bluuebunny/crossref_metadata_2025 huggingface dataset:
Dilation of the Upper Esophageal Sphincter
Authors: Belafsky Peter C.
Published: September 2024

The upper esophageal sphincter (UES) is a 3 to 5 cm long multiplicitous high-pressure zone that connects the hypopharynx to the cervical esophagus. Due to its anatomic location between the arbitrary anatomic boundaries of numerous subspecialties, this region has often been referred to as “no man’s land.” Recent evidence confirming that the UES is not round suggests that conventional dilators designed to distend the cylindrical esophagus may be inappropriate to treat disorders of this region. This has led to the development of devices specifically designed to dilate the kidney shaped UES. The purpose of this manuscript is to review the anatomy and physiology of the UES, educate the reader on the most common indications for UES dilation, and describe the contemporary technique of state-of-the-art dilation of the UES with a novel device designed specifically to treat disorders of the pharyngo-esophageal segment.
Venetoclax-based salvage therapy as a bridge to transplant is feasible and effective in patients with relapsed/refractory AML
Authors: Unglaub Julia M. , Schlenk Richard F. , Middeke Jan Moritz , Krause Stefan W. , Kraus Sabrina , Einsele Hermann , Kramer Michael , Zukunft Sven , Kauer Joseph , Renders Simon , Katelari Elena , Schliemann Christoph , Pabst Caroline , Luft Thomas , Dreger Peter , Röllig Christoph , Bornhäuser Martin , Müller-Tidow Carsten , Sauer Tim
Published: September 2024

The B-cell lymphoma 2 inhibitor venetoclax (VEN) in combination with hypomethylating agents has been approved for first-line treatment of patients with acute myeloid leukemia (AML) ineligible for intensive treatment. VEN-containing treatment strategies may also be effective in relapsed/refractory (R/R) AML; however, comparative studies with conventional therapies for fit patients as a bridge-to-transplant strategy are limited. Using propensity score matching (PSM), we compared 37 patients with R/R AML, who received VEN-based salvage therapy as bridge to allogeneic hematopoietic stem cell transplantation (allo-HCT), with 90 patients from the German Study Alliance Leukemia AML registry, who were treated with non–VEN-containing salvage therapy according to their treating physician’s choice (TPC). The overall response rate among VEN patients was higher than the TPC control cohort (62% vs 42%; P = .049). Overall, 73% of VEN-treated patients vs 63% of TPC patients were bridged to allo-HCT (P = .41). After a median follow-up of 34.3 months for the VEN and 21.0 months for the TPC cohort, the median overall survival (OS) were 15.8 months (95% confidence interval [CI], 10.6 to not evaluable) and 10.5 months (95% CI, 6.8-19.6; P = .15), respectively. PSM revealed a trend toward improved OS for VEN patients (hazard ratio, 0.70; 95% CI, 0.41-1.22; P = .20). Median event-free survival was significantly longer in the VEN cohort (8.0 months) than the TPC cohort (3.7 months; P = .006). Our data suggest that VEN-based salvage therapy is a safe and effective bridge to allo-HCT for this difficult-to-treat AML patient population.
Magrolimab plus rituximab with or without chemotherapy in patients with relapsed/refractory diffuse large B-cell lymphoma
Authors: Maakaron Joseph E. , Asch Adam , Popplewell Leslie , Collins Graham P. , Flinn Ian W. , Ghosh Nilanjan , Keane Colm , Ku Matthew , Mehta Amitkumar , Roschewski Mark , Hacohen-Kleiman Gal , Huo Yanan , Zhang Yi , Renard Camille , Smith Sonali M. , Advani Ranjana
Published: September 2024

Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) ineligible for available salvage therapies have limited options for long-term disease control, necessitating novel treatments. Previously, magrolimab (anti–cluster-of-differentiation-47 antibody) plus rituximab (M+R) demonstrated ability to induce complete responses (CR) in R/R DLBCL. Here, we report 3-year follow-up data from this phase 1b/2 study assessing long-term safety and efficacy of M+R, and initial safety and efficacy of M+R plus gemcitabine-oxaliplatin (M+R-GemOx), in R/R DLBCL. After magrolimab priming, 4 groups of patients received M+R, 10 to 45 mg/kg magrolimab with 375 mg/m2 rituximab; patients receiving M+R-GemOx received 30 or 45 mg/kg magrolimab with 375 mg/m2 rituximab, 1000 mg/m2 gemcitabine, and 100 mg/m2 oxaliplatin. Primary end points were treatment-emergent adverse events (TEAEs) and objective response rate (ORR). Secondary end points included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Of 132 patients treated, 99 received M+R and 33 received M+R-GemOx. Most common any-grade TEAEs were fatigue (M+R, 40%; M+R-GemOx, 70%), infusion-related reactions (M+R, 39%), or anemia (M+R-GemOx, 70%). Treatment-related TEAEs led to magrolimab discontinuation in 7% (M+R) and 6% (M+R-GemOx). One death was considered treatment related (M+R-GemOx, colitis). M+R ORR was 24% (CR, 12%), and median DOR was 9.3 months. Median PFS and OS were 1.8 and 9.2 months, respectively. M+R-GemOx ORR was 52% (CR, 39%); 12-month DOR rate was 66.6% (95% confidence interval, 33.1-86.1). Median PFS and OS were 3.9 months and not reached, respectively. These results demonstrate that M+R with/without GemOx is well tolerated, and M+R-GemOx has clinical activity in patients with R/R DLBCL. This trial was registered at www.clinicaltrials.gov as #NCT02953509.
Risk of bleeding in patients with essential thrombocythemia and extreme thrombocytosis
Authors: Venkat Rathnam K. , Redd Robert A. , Harris Amyah C. , Aryee Martin J. , Marneth Anna E. , Kamaz Baransel , Kim Chulwoo J. , Wazir Mohammed , Weeks Lachelle D. , Stahl Maximilian , DeAngelo Daniel J. , Lindsley R. Coleman , Luskin Marlise R. , Hobbs Gabriela S. , How Joan
Published: September 2024

Approximately 25% of patients with essential thrombocythemia (ET) present with extreme thrombocytosis (ExT), defined as having a platelet count ≥1000 × 109/L. ExT patients may have an increased bleeding risk associated with acquired von Willebrand syndrome. We retrospectively analyzed the risk of bleeding and thrombosis in ExT vs non-ExT patients with ET at Dana-Farber Cancer Institute and Massachusetts General Hospital from 2014 to 2022 to inform treatment decisions. We abstracted the first major bleed, clinically relevant nonmajor bleed (CRNMB), and thrombotic events from medical records. We identified 128 ExT patients (28%) and 323 non-ExT patients (72%). Cumulative incidence of bleeding was not different in ExT vs non-ExT patients (21% vs 13% [P = .28] for major bleed; 16% vs 15% [P = .50] for CRNMB). Very low and low thrombotic risk ExT patients were more likely to be cytoreduced than very low- and low-risk non-ExT patients (69% vs 50% [P = .060] for very low risk; 83% vs 53% [P = .0059] for low risk). However, we found no differences in bleeding between ExT and non-ExT patients when restricting the risk of bleed from diagnosis to cytoreduction start date (28% vs 19% [P = .29] for major bleed; 24% vs 22% [P = .75] for CRNMB). Cumulative incidence of thrombosis was also not different between ExT and non-ExT patients (28% vs 25%; P = .98). This suggests that cytoreduction may not be necessary to reduce bleeding risk based only on a platelet count of 1 million. We identified novel risk factors for bleeding in patients with ET including diabetes mellitus and the DNMT3A mutation.
UM171 enhances fitness and engraftment of gene-modified hematopoietic stem cells from patients with sickle cell disease
Authors: Liu Boya , Klatt Denise , Zhou Yu , Manis John P. , Sauvageau Guy , Pellin Danilo , Brendel Christian , Williams David A.
Published: September 2024

Hematopoietic stem cell (HSC) transplantation with lentiviral vector (LVV)-transduced autologous cells has proven an effective therapeutic strategy for sickle cell disease (SCD). However, ex vivo culture or proliferative stress associated with in vivo reconstitution may amplify any underlying genetic risk of leukemia. We aimed to minimize culture-induced stress and reduce genomic damage during ex vivo culture and enhance stem cell fitness and reconstitution of SCD CD34+ cells transduced with BCL11A shmiR-encoding LVV. UM171, a pyrimidoindole derivative, can expand normal HSCs during in vitro culture and has been shown to be safe and effective using umbilical cord blood. We examined the effect of UM171 during ex vivo LVV transduction of SCD HSCs. Culture of SCD CD34+ HSCs with UM171 during transduction reduced DNA damage and reactive oxygen species, decreased apoptosis, and was associated with increased numbers of immunophenotypically defined long-term HSCs. UM171 increased the engraftment of LVV-transduced human HSCs in immunodeficient mice and barcode tracing revealed increased clonal diversity of engrafting cells. In competitive transplantation assays, analysis of bone marrow showed that cells transduced in the presence of UM171 consistently outcompeted those transduced under control conditions. In summary, exposure of SCD peripheral blood CD34+ cells to UM171 during LVV transduction enhances stem cell fitness. These findings suggest manufacturing of genetically modified HSCs in the presence of UM171 may improve efficacy, safety, and sustainability of gene therapy using ex vivo approaches. BCL11A shmiR-encoding LVV is in clinical trials to treat SCD (NCT03282656), UM171 is in clinical trials to culture umbilical cord blood (NCT02668315).
Occupation and SARS-CoV-2 in Europe: a review
Authors: Rhodes Sarah , Beale Sarah , Daniels Sarah , Gittins Matthew , Mueller William , McElvenny Damien , van Tongeren Martie
Published: September 2024

Introduction

Workplace features such as ventilation, temperature and the extent of contact are all likely to relate to personal risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Occupations relating to healthcare, social care, education, transport and food production and retail are thought to have increased risks, but the extent to which these risks are elevated and how they have varied over time is unclear.

Methods

We searched for population cohort studies conducted in Europe that compared coronavirus disease 2019 (COVID-19) outcomes between two or more different occupational groups. Data were extracted on relative differences between occupational groups, split into four time-periods corresponding to pandemic waves.

Results

We included data from 17 studies. 11 studies used SARS-CoV-2 as their outcome measure and six used COVID-19 hospitalisation and mortality. During waves one and two, the majority of studies saw elevated risks in the five groups that we looked at. Only seven studies used data from wave three onwards. Elevated risks were observed in waves three and four for social care and education workers in some studies.

Conclusions

Evidence relating to occupational differences in COVID-19 outcomes in Europe largely focuses on the early part of the pandemic. There is consistent evidence that the direction and magnitude of differences varied with time. Workers in the healthcare, transport and food production sectors saw highly elevated risks in the early part of the pandemic in the majority of studies but this did not appear to continue. There was evidence that elevated risks of infection in the education and social care sectors may have persisted.
Low-dose pro-resolving mediators temporally reset the resolution response to microbial inflammation
Authors: Serhan Charles N. , Chiang Nan , Nshimiyimana Robert
Published: September 2024

Background

Specialized pro-resolving mediators (SPMs) promote resolution of inflammation, clear infections and stimulate tissue regeneration. These include resolvins, protectins, and maresins. During self-resolving acute inflammation, SPMs are produced and have key functions activating endogenous resolution response for returning to homeostasis. Herein, we addressed whether infections initiated with ongoing inflammation alter resolution programs, and if low-dose repetitive SPM regimen re-programs the resolution response.

Methods

Inflammation was initiated with zymosan (1 mg/mouse) followed by E. coli (105 CFU/mouse) infections carried out in murine peritonitis, and exudates collected at 4-72 h. Leukocytes were enumerated using light microscopy, percentages of PMN, monocytes and macrophages were determined using flow cytometry, and resolution indices calculated. Lipid mediators and SPM profiles were established using mass spectrometry-based metabololipidomics. Repetitive dosing with a SPM panel consisting of RvD1, RvD2, RvD5, MaR1 and RvE2 (0.1 ng/mouse each, i.p.) was given to mice, followed by zymosan challenge. Leukocyte composition, resolution indices and RNA-sequencing were carried out for the repetitive SPM treatments.

Results

E. coli infections initiated acute inflammation-resolution programs with temporal SPM production in the infectious exudates. Zymosan-induced inflammation prior to E. coli peritonitis shifted exudate resolution indices and delayed E. coli clearance. Lipid mediator metabololipidomics demonstrated that E. coli infection with ongoing zymosan-induced inflammation shifted the time course of exudate SPMs, activating a SPM cluster that included RvD1, RvD5 and MaR1 during the initiation phase of infectious inflammation (0-4 h); RvD5 and MaR1 were present also in the resolution phase (24-48 h). To emulate daily SPM regimens used in humans, a repetitive subthreshold dosing of the SPM panel RvD1, RvD2, RvD5, MaR1 and RvE2 each at 0.1 ng per mouse was administered. This low-dose SPM regimen accelerated exudate PMN clearance following zymosan-induced inflammation, and shortened the resolution interval by > 70%. These low-dose SPMs regulated genes and pathways related to immune response, chemokine clearance and tissue repair, as demonstrated by using RNA-sequencing.

Conclusions

Infections encountered during ongoing inflammation in mice reset the resolution mechanisms of inflammation via SPM clusters. Low-dose SPMs activate innate immune responses and pathways towards the resolution response that can be reprogrammed.
Risk of suicide after hospitalizations due to acute physical health conditions—a cohort study of the Norwegian population
Authors: Asheim Andreas , Nilsen Sara Marie , Svedahl Ellen Rabben , Kaspersen Silje L. , Bjerkeset Ottar , Janszky Imre , Bjørngaard Johan Håkon
Published: September 2024

Background

It is well known that individuals recently discharged from psychiatric inpatient care face a high risk of suicide. Severe physical health conditions have also been linked to suicide risk. The risk of suicide following discharge from somatic hospitals is not known for individuals admitted due to acute physical health conditions.

Methods

A Cohort study using data from the entire Norwegian population aged 12 years and older from 2008 to 2022 linked with information on health service use and cause of death. We used Cox regression with age as time axis to estimate sex-adjusted hazard ratios of suicide following discharge for ages 12 to 64 years and 65 years and older. We also performed analyses after excluding hospitalizations with indications of concurrent mental disorders, self-harm, or suicide attempts. To assess individual risk, we performed an adapted case-crossover analysis among discharged patients who died from suicide.

Results

A total of 4 632,980 individuals aged 12 to 64 years and 1,469,265 individuals aged 65 years and older were included. Compared to unexposed individuals at similar ages, we found an increased risk of suicide in the first 4 weeks after discharge, with a hazard ratio (HR) of 7.0 (95% confidence interval (CI) 5.9 to 8.3) among those aged 12 to 64 years and 6.8 (95% CI 5.4 to 8.6) among those 65 years and older. In the younger age group, the risk was attenuated, with a HR of 2.4 (95% CI 1.7 to 3.2) after excluding hospitalizations with indications of concurrent mental disorders, self-harm, or suicide attempts. The corresponding HR was 4.8 (95% CI 3.5 to 6.4) among those 65 years and older, declining to 1.9, (1.2 to 3.1) in weeks 5 to 8 and 1.2 (0.7 to 2.2) in weeks 21 to 24. The case-crossover analysis confirmed that individuals 65 years and older were particularly vulnerable.

Conclusions

The heightened risk of suicide following discharge from acute somatic hospitalization, even in the absence of concurrent mental disorders, self-harm, or prior suicide attempts, underscores the critical need for comprehensive mental health and existential support for patients post-discharge.
CCL5 is essential for axonogenesis and neuronal restoration after brain injury
Authors: Ho Man-Hau , Tsai Yih-Jeng , Chen Chia-Yen , Yang Anastasia , Burnouf Thierry , Wang Yun , Chiang Yung-Hsiao , Hoffer Barry J. , Chou Szu-Yi
Published: September 2024

Background

Traumatic brain injury (TBI) causes axon tearing and synapse degradation, resulting in multiple neurological dysfunctions and exacerbation of early neurodegeneration; the repair of axonal and synaptic structures is critical for restoring neuronal function. C-C Motif Chemokine Ligand 5 (CCL5) shows many neuroprotective activities.

Method

A close-head weight-drop system was used to induce mild brain trauma in C57BL/6 (wild-type, WT) and CCL5 knockout (CCL5-KO) mice. The mNSS score, rotarod, beam walking, and sticker removal tests were used to assay neurological function after mTBI in different groups of mice. The restoration of motor and sensory functions was impaired in CCL5-KO mice after one month of injury, with swelling of axons and synapses from Golgi staining and reduced synaptic proteins-synaptophysin and PSD95. Administration of recombinant CCL5 (Pre-treatment: 300 pg/g once before injury; or post-treatment: 30 pg/g every 2 days, since 3 days after injury for 1 month) through intranasal delivery into mouse brain improved the motor and sensory neurological dysfunctions in CCL5-KO TBI mice.

Results

Proteomic analysis using LC-MS/MS identified that the “Nervous system development and function”-related proteins, including axonogenesis, synaptogenesis, and myelination signaling pathways, were reduced in injured cortex of CCL5-KO mice; both pre-treatment and post-treatment with CCL5 augmented those pathways. Immunostaining and western blot analysis confirmed axonogenesis and synaptogenesis related Semaphorin, Ephrin, p70S6/mTOR signaling, and myelination-related Neuregulin/ErbB and FGF/FAK signaling pathways were up-regulated in the cortical tissue by CCL5 after brain injury. We also noticed cortex redevelopment after long-term administration of CCL5 after brain injury with increased Reelin positive Cajal-Rerzius Cells and CXCR4 expression. CCL5 enhanced the growth of cone filopodia in a primary neuron culture system; blocking CCL5’s receptor CCR5 by Maraviroc reduced the intensity of filopodia in growth cone and also CCL5 mediated mTOR and Rho signalling activation. Inhibiting mTOR and Rho signaling abolished CCL5 induced growth cone formation.

Conclusions

CCL5 plays a critical role in starting the intrinsic neuronal regeneration system following TBI, which includes growth cone formation, axonogenesis and synaptogensis, remyelination, and the subsequent proper wiring of cortical circuits. Our study underscores the potential of CCL5 as a robust therapeutic stratagem in treating axonal injury and degeneration during the chronic phase after mild brain injury.

Graphical Abstract
Qualitative assessment of evidence-informed adolescent mental health policymaking in India: insights from project SAMA
Authors: Ivory Alice , Arelingaiah Mutharaju , Janardhana Navaneetham , Bhola Poornima , Hugh-Jones Siobhan , Mirzoev Tolib
Published: September 2024

Background

The importance of evidence-informed health policymaking is widely recognized. However, many low- and middle-income countries lack evidence-informed mental health policies due to insufficient data, stigma or lack of resources. Various policies address adolescent mental health in India, but published knowledge on their evidence-informed nature is limited. In this paper, we report results of our analysis of the role of evidence in adolescent mental health policymaking in India.

Methods

This paper reports findings from the document analysis of key policy documentation (n = 10) and in-depth interviews with policy actors including policymakers, researchers, practitioners and intermediaries (n = 13). Framework analysis was used, informed by the components of a conceptual framework adapted from the literature: actors, policy and evidence processes, nature of evidence itself and contextual influences.

Results

Results show that adolescent mental health policies in India were generally evidence-informed, with more key evidence becoming generally available from 2010 onwards. Both formal and informal evidence informed mental health policies, particularly agenda-setting and policy development. Mental health policymaking in India is deemed important yet relatively neglected due to competing policy priorities and structural barriers such as stigma. Use of evidence in mental health policymaking reflected differing values, interests, relative powers and ideologies of policy actors. Involvement of government officials in evidence generation often resulted in successful evidence uptake in policy decisions. Policy actors often favoured formal and quantitative evidence, with a tendency to accept global evidence that aligns with personal values.

Conclusions

There is a need to ensure a balanced and complementary combination of formal and informal evidence for policy decisions. Evidence generation, dissemination and use for policy processes should recognize evidence preferences by key stakeholders, while prioritizing locally available evidence where possible. To help this, a balanced involvement of policy actors can ensure complementary perspectives in evidence production and policy agendas. This continued generation and promotion of evidence can also help reduce societal stigma around mental health and promote mental health as a key policy priority.
Do calorie labels change energy purchased in a simulated online food delivery platform? A multi-arm randomised controlled trial
Authors: Luick Madison , Bianchi Filippo , Bain Francis , Bandy Lauren , Doshi Parita , Hilliard Darren , Leung Jovita , Mottershaw Abigail , Stuijfzand Bobby , Whitwell-Mak Jordan , Jebb Susan A. , Harper Hugo , Pechey Rachel
Published: September 2024

Background

As rates of obesity and overweight continue to increase in the UK, calorie labels have been introduced on menus as a policy option to provide information to consumers on the energy content of foods and to enable informed choices. This study tested whether the addition of calorie labels to items in a simulated food delivery platform may reduce the energy content of items selected.

Methods

UK adults (n = 8,780) who used food delivery platforms were asked to use the simulated platform as they would in real life to order a meal for themselves. Participants were randomly allocated to a control condition (no calorie labels) or to one of seven intervention groups: (1) large size calorie labels adjacent to the price (LP), (2) large size label adjacent to the product name (LN), (3) small label adjacent to price (SP), (4) small label adjacent to product name (SN), (5) LP with a calorie label switch-off filter (LP + Off), (6) LP with a switch-on filter (LP + On), or, (7) LP with a summary label of the total basket energy content (LP + Sum). Regression analysis assessed the impact of calorie labels on energy content of foods selected compared to the control condition.

Results

The mean energy selected in the control condition was 1408 kcal (95%CI: 93, 2719). There was a statistically significant reduction in mean energy selected in five of the seven intervention trial arms (LN labels (-60 kcal, 95%CI: -111, -6), SN (-73, 95%CI: -125, -19), LP + Off (-110, 95%CI: -161, -57), LP + On (-109, 95%CI: -159, -57), LP + Sum (-85 kcal, 95%CI: -137, -30). There was no evidence the other two conditions (LP (-33, 95%CI: -88, 24) and SP (-52, 95%CI: -105, 2)) differed from control. There was no evidence of an effect of any intervention when the analysis was restricted to participants who were overweight or obese.

Conclusion

Adding calorie labels to food items in a simulated online food delivery platform reduced the energy content of foods selected in five out of seven labelling scenarios. This study provides useful information to inform the implementation of these labels in a food delivery platform context.
Nutraceuticals and pharmacological to balance the transitional microbiome to extend immunity during COVID-19 and other viral infections
Authors: Kaushal Anju
Published: September 2024

Scope

The underlying medical conditions and gut dysbiosis is known to influence COVID-19 severity in high-risk patients. The current review proposed the optimal usage of nutraceuticals & pharmacological interventions can help regulate the protective immune response and balance the regulatory functionality of gut microbiota.

Many studies have revealed that the probiotic interventions viz., Lactobacillus rhamnosus, L. plantarum & other bacterial spp. reduce IFNγ & TNF-α and increase IL-4 & IL-10 secretions to control the immunostimulatory effects in upper respiratory tract infection. Dietary fibres utilized by beneficial microbiota and microbial metabolites can control the NF-kB regulation. Vitamin C halts the propagation of pathogens and vitamin D and A modulate the GM. Selenium and Flavonoids also control the redox regulations. Interferon therapy can antagonize the viral replications, while corticosteroids may reduce the death rates. BCG vaccine reprograms the monocytes to build trained immunity. Bifidobacterium and related microbes were found to increase the vaccine efficacy. Vaccines against COVID-19 and season flu also boost the immunity profile for robust protection. Over all, the collective effects of these therapeutics could help increase the opportunities for faster recovery from infectious diseases.

Conclusion

The nutraceutical supplements and pharmacological medicines mediate the modulatory functionalities among beneficial microbes of gut, which in turn eliminate pathogens, harmonize the activity of immune cells to secrete essential regulatory molecular receptors and adaptor proteins establishing the homeostasis in the body organs through essential microbiome. Therefore, the implementation of this methodology could control the severity events during clinical sickness and reduce the mortalities.
The assessment of pentraxin 3: a diagnostic and prognostic biomarker in lower respiratory tract infections in children
Authors: Madkour Shaimaa , Mostafa Mona Gamal , El-Kady Huda
Published: September 2024

Background

Pentraxin 3 (PTX3) is an acute-phase reactant that is elevated in the plasma during inflammatory responses. We aimed to evaluate the utility of PTX3 as a clinical marker in children with lower respiratory tract infections (LRTIs) and the association between PTX3 and LRTIs severity.

Methods

We included 60 patients admitted to Fayoum University Hospital with LRTIs fulfilling the WHO criteria for diagnosing LRTIs. We collected data on peak temperature, respiratory rate, heart rate, oxygen saturation upon admission, and length of hospital stay. The complete blood count (CBC), C-reactive protein (CRP) level, and PTX3 were measured upon admission.

Results

PTX3 levels were significantly correlated with peak temperature, duration of hospital stay, the Pediatric Respiratory Severity Score (PRESS), total leucocytic count (TLC), CRP, and blood cultures.

Conclusion

PTX-3 represented the severity of the disease and predicted the prognosis. Pentraxin levels demonstrate a statistically significant sensitivity of (93.3%) and a specificity of (70%) at the cut-off value (of 8.84) with an area under the curve (90.7%) in the diagnosis of LRTIs.
Progression prediction of coronary artery lesions by echocardiography-based ultrasomics analysis in Kawasaki disease
Authors: Xu Dan , Feng Chen-Hui , Cao Ai-Mei , Yang Shuai , Tang Zhen-Chao , Li Xiao-Hui
Published: September 2024

Background

Echocardiography-based ultrasomics analysis aids Kawasaki disease (KD) diagnosis but its role in predicting coronary artery lesions (CALs) progression remains unknown. We aimed to develop and validate a predictive model combining echocardiogram-based ultrasomics with clinical parameters for CALs progression in KD.

Methods

Total 371 KD patients with CALs at baseline were enrolled from a retrospective cohort (cohort 1, n = 316) and a prospective cohort (cohort 2, n = 55). CALs progression was defined by increased Z scores in any coronary artery branch at the 1-month follow-up. Patients in cohort 1 were split randomly into training and validation set 1 at the ratio of 6:4, while cohort 2 comprised validation set 2. Clinical parameters and ultrasomics features at baseline were analyzed and selected for models construction. Model performance was evaluated by area under the receiver operating characteristic curve (AUROC), area under the precision-recall curve (AUPRC) and decision curve analysis (DCA) in the training and two validation sets.

Results

At the 1-month follow-ups, 65 patients presented with CALs progression. Three clinical parameters and six ultrasomics features were selected to construct the model. The clinical-ultrasomics model exhibited a good predictive capability in the training, validation set 1 and set 2, achieving AUROCs of 0.83 (95% CI, 0.75–0.90), 0.84 (95% CI, 0.74–0.94), and 0.73 (95% CI, 0.40–0.86), respectively. Moreover, the AUPRC values and DCA of three model demonstrated that the clinical-ultrasomics model consistently outperformed both the clinical model and the ultrasomics model across all three sets, including the training set and the two validation sets.

Conclusions

Our study demonstrated the effective predictive capacity of a prediction model combining echocardiogram-based ultrasomics features and clinical parameters in predicting CALs progression in KD.
Structured multicellular intestinal spheroids (SMIS) as a standardized model for infection biology
Authors: Kraski Angelina , Migdał Paweł , Klopfleisch Robert , Räckel Clara , Sharbati Jutta , Heimesaat Markus M. , Alter Thomas , Hanisch Carlos , Gölz Greta , Einspanier Ralf , Sharbati Soroush
Published: September 2024

Background

3D cell culture models have recently garnered increasing attention for replicating organ microarchitecture and eliciting in vivo-like responses, holding significant promise across various biological disciplines. Broadly, 3D cell culture encompasses organoids as well as single- and multicellular spheroids. While the latter have found successful applications in tumor research, there is a notable scarcity of standardized intestinal models for infection biology that mimic the microarchitecture of the intestine. Hence, this study aimed to develop structured multicellular intestinal spheroids (SMIS) specifically tailored for studying molecular basis of infection by intestinal pathogens.

Results

We have successfully engineered human SMIS comprising four relevant cell types, featuring a fibroblast core enveloped by an outer monolayer of enterocytes and goblet cells along with monocytic cells. These SMIS effectively emulate the in vivo architecture of the intestinal mucosal surface and manifest differentiated morphological characteristics, including the presence of microvilli, within a mere two days of culture. Through analysis of various differentiation factors, we have illustrated that these spheroids attain heightened levels of differentiation compared to 2D monolayers. Moreover, SMIS serve as an optimized intestinal infection model, surpassing the capabilities of traditional 2D cultures, and exhibit a regulatory pattern of immunological markers similar to in vivo infections after Campylobacter jejuni infection. Notably, our protocol extends beyond human spheroids, demonstrating adaptability to other species such as mice and pigs.

Conclusion

Based on the rapid attainment of enhanced differentiation states, coupled with the emergence of functional brush border features, increased cellular complexity, and replication of the intestinal mucosal microarchitecture, which allows for exposure studies via the medium, we are confident that our innovative SMIS model surpasses conventional cell culture methods as a superior model. Moreover, it offers advantages over stem cell-derived organoids due to scalability and standardization capabilities of the protocol. By showcasing differentiated morphological attributes, our model provides an optimal platform for diverse applications. Furthermore, the investigated differences of several immunological factors compared to monotypic monolayers after Campylobacter jejuni infection underline the refinement of our spheroid model, which closely mimics important features of in vivo infections.
fSCIG 10% in pediatric primary immunodeficiency diseases: a European post-authorization safety study
Authors: Čižnár Peter , Roderick Marion , Schneiderova Helen , Jeseňák Miloš , Kriván Gergely , Brodszki Nicholas , Jolles Stephen , Atisso Charles , Fielhauer Katharina , Saeed-Khawaja Shumyla , McCoy Barbara , Yel Leman
Published: September 2024

Background

The safety, tolerability, and immunogenicity of hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) 10% (dual-vial unit of human immunoglobulin 10% and recombinant human hyaluronidase [rHuPH20]) were assessed in children with primary immunodeficiency diseases (PIDs).

Methods

This phase 4, post-authorization, prospective, interventional, multicenter study (NCT03116347) conducted in the European Economic Area, enrolled patients aged 2 to < 18 years with a documented PID diagnosis who had received immunoglobulin therapy for ≥ 3 months before enrollment. New fSCIG 10% starters underwent fSCIG 10% dose ramp-up for ≤ 6 weeks (epoch 1) before receiving fSCIG 10% for ≤ 3 years (epoch 2); patients pretreated with fSCIG 10% entered epoch 2 directly. The primary outcome was the number and rate (per infusion) of all noninfectious treatment-related serious and severe adverse events (AEs).

Results

In total, 42 patients were enrolled and dosed (median [range] age: 11.5 [3–17] years; 81% male; 23 new starters; 19 pretreated). Overall, 49 related noninfectious, treatment-emergent AEs (TEAEs) were reported in 15 patients; most were mild in severity (87.8%). No treatment-related serious TEAEs were reported. Two TEAEs (infusion site pain and emotional distress) were reported as severe and treatment-related in a single new fSCIG 10% starter. The rate of local TEAEs was lower in pretreated patients (0.1 event/patient-year) versus new starters (1.3 events/patient-year). No patients tested positive for binding anti-rHuPH20 antibodies (titer of ≥ 1:160).

Conclusions

No safety signals were identified, and the incidence of local AEs declined over the duration of fSCIG 10% treatment. This study supports fSCIG 10% long-term safety in children with PIDs.

Trial registration number (ClinicalTrials.gov)

NCT03116347.
A system of ODEs for representing trends of CGM signals
Authors: Aliffi Giulia Elena , Nastasi Giovanni , Romano Vittorio , Pitocco Dario , Rizzi Alessandro , Moore Elvin J. , De Gaetano Andrea
Published: September 2024

Diabetes Mellitus is a metabolic disorder which may result in severe and potentially fatal complications if not well-treated and monitored. In this study, a quantitative analysis of the data collected using CGM (Continuous Glucose Monitoring) devices from eight subjects with type 2 diabetes in good metabolic control at the University Polyclinic Agostino Gemelli, Catholic University of the Sacred Heart, was carried out. In particular, a system of ordinary differential equations whose state variables are affected by a sequence of stochastic perturbations was proposed and used to extract more informative inferences from the patients’ data. For this work, Matlab and R programs were used to find the most appropriate values of the parameters (according to the Akaike Information Criterion (AIC) and the Bayesian Information Criterion (BIC)) for each patient. Fitting was carried out by Particle Swarm Optimization to minimize the ordinary least squares error between the observed CGM data and the data from the ODE model. Goodness of fit tests were made in order to assess which probability distribution was best suitable for representing the waiting times computed from the model parameters. Finally, both parametric and non-parametric density estimation of the frequency histograms associated with the variability of the glucose elimination rate from blood were conducted and their representative parameters assessed from the data. The results show that the chosen models succeed in capturing most of the glucose fluctuations for almost every patient.
A growth-effective age-based periodic site-index for the estimation of dynamic forest site productivity under environmental changes
Authors: Yue Chaofang , Kahle Hans-Peter , Klädtke Joachim , Kohnle Ulrich
Published: September 2024

Key message

A novel periodic site index is introduced for the quantification of dynamic forest site productivity. The measure is age-independent, sensitive to environmental changes and efficient for the estimation and prediction of stand height and stand volume increment.

Context

Accurate and up-to-date prediction of site productivity is crucial for the sustainable management of forest ecosystems, especially under environmental changes.

Aims

The aim of this study was to introduce a novel concept: a periodic site index based on growth-effective age for the quantification of dynamic forest site productivity.

Methods

The growth-effective age based periodic site index is estimated from repeated or multi-temporal measurements of stand dominant height. Furthermore, a recursive procedure to update the underlying site index model is presented by using repeated measurements of stand dominant height. The database used in this study comprised repeated measurements of 945 Norway spruce (Picea abies L.) experimental plots at 508 different locations in Southwest Germany.

Results

The evaluation shows that periodic site index is statistically superior to the conventional site index, based on chronological stand age, for estimating stand height and stand volume increment. The analysis of temporal differences between growth-effective stand age and chronological stand age and between periodic site index and conventional site index in the period 1900 to 2020 reveals trends referring to stand age and site productivity, which corroborate earlier regional studies on forest growth trends due to environmental changes.

Conclusions

The periodic site index is a better indicator for site productivity than conventional site index. Under conditions of environmental changes, conventional site index is biased, whereas the growth-effective age based site index provides an unbiased estimate of stand height development. With the more widespread application of remote sensing techniques, such as airborne laser scanning, the availability of multi-temporal stand height data will increase in the near future. The novel concept provides an adaptive modeling approach perfectly suited to these data for an improved estimation and prediction of forest site productivity under environmental changes and can straightforwardly be applied also to uneven-aged and multi-species stands.
Debris-flow monitoring on volcanoes via a novel usage of a laser rangefinder
Authors: Iezzi Alexandra M. , Bryant Emily , Thelen Weston A. , Gabrielson Craig , Moran Seth C. , Patrick Matthew R. , Younger E. Frank , Obryk Maciej K.
Published: September 2024

Mount Rainier has had at least 11 large lahars over the last 6,000 years, including one occurring without evidence of eruptive activity. This prompted the creation of a lahar detection system that uses a combination of seismic, infrasound, and tripwires. We test a laser rangefinder placed on a river channel bank for detecting and confirming mass movements flowing past a station as an alternative to the physical tripwires. After testing the device at an experimental debris-flow flume, the laser rangefinder successfully captured a small debris flow on Mount Rainier in 2023, confirming its effectiveness as a lahar detection and monitoring tool. Over the 2-month deployment at Mount Rainier, we find that spurious recordings in the laser rangefinder data (noise) tend to correlate with high humidity, and that periods of noise do not correlate with increased co-located seismic amplitude. Therefore, the impact of the noise on future alarms can be mitigated by coupling a laser rangefinder alarm with that of independent datasets.
Comparing subjective quality of recovery between remimazolam- and propofol-based total intravenous anesthesia for surgical procedures: a meta-analysis
Authors: Hung Kuo-Chuan , Wang Wei-Ting , Liu Wei-Cheng , Hsu Chih-Wei , Huang Yen-Ta , Wu Jheng-Yan , Chen I-Wen
Published: September 2024

Background

Remimazolam is a novel ultra-short-acting benzodiazepine that has been recently introduced as an alternative to propofol for general anesthesia. While both agents have been compared in terms of safety and efficacy, their relative effects on postoperative quality of recovery (QoR) remain unclear. Therefore, this meta-analysis aimed to compare the effects of remimazolam and propofol on subjective QoR in surgical patients who underwent general anesthesia.

Methods

Medline, Embase, Google Scholar, and the Cochrane Central Register of Controlled Trials were searched from inception to May 28, 2024 to identify randomized controlled trials comparing remimazolam and propofol in terms of postoperative QoR. The Cochrane risk-of-bias tool (RoB 2) was used to assess study quality. QoR score on postoperative day (POD) 1 (primary outcome), QoR scores on PODs 2–3, QoR dimensions, time to loss of consciousness, other recovery characteristics, and rescue analgesia requirement were evaluated using random-effects meta-analyses.

Results

This meta-analysis included 13 studies published between 2022 and 2024 involving 1,418 patients. QoR was evaluated using either the QoR-15 (10 studies) or QoR-40 (3 studies) questionnaire. The pooled results indicated no significant difference in the QoR scores on POD 1 (standardized mean difference: 0.02, 95% confidence interval [CI]: − 0.20, 0.23,P = 0.88, I2 = 73%) and PODs 2–3 between remimazolam and propofol. Furthermore, no significant differences were observed in QoR dimensions, length of postanesthesia care unit (PACU) stay, and time to extubation as well as in the risks of agitation and postoperative nausea and vomiting. Patients administered remimazolam exhibited slower anesthetic induction (mean difference (MD): 32.27 s) but faster recovery of consciousness (MD: − 1.60 min) than those administered propofol. Moreover, remimazolam was associated with a lower risk of rescue analgesia requirement in the PACU (risk ratio: 0.62, 95% CI: 0.43, 0.89,P = 0.009,I2 = 0%) but not in the ward.

Conclusion

Remimazolam is a potential alternative to propofol for general anesthesia as it offers similar QoR to the latter and has advantages in terms of consciousness recovery and immediate postoperative analgesia requirement.
Effects of high solid content and straw proportion on volatile fatty acids production from straw, sludge and food wastes: performance and microbial community characteristics
Authors: Chen Yu-Wei , Feng Gao , Hong Xia , Wang Meng , Zhang Quan , Sun Zhao-Yong , Chen Ya-Ting , Tang Yue-Qin
Published: September 2024

Anaerobic digestion (AD) is an efficient technology for treating organic solid wastes, and the volatile fatty acids (VFAs) produced during AD have significant value due to their wide range of applications and higher added value compared to methane. This study investigated the long-term effects of high solid content and straw proportion in mixed substrates (straw, sludge, and food wastes) on VFAs production through semi-continuous reactors under thermophilic and mesophilic conditions. Results showed that both reactors achieved a maximum VFAs concentration of ~ 22 g/L as the straw proportion increased to 50%. Acetate (48.3 – 64.5%) was the main component of produced VFAs in both reactors, while butyrate and propionate production in thermophilic temperature were superior compared to mesophilic conditions. Microbial community analysis revealed that Defluviitoga plays a pivotal role in acidogenesis within both reactors; besides, unclassified Hungateiclostridiaceae and Caproiciproducen were found to be dominant in thermophilic reactor, while Lachnospiraceae_NK3A20_group and Rikenellaceae_RC9_gut_group were essential for VFAs production under mesophilic conditions. These findings provide valuable insights for the biotechnological exploration of acidogenic fermentation for large-scale mechanized production of VFAs from agricultural wastes.
Description of bone health in adolescents and young persons with Klinefelter syndrome – results from a pilot study
Authors: Spiekermann Julia , Höppner Jakob , Ibnukhsein Eliena , Sinningen Kathrin , Hanusch Beatrice , Kiewert Cordula , Siggelkow Heide , Grasemann Corinna
Published: September 2024

Background

In adults with Klinefelter syndrome (KS), impaired bone health with reduced bone mineral density (BMD) has been described even in the presence of testosterone replacement therapy. The aim of the present study was to characterize bone health in young patients with KS.

Patients and methods

20 participants aged 16.10 ± 4.28 years with KS (7 with testosterone replacement therapy) were included in the KliBONE study (DRKS 00024870). Medical history, clinical, radiographic and biochemical parameters of bone health and metabolism were obtained. Radiographic bone health index (BHI) was assessed via automated digital X-ray radiogrammetry of the left hand or via dual energy X-ray absorptiometry (DXA) of the lumbar spine and left femur in participants ≥ 16 years. Peripheral blood mononuclear cells were differentiated into osteoclasts and quantified in 7 participants and 7 healthy controls.

Results

Mean BHI SDS was − 1.42 ± 1.22 and mean BMD z-score at the lumbar vertebrae (L1-4) was − 0.92 ± 1.00. 25-OH-vitamin D levels < 20 ng/ml were detected in 8/20. Other parameters of bone metabolism (bone-specific alkaline phosphatase, PTH, ß-crosslaps and osteocalcin) were within age-appropriate reference ranges. Serum leptin SDS was elevated (mean 2.15 ± 1.19). The number of osteoclasts in participants with KS did not differ from that of controls.

Conclusion

BHI SDS and BMD z-scores were lower than expected in young individuals with KS despite age-appropriate bone turnover markers and no apparent pathology in osteoclast differentiation. The cause of the early-onset bone phenotype requires further investigation.