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Consensus definition and diagnostic criteria for neonatal encephalopathy—study protocol for a real-time modified delphi study
Full text linkBackground: ‘Neonatal encephalopathy’ (NE) describes a group of conditions in term infants presenting in the earliest days after birth with disturbed neurological function of cerebral origin. NE is aetiologically heterogenous; one cause is peripartum hypoxic ischaemia. Lack of uniformity in the terminology used to describe NE and its diagnostic criteria creates difficulty in the design and interpretation of research and complicates communication with families. The DEFINE study aims to use a modified Delphi approach to form a consensus definition for NE, and diagnostic criteria. Methods: Directed by an international steering group, we will conduct a systematic review of the literature to assess the terminology used in trials of NE, and with their guidance perform an online Real-time Delphi survey to develop a consensus diagnosis and criteria for NE. A consensus meeting will be held to agree on the final terminology and criteria, and the outcome disseminated widely. Discussion: A clear and consistent consensus-based definition of NE and criteria for its diagnosis, achieved by use of a modified Delphi technique, will enable more comparability of research results and improved communication among professionals and with families. Impact: The terms Neonatal Encephalopathy and Hypoxic Ischaemic Encephalopathy tend to be used interchangeably in the literature to describe a term newborn with signs of encephalopathy at birth. This creates difficulty in communication with families and carers, and between medical professionals and researchers, as well as creating difficulty with performance of research. The DEFINE project will use a Real-time Delphi approach to create a consensus definition for the term ‘Neonatal Encephalopathy’. A definition formed by this consensus approach will be accepted and utilised by the neonatal community to improve research, outcomes, and parental experience
How accurate is high-resolution computed tomography of the chest in differentiating between pulmonary invasive fungal infections and other pulmonary infections in children with cancer?
No full textBACKGROUND: Pulmonary invasive fungal infections pose a serious risk for immunocompromised patients. Although diagnostic imaging plays an important role in the early detection of pulmonary invasive fungal infections, radiological differentiation between invasive fungal infection and other pulmonary infections is challenging. OBJECTIVE: The aim of this study was to assess the accuracy of chest high-resolution computed tomography (HRCT) in the differentiation between pulmonary invasive fungal infections and other pulmonary infections in paediatric cancer patients. MATERIALS AND METHODS: In this retrospective study, baseline HRCTs of patients with probable or proven invasive fungal infections and other pulmonary infections were blindly assessed by two radiologists, followed by a consensus reading. The scoring form included imaging characteristics and radiological invasive fungal infection probability assessment. Inter-rater reliability was determined with Cohen's kappa. RESULTS: Chest HRCTs (n = 77) of paediatric cancer patients with pulmonary invasive fungal infections (n = 45) and with other pulmonary infections (n = 32) were evaluated. In the consensus reading, nodules with halo sign and wedge-shaped consolidations were observed significantly more in pulmonary invasive fungal infections than in other pulmonary infections (86.7% vs. 34.4% and 28.9% vs. 9.4%), and ground-glass opacities were observed less frequently (61.4% vs. 87.5%). The kappa values for the individual imaging characteristics ranged from 0.121 to 0.408. Sensitivity of the HRCT to diagnose a pulmonary invasive fungal infection ranged from 0.78 to 0.80, and specificity from 0.66 to 0.88. CONCLUSION: The accuracy of chest HRCTs in differentiating between invasive fungal infections and other pulmonary infections is poor. There are two main reasons for this: no individual imaging characteristic was found to be able to fully distinguish between invasive fungal infections and other pulmonary infections, and the agreement between radiologists was only moderate
Prevalence of lower extremity edema following inguinal lymphadenectomy: A systematic review and meta-analysis
Full text linkBackground: Lower extremity lymphedema (LEL) can develop because of inguinal lymph node dissection in the treatment of gynecologic, genitourinary, and dermatological malignancies. To optimize patient counseling and patient selection for microsurgical interventions aimed at preventing or treating LEL, its prevalence and associated patient characteristics must be accurately documented. This systematic review and meta-analysis provides a comprehensive overview of literature on the reported prevalence of LEL in patients undergoing inguinal lymphadenectomy. Methods: From Embase, PubMed, and Web of Science databases, 23 studies were identified that met the inclusion criteria. This review was conducted in accordance with the preferred reporting items for systematic reviews and meta-analyses guidelines. Risk of bias was assessed using the Risk of Bias in Non-randomized Studies-of Exposure tool. Results: Random-effects meta-analyses of proportions estimated a 24% (95% confidence interval [CI]: 17-31) pooled prevalence of LEL with a high degree of heterogeneity between the studies (I2=96%, p < 0.01). Subgroup analysis revealed significant differences in LEL prevalence based on the indications for inguinal lymphadenectomy. The pooled LEL prevalence was 25.75% (95% CI: 0.00-96.16) for patients who underwent lymphadenectomy for melanoma, 12.22% (95% CI: 1.03-23.40) for penile cancer, 30.96% (95% CI: 21.08-40.84) for vulvar cancer, and 13.62% (95% CI: 0.00-51.02) for miscellaneous indications. Conclusion: The findings from this study emphasize the importance of considering malignancy etiology when assessing the risk of LEL following inguinal lymphadenectomy. This knowledge could aid physicians in informing patients about the risk of LEL, while also facilitating proper patient selection for microsurgical interventions
A Systematic Review of Challenges and Opportunities in the Implementation of Managed Entry Agreements for Advanced Therapy Medicinal Products
Full text linkPURPOSE: Managed Entry Agreements (MEAs) are agreements between firms and competent authorities for pricing and reimbursement, designed to enable coverage of new medicines while managing uncertainties around their financial impact or performance. Although these agreements can facilitate patient access, their complexity and costs seem to dampen enthusiasm for implementation. Nevertheless, MEAs remain a potential route, particularly for high-cost drugs with uncertain value claims. Given their pivotal role in bridging Advanced Therapy Medicinal Products (ATMPs) to patients, their foreseeable future implementation calls for a specific investigation of their associated challenges and opportunities. Therefore, this work aims to identify challenges and opportunities in implementing MEAs specifically for ATMPs. METHODS: A systematic literature review was conducted on PubMed, MEDLINE, Scopus, and Google Scholar, based on the updated Preferred Reporting Items for Systematic Review and Meta-Analysis. This has been supplemented by a snowball search. Through the thematic content analysis, opportunities and challenges were identified and grouped into themes and subthemes. Afterward, the subgroup analysis was performed to investigate challenges and opportunities with outcome-based agreements (OBAs) versus financial-based agreements (FBAs), jurisdiction, and ATMP type. FINDINGS: Of the 787 peer-reviewed articles, 42 met the inclusion criteria. Challenges and opportunities were clustered into the mentioned themes: evidence generation and data management, financial and reimbursement, administration and resources, negotiation, and governance, law, and regulations. Of note, no specific challenges or opportunities were found to be cell- or gene-therapy-specific, but certain challenges seem amplified for ATMPs. Several differences emerged per MEA type and jurisdiction. OBAs are described to reward innovative and effective treatments and boost research and development (R&D) returns. FBAs improve cost-effectiveness ratios but can negatively affect curative ATMP's revenues. Still, their versatility facilitates payer engagement in MEA combinations (eg, OBA with spread payments). The US decentralized health care system reported additional implementation challenges to OBAs. Each payer internally decides on reimbursement, and coordination among private payers is hindered by antitrust law. Yet, a new Cell and Gene Therapy Access model has been proposed. This would allow manufacturers to negotiate OBAs directly with the Centers for Medicare & Medicaid Services avoiding individual negotiation with each state. In Europe, there is an evident interest in implementing spread payments, yet accounting rules currently hamper their implementation. IMPLICATIONS: This work offers insights into challenges and opportunities in MEAs implementation for ATMPs by investigating differences in MEA types and jurisdictions. Our findings provide significant insights that may help move successful MEA implementation forward, improving patient access to ATMPs
Early warning systems for identifying severe maternal outcomes: findings from the WHO global maternal sepsis study
Full text linkBackground: Infections and sepsis are leading causes of morbidity and mortality in women during pregnancy and the post-pregnancy period. Using data from the 2017 WHO Global Maternal Sepsis Study, we explored the use of early warning systems (EWS) in women at risk of sepsis-related severe maternal outcomes. Methods: On April 27, 2023, we searched the literature for EWS in clinical use or research in obstetric populations. We calculated the proportion of women for whom each existing EWS identified them as at risk for developing severe maternal outcomes by infection severity (complications and severe maternal outcomes). Sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratios, and J statistics were calculated to assess EWS performance. Machine learning was used to test the diagnostic potential of routine maternal sepsis markers. Findings: 21 EWS were assessed in 2560 women from 46 countries with suspected or confirmed infections. The NICE Risk Stratification tool, Modified Shock Index, maternity Systemic Inflammatory Response Syndrome, and Early Maternal Infection Prompts scores had high sensitivity (88.1–97.5%) for identifying sepsis-related severe maternal outcomes. The quick Sequential Organ Failure Assessment (SOFA) in Pregnancy score and Obstetrically modified SOFA had high specificity (90.4–100%) for identifying women with sepsis-related severe maternal outcomes. Furthermore, combinations of sepsis markers had very low sensitivity and high specificity using machine learning. Interpretation: No score demonstrated enough diagnostic accuracy to be used alone to identify sepsis. However, obstetric—and sepsis-specific EWS performed better for early identification of maternal sepsis than non-obstetric and non-sepsis-specific scoring systems. There are limitations to applying EWS to real-world data, mainly due to the incompleteness of medical data that hinders EWS effectiveness. There is a need to continue developing and testing criteria for early identification of maternal sepsis. Funding: UNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), WHO, Merck for Mothers, U.S. Agency for International Development, Wellcome Trust, and National Institute for Health and Care Research
Evaluation and clinical applicability of angiography-derived assessment of coronary microcirculatory resistance: a [15O]H2O PET study
No full textThe introduction of wire-free microcirculatory resistance index from functional angiography (angio-IMR) promises swift detection of coronary microvascular dysfunction, however it has not been properly validated. We sought to validate angio-IMR against invasive IMR and PET derived microvascular resistance (MVR). Moreover, we studied if angio-IMR could aid in the detection of ischemia with non-obstructive coronary arteries (INOCA). In this investigator-initiated study symptomatic patients underwent [15O]H2O positron emission tomography (PET) and invasive angiography with 3-vessel fractional flow reserve (FFR). Invasive IMR was measured in 40 patients. Angio-IMR and QFR were computed retrospectively. MVR was defined as the ratio of mean distal coronary pressure to PET derived coronary flow. PET and QFR/angio-IMR analyses were performed by blinded core labs. The right coronary artery was excluded. A total of 211 patients (mean age 61 ± 9, 148 (70%) male) with 312 vessels with successful angio-IMR analyses were included. Angio-IMR correlated moderately with invasive IMR (r = 0.48, p < 0.01), whereas no correlation was found between angio-IMR and MVR (r=-0.07, p = 0.25). Angio-IMR did not differ for vessels without obstructive coronary artery disease (CAD) (FFR-) but with reduced stress perfusion (PET+) compared to vessels without obstructive CAD (FFR-) with normal stress perfusion (PET-) (median 28.19 IQR 20.42–38.99 vs. 31.67 IQR 23.47–40.63, p = 0.40). Angio-IMR correlated moderately with invasively measured IMR, whereas angio-IMR did not correlate with PET derived MVR. Moreover, angio-IMR did not reliably identify patients with INOCA
Ischemia during exercise stress testing, an indication of coronary vasomotor dysfunction?
Full text linkBackground: Recently it has been suggested that coronary microvascular dysfunction (CMD) may explain the high false-positive rate of exercise electrocardiographic stress testing (EST). However, patients with angina but non-obstructive coronary artery disease (ANOCA) present with a broader spectrum of coronary vasomotor dysfunction (CVDys), namely coronary artery spasm (CAS), CMD or a combination of both. We aim to investigate the diagnostic value of EST for the entire CVDys spectrum. Methods: We included patients who underwent coronary function testing (CFT) in the Radboud University Medical Center. For each patient we requested the most recent EST report. ESTs were denoted as positive for ischemia if clinically significant ST-segment depression was detected. We calculated the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) with 95% confidence intervals for the diagnosis of CVDys and its endotypes. Results: Of the 105 included patients (87 % women, mean age 57 (±8) years), 22 (21 %) had ischemia during EST. CVDys was diagnosed in 94 patients (90 %), of whom 58 patients had an isolated endotype (CAS: n = 51, CMD: n = 7) and 36 patients had CAS and CMD. Ischemia during EST yielded a high specificity and PPV for CVDys (specificity: 100 % (71.5–100 %), PPV: 100 % (84.6–100 %)), which remained reasonably similar for CAS (specificity: 94.4 % (72.7–99.9 %), PPV: 95.5 % (77.2–99.9 %)), but was lower for CMD (specificity: 85.5 % (74.2–93.1 %), PPV: 59.1 % (36.4–79.3 %)). Conclusions: Ischemia during EST is highly specific for CVDys in general and can be an indicator for CAS and to a lesser extent for CMD in patients with ANOCA
Understanding Parkinson's: The microbiome and machine learning approach
Full text linkObjective: Given that Parkinson's disease is a progressive disorder, with symptoms that worsen over time, our goal is to enhance the diagnosis of Parkinson's disease by utilizing machine learning techniques and microbiome analysis. The primary objective is to identify specific microbiome signatures that can reproducibly differentiate patients with Parkinson's disease from healthy controls. Methods: We used four Parkinson-related datasets from the NCBI repository, focusing on stool samples. Then, we applied a DADA2-based script for amplicon sequence processing and the Recursive Ensemble Feature Selection (REF) algorithm for biomarker discovery. The discovery dataset was PRJEB14674, while PRJNA742875, PRJEB27564, and PRJNA594156 served as testing datasets. The Extra Trees classifier was used to validate the selected features. Results: The Recursive Ensemble Feature Selection algorithm identified 84 features (Amplicon Sequence Variants) from the discovery dataset, achieving an accuracy of over 80%. The Extra Trees classifier demonstrated good diagnostic accuracy with an area under the receiver operating characteristic curve of 0.74. In the testing phase, the classifier achieved areas under the receiver operating characteristic curves of 0.64, 0.71, and 0.62 for the respective datasets, indicating sufficient to good diagnostic accuracy. The study identified several bacterial taxa associated with Parkinson's disease, such as Lactobacillus, Bifidobacterium, and Roseburia, which were increased in patients with the disease. Conclusion: This study successfully identified microbiome signatures that can differentiate patients with Parkinson's disease from healthy controls across different datasets. These findings highlight the potential of integrating machine learning and microbiome analysis for the diagnosis of Parkinson's disease. However, further research is needed to validate these microbiome signatures and to explore their therapeutic implications in developing targeted treatments and diagnostics for Parkinson's disease
Psychosocial and cognitive determinants of 10-year depressive symptom trajectories in patients with cardiovascular disease: The SMART-Medea Study
Full text linkBackground: Middle-aged and older adults presenting clinically relevant depressive symptoms are often undiagnosed. Understanding the determinants of late-life depressive symptoms could improve prognosis. Further, individuals with manifest cardiovascular disease (CVD) are at an increased risk of depression. This study investigated if psychosocial and cognitive factors are associated with depressive symptom trajectories in individuals with CVD. Methods: Longitudinal data from the SMART-Medea study of 752 participants (median age 62 years, women 18 %) with a history of CVD was used. Psychosocial determinants (i.e., history of depression, anxiety, neuroticism, locus of control, adverse childhood events, recent adverse events, social support, and somatization) and cognition (i.e., memory functioning, working memory, executive functioning, and processing speed) were assessed via multinomial logistic regressions with depressive symptoms trajectories as outcome (i.e., “never depressed” (reference), “energy/sleep difficulties”, “mild depressive symptoms” and “fluctuating severe depression”). Depressive symptom trajectories were based off of longitudinal PHQ-9 scores and created using latent class analysis. Analyses were adjusted for age, sex/gender, and education. Results: All psychosocial factors were associated with depressive symptom trajectories, except for social support, with increasing associations from the “energy/sleep difficulties” to the “fluctuating severe depression”. For cognitive factors, only memory functioning was associated with decreased odds of “fluctuating severe depression” (OR = 0.63, 95 % CI = 0.47–0.85). Limitations: The study population consisted of mostly white male participants with CVD; thus, the generalizability to other populations is low. Conclusions: Our findings emphasize that a wide range of psychosocial factors are associated with mild as well as severe trajectories of depressive symptoms in patients with manifest CVD. Focusing on psychosocial factors could improve one's prognosis of depressive symptomology
STAT1 regulates immune-mediated intestinal stem cell proliferation and epithelial regeneration
Full text linkThe role of the immune system in regulating tissue stem cells remains poorly understood, as does the relationship between immune-mediated tissue damage and regeneration. Graft vs. host disease (GVHD) occurring after allogeneic bone marrow transplantation (allo-BMT) involves immune-mediated damage to the intestinal epithelium and its stem cell compartment. To assess impacts of T-cell-driven injury on distinct epithelial constituents, we have performed single cell RNA sequencing on intestinal crypts following experimental BMT. Intestinal stem cells (ISCs) from GVHD mice have exhibited global transcriptomic changes associated with a substantial Interferon-γ response and upregulation of STAT1. To determine its role in crypt function, STAT1 has been deleted within murine intestinal epithelium. Following allo-BMT, STAT1 deficiency has resulted in reduced epithelial proliferation and impaired ISC recovery. Similarly, epithelial Interferon-γ receptor deletion has also attenuated proliferation and ISC recovery post-transplant. Investigating the mechanistic basis underlying this epithelial response, ISC STAT1 expression in GVHD has been found to correlate with upregulation of ISC c-Myc. Furthermore, activated T cells have stimulated Interferon-γ-dependent epithelial regeneration in co-cultured organoids, and Interferon-γ has directly induced STAT1-dependent c-Myc expression and ISC proliferation. These findings illustrate immunologic regulation of a core tissue stem cell program after damage and support a role for Interferon-γ as a direct contributor to epithelial regeneration