at least one year were included in the study. The dogs ranged in age from 8 months to 12 years and were of different races and sexes. After long-term observation, a qualitative analysis was performed and factors that may play a role in the early detection of the disease were listed. RESULTS: The results of the search for the different factors have been compiled into two groups, focussing on the actual handling of the patient biological sample from collection, processing, storage until transport, preparation of the sample,and detection. Focus on the actual work and behaviour of the dog and handler. CONCLUSION: There are many factors; however, it is worth addressing them because the canine sense of smell is one of the possible uses as a diagnostic method.

• Publication type
• Journal Article MeSH

UNLABELLED: The aim of this study was to identify parameters influencing DNA extraction and PCR amplification efficiencies in an attempt to standardize Mucorales qPCR. The Fungal PCR Initiative Mucorales Laboratory Working Group distributed two panels of simulated samples to 26 laboratories: Panel A (six sera spiked with Mucorales DNA and one negative control serum) and Panel B (six Mucorales DNA extracts). Panel A underwent DNA extraction in each laboratory according to the local procedure and were sent to a central laboratory for testing using three different qPCR techniques: one in-house qPCR assay and two commercial assays (MucorGenius and Fungiplex). Panel B DNA extracts were PCR amplified in each laboratory using local procedures: nine in-house qPCR assays and two commercial kits (MucorGenius and MycoGENIE). All data were compiled and anonymously analyzed at the central laboratory. For Panel A, a total of six different automated platforms and five manual extraction methods were used. Positive rates were 64%, 70%, and 89%, for the MucorGenius, Fungiplex, and the in-house qPCR assay, respectively. Using a large volume of serum for DNA extraction provided the highest analytical sensitivity (82.5% for 1 mL compared with 62.7% for smaller volumes, P < 0.01). For Panel B, five in-house qPCR assays and two commercial kits had >78% positivity. Using larger PCR input volumes (≥7 μL) was associated with the highest sensitivity at 95.5% compared to 58.3% when lower input volumes were used (P < 0.01). Using larger sample volumes for nucleic acid extraction and DNA template volumes for PCR amplification significantly improves the performance of Mucorales qPCR when testing serum. IMPORTANCE: Mucormycosis is a life-threatening mold infection affecting immunosuppressed patients but also other patients with diabetes or trauma. Better survival is linked to shorter delays in diagnosis and treatment initiation. Detection of Mucorales-free DNA in serum or plasma using quantitative PCR allows a prompt diagnosis and earlier treatment. Several techniques and protocols of quantitative Mucorales PCR are used in Europe, and improving performance remains a common objective of laboratories participating in the fungal PCR Initiative Working Group. This study, which combined results from 26 laboratories in Europe, showed that the main parameters underpinning sensitivity are the preanalytical variables (volume of serum used for DNA extraction and DNA template volume), irrespective of the extraction platforms and qPCR assay/platform.

• MeSH
• Molecular Diagnostic Techniques standards   methods   MeSH
• DNA, Fungal * blood   genetics   MeSH
• Real-Time Polymerase Chain Reaction * standards   methods   MeSH
• Humans MeSH
• Mucorales * genetics   isolation & purification   MeSH
• Mucormycosis * diagnosis   microbiology   blood   MeSH
• Sensitivity and Specificity * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Evaluation Study MeSH

AIMS: Ossifying fibromyxoid tumour is a rare mesenchymal neoplasm predominantly affecting adults characterised by a multinodular growth pattern and the presence of a fibrous pseudocapsule with areas of ossification. Prompted by the recognition of a non-ossifying ossifying fibromyxoid tumour with lipomatous differentiation which caused diagnostic difficulty, we sought to further explore cases of ossifying fibromyxoid tumour with non-osseous heterologous elements. METHODS AND RESULTS: A search of our institutional and consultation archives revealed three additional cases that demonstrated lipomatous components and two cases with cartilaginous differentiation. RNA-sequencing revealed fusions involving PHF1 (n = 4) or EPC1 (n = 1) in all (five of five) cases tested, including EPC1::PHC1 and JAZF1::PHF1 fusions, which have not been reported before in ossifying fibromyxoid tumour. CONCLUSION: These six cases expand the histomorphological spectrum of ossifying fibromyxoid tumour, introducing lipomatous differentiation as a hitherto undocumented feature. Awareness of these rare variants will ensure appropriate diagnosis and clinical management.

• MeSH
• Cell Differentiation MeSH
• Cartilage pathology   MeSH
• Diagnosis, Differential MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Lipoma * pathology   diagnosis   genetics   MeSH
• Soft Tissue Neoplasms * pathology   diagnosis   genetics   MeSH
• Fibroma, Ossifying * pathology   diagnosis   genetics   MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH

BACKGROUND: Presensitized patients with circulating donor-specific antibodies (DSAs) before transplantation are at risk for antibody-mediated rejection (AMR). Peritransplant desensitization mitigates but does not eliminate the alloimmune response. We examined the possibility that subthreshold AMR activity undetected by histology could be operating in some early biopsies. METHODS: Transcriptome of kidney allograft biopsies performed within the first month in presensitized patients (DSA+) who had received desensitization and did not develop active/probable AMR by histology (R-) was compared with biopsies showing active/probable AMR (R+/DSA+). As negative controls, biopsies without rejection by histology in patients without DSA at transplantation were used (R-/DSA-). RNA sequencing from biopsies selected from the biobank was used in cohort 1 (n = 32) and microarray, including the molecular microscope (Molecular Microscope Diagnostic System [MMDx]) algorithm, in recent cohort 2 (n = 30). RESULTS: The transcriptome of R-/DSA+ was similar to R+/DSA+ as these groups differed in 14 transcripts only. Contrarily, large differences were found between both DSA+ groups and negative controls. Fast gene set enrichment analyses showed upregulation of the immune system in both DSA+ groups (gene ontology terms: adaptive immune response, humoral immune response, antigen receptor-mediated signaling, and B-cell receptor signaling or complement activation) when compared with negative controls. MMDx assessment in cohort 2 classified 50% of R-/DSA+ samples as AMR and found no differences in AMR molecular scores between R+ and R- DSA+ groups. In imlifidase desensitization, MMDx series showed a gradual increase in AMR scores over time. CONCLUSIONS: Presensitized kidney transplant recipients exhibited frequent molecular calls of AMR in biopsy-based transcript diagnostics despite desensitization therapy and negative histology.

• Publication type
• Journal Article MeSH

BACKGROUND: Daratumumab, an anti-CD38 monoclonal antibody, has been approved for the treatment of multiple myeloma. Data are needed regarding the use of daratumumab for high-risk smoldering multiple myeloma, a precursor disease of active multiple myeloma for which no treatments have been approved. METHODS: In this phase 3 trial, we randomly assigned patients with high-risk smoldering multiple myeloma to receive either subcutaneous daratumumab monotherapy or active monitoring. Treatment was continued for 39 cycles, for 36 months, or until confirmation of disease progression, whichever occurred first. The primary end point was progression-free survival; progression to active multiple myeloma was assessed by an independent review committee in accordance with International Myeloma Working Group diagnostic criteria. RESULTS: Among the 390 enrolled patients, 194 were assigned to the daratumumab group and 196 to the active-monitoring group. With a median follow-up of 65.2 months, the risk of disease progression or death was 51% lower with daratumumab than with active monitoring (hazard ratio, 0.49; 95% confidence interval [CI], 0.36 to 0.67; P<0.001). Progression-free survival at 5 years was 63.1% with daratumumab and 40.8% with active monitoring. A total of 15 patients (7.7%) in the daratumumab group and 26 patients (13.3%) in the active-monitoring group died (hazard ratio, 0.52; 95% CI, 0.27 to 0.98). Overall survival at 5 years was 93.0% with daratumumab and 86.9% with active monitoring. The most common grade 3 or 4 adverse event was hypertension, which occurred in 5.7% and 4.6% of the patients in the daratumumab group and the active-monitoring group, respectively. Adverse events led to treatment discontinuation in 5.7% of the patients in the daratumumab group, and no new safety concerns were identified. CONCLUSIONS: Among patients with high-risk smoldering multiple myeloma, subcutaneous daratumumab monotherapy was associated with a significantly lower risk of progression to active multiple myeloma or death and with higher overall survival than active monitoring. No unexpected safety concerns were identified. (Funded by Janssen Research and Development; AQUILA ClinicalTrials.gov number, NCT03301220.).

• MeSH
• Progression-Free Survival MeSH
• Adult MeSH
• Smoldering Multiple Myeloma * diagnosis   mortality   therapy   MeSH
• Injections, Subcutaneous MeSH
• Kaplan-Meier Estimate MeSH
• Middle Aged MeSH
• Humans MeSH
• Multiple Myeloma * diagnosis   epidemiology   prevention & control   MeSH
• Antibodies, Monoclonal * administration & dosage   adverse effects   MeSH
• Watchful Waiting * statistics & numerical data   MeSH
• Disease Progression MeSH
• Antineoplastic Agents * administration & dosage   adverse effects   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH
• Comparative Study MeSH

PURPOSE: We set out to develop a publicly available tool that could accurately diagnose spinal muscular atrophy (SMA) in exome, genome, or panel sequencing data sets aligned to a GRCh37, GRCh38, or T2T reference genome. METHODS: The SMA Finder algorithm detects the most common genetic causes of SMA by evaluating reads that overlap the c.840 position of the SMN1 and SMN2 paralogs. It uses these reads to determine whether an individual most likely has 0 functional copies of SMN1. RESULTS: We developed SMA Finder and evaluated it on 16,626 exomes and 3911 genomes from the Broad Institute Center for Mendelian Genomics, 1157 exomes and 8762 panel samples from Tartu University Hospital, and 198,868 exomes and 198,868 genomes from the UK Biobank. SMA Finder's false-positive rate was below 1 in 200,000 samples, its positive predictive value was greater than 96%, and its true-positive rate was 29 out of 29. Most of these SMA diagnoses had initially been clinically misdiagnosed as limb-girdle muscular dystrophy. CONCLUSION: Our extensive evaluation of SMA Finder on exome, genome, and panel sequencing samples found it to have nearly 100% accuracy and demonstrated its ability to reduce diagnostic delays, particularly in individuals with milder subtypes of SMA. Given this accuracy, the common misdiagnoses identified here, the widespread availability of clinical confirmatory testing for SMA, and the existence of treatment options, we propose that it is time to add SMN1 to the American College of Medical Genetics list of genes with reportable secondary findings after genome and exome sequencing.

• MeSH
• Algorithms MeSH
• Exome genetics   MeSH
• Genome, Human genetics   MeSH
• Genomics methods   MeSH
• Humans MeSH
• Survival of Motor Neuron 1 Protein genetics   MeSH
• Survival of Motor Neuron 2 Protein genetics   MeSH
• Sequence Analysis, DNA methods   MeSH
• Exome Sequencing MeSH
• Muscular Atrophy, Spinal * genetics   diagnosis   MeSH
• High-Throughput Nucleotide Sequencing MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

OBJECTIVE: Epilepsy surgery in the operculoinsular cortex is challenging due to the difficult delineation of the epileptogenic zone and the high risk of postoperative deficits. METHODS: Pre- and postsurgical data from 30 pediatric patients who underwent operculoinsular cortex surgery at the Motol Epilepsy Center Prague from 2010 to 2022 were analyzed. RESULTS: Focal cortical dysplasia (FCD; n = 15, 50%) was the predominant cause of epilepsy, followed by epilepsy-associated tumors (n = 5, 17%) and tuberous sclerosis complex (n = 2, 7%). In eight patients where FCD was the most likely etiology, the histology was negative. Seven patients (23%) displayed normal magnetic resonance imaging results. Seizures exhibited diverse semiology and propagation patterns (frontal, perisylvian, and temporal). The ictal and interictal electroencephalographic (EEG) findings were mostly extensive. Multimodal imaging and advanced postprocessing were frequently used. Stereo-EEG was used for localizing the epileptogenic zone and eloquent cortex in 23 patients (77%). Oblique electrodes were used as guides for better neurosurgeon orientation. The epileptogenic zone was in the dominant hemisphere in 16 patients. At the 2-year follow-up, 22 patients (73%) were completely seizure-free, and eight (27%) experienced a seizure frequency reduction of >50% (International League Against Epilepsy class 3 and 4). Fourteen patients (47%) underwent antiseizure medication tapering; treatment was completely withdrawn in two (7%). Nineteen patients (63%) remained seizure-free following the definitive outcome assessment (median = 6 years 5 months, range = 2 years to 13 years 5 months postsurgery). Six patients (20%) experienced corona radiata or basal ganglia ischemia; four (13%) improved to mild and one (3%) to moderate hemiparesis. Two patients (7%) operated on in the anterior insula along with frontotemporal resection experienced major complications: pontine ischemia and postoperative brain edema. SIGNIFICANCE: Epilepsy surgery in the operculoinsular cortex can lead to excellent patient outcomes. A comprehensive diagnostic approach is crucial for surgical success. Rehabilitation brings a great chance for significant recovery of postoperative deficits.

• MeSH
• Child MeSH
• Electroencephalography * MeSH
• Epilepsy surgery   diagnostic imaging   MeSH
• Cohort Studies MeSH
• Infant MeSH
• Humans MeSH
• Magnetic Resonance Imaging MeSH
• Malformations of Cortical Development surgery   complications   diagnostic imaging   MeSH
• Adolescent MeSH
• Cerebral Cortex diagnostic imaging   surgery   MeSH
• Neurosurgical Procedures methods   MeSH
• Child, Preschool MeSH
• Retrospective Studies MeSH
• Treatment Outcome MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

OBJECTIVES: To prospectively validate the diagnostic performance of a non-invasive point-of-care tool (Rapid IAI System), including vaginal alpha-fetoprotein and interleukin-6, to predict the occurrence of intra-amniotic inflammation in a Spanish cohort of patients admitted with a diagnosis of preterm labor and intact membranes. METHODS: From 2017 to 2022, we prospectively evaluated a cohort of pregnant women diagnosed with preterm labor and intact membranes admitted below 34+0 weeks who underwent amniocentesis to rule-in/out intra-amniotic infection and/or inflammation. Vaginal sampling was performed at the time of amniocentesis or within 24-48 h. Amniotic fluid IL-6, vaginal alpha-fetoprotein and vaginal IL-6 concentrations were measured using a point-of-care tool provided by Hologic Inc., "Rapid IAI System". We defined intra-amniotic inflammation when amniotic fluid IL-6 values were greater than 11.3 ng/mL. During recruitment, clinicians were blinded to the results of the point-of-care tool. The original prediction model proposed by Hologic Inc. to predict intra-amniotic inflammation was validated in this cohort of patients. RESULTS: We included 151 patients diagnosed with preterm labor and intact membranes. Among these, 29 (19.2 %) had intra-amniotic inflammation. The algorithm including vaginal IL-6 and alpha-fetoprotein showed an area under curve to predict intra-amniotic inflammation of 80.3 % (±5.3 %) with a sensitivity of 72.4 %, specificity of 84.6 %, positive predictive valuve (PPV) of 52.5 %, negative predictive value (NPV) of 92.9 %, and a positive likelihood ratio (LR+) of 4.6 and negative likelihood ratio (LR-) of 0.33. CONCLUSIONS: External validation of a non-invasive rapid point-of-care tool, including vaginal alpha-fetoprotein and IL-6, showed very good diagnostic performance for predicting the absence of intra-amniotic inflammation in women with preterm labor and intact membranes.

• MeSH
• alpha-Fetoproteins * analysis   metabolism   MeSH
• Amniocentesis methods   MeSH
• Chorioamnionitis * diagnosis   MeSH
• Adult MeSH
• Risk Assessment methods   MeSH
• Interleukin-6 * analysis   blood   metabolism   MeSH
• Humans MeSH
• Amniotic Fluid * metabolism   chemistry   MeSH
• Point-of-Care Testing MeSH
• Obstetric Labor, Premature * diagnosis   MeSH
• Predictive Value of Tests MeSH
• Prospective Studies MeSH
• Pregnancy MeSH
• Vagina metabolism   MeSH
• Point-of-Care Systems MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Validation Study MeSH

PURPOSE: Genetic testing in consanguineous families advances the general comprehension of pathophysiological pathways. However, short stature (SS) genetics remain unexplored in a defined consanguineous cohort. This study examines a unique pediatric cohort from Sulaimani, Iraq, aiming to inspire a genetic testing algorithm for similar populations. METHODS: Among 280 SS referrals from 2018-2020, 64 children met inclusion criteria (from consanguineous families; height ≤ -2.25 SD), 51 provided informed consent (30 females; 31 syndromic SS) and underwent investigation, primarily via exome sequencing. Prioritized variants were evaluated by the American College of Medical Genetics and Genomics standards. A comparative analysis was conducted by juxtaposing our findings against published gene panels for SS. RESULTS: A genetic cause of SS was elucidated in 31 of 51 (61%) participants. Pathogenic variants were found in genes involved in the GH-IGF-1 axis (GHR and SOX3), thyroid axis (TSHR), growth plate (CTSK, COL1A2, COL10A1, DYM, FN1, LTBP3, MMP13, NPR2, and SHOX), signal transduction (PTPN11), DNA/RNA replication (DNAJC21, GZF1, and LIG4), cytoskeletal structure (CCDC8, FLNA, and PCNT), transmembrane transport (SLC34A3 and SLC7A7), enzyme coding (CYP27B1, GALNS, and GNPTG), and ciliogenesis (CFAP410). Two additional participants had Silver-Russell syndrome and 1 had del22q.11.21. Syndromic SS was predictive in identifying a monogenic condition. Using a gene panel would yield positive results in only 10% to 33% of cases. CONCLUSION: A tailored testing strategy is essential to increase diagnostic yield in children with SS from consanguineous populations.

• MeSH
• Algorithms MeSH
• Child MeSH
• Genetic Testing * methods   MeSH
• Humans MeSH
• Adolescent MeSH
• Mutation genetics   MeSH
• Dwarfism genetics   diagnosis   MeSH
• Consanguinity * MeSH
• Growth Disorders genetics   diagnosis   MeSH
• Child, Preschool MeSH
• Pedigree MeSH
• Exome Sequencing methods   MeSH
• Body Height genetics   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Iraq MeSH

BACKGROUND: The knowledge and proficiency of primary care practitioners (PCPs) in diagnosing and managing irritable bowel syndrome (IBS) remain generally low and variable internationally. This variability is partly due to a lack of familiarity with the Rome Foundation diagnostic criteria and treatment guidelines for this condition. METHODS: We conducted an electronic survey of PCPs in the United States and nine European countries to assess their understanding of IBS pathophysiology; the use of Rome IV criteria in diagnosis, knowledge of and frequency in prescribing various recommended treatments; and the likelihood of referring patients with suspected IBS to subspecialists. RESULTS: Most PCPs in the United States and Europe perceive IBS as a diagnosis of exclusion rather than a definitive diagnosis. They also believe IBS is underdiagnosed in primary care and challenging to diagnose confidently. The majority of PCPs consider diet as a crucial component of IBS management. Notably, US PCPs reported greater confidence than their European counterparts in recommending dietary interventions such as increased dietary fiber, a low FODMAP diet, and gluten restriction. Conversely, both groups exhibited moderate to high confidence in recommending over-the-counter treatments. European PCPs showed greater confidence in treating IBS with antispasmodics and secretagogues, while US PCPs expressed greater confidence in prescribing neuromodulators. Additionally, US PCPs were more likely to refer patients with suspected IBS to a gastroenterologist, whereas both US and European PCPs showed similar referral patterns to dietitians and referred very few patients to mental health providers. Both US and European PCPs reported that IBS is moderately to extremely difficult to treat effectively and emphasized the importance of a strong and longitudinal doctor-patient relationship in managing the condition. CONCLUSION: Despite the Rome Foundation recommendations and criteria to support a positive diagnosis of IBS, most PCPs still rely on exclusionary investigations such as endoscopy and a serologic workup, while a significant percentage suggest referring patients to gastroenterologists.

• MeSH
• Physicians, Primary Care MeSH
• Practice Patterns, Physicians' * statistics & numerical data   MeSH
• Humans MeSH
• Attitude of Health Personnel MeSH
• Primary Health Care MeSH
• Surveys and Questionnaires MeSH
• Irritable Bowel Syndrome * diagnosis   therapy   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Europe MeSH
• United States MeSH