bluuebunny/crossref_metadata_2025 huggingface dataset:
Contemporary demographics, diagnostics and outcomes in non-bacterial thrombotic endocarditis
Authors: Quintero-Martinez Juan A , Hindy Joya-Rita , El Zein Said , Michelena Hector I , Nkomo Vuyisile T , DeSimone Daniel C , Baddour Larry M
Published: May 2022

Objective

Non-bacterial thrombotic endocarditis (NBTE) is a syndrome characterised by cardiac valve vegetations and/or thickening due to non-infective mechanisms. Nowadays, a premortem diagnosis of NBTE is possible based on echocardiographic findings. Therefore, to better characterise this disease, we performed a contemporary review of the epidemiology, demographics, diagnosis and clinical outcomes of these patients.

Methods

Adults with a diagnosis of NBTE seen within the Mayo Clinic Enterprise from December 2014 to December 2021 were included. NBTE diagnosis was identified by clinicians representing at least two specialties including cardiology, infectious diseases, rheumatology and oncology. Patients with positive blood cultures, infective endocarditis, culture-negative endocarditis and denial of research authorisation were excluded. All patients had a 1-year follow-up.

Results

Forty-eight cases were identified; mean age was 60.0±13.8 years, 75% were female. The most prevalent comorbidities were malignancy (52.1%) and connective tissue disease (37.5%). Valvular abnormalities included 41 (85.4%) patients with vegetations, 43 (89.6%) patients with thickening and 26 (54.2%) with moderate to severe regurgitation. Thirty-eight (79.2%) patients had an embolic event (stroke in 26 (54.2%) patients) within 1 month of NBTE diagnosis and 16 (33.3%) patients died within 1 year of NBTE diagnosis. Metastatic tumours and lung cancer were associated with 1-year all-cause mortality (p=0.0017 and p=0.0004, respectively).

Conclusions

NBTE was more prevalent in females and embolic complications were the most frequent clinical finding. Overall, patients with NBTE had a poor prognosis, particularly in those with lung cancer or metastatic tumours. Further studies in patients with NBTE are needed given its morbidity and mortality.
Beyond the routine CBC: machine learning and statistical analyses identify research CBC parameter associations with myelodysplastic syndromes and specific underlying pathogenic variants
Authors: Pozdnyakova Olga , Niculescu Radu Stefan , Kroll Tracey , Golemme Lisa , Raymond Nolan , Briggs Debra , Kim Annette
Published: May 2022

Aims

Given the time, expense and clinical expertise required for a myelodysplastic syndrome (MDS) diagnosis, there is a clear need for a cost-effective screening laboratory test that can rapidly and accurately distinguish patients with cytopenias related to MDS from other causes.

Methods

We measured conventional and research use only complete blood cell (CBC) parameters using the Sysmex XN-series haematology analyser in 102 MDS patients (70 patients with active MDS and 32 patients in remission), 43 patients with cytopenia without morphological evidence of MDS and 484 age-adjusted controls. A variety of algorithms, including random forest machine learning, were used to construct parameter-based models to predict the presence of MDS using both CBC and molecular data or CBC data alone and correlated individual pathogenic variants/genetic pathways with CBC parameters changes.

Results

Using the CBC parameters alone, our predictive model for active MDS showed a 0.86 receiver operating characteristic curve (ROC)/area under the ROC curve (AUC), with 0.87 sensitivity and 0.72 specificity; with the addition of the molecular and demographic status, the ROC/AUC improved to 0.93, sensitivity to 0.89 and specificity to 0.84. The most discriminatory MDS parameters were reflective of dysplastic neutrophil morphology, red cell count fragmentation and degree of platelet immaturity. Specific patterns of parameters were associated with individual gene pathogenic variants or affected pathways.

Conclusions

CBC research parameters can be used as an adjunct to the haematological workup of cytopenia(s) to help screen for patients with high likelihood of MDS.
Sociodemographic disparities in COVID-19 burden: changing patterns over four pandemic waves in Israel
Authors: Luxenburg Osnat , Singer Clara , Myers Vicki , Wilf-Miron Rachel , Saban Mor
Published: May 2022

Background

Worldwide, the COVID-19 pandemic hit weakest populations hardest, with socioeconomic (SE), racial and ethnic disparities in COVID-19 burden. The study aimed to analyse patterns of SE and ethnic disparities in morbidity, hospitalisation, and vaccination throughout four pandemic waves.

Methods

A retrospective-archive study was conducted in Israel from 11 March 2020 to 1 December 2021, with data on confirmed cases, hospitalisations, mortality and vaccinations (three doses), obtained from the Israeli Ministry of Health’s open COVID-19 database, covering 98.8% of the population, by SE and ethnic characteristics of localities.

Findings

At the outbreak of the pandemic, there was a higher caseload in Jewish, compared with Arab localities. In the second and third waves, low SE and Arab minority populations suffered 2–3 times higher morbidity, with a similar but attenuated pattern in the fourth wave. A similar trend was observed in hospitalisation of confirmed patients. COVID-19-associated mortality did not demonstrate a clear SE gradient.

A strong social gradient in vaccine uptake was demonstrated throughout the period, with 71% and 74% double vaccinated in the two highest SE clusters, and 43% and 27% in the two lowest clusters by December 2021. Uptake of the third dose was 57%–60% in the highest SE clusters and 31%–25% in the lowest clusters. SE disparities in vaccine uptake were larger among the younger age groups and gradually increased from first to third doses.

Conclusions

Israel was among the first to lead a rapid vaccination drive, as well as to experience a fourth wave fuelled by diminishing immunity and the delta variant. SE and ethnic disparities were evident throughout most of the pandemic months, though less so for mortality. Despite higher COVID-19 burden, vaccine uptake was lower in disadvantaged groups, with greater disparities in the younger population which widened with subsequent doses.
Antigen mimicry as an effective strategy to induce CSPG4-targeted immunity in dogs with oral melanoma: a veterinary trial
Authors: Riccardo Federica , Tarone Lidia , Camerino Mariateresa , Giacobino Davide , Iussich Selina , Barutello Giuseppina , Arigoni Maddalena , Conti Laura , Bolli Elisabetta , Quaglino Elena , Merighi Irene Fiore , Morello Emanuela , Dentini Alfredo , Ferrone Soldano , Buracco Paolo , Cavallo Federica
Published: May 2022

Background

Melanoma is the most lethal form of skin cancer in humans. Conventional therapies have limited efficacy, and overall response is still unsatisfactory considering that immune checkpoint inhibitors induce lasting clinical responses only in a low percentage of patients. This has prompted us to develop a vaccination strategy employing the tumor antigen chondroitin sulfate proteoglycan (CSPG)4 as a target.

Methods

To overcome the host’s unresponsiveness to the self-antigen CSPG4, we have taken advantage of the conservation of CSPG4 sequence through phylogenetic evolution, so we have used a vaccine, based on a chimeric DNA molecule encompassing both human (Hu) and dog (Do) portions of CSPG4 (HuDo-CSPG4). We have tested its safety and immunogenicity (primary objectives), along with its therapeutic efficacy (secondary outcome), in a prospective, non-randomized, veterinary clinical trial enrolling 80 client-owned dogs with surgically resected, CSPG4-positive, stage II–IV oral melanoma.

Results

Vaccinated dogs developed anti-Do-CSPG4 and Hu-CSPG4 immune response. Interestingly, the antibody titer in vaccinated dogs was significantly associated with the overall survival. Our data suggest that there may be a contribution of the HuDo-CSPG4 vaccination to the improvement of survival of vaccinated dogs as compared with controls treated with conventional therapies alone.

Conclusions

HuDo-CSPG4 adjuvant vaccination was safe and immunogenic in dogs with oral melanoma, with potential beneficial effects on the course of the disease. Thanks to the power of naturally occurring canine tumors as predictive models for cancer immunotherapy response, these data may represent a basis for the translation of this approach to the treatment of human patients with CSPG4-positive melanoma subtypes.
CD4+T-cell epitope-based heterologous prime-boost vaccination potentiates anti-tumor immunity and PD-1/PD-L1 immunotherapy
Authors: Xiao Minglu , Xie Luoyingzi , Cao Guoshuai , Lei Shun , Wang Pengcheng , Wei Zhengping , Luo Yuan , Fang Jingyi , Yang Xingxing , Huang Qizhao , Xu Lifan , Guo Junyi , Wen Shuqiong , Wang Zhiming , Wu Qing , Tang Jianfang , Wang Lisha , Chen Xiangyu , Chen Cheng , Zhang Yanyan , Yao Wei , Ye Jianqiang , He Ran , Huang Jun , Ye Lilin
Published: May 2022

Background

Antitumor therapeutic vaccines are generally based on antigenic epitopes presented by major histocompatibility complex (MHC-I) molecules to induce tumor-specific CD8+T cells. Paradoxically, continuous T cell receptor (TCR) stimulation from tumor-derived CD8+T-cell epitopes can drive the functional exhaustion of tumor-specific CD8+T cells. Tumor-specific type-I helper CD4+T (TH1) cells play an important role in the population maintenance and cytotoxic function of exhausted tumor-specific CD8+T cells in the tumor microenvironment. Nonetheless, whether the vaccination strategy targeting MHC-II-restricted CD4+T-cell epitopes to induce tumor-specific TH1 responses can confer effective antitumor immunity to restrain tumor growth is not well studied. Here, we developed a heterologous prime-boost vaccination strategy to effectively induce tumor-specific TH1 cells and evaluated its antitumor efficacy and its capacity to potentiate PD-1/PD-L1 immunotherapy.

Methods

Listeria monocytogenesvector and influenza A virus (PR8 strain) vector stably expressing lymphocytic choriomeningitis virus (LCMV) glycoprotein-specific I-Ab-restricted CD4+T cell epitope (GP61–80) or ovalbumin-specific CD4+T cell epitope (OVA323-339) were constructed and evaluated their efficacy against mouse models of melanoma and colorectal adenocarcinoma expressing lymphocytic choriomeningitis virus glycoprotein and ovalbumin. The impact of CD4+T cell epitope-based heterologous prime-boost vaccination was detected by flow-cytometer, single-cell RNA sequencing and single-cell TCR sequencing.

Results

CD4+T cell epitope-based heterologous prime-boost vaccination efficiently suppressed both mouse melanoma and colorectal adenocarcinoma. This vaccination primarily induced tumor-specific TH1 response, which in turn enhanced the expansion, effector function and clonal breadth of tumor-specific CD8+T cells. Furthermore, this vaccination strategy synergized PD-L1 blockade mediated tumor suppression. Notably, prime-boost vaccination extended the duration of PD-L1 blockade induced antitumor effects by preventing the re-exhaustion of tumor-specific CD8+T cells.

Conclusion

CD4+T cell epitope-based heterologous prime-boost vaccination elicited potent both tumor-specific TH1 and CTL response, leading to the efficient tumor control. This strategy can also potentiate PD-1/PD-L1 immune checkpoint blockade (ICB) against cancer.
Anti-CSF-1R emactuzumab in combination with anti-PD-L1 atezolizumab in advanced solid tumor patients naïve or experienced for immune checkpoint blockade
Authors: Gomez-Roca Carlos , Cassier Philippe , Zamarin Dmitriy , Machiels Jean-Pascal , Luis Perez Gracia Jose , Stephen Hodi F , Taus Alvaro , Martinez Garcia Maria , Boni Valentina , Eder Joseph P , Hafez Navid , Sullivan Ryan , Mcdermott David , Champiat Stephane , Aspeslagh Sandrine , Terret Catherine , Jegg Anna-Maria , Jacob Wolfgang , Cannarile Michael A , Ries Carola , Korski Konstanty , Michielin Francesca , Christen Randolph , Babitzki Galina , Watson Carl , Meneses-Lorente Georgina , Weisser Martin , Rüttinger Dominik , Delord Jean-Pierre , Marabelle Aurelien
Published: May 2022

Background

This phase 1b study (NCT02323191) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of colony-stimulating factor-1 receptor-blocking monoclonal antibody (mAb) emactuzumab in combination with the programmed cell death-1 ligand (PD-L1)-blocking mAb atezolizumab in patients with advanced solid tumors naïve or experienced for immune checkpoint blockers (ICBs).

Methods

Emactuzumab (500–1350 mg flat) and atezolizumab (1200 mg flat) were administered intravenously every 3 weeks. Dose escalation of emactuzumab was conducted using the 3+3 design up to the maximum tolerated dose (MTD) or optimal biological dose (OBD). Extension cohorts to evaluate pharmacodynamics and clinical activity were conducted in metastatic ICB-naive urothelial bladder cancer (UBC) and ICB-pretreated melanoma (MEL), non-small cell lung cancer (NSCLC) and UBC patients.

Results

Overall, 221 patients were treated. No MTD was reached and the OBD was determined at 1000 mg of emactuzumab in combination with 1200 mg of atezolizumab. Grade ≥3 treatment-related adverse events occurred in 25 (11.3%) patients of which fatigue and rash were the most common (14 patients (6.3%) each). The confirmed objective response rate (ORR) was 9.8% for ICB-naïve UBC, 12.5% for ICB-experienced NSCLC, 8.3% for ICB-experienced UBC and 5.6% for ICB-experienced MEL patients, respectively. Tumor biopsy analyses demonstrated increased activated CD8 +tumor infiltrating T lymphocytes (TILs) associated with clinical benefit in ICB-naïve UBC patients and less tumor-associated macrophage (TAM) reduction in ICB-experienced compared with ICB-naïve patients.

Conclusion

Emactuzumab in combination with atezolizumab demonstrated a manageable safety profile with increased fatigue and skin rash over usual atezolizumab monotherapy. A considerable ORR was particularly seen in ICB-experienced NSCLC patients. Increase ofCD8 +TILs under therapy appeared to be associated with persistence of a TAM subpopulation.
Small extracellular vesicles induce resistance to anti-GD2 immunotherapy unveiling tipifarnib as an adjunct to neuroblastoma immunotherapy
Authors: Liu Xiaoming , Wills Carson A , Chen Longgui , Zhang Jiawen , Zhao Yuanjun , Zhou Mi , Sundstrom Jeffrey M , Schell Todd , Spiegelman Vladimir S , Young Megan M , Wang Hong-Gang
Published: May 2022

Background

Anti-GD2 monoclonal antibody immunotherapy has significantly improved the overall survival rate for high-risk neuroblastoma patients. However, 40% of patients fail to respond or develop resistance to treatment, and the molecular mechanisms by which this occurs remain poorly understood. Tumor-derived small extracellular vesicles (sEVs) have emerged as critical regulators in modulating the response to immunotherapy. In this study, we investigated the role of neuroblastoma-derived sEVs in promoting resistance to the anti-GD2 monoclonal antibody dinutuximab. Moreover, to determine whether pharmacologic inhibition of sEV secretion sensitizes tumors to dinutuximab treatment, we combined dinutuximab with tipifarnib, a farnesyltransferase inhibitor that inhibits sEV secretion.

Methods

We investigated the role of neuroblastoma-derived sEVs in modulating the response to dinutuximab by utilizing the syngeneic 9464D-GD2 mouse model. The effect of neuroblastoma-derived sEVs in modulating the tumor microenvironment (TME) and host immune system were evaluated by RNA-sequencing and flow cytometry. Importantly, we used this mouse model to investigate the efficacy of tipifarnib in sensitizing neuroblastoma tumors to dinutuximab. The effect of tipifarnib on both the TME and host immune system were assessed by flow cytometry.

Results

We demonstrated that neuroblastoma-derived sEVs significantly attenuated the efficacy of dinutuximabin vivoand modulated tumor immune cell infiltration upon dinutuximab treatment to create an immunosuppressive TME that contains more tumor-associated macrophages and fewer tumor-infiltrating NK cells. In addition, we demonstrated that neuroblastoma-derived sEVs suppress splenic NK cell maturationin vivoand dinutuximab-induced NK cell-mediated antibody-dependent cellular cytotoxicityin vitro. Importantly, tipifarnib drastically enhanced the efficacy of dinutuximab-mediated inhibition of tumor growth and prevented the immunosuppressive effects of neuroblastoma-derived sEVsin vivo.

Conclusions

These preclinical findings uncover a novel mechanism by which neuroblastoma-derived sEVs modulate the immune system to promote resistance to dinutuximab and suggest that tipifarnib-mediated inhibition of sEV secretion may serve as a viable treatment strategy to enhance the antitumor efficacy of anti-GD2 immunotherapy in high-risk neuroblastoma patients.
Gain-of-function p.F28S variant inRAC3disrupts neuronal differentiation, migration and axonogenesis during cortical development, leading to neurodevelopmental disorder
Authors: Nishikawa Masashi , Scala Marcello , Umair Muhammad , Ito Hidenori , Waqas Ahmed , Striano Pasquale , Zara Federico , Costain Gregory , Capra Valeria , Nagata Koh-ichi
Published: May 2022

Background

RAC3encodes a Rho family small GTPase that regulates the behaviour and organisation of actin cytoskeleton and intracellular signal transduction. Variants inRAC3can cause a phenotypically heterogeneous neurodevelopmental disorder with structural brain anomalies and dysmorphic facies. The pathomechanism of this recently discovered genetic disorder remains unclear.

Methods

We investigated an early adolescent female with intellectual disability, drug-responsive epilepsy and white matter abnormalities. Through exome sequencing, we identified the novel de novo variant (NM_005052.3): c.83T>C (p.Phe28Ser) inRAC3. We then examined the pathophysiological significance of the p.F28S variant in comparison with the recently reported disease-causing p.Q61L variant, which results in a constitutively activated version of RAC3.

Results

In vitro analyses revealed that the p.F28S variant was spontaneously activated by substantially increased intrinsic GTP/GDP-exchange activity and bound to downstream effectors tested, such as PAK1 and MLK2. The variant suppressed the differentiation of primary cultured hippocampal neurons and caused cell rounding with lamellipodia. In vivo analyses using in utero electroporation showed that acute expression of the p.F28S variant caused migration defects of excitatory neurons and axon growth delay during corticogenesis. Notably, defective migration was rescued by a dominant negative version of PAK1 but not MLK2.

Conclusion

Our results indicate that RAC3 is critical for brain development and the p.F28S variant causes morphological and functional defects in cortical neurons, likely due to the hyperactivation of PAK1.
Favourable arterial, tissue-level and venous collaterals correlate with early neurological improvement after successful thrombectomy treatment of acute ischaemic stroke
Authors: Faizy Tobias Djamsched , Mlynash Michael , Kabiri Reza , Christensen Soren , Kuraitis Gabriella , Meyer Lukas , Bechstein Matthias , Van Horn Noel , Lansberg Maarten G , Albers Greg , Fiehler Jens , Wintermark Max , Heit Jeremy J
Published: May 2022

Background and purpose

Early neurological improvement (ENI) after thrombectomy is associated with better long-term outcomes in patients with acute ischaemic stroke due to large vessel occlusion (AIS-LVO). Whether cerebral collaterals influence the likelihood of ENI is poorly described. We hypothesised that favourable collateral perfusion at the arterial, tissue-level and venous outflow (VO) levels is associated with ENI after thrombectomy.

Materials and methods

Multicentre retrospective study of patients with AIS-LVO treated by thrombectomy. Tissue-level collaterals (TLC) were measured on cerebral perfusion studies by the hypoperfusion intensity ratio. VO and pial arterial collaterals (PAC) were determined by the Cortical Vein Opacification Score and the modified Tan scale on CT angiography, respectively. ENI was defined as improvement of ≥8 points or a National Institutes of Health Stroke Scale score of 0 hour or 1 24 hours after treatment. Multivariable regression analyses were used to determine the association of collateral biomarkers with ENI and good functional outcomes (modified Rankin Scale 0–2).

Results

646 patients met inclusion criteria. Favourable PAC (OR: 1.9, CI 1.2 to 3.1; p=0.01), favourable VO (OR: 3.3, CI 2.1 to 5.1; p<0.001) and successful reperfusion (OR: 3.1, CI 1.7 to 5.8; p<0.001) were associated with ENI, but favourable TLC were not (p=0.431). Good functional outcomes at 90-days were associated with favourable TLC (OR: 2.2, CI 1.4 to 3.6; p=0.001), VO (OR: 5.7, CI 3.5 to 9.3; p<0.001) and ENI (OR: 5.7, CI 3.3 to 9.8; p<0.001), but not PAC status (p=0.647).

Conclusion

Favourable PAC and VO were associated with ENI after thrombectomy. Favourable TLC predicted longer term functional recovery after thrombectomy, but the impact of TLC on ENI is strongly dependent on vessel reperfusion.
Neurocognitive functioning and symptoms across levels of collision and contact in male high school athletes
Authors: Oldham Jessie R. , Howell David , Lanois Corey , Berkner Paul , Iverson Grant L. , Mannix Rebekah , Meehan William
Published: May 2022

Objective

We sought to determine whether male collision sport athletes perform worse on computerised neurocognitive assessments and report higher symptom burdens than athletes in contact (but not collision) sports and athletes in non-contact sports.

Methods

This cross-sectional study used data collected by the Massachusetts Concussion Management Coalition on high school boys who underwent computerised neurocognitive testing between 2009 and 2018. We divided sports participation in three different sport types: (1) collision, (2) contact, non-collision and (3) non-contact. Our outcomes included the four computerised neurocognitive composite scores (verbal memory, visual memory, visual motor speed and reaction time) and the total symptom score. The independent variable was sport type (collision, contact, non-contact), adjusted for age, concussion history and comorbidities.

Results

Of the 92 979 athletes (age: 15.59±2.08 years) included in our study, collision sport athletes performed minimally but significantly worse than other athletes on neurocognitive composite scores (verbal memory: β=−1.64, 95% CI −1.85 to –1.44; visual memory: β=−1.87, 95% CI −2.14 to –1.60; visual motor speed: β=−2.12, 95% CI −2.26 to –1.97; reaction time: β=0.02, 95% CI 0.02 to 0.02). Collision and contact sport athletes also had slightly but significantly lower total symptom scores (collision: 3.99±7.17; contact: 3.78±6.81; non-contact: 4.32±7.51, p<0.001, η2=0.001) than non-contact sport athletes.

Conclusion

There are minimal observed differences in performance on neurocognitive assessments between collision sport, contact sport and non-contact sport athletes. The repetitive subconcussive head impacts associated with collision sport participation do not appear to negatively affect self-reported symptoms or neurocognitive functioning in current youth athletes.
APOE ɛ4dose associates with increased brain iron and β-amyloid via blood–brain barrier dysfunction
Authors: Uchida Yuto , Kan Hirohito , Sakurai Keita , Horimoto Yoshihiko , Hayashi Emi , Iida Akihiko , Okamura Nobuyuki , Oishi Kenichi , Matsukawa Noriyuki
Published: May 2022

Objective

To examine the effect of apolipoprotein E (APOE)ɛ4dose on blood–brain barrier (BBB) clearance function, evaluated using an advanced MRI technique and analyse its correlation with brain iron and β-amyloid accumulation in the early stages of the Alzheimer’s continuum.

Methods

In this single-centre observational prospective cohort study, 24APOE ɛ4non-carriers, 22 heterozygotes and 20 homozygotes in the early stages of the Alzheimer’s continuum were scanned with diffusion-prepared arterial spin labelling, which estimates the water exchange rate across the BBB (kw). Participants also underwent quantitative susceptibility mapping, [11C]Pittsburgh compound B-positron emission tomography and neuropsychological testing. Using an atlas-based approach, we compared the regional kwof the whole brain among the groups and analysed its correlation with the neuroradiological and neuropsychological findings.

Results

The BBB kwvalues in the neocortices differed significantly among the groups (APOE ɛ4non-carriers>heterozygotes>homozygotes). These values correlated with brain iron levels (frontal lobe:r=−0.476, 95% CI=−0.644 to −0.264, p=0.011; medial temporal lobe:r=−0.455, 95% CI=−0.628 to −0.239, p=0.017), β-amyloid loads (frontal lobe:r=−0.504, 95% CI=−0.731 to −0.176, p=0.015; medial temporal lobe:r=−0.452, 95% CI=−0.699 to −0.110, p=0.036) and neuropsychological scores, after adjusting for age, sex andAPOE ɛ4dose.

Interpretation

Our results suggest that an increasedAPOE ɛ4dose is associated with decreased effective brain-waste clearance, such as iron and β-amyloid, through the BBB.
Serum GFAP differentiates Alzheimer’s disease from frontotemporal dementia and predicts MCI-to-dementia conversion
Authors: Oeckl Patrick , Anderl-Straub Sarah , Von Arnim Christine A F , Baldeiras Inês , Diehl-Schmid Janine , Grimmer Timo , Halbgebauer Steffen , Kort Anna M , Lima Marisa , Marques Tainá M , Ortner Marion , Santana Isabel , Steinacker Petra , Verbeek Marcel M , Volk Alexander E , Ludolph Albert C , Otto Markus
Published: May 2022

Objective

Reactive astrogliosis is a hallmark of Alzheimer’s disease (AD) and frontotemporal dementia (FTD) but differences between the diseases and time course are unclear. Here, we used serum levels of the astroglial marker glial fibrillary acidic protein (GFAP) to investigate differences in patients with AD dementia, mild cognitive impairment (MCI)-AD and behavioural variant FTD (bvFTD).

Methods

This multicentre study included serum samples from patients diagnosed with AD dementia (n=230), MCI-AD (n=111), bvFTD (n=140) and controls (n=129). A subgroup of patients with MCI-AD (n=32) was longitudinally followed-up for 3.9±2.6 years after sample collection. Serum levels of GFAP, neurofilament light chain (NfL) and pTau181 were measured by Simoa (Quanterix) and Ella (ProteinSimple).

Results

In total, samples from 610 individuals from four clinical centres were investigated in this study. Serum GFAP levels in AD dementia were increased (median 375 pg/mL, IQR 276–505 pg/mL) compared with controls (167 pg/mL, IQR 108–234 pg/mL) and bvFTD (190 pg/mL, IQR 134–298 pg/mL, p<0.001). GFAP was already increased in the early disease phase (MCI-AD, 300 pg/mL, IQR 232–433 pg/mL, p<0.001) and was higher in patients with MCI-AD who developed dementia during follow-up (360 pg/mL, IQR 253–414 pg/mL vs 215 pg/mL, IQR 111–266 pg/mL, p<0.01, area under the curve (AUC)=0.77). Diagnostic performance of serum GFAP for AD (AUC=0.84, sensitivity 98%, specificity 60%, likelihood ratio 2.5) was comparable to serum pTau181 (AUC=0.89, sensitivity 80%, specificity 87%, likelihood ratio 6.0) but superior to serum NfL (AUC=0.71, sensitivity 92%, specificity 49%, likelihood ratio 1.8).

Conclusions

Our data indicate a different type of reactive astrogliosis in AD and bvFTD and support serum GFAP as biomarker for differential diagnosis and prediction of MCI-to-dementia conversion.
Exploring in vivo multiple sclerosis brain microstructural damage through T1w/T2w ratio: a multicentre study
Authors: Margoni Monica , Pagani Elisabetta , Meani Alessandro , Storelli Loredana , Mesaros Sarlota , Drulovic Jelena , Barkhof Frederik , Vrenken Hugo , Strijbis Eva , Gallo Antonio , Bisecco Alvino , Pareto Deborah , Sastre-Garriga Jaume , Ciccarelli Olga , Yiannakas Marios , Palace Jacqueline , Preziosa Paolo , Rocca Maria A , Filippi Massimo
Published: May 2022

Objectives

To evaluate white matter and grey matter T1-weighted (w)/T2w ratio (T1w/T2w ratio) in healthy controls and patients with multiple sclerosis, and its association with clinical disability.

Methods

In this cross-sectional study, 270 healthy controls and 434 patients with multiple sclerosis were retrospectively selected from 7 European sites. T1w/T2w ratio was obtained from brain T2w and T1w scans after intensity calibration using eyes and temporal muscle.

Results

In healthy controls, T1w/T2w ratio increased until 50–60 years both in white and grey matter. Compared with healthy controls, T1w/T2w ratio was significantly lower in white matter lesions of all multiple sclerosis phenotypes, and in normal-appearing white matter and cortex of patients with relapsing-remitting and secondary progressive multiple sclerosis (p≤0.026), but it was significantly higher in the striatum and pallidum of patients with relapsing-remitting, secondary progressive and primary progressive multiple sclerosis (p≤0.042). In relapse-onset multiple sclerosis, T1w/T2w ratio was significantly lower in white matter lesions and normal-appearing white matter already at Expanded Disability Status Scale (EDSS) <3.0 and in the cortex only for EDSS ≥3.0 (p≤0.023). Conversely, T1w/T2w ratio was significantly higher in the striatum and pallidum for EDSS ≥4.0 (p≤0.005). In primary progressive multiple sclerosis, striatum and pallidum showed significantly higher T1w/T2w ratio beyond EDSS=6.0 (p≤0.001). In multiple sclerosis, longer disease duration, higher EDSS, higher brain lesional volume and lower normalised brain volume were associated with lower lesional and cortical T1w/T2w ratio and a higher T1w/T2w ratio in the striatum and pallidum (β from −1.168 to 0.286, p≤0.040).

Conclusions

T1w/T2w ratio may represent a clinically relevant marker sensitive to demyelination, neurodegeneration and iron accumulation occurring at the different multiple sclerosis phases.
MR T2-relaxation time as an indirect measure of brain water content and disease activity in NMOSD
Authors: Cacciaguerra Laura , Pagani Elisabetta , Radaelli Marta , Mesaros Sarlota , Martinelli Vittorio , Ivanovic Jovana , Drulovic Jelena , Filippi Massimo , Rocca Maria A
Published: May 2022

Objective

Since astrocytes at the blood–brain barrier are targeted by neuromyelitis optica spectrum disorder (NMOSD), this study aims to assess whether patients with NMOSD have a subclinical accumulation of brain water and if it differs according to disease activity.

Methods

Seventy-seven aquaporin-4-positive patients with NMOSD and 105 healthy controls were enrolled at two European centres. Brain dual-echo turbo spin-echo MR images were evaluated and maps of T2 relaxation time (T2rt) in the normal-appearing white matter (NAWM), grey matter and basal ganglia were obtained. Patients with a clinical relapse within 1 month before or after MRI acquisition were defined ‘active’. Differences between patients and controls were assessed using z-scores of T2rt obtained with age-adjusted and sex-adjusted linear models from each site. A stepwise binary logistic regression was run on clinical and MRI variables to identify independent predictors of disease activity.

Results

Patients had increased T2rt in both white and grey matter structures (p range: 0.014 to <0.0001). Twenty patients with NMOSD were defined active. Despite similar clinical and MRI features, active patients had a significantly increased T2rt in the NAWM and grey matter compared with those clinically stable (p range: 0.010–0.002). The stepwise binary logistic regression selected the NAWM as independently associated with disease activity (beta=2.06, SE=0.58, Nagelkerke R2=0.46, p<0.001).

Conclusions

In line with the research hypothesis, patients with NMOSD have increased brain T2rt. The magnitude of this alteration might be useful for identifying those patients with active disease.
TEARS: a longitudinal investigation of the prevalence, psychological associations and trajectory of poststroke emotionalism
Authors: Broomfield Niall McIntyre , West Robert , Barber Mark , Quinn Terence J , Gillespie David , Walters Matthew , House Allan
Published: May 2022

Objective

There are few longitudinal studies of poststroke emotionalism (PSE) and our understanding of the psychological associations of PSE is limited, constraining assessment of existing interventions and the development of new therapies. This study aimed to assess the prevalence and course of PSE over the first year poststroke, and its psychological associations.

Methods

Consenting stroke survivors who were physically and cognitively able to participate were assessed within 2 weeks, 6 and 12 months of stroke to determine PSE point prevalence using a diagnostic, semistructured PSE interview (Testing Emotionalism After Recent Stroke-Diagnostic Interview). At the same assessments, neuropsychological and disability status were determined using Hospital Anxiety and Depression Scale, Abbreviated Mental Test, National Institute of Health Stroke Scale, Barthel Index and Euro-Qol.

Results

Two hundred and seventy seven stroke survivors were recruited between 1 October 2015 and 30 September 2018. Diagnostic data were available at baseline for 228 of 277 cohort participants. Point prevalence for PSE was 27.2% at 2 weeks; estimated prevalence at 6 months adjusted for baseline was 19.9% and at 12 months 22.3%. PSE was associated with symptoms of anxiety and event-related distress.

Interpretation

PSE affects at least one in five stroke patients acutely following their stroke, and continues to affect one in eight longer term. PSE is associated with anxiety and event-related distress but is not simply a manifestation of mood disorder over time. Such psychological correlates may have implications for longer term social rehabilitation.
Muscle biochemical and pathological diagnosis in Pompe disease
Authors: Saito Yoshihiko , Nakamura Kimitoshi , Fukuda Tokiko , Sugie Hideo , Hayashi Shinichiro , Noguchi Satoru , Nishino Ichizo
Published: May 2022

Background and objectives

Pompe disease is reportedly less prevalent in Japan than in neighbouring countries, raising a possibility that some patients may be overlooked. Therefore, all muscle biopsy samples received at our institute were screened for Pompe disease to determine the accuracy of the disease prevalence.

Methods

The acid α-glucosidase (GAA) activity was assayed using 10 µm frozen muscle sections from 2408 muscle biopsies received between July 2015 and January 2018. Genetic analysis was performed for samples with decreased activity. The number of myopathologically diagnosed patients was retrospectively assessed.

Results

The GAA activity was distributed similarly to previous results from dried blood spot screening. GAA activity measured using muscle sections corresponded to that measured using muscle blocks. Of 163 patients with GAA activity <3 nmol/hour/mg protein, 43 (26%) patients had homozygous pseudodeficiency alleles inGAA(p.G576S and p.E689K). In the retrospective analysis, the number of patients diagnosed with Pompe disease via muscle biopsies decreased to zero over time.

Discussion

Muscle pathology is an accurate method to diagnose Pompe disease. It is unlikely that a significant number of patients with Pompe disease are overlooked. Pathological variants were rare, and the majority carried a pseudodeficiency allele, which further supports our conclusion.
Kotter’s 8 stages of change: implementation of clinical screening protocols for assessing patients for COVID-19 – a review of an academic medical centre’s preparedness
Authors: Ravi Shashank , Patel Sunny R , Laurence Sheneé K , Sebok-Syer Stefanie S , Gharahbaghian Laleh
Published: May 2022

Background

COVID-19 screening protocols rapidly evolved as a result of changing Centers for Disease Control and Prevention (CDC) and California Department of Public Health (CDPH) recommendations. These protocols led to operational improvements at one large academic medical centre using change management methods explained in Kotter’s 8-stage change model.

Methods

We reviewed all iterations of clinical process maps for identifying, isolating and assessing COVID-19 infections in paediatric and adult populations within one emergency department (ED) from 28 February 2020 to 5 April 2020. We incorporated CDC and CDPH criteria for the various roles of healthcare workers in ED patient assessment.

Results

Using Kotter’s 8-stage change model, we outlined the chronological evolution of basic screening criteria, as well as how these were reviewed, modified and implemented during the onset and through the time of greatest uncertainty of COVID-19 in the USA. Our results demonstrate a successful creation, and subsequent execution, of rapidly changing protocols across a large workforce.

Conclusion

We effectively applied a business change management framework to the hospital management response during a pandemic; we share these experiences and challenges to inform and guide future operational decision making during times of rapid change.
Clinical and histological findings at second but not at first kidney biopsy predict end-stage kidney disease in a large multicentric cohort of patients with active lupus nephritis
Authors: Gatto Mariele , Radice Francesca , Saccon Francesca , Calatroni Marta , Frontini Giulia , Trezzi Barbara , Zen Margherita , Ghirardello Anna , Tamborini Francesco , Binda Valentina , L'Imperio Vincenzo , Doria Andrea , Vaglio Augusto , Sinico Renato Alberto , Moroni Gabriella , Iaccarino Luca
Published: May 2022

Objective

To investigate second kidney biopsy as predictor of end-stage kidney disease (ESKD) in active lupus nephritis (LN).

Methods

Patients with biopsy-proven LN (International Society of Nephrology/Renal Pathology Society 2003) who had undergone a second kidney biopsy between January 1990 and December 2018 were included. Clinical and histological findings at first and at second biopsy were analysed with Cox proportional hazard models to predict ESKD, defined as start of kidney replacement therapy. Survival curves were calculated with Kaplan-Meier method.

Results

Ninety-two patients with LN were included, 87% females, mean follow-up 17.9±10.1 years. Reasons for second kidney biopsy encompassed nephritic flares (n=28, 30.4%), proteinuric flares (n=46, 50%) or lack of renal response (n=18, 19.5%). Class switch from first biopsy occurred in 50.5% of cases, mainly from non-proliferative towards proliferative classes. Class IV remained stable in over 50% of cases. Twenty-five patients (27.2%) developed ESKD, mostly belonging to the nephritic flare group (17/28, 60.7%). Independent predictors of ESKD at second biopsy were activity index (AI; (HR 95% CI) 1.20 (1.03 to 1.41), p=0.022), chronicity index (CI; 1.41 (1.09 to 1.82), p=0.008) and 24h-proteinuria (1.22 (1.04 to 1.42), p=0.013). AI≥2 (log-rank p=0.031), CI >4 (log-rank p=0.001) or proteinuria ≥3.5 g/day (log-rank=0.009) identified thresholds for higher ESKD risk. In a subgroup analysis, glomerular activity and tubular chronicity mostly accounted for AI and CI association with ESKD. No histological or laboratory predictors emerged at first biopsy (95% CI): AI: 0.88 to 1.19; CI: 0.66 to 1.20; proteinuria 0.85 to 1.08.

Conclusions

Findings at second but not at first kidney biopsy in patients with persistently active or relapsing LN inform about ESKD development in a long-term follow-up.
Imagination and idealism in the medical sciences of an ageing world
Authors: Farrelly Colin
Published: May 2022

Imagination and idealism are particularly important creative epistemic virtues for the medical sciences if we hope to improve the health of the world’s ageing population. To date, imagination and idealism within the medical sciences have been dominated by a paradigm of disease control, a paradigm which has realised significant, but also limited, success. Disease control proved particularly successful in mitigating the early-life mortality risks from infectious diseases, but it has proved less successful when applied to the chronic diseases of late life (like cancer). The time is ripe for the emergence and prominence of a supplementary medical research paradigm, the paradigm of ‘healthy ageing’ which prioritises the goal of rate (of ageing) control rather than disease control. This is the difference between extending the human healthspan versus extending survival by managing (or trying to eliminate) the multi-morbidities, frailty and disability currently prevalent in late life. The idealism of the disease control paradigm is myopic because it ignores the health constraints imposed by the inborn ageing process itself, a biological reality which is already inflicting significant economic and disease burdens on the world’s ageing populations. Unless the medical sciences retard the rate of biological ageing, these problems will continue to be amplified as larger numbers of persons survive into late life.
Fatherlessness, sperm donors and ‘so what?’ parentage: arguing against the immorality of donor conception through ‘world literature’
Authors: Halden Grace
Published: May 2022

Is biology and knowing biological ancestral information essential to the construction of identity? Bioethicist James David Velleman believes this is the case and argues that donor gamete conception is immoral because a portion of genetic heritage will be unknown. Velleman is critical of sperm donation and the absence of a biological father in donor-assisted families. His bioethical work, specifically the 2005 article ‘Family History’, is oft-cited in articles debating the ethics surrounding gamete donations and diverse family formations. However, I wonder to what extent Velleman’s ethical stance is exhibited in contemporary culture? Velleman suggests that innate knowledge of bio-superiority helps readers and audiences appreciate the importance of biological family structures in literature and film; he says, ‘When people deny the importance of biological ties, I wonder how they can read world literature with any comprehension’ (2005, 369). Velleman understands the stories of Oedipus, Moses, Telemachus and Luke Skywalker as demonstrating a universal cultural comprehension that genetics are essential to identity construction. I adopt Velleman’s list of stories and ask if they really can support an antidonation sentiment and suggest that most of the stories actually support diverse family structures. By exploring the significance of story-telling in cultural understandings of family and identity, it is possible to identify the ways in which story-telling can impact how society negotiates complex issues such as assisted reproduction, donor conception and donor industry regulation.
A mini-review of intrasaccular flow diverters
Authors: Hecker Constantin , Broussalis Erasmia , Griessenauer Christoph J , Killer-Oberpfalzer Monika
Published: May 2022

Treatment of wide-necked complex intracranial aneurysms continues to challenge neurointerventionalists. Intrasaccular flow diverters have expanded the armamentarium considerably and are now used extensively. While five types of devices have already obtained the CE mark for use within Europe, only the Woven EndoBridge (WEB) device is approved by the US Food and Drug Administration. Other intrasaccular devices are the Luna/Artisse Aneurysm Embolization System (Medtronic), the Medina Embolic Device (Medtronic), the Contour Neurovascular System (Cerus), and the Neqstent Coil Assisted Flow Diverter (Cerus). This mini review will provide a compact overview of these devices and a summary of the current literature.
Early-onset cardiac dysfunction following allogeneic haematopoietic stem cell transplantation
Authors: Moriyama Shohei , Fukata Mitsuhiro , Hieda Michinari , Yokoyama Taku , Yoshimoto Goichi , Kusaba Hitoshi , Nakashima Yasuhiro , Miyamoto Toshihiro , Maruyama Toru , Akashi Koichi
Published: May 2022

Objective

Heart failure following allogeneic haematopoietic stem cell transplantation (allo-HSCT) is a serious complication that requires early detection; however, the clinical implications of early-onset cancer therapy-related cardiac dysfunction (CTRCD) following allo-HSCT remain unclear. We investigated the determinants and prognostic impact of early-onset CTRCD in allo-HSCT recipients.

Methods

The records of 136 patients with haematological malignancies who underwent allo-HSCT at our institute were retrospectively reviewed. Early-onset CTRCD was defined as a decrease in left ventricular ejection fraction (LVEF) of ≥10% and an LVEF of ≤53% within 100 days after HSCT.

Results

Early-onset CTRCD was diagnosed in 23 out of 136 included patients (17%), and the median duration from HSCT to CTRCD diagnosis was 24 (9–35) days. Patients were followed up for 347 (132–1268) days. In multivariate logistic regression analysis, cumulative doxorubicin dosage (each 10 mg/m2) and severity of acute graft-versus-host disease (GVHD/grade) were independent indicators of early-onset CTRCD (OR (95% CI) 1.04 (1.00 to 1.07); p=0.032; OR (95% CI) 1.87 (1.19 to 2.95), p=0.004, respectively). The overall and primary disease death rates were significantly higher in allo-HSCT recipients with early-onset CTRCD than in those without early-onset CTRCD (HR (95% CI) 1.98 (1.11 to 3.52), p=0.016; HR (95% CI) 2.96 (1.40 to 6.29), p=0.005, respectively), independent of primary disease type, remission status and transplantation type.

Conclusions

Severe acute GVHD and higher cumulative anthracycline are two significant determinants of early-onset CTRCD. Early-onset CTRCD following allo-HSCT regulates survival in patients with haematological malignancies.
Efficacy of tofacitinib in patients with rheumatoid arthritis stratified by baseline body mass index: an analysis of pooled data from phase 3 studies
Authors: Dikranian Ara H , Gonzalez-Gay Miguel A , Wellborne Frank , Álvaro-Gracia José María , Takiya Liza , Stockert Lori , Paulissen Jerome , Shi Harry , Tatulych Svitlana , Curtis Jeffrey R
Published: May 2022

Objective

Tofacitinib is an oral Janus kinase for the treatment of rheumatoid arthritis (RA). This post hoc analysis assessed whether baseline body mass index (BMI) impacts tofacitinib efficacy in patients with RA.

Methods

Pooled data from six phase 3 studies in patients receiving tofacitinib 5 mg (N=1589) or 10 mg (N=1611) twice daily or placebo (advancing to active treatment at months 3 or 6; N=680), ±conventional synthetic disease-modifying antirheumatic drugs, were stratified by baseline BMI (<25, 25 to <30, ≥30 kg/m2). Endpoints (through to month 6) were assessed descriptively: American College of Rheumatology 20/50/70 response rates; changes from baseline (∆) in Disease Activity Score in 28 joints, erythrocyte sedimentation rate (DAS28-4(ESR)), DAS28-4(C-reactive protein), Clinical Disease Activity Index (CDAI), Health Assessment Questionnaire-Disability Index (HAQ-DI) and pain; and proportions of patients achieving DAS28-4(ESR) ≥1.2 and HAQ-DI ≥0.22 decreases from baseline, low disease activity (DAS28-4(ESR) ≤3.2 or CDAI ≤10) and radiographic non-progression (Δmodified Total Sharp Score ≤0.5; months 12 and 24). Estimates were adjusted using multivariable models for selected outcomes. Univariate/multivariable regression analyses determined predictors of month 6 outcomes.

Results

Of 3880 patients included, 1690 (43.6%), 1173 (30.2%) and 1017 (26.2%) had baseline BMI <25, 25 to <30 and ≥30 kg/m2, respectively. Tofacitinib showed greater efficacy improvements versus placebo in each BMI category. Differences in efficacy outcomes (adjusted and unadjusted) were generally not clinically meaningful across BMI categories within treatment groups. In regression analyses, BMI was not consistently associated with selected outcomes.

Conclusions

Baseline BMI did not consistently affect tofacitinib response suggesting that tofacitinib is an effective oral treatment option for adults with moderate to severe RA regardless of baseline BMI, including patients with BMI ≥30 kg/m2.

Trial registration numbers

NCT00814307, NCT01039688; NCT00960440; NCT00847613; NCT00856544; NCT00853385.