bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bilateral Choroidal Infiltrates as the Initial Manifestation of Waldenström Macroglobulinemia Relapse
Authors: Tan Jason , Chandra Varun , Hall Anthony J. 
Published: July 2021

Purpose: This work describes a case of Waldenström macroglobulinemia (WM) relapse presenting with unilateral blurred vision. Method: A case report is presented. Results: A 60-year-old woman with a history of WM in remission was referred for suspicious peripheral choroidal lesions and left optic disc swelling. Magnetic resonance imaging revealed optic nerve and cranial nerve infiltration consistent with central nervous system invasion from WM relapse, called Bing-Neel syndrome. Irradiation of the optic nerve and systemic targeted therapy were successful in addressing the ocular features as well as reducing immunoglobulin M paraprotein levels and lymphoproliferative disease burden. Conclusions: We described the first documented case to our knowledge of intraocular involvement as the earliest sign of relapse of WM. Ophthalmology assessment is warranted in patients with a history of WM who present with new ocular symptoms to aid early detection and treatment of this disease.
Severe thrombocytopenia is sufficient for fetal and neonatal intracerebral hemorrhage to occur
Authors: Farley Alison , Lloyd Sarah , Dayton Merle , Biben Christine , Stonehouse Olivia , Taoudi Samir 
Published: July 2021

Abstract
Intracerebral hemorrhage (ICH) has a devastating impact on the neonatal population. Whether thrombocytopenia is sufficient to cause ICH in neonates is still being debated. In this study, we comprehensively investigated the consequences of severe thrombocytopenia on the integrity of the cerebral vasculature by using 2 orthogonal approaches: by studying embryogenesis in the Nfe2−/− mouse line and by using biologics (anti-GP1Bα antibodies) to induce severe thrombocytopenia at defined times during development. By using a mouse model, we acquired data demonstrating that platelets are required throughout fetal development and into neonatal life for maintaining the integrity of the cerebral vasculature to prevent hemorrhage and that the location of cerebral hemorrhage is dependent on when thrombocytopenia occurs during development. Importantly, this study demonstrates that fetal and neonatal thrombocytopenia-associated ICH occurs within regions of the brain which, in humans, could lead to neurologic damage.
Type I interferon is induced by hemolysis and drives antibody-mediated erythrophagocytosis in sickle cell disease
Authors: Liu Yunfeng , Pal Mouli , Bao Weili , Shi Patricia A. , Lobo Cheryl A. , An Xiuli , Manwani Deepa , Zhong Hui , Yazdanbakhsh Karina 
Published: July 2021

AbstractPatients with sickle cell disease (SCD) suffer from intravascular hemolysis-associated vascular injury and tissue damage. Classical monocytes (CMo), which are the most abundant of circulating monocytes, are activated in SCD, but the cause and consequences of activation remain incompletely understood. We found a positive correlation between total plasma heme levels and circulating interferon-α (IFN-α) in patients with SCD along with upregulation of the type I IFN (IFN-I) inducible genes in sort-purified SCD patients’ CMo by transcriptome analysis. We demonstrated that hemolysis led to IFN-I expression, predominantly by mouse liver monocyte and macrophages (Mⲫ), primarily through Tank kinase binding 1 (TBK1)/IκB kinase-ε (IKKε) but not TLR4. In response to hemolysis-induced IFN-I, mouse CMo migrated to the liver and differentiated into monocyte-derived Mⲫ, increasing their numbers by sixfold with acute hemin treatment. Hemolysis-driven IFN-I activity also led to the induction of Fc receptor CD64 expression on monocyte and Mⲫ populations, enhancing alloantibody-mediated erythrophagocytosis in SCD both in vivo in mice and in in vitro human cultures. Altogether, these data demonstrate IFN-I response to hemolysis as a novel activation pathway in monocytes and Mⲫ in SCD, opening the possibility for development of IFN-I-based diagnostics and therapeutics against alloantibody-mediated erythrophagocytosis.
Treatment of sickle cell disease by increasing oxygen affinity of hemoglobin
Authors: Henry Eric R. , Metaferia Belhu , Li Quan , Harper Julia , Best Robert B. , Glass Kristen E. , Cellmer Troy , Dunkelberger Emily B. , Conrey Anna , Thein Swee Lay , Bunn H. Franklin , Eaton William A. 
Published: July 2021

Abstract
The issue of treating sickle cell disease with drugs that increase hemoglobin oxygen affinity has come to the fore with the US Food and Drug Administration approval in 2019 of voxelotor, the only antisickling drug approved since hydroxyurea in 1998. Voxelotor reduces sickling by increasing the concentration of the nonpolymerizing, high oxygen affinity R (oxy) conformation of hemoglobin S (HbS). Treatment of sickle cell patients with voxelotor increases Hb levels and decreases indicators of hemolysis, but with no indication as yet that it reduces the frequency of pain episodes. In this study, we used the allosteric model of Monod, Wyman, and Changeux to simulate whole-blood oxygen dissociation curves and red cell sickling in the absence and presence of voxelotor under the in vivo conditions of rapid oxygen pressure decreases. Our modeling agrees with results of experiments using a new robust assay, which shows the large, expected decrease in sickling from the drug. The modeling indicates, however, that the increase in oxygen delivery from reduced sickling is largely offset by the increase in oxygen affinity. The net result is that the drug increases overall oxygen delivery only at the very lowest oxygen pressures. However, reduction of sickling mitigates red cell damage and explains the observed decrease in hemolysis. More importantly, our modeling of in vivo oxygen dissociation, sickling, and oxygen delivery suggests that drugs that increase fetal Hb or decrease mean corpuscular hemoglobin concentration (MCHC) should be more therapeutically effective than drugs that increase oxygen affinity.
Remission, treatment failure, and relapse in pediatric ALL: an international consensus of the Ponte-di-Legno Consortium
Authors: Buchmann Swantje , Schrappe Martin , Baruchel Andre , Biondi Andrea , Borowitz Michael , Campbell Myriam , Cario Gunnar , Cazzaniga Giovanni , Escherich Gabriele , Harrison Christine J. , Heyman Mats , Hunger Stephen P. , Kiss Csongor , Liu Hsi-Che , Locatelli Franco , Loh Mignon L. , Manabe Atsushi , Mann Georg , Pieters Rob , Pui Ching-Hon , Rives Susana , Schmiegelow Kjeld , Silverman Lewis B. , Stary Jan , Vora Ajay , Brown Patrick 
Published: July 2021

Abstract
Comparison of treatment strategies in de novo pediatric acute lymphoblastic leukemia (ALL) requires standardized measures of efficacy. Key parameters that define disease-related events, including complete remission (CR), treatment failure (TF; not achieving CR), and relapse (loss of CR) require an updated consensus incorporating modern diagnostics. We collected the definitions of CR, TF, and relapse from recent and current pediatric clinical trials for the treatment of ALL, including the key components of response evaluation (timing, anatomic sites, detection methods, and thresholds) and found significant heterogeneity, most notably in the definition of TF. Representatives of the major international ALL clinical trial groups convened to establish consensus definitions. CR should be defined at a time point no earlier than at the end of induction and should include the reduction of blasts below a specific threshold in bone marrow and extramedullary sites, incorporating minimal residual disease (MRD) techniques for marrow evaluations. TF should be defined as failure to achieve CR by a prespecified time point in therapy. Relapse can only be defined in patients who have achieved CR and must include a specific threshold of leukemic cells in the bone marrow confirmed by MRD, the detection of central nervous system leukemia, or documentation of extramedullary disease. Definitions of TF and relapse should harmonize with eligibility criteria for clinical trials in relapsed/refractory ALL. These consensus definitions will enhance the ability to compare outcomes across pediatric ALL trials and facilitate development of future international collaborative trials.
Campylobacter insulaenigrae bacteremia with meningitis: a case report
Authors: Kyotani Moe , Kenzaka Tsuneaki , Akita Hozuka , Arakawa Soichi 
Published: July 2021

Abstract
Background
The bacterium Campylobacter insulaenigrae was first isolated from marine mammals of Scotland in 2004. Only one case of C. insulaenigrae infection in humans has been previously reported.

Case presentation
An 89-year-old Japanese man without dementia was admitted to our hospital, because he presented with a fever of 38 °C and weakness in right leg since 5 days. He had organized chronic subdural hematoma (CSH), and no history of pre-infection. At the time of admission, he had paralysis of the extraocular muscle, ataxia, and low manual muscle test score of the right side. He was suspected to have Miller Fisher syndrome; however, these symptoms improved without any treatment. On day 22 in the hospital, the patient presented a fever of 38.8 °C, left cranial nerve disorder, and hemiplegia. On day 25, the patient presented with signs of meningeal irritation; cerebrospinal fluid examination indicated an increase in the number of apocytes and a low glucose level. A contrast magnetic resonance imaging (MRI) scan of the patient’s head indicated a contrast enhancement effect in his right meninges. The blood culture showed presence of spirillums; 16S rRNA gene sequencing confirmed that the spirillums in the blood culture were Campylobacter insulaenigrae (C. insulaenigrae). We started treatment with meropenem for bacteremia and meningitis. When the symptoms improved, meropenem was replaced with ampicillin, based on the result of the drug sensitivity test. The treatment continued for 4 weeks.

Conclusions
We report the first case of meningitis caused by C. insulaenigrae bacteremia in humans, and the second clinical report of C. insulaenigrae infection in humans. The bacterial strains isolated from humans and marine mammals had different genotypes. This suggests that different genotypes could be responsible for differences in the hosts. Further case studies are needed to establish the reasons behind the difference in the manifestations of C. insulaenigrae infections reported so far.
Lymphocyte subset alterations with disease severity, imaging manifestation, and delayed hospitalization in COVID-19 patients
Authors: Wu Daxian , Wu Xiaoping , Huang Jiansheng , Rao Qunfang , Zhang Qi , Zhang Wenfeng 
Published: July 2021

Abstract
Background
COVID-19 continuously threated public health heavily. Present study aimed to investigate the lymphocyte subset alterations with disease severity, imaging manifestation, and delayed hospitalization in COVID-19 patients.

Methods
Lymphocyte subsets was classified using flow cytometry with peripheral blood collected from 106 patients.

Results
Multivariate logistic regression showed that chest tightness, lymphocyte count, and γ-glutamyl transpeptidase were the independent predictors for severe COVID-19. The T cell, CD4+ T cell and B cell counts in severe patients were significantly lower than that in mild patients (p = 0.004, 0.003 and 0.046, respectively). Only the T cell count was gradually decreased with the increase of infiltrated quadrants of lesions in computed tomography (CT) (p = 0.043). The T cell, CD4+ T cell, and CD8+ T cell counts were gradually decreased with the increase of infiltrated area of the maximum lesion in CT (p = 0.002, 0.003, 0.028; respectively). For severe patients, the counts of T cell, CD4+ T cell, CD8+ T cell gradually decreased with the increased delayed hospitalization (p = 0.001, 0.03, and <  0.001, respectively). The proportions of T cell, CD8+ T cell gradually decreased with the increased delayed hospitalization (both p <  0.001), but the proportions of NK cell, B cell gradually increased with the increased delayed hospitalization (p = 0.007, and 0.002, respectively). For mild patients, only the NK cell count was gradually decreased with the increased delayed hospitalization (p = 0.012).

Conclusion
T lymphocyte and its subset negatively correlated with disease severity, CT manifestation and delayed hospitalization. The counts of lymphocyte subset were changed more profound than their proportions.
The DANTE trial protocol: a randomised phase III trial to evaluate the Duration of ANti-PD-1 monoclonal antibody Treatment in patients with metastatic mElanoma
Authors: Coen Oliver , Corrie Pippa , Marshall Helen , Plummer Ruth , Ottensmeier Christian , Hook Jane , Bell Sue , Sagoo Gurdeep S. , Meads David , Bestall Janine , Velikova Galina , Gallagher Ferdia A. , Smith Alexandra , Howard Helen , Mason Ellen , Katona Eszter , Silva Shobha , Collinson Michelle , Rodwell Simon , Danson Sarah 
Published: July 2021

Abstract
Background
Immunotherapy is revolutionising the treatment of patients diagnosed with melanoma and other cancers. The first immune checkpoint inhibitor, ipilimumab (targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)), showed a survival advantage over standard chemotherapy. Subsequently the anti-programmed cell death protein 1 (PD-1) antibodies, nivolumab and pembrolizumab were shown to be more effective than ipilimumab. Ipilimumab combined with nivolumab gives an incremental gain in overall survival compared with nivolumab alone but increases the risk of severe, potentially life-threatening toxicities. In contrast to ipilimumab monotherapy, anti-PD-1 antibodies are licensed to be continued until disease progression. Follow-up of patients recruited to the first trials evaluating 2 years of pembrolizumab showed that three-quarters of responding patients continue responding after stopping treatment. Suggestive of early response, we hypothesised that continuing anti-PD-1 treatment beyond 1 year in progression-free patients may be unnecessary and so designed the DANTE trial.

Methods
DANTE is a multicentre, randomised, phase III, non-inferiority trial to evaluate the duration of anti-PD-1 therapy in patients with metastatic (unresectable stage III and stage IV) melanoma. It uses a two-stage recruitment strategy, registering patients before they complete 1 year of first-line anti-PD-1 +/− CTLA-4 therapy and randomising eligible patients who have received 12 months of treatment and are progression-free at 1 year. At randomisation, 1208 patients are assigned (1:1) to either 1) continue anti-PD-1 treatment until disease progression/ unacceptable toxicity/ for at least 2 years in the absence of disease progression/ unacceptable toxicity or 2) to stop treatment. Randomisation stratifies for baseline prognostic factors. The primary outcome is progression-free survival at 3, 6, 9 and 12 months and then, 6-monthly for up to 4-years. Secondary outcomes collected at all timepoints include overall survival, response-rate and duration and safety, with quality of life and cost-effectiveness outcomes collected 3-monthly for up to 18-months. Sub-studies include a qualitative analysis of patient acceptance of randomisation and sample collection to inform future translational studies into response/ toxicity biomarkers.

Discussion
DANTE is a unique prospective trial investigating the optimal duration of anti-PD-1 therapy in metastatic melanoma patients. Outcomes will inform future use of these high burden drugs.

Trial registration
ISRCTN15837212, 31 July 2018.
Integrating data from multidisciplinary Management of Malignant Pleural Mesothelioma: a cohort study
Authors: Saracino Laura , Bortolotto Chandra , Tomaselli Stefano , Fraolini Elia , Bosio Matteo , Accordino Giulia , Agustoni Francesco , Abbott David M. , Pozzi Emma , Eleftheriou Dimitrios , Morbini Patrizia , Rinaldi Pietro , Primiceri Cristiano , Lancia Andrea , Comoli Patrizia , Filippi Andrea R. , Stella Giulia M. 
Published: July 2021

Abstract
Background
Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy that most commonly affects the pleural layers. MPM has a strong association with asbestos, mainly caused by exposure to its biopersistent fibers in at least 80% of cases. Individuals with a chronic exposure to asbestos might develop disease with a 20–40-year latency with few or no symptoms. Such has been the case in the Italian regions of Piedmont and Lombardy, where industrial production of materials laden with asbestos, mainly cements, has been responsible for the onset of a large epidemic. Since 2018, a multidisciplinary team at San Matteo hospital in Pavia has been collecting data on over 100 patients with MPM. The main goal of this project is to define and describe an integrated profile for each MPM case at diagnosis by using data mining and partition analysis.

Methods
Here we bring together exhaustive epidemiologic, histologic and radiologic data of 88 MPM patients that came to our observation and draw correlations with predictive and prognostic significance.

Results
The median overall survival (OS) was 15.6 months. Most patients presented with pleural effusion, irrespective of disease stage. Quite unexpectedly, no statistically significant association was demonstrated between OS and TNM disease stage at diagnosis. Although average OS is similar in male and female patients, partition analysis of data underlined a significant differential hierarchy of predictor categories based on patient gender. In females with no smoking history, full chemotherapeutic regimens are associated with better outcomes. Moreover, concerning second line treatments, vinorelbine emerged as the most advantageous choice for female patients, whereas in the male subgroup no statistically significant difference resulted between gemcitabine and vinorelbine.

Conclusion
A multidisciplinary approach to MPM is mandatory to define better therapeutic approaches, personalize the management and improve patient outcomes.
Health services use by children identified as heterozygous hemoglobinopathy mutation carriers via newborn screening
Authors: Khangura Sara D. , Potter Beth K. , Davies Christine , Ducharme Robin , Bota A. Brianne , Hawken Steven , Wilson Kumanan , Karaceper Maria D. , Klaassen Robert J. , Little Julian , Simpson Ewurabena , Chakraborty Pranesh 
Published: July 2021

Abstract
Background
Newborn screening (NBS) for sickle cell disease incidentally identifies heterozygous carriers of hemoglobinopathy mutations. In Ontario, Canada, these carrier results are not routinely disclosed, presenting an opportunity to investigate the potential health implications of carrier status. We aimed to compare rates of health services use among children identified as carriers of hemoglobinopathy mutations and those who received negative NBS results.

Methods
Eligible children underwent NBS in Ontario from October 2006 to March 2010 and were identified as carriers or as screen-negative controls, matched to carriers 5:1 based on neighbourhood and timing of birth. We used health care administrative data to determine frequencies of inpatient hospitalizations, emergency department (ED) visits, and physician encounters through March 2012, using multivariable negative binomial regression to compare rates of service use in the two cohorts. We analyzed data from 4987 carriers and 24,935 controls.

Results
Adjusted incidence rate ratios (95% CI) for service use in carriers versus controls among children < 1 year of age were: 1.11 (1.06–1.17) for ED visits; 0.97 (0.89–1.06) for inpatient hospitalization; and 1.02 (1.00–1.04) for physician encounters. Among children ≥1 year of age, adjusted rate ratios were: 1.03 (0.98–1.07) for ED visits; 1.14 (1.03–1.25) for inpatient hospitalization and 0.92 (0.90–0.94) for physician encounters.

Conclusions
While we identified statistically significant differences in health services use among carriers of hemoglobinopathy mutations relative to controls, effect sizes were small and directions of association inconsistent across age groups and health service types. Our findings are consistent with the assumption that carrier status is likely benign in early childhood.
A multi-country analysis of the prevalence and factors associated with bullying victimisation among in-school adolescents in sub-Saharan Africa: evidence from the global school-based health survey
Authors: Aboagye Richard Gyan , Seidu Abdul-Aziz , Hagan John Elvis , Frimpong James Boadu , Budu Eugene , Adu Collins , Ayilu Raymond K. , Ahinkorah Bright Opoku 
Published: July 2021

Abstract
Background
Over the past few years, there has been growing public and research interest in adolescents’ experiences with various forms of bullying victimisation because of their psychological, emotional, and/ or physical consequences. The present study examined the prevalence of bullying victimisation and its associated factors among in-school adolescents in sub-Saharan Africa.

Methods
Using data from the Global School-based Health Survey (GSHS) from 2010 to 2017 of eleven sub-Saharan African countries, a sample of 25,454 in-school adolescents was used for analysis. Statistical analyses included frequencies, percentages, Pearson chi-square and multivariable logistic regression. Results were presented as adjusted odds ratios (aOR) at 95% confidence intervals (CIs).

Results
The overall prevalence of bullying victimisation among the respondents was 38.8%. The prevalence was lowest in Mauritius (22.2%) and highest in Sierra Leone (54.6%). Adolescents who felt lonely [aOR = 1.66, 95% CI = 1.53, 1.80], had history of anxiety [aOR = 1.53, 95% CI = 1.41, 1.66], suicidal ideation [aOR = 1.28, 95% CI = 1.17, 1.39], suicidal attempt [aOR = 1.86, 95% CI = 1.72, 2.02], current users of marijuana [aOR = 1.59, 95% CI = 1.38, 1.84], and truants at [aOR = 1.43, 95% CI = 1.34, 1.52] were more likely to be victims of bullying. Conversely, adolescents who had peer support were less likely to be victims of bullying [aOR = 0.78, 95% CI = 0.73, 0.82]. Adolescents aged 15 years or older had lower odds of experiencing bullying victimization compared to their counterparts aged 14 years or younger [aOR = 0.74, 95% CI = 0.69, 0.78].

Conclusion
Our findings suggest that age, loneliness, anxiety, suicidal ideation, suicidal attempt, and current use of marijuana are associated with increased risk of bullying victimisation. School-wide preventative interventions (e.g., positive behavioural strategies- Rational Emotive Behavioral Education, [REBE], peer educator network systems, face-face counseling sessions, substance use cessation therapy) are essential in promoting a positive school climate and reduce students’ bullying victimisation behaviours.