Categorization systems for tick-borne encephalitis virus (TBEV) infection lack consistency in classifying disease severity. To evaluate the need for a standard, consensus-based categorisation system for TBEV infection across subtypes, we gathered an expert panel of clinicians and scientists with diverse expertise in TBEV infection. Consensus was sought using the Delphi technique, which consisted of 2 web-based survey questionnaires and a final, virtual, consensus-building exercise. Ten panellists representing 8 European countries participated in the Delphi exercise, with specialities in neurology, infectious disease, paediatrics, immunology, virology, and epidemiology. Panellists reached unanimous consensus on the need for a standardised, international categorisation system to capture both clinical presentation and severity of TBEV infection. Ideally, such a system should be feasible for use at bedside, be clear and easy to understand, and capture both the acute and follow-up phases of TBEV infection. Areas requiring further discussion were (1) the timepoints at which assessments should be made and (2) whether there should be a separate system for children. This Delphi panel study found that a critical gap persists in the absence of a feasible and practical classification system for TBEV infection. Specifically, the findings of our Delphi exercise highlight the need for the development of a user-friendly classification system that captures the acute and follow-up (i.e., outcome) phases of TBEV infection and optimally reflects both clinical presentation and severity. Development of a clinical categorisation system will enhance patient care and foster comparability among studies, thereby supporting treatment development, refining vaccine strategies, and fortifying public health surveillance.
- MeSH
- Delphi Technique * MeSH
- Encephalitis, Tick-Borne * epidemiology virology diagnosis MeSH
- Consensus MeSH
- Humans MeSH
- Encephalitis Viruses, Tick-Borne * classification MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Limited licensed medications are available for multiple sclerosis (MS) in pediatric patients. OBJECTIVE: To evaluate the efficacy, safety, and tolerability of alemtuzumab in pediatric patients with relapsing-remitting multiple sclerosis (RRMS) and disease activity on prior disease-modifying therapies (DMTs). METHODS: LemKids was a multicenter, multinational, single-arm, open-label, switch (from ongoing DMT to alemtuzumab treatment) study in pediatric RRMS patients (aged 10-<18 years), with disease activity on DMT. The primary endpoint was a comparison of the number of new/enlarging T2 lesions on the magnetic resonance imaging of the brain between the prior-DMT period and alemtuzumab treatment. RESULTS: This study was prematurely terminated due to low enrollment and an European Medicines Agency Article-20 pharmacovigilance review of alemtuzumab in adult RRMS. Of 46 screened patients, 16 were enrolled; 12 completed prior-DMT treatment period; 11 received alemtuzumab of whom 7 completed treatment. Patients on alemtuzumab developed fewer new/enlarging T2 lesions compared with prior-DMT (7 vs 178, relative risk (95% confidence interval): 0.04 (0.01-0.14)). No significant pharmacodynamic changes or safety concerns were noted in this limited dataset. CONCLUSION: Alemtuzumab treatment was associated with a low number of new/enlarging T2 lesions in pediatric patients with RRMS and was safe and well tolerated in seven patients during infusion and the initial 4 months.
- MeSH
- Alemtuzumab * adverse effects MeSH
- Child MeSH
- Immunologic Factors * adverse effects administration & dosage MeSH
- Humans MeSH
- Magnetic Resonance Imaging MeSH
- Adolescent MeSH
- Multiple Sclerosis, Relapsing-Remitting * drug therapy diagnostic imaging MeSH
- Treatment Outcome MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
BACKGROUND AND OBJECTIVE: Non-muscle-invasive bladder cancer (NMIBC) poses a significant clinical challenge, particularly when failing bacillus Calmette-Guérin (BCG) therapy, necessitating alternative treatments. Despite radical cystectomy being the recommended treatment, many patients are unfit or unwilling to undergo this invasive procedure, highlighting the need for effective bladder-sparing therapies. This review aims to summarize and report the evidence on the efficacy and to estimate the costs of bladder-preserving strategies used in NMIBC recurrence after failure of intravesical BCG therapy. METHODS: We systematically searched online databases for prospective studies investigating intravesical therapy, systemic therapy, or combination of both in patients treated previously with BCG. Owing to significant heterogeneity across the studies, a meta-analysis was inappropriate. A sensitivity analysis was performed in an exploratory manner. We used a decision-analytic Markov model to compare novel U.S. Food and Drug Administration-approved treatments with a 2-yr time horizon. KEY FINDINGS AND LIMITATIONS: A total of 57 studies published between 1998 and 2024, with 68 unique study arms and consisting of 2589 patients, were identified. The 3-mo overall response rate (ORR) across all studies, complete response rate (CRR) in concomitant carcinoma in situ (CIS) or CIS only disease, and recurrence-free rate (RFR) in papillary disease were estimated to be 52.4% (95% confidence interval [CI]: 45.4-59.2), 52.8% (95% CI: 42.9-62.6), and 26.4% (95% CI: 13.3-45.6), respectively. The 12-mo ORR, CRR, and RFR were estimated to be 78% (95% CI: 52.9-91.8), 27.8% (95% CI: 21.3-35.4), and 25.4% (95% CI: 18.2-34.2), respectively. The progression rate was estimated to be 13% (95% CI: 9-18.2). The mean proportion of patients treated with radical cystectomy was estimated to be 24.7 (range 0-85.7). The reported toxicity grades were overall mild, with a median of 3.4% (range 0-33.3%) participants experiencing a dose limiting toxicity. Compared with using radical cystectomy to treat patients failing BCG therapy, at a willingness-to-pay threshold of 100 000 USD, nadofaragene firadenovec was cost effective, with an incremental cost-effectiveness ratio (ICER) of 10 014 USD per quality-adjusted life year (QALY), while nogapendekin alfa inbakicept was less cost effective than nadofaragene firadenovec (ICER of 44 602 USD per QALY). Pembrolizumab, which dominated, was both less costly and more effective than the other strategies. CONCLUSIONS AND CLINICAL IMPLICATIONS: Salvage bladder-sparing therapies show a response rate of around 50% at 3 mo in patients with NMIBC failing BCG. However, long-term data are heterogeneous. Nevertheless, recently developed agents show promising tumor control activity. In the rapidly evolving landscape of urothelial cancer, some of these treatment strategies might be cost effective and improve patients' quality of life. The findings of our review highlight the need for novel, more effective therapeutic strategies. PATIENT SUMMARY: In this study, we reviewed the evidence on the efficacy of bladder-preserving strategies used in patients with bladder cancer recurrence after failing bacillus Calmette-Guérin (BCG) therapy. We found that these strategies show a response rate of around 50% at 3 mo. However, long-term data are heterogeneous. Nevertheless, recently developed agents show promising tumor control activity. In the rapidly evolving landscape of urothelial cancer, some of these treatment strategies might be cost effective and improve patients' quality of life.
- MeSH
- Adjuvants, Immunologic * therapeutic use economics MeSH
- Cost-Benefit Analysis * MeSH
- Administration, Intravesical MeSH
- BCG Vaccine * therapeutic use economics MeSH
- Neoplasm Invasiveness MeSH
- Humans MeSH
- Neoplasm Recurrence, Local MeSH
- Non-Muscle Invasive Bladder Neoplasms MeSH
- Urinary Bladder Neoplasms * drug therapy pathology therapy economics MeSH
- Treatment Failure MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
- Systematic Review MeSH
OBJECTIVES: The development of External Quality Assessment Schemes (EQAS) for clinical flow cytometry (FCM) is challenging in the context of rare (immunological) diseases. Here, we introduce a novel EQAS monitoring the primary immunodeficiency Orientation Tube (PIDOT), developed by EuroFlow, in both a 'wet' and 'dry' format. This EQAS provides feedback on the quality of individual laboratories (i.e., accuracy, reproducibility and result interpretation), while eliminating the need for sample distribution. METHODS: In the wet format, marker staining intensities (MedFIs) within landmark cell populations in PIDOT analysis performed on locally collected healthy control (HC) samples, were compared to EQAS targets. In the dry format, participants analyzed centrally distributed PIDOT flow cytometry data (n=10). RESULTS: We report the results of six EQAS rounds across 20 laboratories in 11 countries. The wet format (212 HC samples) demonstrated consistent technical performance among laboratories (median %rCV on MedFIs=34.5 %; average failure rate 17.3 %) and showed improvement upon repeated participation. The dry format demonstrated effective proficiency of participants in cell count enumeration (range %rCVs 3.1-7.1 % for the major lymphoid subsets), and in identifying lymphoid abnormalities (79.3 % alignment with reference). CONCLUSIONS: The PIDOT-EQAS allows laboratories, adhering to the standardized EuroFlow approach, to monitor interlaboratory variations without the need for sample distribution, and provides them educational support to recognize rare clinically relevant immunophenotypic patterns of primary immunodeficiencies (PID). This EQAS contributes to quality improvement of PID diagnostics and can serve as an example for future flow cytometry EQAS in the context of rare diseases.
BACKGROUND & AIMS: Homozygous Pi∗Z mutation in alpha-1 antitrypsin (Pi∗ZZ genotype) predisposes to pulmonary loss-of-function and hepatic gain-of-function injury. To facilitate selection into clinical trials typically targeting only 1 organ, we systematically evaluated an international, multicenter, longitudinal, Pi∗ZZ cohort to uncover natural disease course and surrogates for future liver- and lung-related endpoints. METHODS: Cohort 1 recruited 737 Pi∗ZZ individuals from 25 different centers without known liver comorbidities who received a baseline clinical and laboratory assessment as well as liver stiffness measurement (LSM). A follow-up interview was performed after at least 6 months. Cohort 2 consisted of 135 Pi∗ZZ subjects without significant liver fibrosis, who received a standardized baseline and follow-up examination at least 2 years later, both including LSM. RESULTS: During 2634 patient-years of follow-up, 39 individuals died, with liver and lung being responsible for 46% and 36% of deaths, respectively. Forty-one Pi∗ZZ subjects who developed a hepatic endpoint presented with significantly higher baseline liver fibrosis surrogates, that is, LSM (24 vs 5 kPa, P < .001) and aspartate aminotransferase-to-platelet ratio index (1.1 vs 0.3 units, P < .001). Liver-related endpoints within 5 years were most accurately predicted by LSM (area under the curve 0.95) followed by aspartate aminotransferase-to-platelet ratio index (0.92). Baseline lung parameters displayed only a moderate predictive utility for lung-related endpoints within 5 years (forced expiratory volume in the first second area under the curve 0.76). Fibrosis progression in those with no/mild fibrosis at baseline was rare and primarily seen in those with preexisting risk factors. CONCLUSIONS: Noninvasive liver fibrosis surrogates accurately stratify liver-related risks in Pi∗ZZ individuals. Our findings have direct implications for routine care and future clinical trials of Pi∗ZZ patients.
- MeSH
- alpha 1-Antitrypsin * genetics blood MeSH
- Biomarkers blood MeSH
- Time Factors MeSH
- alpha 1-Antitrypsin Deficiency * genetics diagnosis complications MeSH
- Adult MeSH
- Elasticity Imaging Techniques MeSH
- Genotype MeSH
- Homozygote MeSH
- Liver Cirrhosis * genetics diagnosis MeSH
- Middle Aged MeSH
- Humans MeSH
- Longitudinal Studies MeSH
- Mutation MeSH
- Lung physiopathology pathology diagnostic imaging MeSH
- Lung Diseases genetics etiology diagnosis MeSH
- Disease Progression * MeSH
- Risk Factors MeSH
- Severity of Illness Index MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
Acute kidney injury (AKI) due to gentamicin nephrotoxicity is a significant concern in clinical medicine, particularly in patients receiving prolonged or high-dose gentamicin therapy. Gentamicin is an aminoglycoside antibiotic frequently used in the treatment of a range of bacterial infections. However, its use is associated with nephrotoxicity which can manifest as AKI. Due to this, it is crucial to diagnose promptly and manage treatment effectively. Ongoing studies are therefore focusing on non-protein-coding RNAs as potential biomarkers for AKI. Numerous microRNAs (miRNAs) have been implicated in gentamicin-induced nephrotoxicity and AKI. They participate in pathways associated with inflammation, cell death, and oxidative stress and each of these factors play critical roles in the development of gentamicin-induced kidney injury. Research studies have demonstrated changes in the expression levels of these miRNAs in response to gentamicin exposure both in vitro and in in vivo models, as well as in human clinical trials involving patients receiving gentamicin therapy. The dysregulation of these miRNAs correlates with the severity of kidney injury and may serve as sensitive biomarkers for early detection and monitoring of AKI induced by gentamicin.
- MeSH
- Acute Kidney Injury * chemically induced diagnosis MeSH
- Anti-Bacterial Agents * adverse effects MeSH
- Biomarkers * MeSH
- Gentamicins * adverse effects MeSH
- Humans MeSH
- MicroRNAs * MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Plasma circulating donor-derived cell-free DNA (ddcfDNA) can be used to noninvasively monitor acute rejection of heart transplants (HTx). This study utilized digital droplet PCR to analyze ddcfDNA concentrations (measured in copies per milliliter) and the fractional abundance (%ddcfDNA) to differentiate between donor and recipient DNA on the basis of single nucleotide polymorphism (SNP) homozygosity. Seventy-seven patients participated in a study, providing 300 plasma samples. Both markers, mean ddcfDNA (cp/mL) and %ddcfDNA, showed similar decreasing trends following the HTx, (R2 < 0.2; p < 0.001). Significantly higher levels of ddcfDNA (cp/mL) and %ddcfDNA were observed during episodes of acute rejection (AR) compared to non-rejection samples (p < 0.001). Additionally, antibody-mediated rejection (AMR) was associated with increased %ddcfDNA levels compared to non-rejection and to acute cellular rejection samples (p < 0.001 and p < 0.01). A logistic regression model identified %ddcfDNA as an early predictor of AMR risk 10-19 days post-heart transplant (odds ratio 158, p < 0.02). Performance analysis established an optimal %ddcfDNA threshold of 0.125% for AMR detection, correctly identifying all patients without subsequent AMR. These findings suggest that early %ddcfDNA measurements post-HTx can accurately identify individuals unlikely to develop AMR during the first posttransplant year.
- MeSH
- Biomarkers * blood MeSH
- Early Diagnosis MeSH
- Tissue Donors * MeSH
- Adult MeSH
- Isoantibodies * immunology MeSH
- Middle Aged MeSH
- Humans MeSH
- Follow-Up Studies MeSH
- Graft Survival MeSH
- Prognosis MeSH
- Graft Rejection * diagnosis etiology blood MeSH
- Risk Factors MeSH
- Heart Transplantation * adverse effects MeSH
- Cell-Free Nucleic Acids * blood genetics MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Severe combined immunodeficiency (SCID) is a fatal but treatable inborn error of immunity (IEI). Newborn screening (NBS) using T-cell receptor excision circles (TREC) has been adopted globally, with very few countries incorporating kappa recombination excision circles (KREC) to also detect early B-cell development disorders, such as X-linked agammaglobulinemia (XLA). OBJECTIVE: To evaluate the effectiveness of a 2-year pilot SCID NBS program in the Czech Republic, emphasising the utility of combined TREC/KREC screening. METHODS: Between January 2022 and December 2023, a dual TREC/KREC NBS pilot was conducted across the Czech Republic, alongside spinal muscular atrophy (SMA) screening. Approximately 200,000 newborns were screened using quantitative real-time PCR on dried blood spots collected 48-72 h after birth. RESULTS: The pilot referred 58 newborns, identifying 21 cases of IEI, including two SCID cases, with an overall incidence of TREC/KREC screenable IEI of 10.5/100,000 newborns. SCID incidence was 1/100,000. KREC screening proved invaluable, detecting 10 cases of congenital agammaglobulinemia including novel non-XLA forms, which increased the estimated incidence of agammaglobulinemia in the Czech Republic sixfold. Over one-third of low KREC results were linked to maternal immunosuppression. CONCLUSION: The Czech pilot demonstrated the effectiveness of integrated TREC/KREC NBS in detecting both T- and B-cell immunodeficiencies. As of 2024, SCID and SMA screening are included in the nationwide NBS, with KREC screening significantly improving early detection of B-cell disorders.
- MeSH
- Agammaglobulinemia diagnosis MeSH
- B-Lymphocytes immunology MeSH
- Genetic Diseases, X-Linked MeSH
- Humans MeSH
- Infant, Newborn MeSH
- Neonatal Screening * methods MeSH
- Pilot Projects MeSH
- Receptors, Antigen, T-Cell * genetics MeSH
- Severe Combined Immunodeficiency * diagnosis genetics epidemiology MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Infant, Newborn MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Czech Republic MeSH
Influenza is a significant global health problem, causing disease and hospitalisations in elderly individuals and infants. While updated vaccines are available every year, their effectiveness is moderate at best. FLUniversal is a European Union funded consortium, aiming to develop a universal influenza vaccine by bringing together partners with expertise in different areas of vaccine development. An intranasal live attenuated vaccine, DeltaFLU, will be produced using an innovative platform; preclinical assessment in animal models and clinical studies using a controlled human infection model (CHIM) will be conducted for assessment of safety, immunogenicity and protective efficacy; and finally, comprehensive immunological analysis of blood and nasal mucosa will elucidate vaccine responses and potential new correlates of protection (CoPs). In addition to a universal influenza vaccine, listed as a top priority by the EU, FLUniversal seeks to deliver an enhanced vaccine manufacturing technology that is superior in terms of efficiency, production costs and production speed - especially critical in the face of a potential new pandemic. Moreover, an influenza CHIM with a focus on harmonisation of clinical procedures and assays will be established to generate translatable and reproducible data. Newly generated knowledge on mechanisms of protection, CoPs and new molecular analysis tools may significantly contribute to our knowledge on influenza infection and influenza vaccines. In conclusion, FLUniversal is an innovative and ambitious public-private partnership, aiming to present a new development pathway for influenza vaccines, and maximising impact by bringing together leading partners from academy and industry with a shared purpose of collaboration and innovation.
- MeSH
- Administration, Intranasal MeSH
- Vaccines, Attenuated immunology administration & dosage MeSH
- Influenza, Human * prevention & control immunology MeSH
- European Union MeSH
- Humans MeSH
- Public-Private Sector Partnerships * MeSH
- Influenza Vaccines * immunology administration & dosage MeSH
- Vaccine Development * MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Cíl: Fénixin má endoteliální ochranné a protizánětlivé vlastnosti a je spojován s rozvojem hypertenze. Vzhledem k tomu, že endoteliální dysfunkce hrají významnou roli v patofyziologii preeklampsie, zaměřili jsme se na vyšetření sérových hladin fénixinu-14 a fénixinu-20 u těhotných žen s diagnostikovanou preeklampsií. Materiál a metody: V této průřezové případové studii tvořilo 45 těhotných žen s diagnostikovanou preeklampsií skupinu preeklampsie, zatímco 45 zdravých těhotných žen, které odpovídaly skupině preeklampsie věkem, indexem tělesné hmotnosti a gestačním věkem plodu, sloužilo jako kontrolní skupina. Pro analýzu hladin fénixinu-14 a fénixinu-20 ve vzorcích séra byly použity komerční soupravy. Výsledky: Bylo zjištěno, že ve skupině s preeklampsií byla hladina fénixinu-14 v séru 390,3 pg/ml, zatímco v kontrolní skupině byla 393,2 pg/ml (p = 0,434). Hladina fénixinu-20 v séru ve skupině s preeklampsií byla 346,6 pg/ml a v kontrolní skupině 379,9 pg/ml (p = 0,278). Když byla skupina s preeklampsií rozdělena do podskupin podle závažnosti onemocnění a počátku onemocnění a porovnána s kontrolní skupinou, v hladinách sérového fénixinu-14 a fénixinu-20 mezi skupinami nebyl nalezen žádný významný rozdíl. Závěr: V této studii byly sérové hladiny fénixinu-14 a fénixinu-20 u preeklampsie a u kontrolní skupiny podobné. Ačkoli je velikost vzorku příliš malá na to, aby bylo možné vyvodit definitivní závěr, zjištění naznačují, že fénixin-14 ani fénixin-20 v patofyziologii preeklampsie nehraje roli.
Objective: Phoenixin has endothelial protective and anti-inflammatory properties, but has been associated with the development of hypertension. Given that endothelial dysfunction plays a significant role in the pathophysiology of preeclampsia, we aimed to investigate the serum levels of phoenixin-14 and phoenixin-20 in pregnant women diagnosed with preeclampsia. Materials and methods: In this cross-sectional case-control study, 45 pregnant women diagnosed with preeclampsia comprised the preeclampsia group, while 45 healthy pregnant women, matched to the preeclampsia group by age, body mass index, and gestational age, served as the control group. Commercial kits were used to analyze phoenixin-14 and phoenixin-20 levels in serum samples. Results: Serum phoenixin-14 level was 390.3 pg/mL in the preeclampsia group and 393.2 pg/mL in the control group (P = 0.434). While the serum phoenixin-20 level was 346.6 pg/mL in the preeclampsia group, it was 379.9 pg/mL in the control group (P = 0.278). When the preeclampsia group was divided into subgroups according to the severity of the disease and the onset of the disease and compared with the control group, no significant difference was found between the groups regarding serum phoenixin-14 and phoenixin-20 levels. Conclusion: In this study, serum levels of phoenixin-14 and phoenixin-20 were similar in both the preeclampsia and control groups. Although the sample size is too small to draw a definitive conclusion, findings suggest that phoenixin-14 and phoenixin-20 do not play a role in the pathophysiology of preeclampsia.
- Keywords
- phoenixin 14, phoenixin 20,
- MeSH
- Biomarkers blood MeSH
- Pregnancy Complications classification blood MeSH
- Humans MeSH
- Neuropeptides * analysis classification blood MeSH
- Pre-Eclampsia * diagnosis epidemiology blood MeSH
- Cross-Sectional Studies MeSH
- Pregnant People MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Geographicals
- Turkey MeSH
