bluuebunny/crossref_metadata_2025_split huggingface dataset:
Associations between attainment of incentivised primary care indicators and emergency hospital admissions among type 2 diabetes patients: a population-based historical cohort study
Authors: Gunn Laura H , McKay Ailsa J , Molokhia Mariam , Valabhji Jonathan , Molina German , Majeed Azeem , Vamos Eszter P 
Published: April 2021

Objectives England has invested considerably in diabetes care over recent years through programmes such as the Quality and Outcomes Framework and National Diabetes Audit. However, associations between specific programme indicators and key clinical endpoints, such as emergency hospital admissions, remain unclear. We aimed to examine whether attainment of Quality and Outcomes Framework and National Diabetes Audit primary care diabetes indicators is associated with diabetes-related, cardiovascular, and all-cause emergency hospital admissions. Design Historical cohort study. Setting A total of 330 English primary care practices, 2010–2017, using UK Clinical Practice Research Datalink. Participants A total of 84,441 adults with type 2 diabetes. Main Outcome Measures The primary outcome was emergency hospital admission for any cause. Secondary outcomes were (1) diabetes-related and (2) cardiovascular-related emergency admission. Results There were 130,709 all-cause emergency admissions, 115,425 diabetes-related admissions and 105,191 cardiovascular admissions, corresponding to unplanned admission rates of 402, 355 and 323 per 1000 patient-years, respectively. All-cause hospital admission rates were lower among those who met HbA1c and cholesterol indicators (incidence rate ratio = 0.91; 95% CI 0.89–0.92; p < 0.001 and 0.87; 95% CI 0.86–0.89; p < 0.001), respectively), with similar findings for diabetes and cardiovascular admissions. Patients who achieved the Quality and Outcomes Framework blood pressure target had lower cardiovascular admission rates (incidence rate ratio = 0.98; 95% CI 0.96–0.99; p = 0.001). Strong associations were found between completing 7–9 (vs. either 4–6 or 0–3) National Diabetes Audit processes and lower rates of all admission outcomes ( p-values < 0.001), and meeting all nine National Diabetes Audit processes had significant associations with reductions in all types of emergency admissions by 22% to 26%. Meeting the HbA1c or cholesterol Quality and Outcomes Framework indicators, or completing 7–9 National Diabetes Audit processes, was also associated with longer time-to-unplanned all-cause, diabetes and cardiovascular admissions. Conclusions Attaining Quality and Outcomes Framework-defined diabetes intermediate outcome thresholds, and comprehensive completion of care processes, may translate into considerable reductions in emergency hospital admissions. Out-of-hospital diabetes care optimisation is needed to improve implementation of core interventions and reduce unplanned admissions.
Relationship Pattern of Personality Disorder Traits in Major Psychiatric Disorders: A Cross-Sectional Study
Authors: Saini Bhavneesh , Bansal Pir Dutt , Bahetra Mamta , Sharma Arvind , Bansal Priyanka , Singh Baltej , Moria Kavita , Kumar Rakesh 
Published: April 2021

Background: Normal personality development, gone awry due to genetic or environmental factors, results in personality disorders (PD). These often coexist with other psychiatric disorders, affecting their outcome adversely. Considering the heterogeneity of data, more research is warranted. Methods: This was a cross-sectional study on personality traits in psychiatric patients of a tertiary hospital, over 1 year. Five hundred and twenty-five subjects, aged 18–45 years, with substance, psychotic, mood, or neurotic disorders were selected by convenience sampling. They were evaluated for illness-related variables using psychiatric pro forma; diagnostic confirmation and severity assessment were done using ICD-10 criteria and suitable scales. Personality assessment was done using the International Personality Disorder Examination after achieving remission. Results: Prevalence of PD traits and PDs was 56.3% and 4.2%, respectively. While mood disorders were the diagnostic group with the highest prevalence of PD traits, it was neurotic disorders for PDs. Patients with PD traits had a past psychiatric history and upper middle socioeconomic status (SES); patients with PDs were urban and unmarried. Both had a lower age of onset of psychiatric illness. Psychotic patients with PD traits had higher and lower PANSS positive and negative scores, respectively. The severity of personality pathology was highest for mixed cluster and among neurotic patients. Clusterwise prevalence was cluster C > B > mixed > A (47.1%, 25.2%, 16.7%, and 11.4%). Among subtypes, anankastic (18.1%) and mixed (16.7%) had the highest prevalence. Those in the cluster A group were the least educated and with lower SES than others. Conclusions: PD traits were present among 56.3% of the patients, and they had many significant sociodemographic and illness-related differences from those without PD traits. Cluster C had the highest prevalence. Among patients with psychotic disorders, those with PD traits had higher severity of psychotic symptoms.
“6 Anatomical Landmarks” Technique for Satisfactory Free-Hand Orbital Reconstruction With Standard Preformed Titanium Mesh
Authors: Canzi Gabriele , Corradi Federica , Novelli Giorgio , Bozzetti Alberto , Sozzi Davide 
Published: April 2021

Study Design: Retrospective study. Objective: Resolution of clinical signs and symptoms following orbital fractures depends on the accurate restoration of the orbital volume. Computer-Assisted procedures and Patient Specific Implants represent modern solutions, but they require additional resources. A more reproducible option is the use of standard preformed titanium meshes, widely available and cheaper; with their use quality of results is proportional to the accuracy with which they are positioned. This work identifies 6 reproducible and constant anatomical landmarks, as an intraoperative guide for the precise positioning of titanium preformed meshes. Methods: 90 patients treated at the Maxillofacial Surgery Department, Niguarda Trauma Center, Milan, for unilateral orbital reconstruction (January 2012 to December 2018), were studied. In all cases reconstruction was performed respecting the 6 proposed anatomical landmarks. The outcomes analyzed are: post-operative CT adherence to the 6 anatomical markers and symmetry achieved respect to controlateral orbit; number/year of re-interventions and duration of surgery; resolution of clinical defects (at least 12-months follow-up); incidence of complications. Results: Satisfactory results were obtained in terms of restoration of orbital size, shape and volume. Clinical defects early recovered with a low incidence of complications and re-interventions. Operating times and radiological accuracy have shown a progressive improvement during years of application of this technique. Conclusions: The proposed “6 anatomical landmarks” is an easy free-hand technique that allows everyone to obtain high levels of reconstructive accuracy and it should be a skill of all surgeons who deal with orbital reconstruction in daily clinical activity.
Predictors of six-month inability to return to work in previously employed subjects after mild traumatic brain injury: A TRACK-TBI pilot study
Authors: Yue John K , Phelps Ryan RL , Hemmerle Debra D , Upadhyayula Pavan S , Winkler Ethan A , Deng Hansen , Chang Diana , Vassar Mary J , Taylor Sabrina R , Schnyer David M , Lingsma Hester F , Puccio Ava M , Yuh Esther L , Mukherjee Pratik , Huang Michael C , Ngwenya Laura B , Valadka Alex B , Markowitz Amy J , Okonkwo David O , Manley Geoffrey T ,   TRACK-TBI Investigators
Published: April 2021

Introduction Return to work (RTW) is an important milestone of mild traumatic brain injury (mTBI) recovery. The objective of this study was to evaluate whether baseline clinical variables, three-month RTW, and three-month postconcussional symptoms (PCS) were associated with six-month RTW after mTBI. Methods Adult subjects from the prospective multicenter Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot study with mTBI (Glasgow Coma Scale 13–15) who were employed at baseline, with completed three- and six-month RTW status, and three-month Acute Concussion Evaluation (ACE), were extracted. Univariate and multivariable analyses were performed for six-month RTW, with focus on baseline employment, three-month RTW, and three-month ACE domains (physical, cognitive, sleep, and/or emotional postconcussional symptoms (PCS)). Odds ratios (OR) and 95% confidence intervals [CI] were reported. Significance was assessed at p < 0.05. Results In 152 patients aged 40.7 ± 15.0 years, 72% were employed full-time at baseline. Three- and six-month RTW were 77.6% and 78.9%, respectively. At three months, 59.2%, 47.4%, 46.1% and 31.6% scored positive for ACE physical, cognitive, sleep, and emotional PCS domains, respectively. Three-month RTW predicted six-month RTW (OR = 19.80, 95% CI [7.61–51.52]). On univariate analysis, scoring positive in any three-month ACE domain predicted inability for six-month RTW (OR = 0.10–0.11). On multivariable analysis, emotional symptoms predicted inability to six-month RTW (OR = 0.19 [0.04–0.85]). Subjects who scored positive in all four ACE domains were more likely to be unable to RTW at six months (4 domains: 58.3%, vs. 0-to-3 domains: 9.5%; multivariable OR = 0.09 [0.02–0.33]). Conclusions Three-month post-injury is an important time point at which RTW status and PCS should be assessed, as both are prognostic markers for six-month RTW. Clinicians should be particularly vigilant of patients who present with emotional symptoms, and patients with symptoms across multiple PCS categories, as these patients are at further risk of inability to RTW and may benefit from targeted evaluation and support.
Using the Remnant Anterior Cruciate Ligament to Improve Knee Stability: Biomechanical Analysis Using a Cadaveric Model
Authors: Nhan Derek T. , Belkoff Stephen M. , Singh Prerna , Sullivan Brian T. , Klyce Walter , Lee R. Jay 
Published: April 2021

Background: Injured anterior cruciate ligament (ACL) tissue retains proprioceptive nerve fibers, vascularity, and biomechanical properties. For these reasons, remnant ACL tissue is often preserved during the treatment of ACL injuries. Purpose: To assess through a cadaveric model whether reorienting and retensioning the residual ACL via an osteotomy improves knee stability after partial ACL tear, with substantial remnant tissue and intact femoral and tibial attachments. Study Design: Controlled laboratory study. Methods: In 8 adult cadaveric knees, we measured anterior tibial translation and rotational laxity at 30° and 90° of flexion with the ACL in its native state and in 3 conditions: partial tear, retensioned, and ACL-deficient. The partial-tear state consisted of a sectioned anteromedial ACL bundle. Results: In the native state, the translation was 10 ± 2.7 mm (mean ± SD) at 30° of flexion and 8.4 ± 3.6 mm at 90° of flexion. Anterior translation of the knees in the partial-tear state (14 ± 2.7 mm at 30° and 12 ± 2.7 mm at 90°) was significantly greater than baseline ( P < .001 for both). Translation in the ACL-retensioned state (9.2 ± 1.7 mm at 30° and 7.2 ± 2.1 mm at 90°) was significantly less than in the ACL-deficient state ( P < .001 for both), and translation was not significantly different from that of the intact state. For ACL-deficient knees, translation (20 ± 4.3 mm at 30° and 16 ± 4.4 mm at 90°) was significantly greater than all other states ( P < .001 for all). Although rotational testing demonstrated the least laxity at 30° and 90° of flexion in the retensioned and intact states and the most laxity in the ACL-deficient state, rotation was not significantly different among any of the experimental states. Conclusion: In a cadaveric model of an incomplete ACL tear, a reorienting and retensioning core osteotomy at the tibial insertion of the remnant ACL improved anteroposterior translation of the knee without compromising its rotational laxity. Clinical Relevance: The findings of this study support the concept of ACL tissue reorienting and retensioning in the treatment of ACL laxity as an area for future investigation.
Sequential Infusion of Anti-CD22 and Anti-CD19 Chimeric Antigen Receptor T Cells for Adult Patients with Refractory/Relapsed B-Cell Acute Lymphoblastic Leukemia
Authors: Huang Liang , Wang Na , Li Chunrui , Cao Yang , Xiao Yi , Xiao Min , Zhang Yicheng , Zhang Tongcun , Zhou Jianfeng 
Published: April 2021

Abstract

Clinical trials of second generation chimeric antigen receptor engineered T cells (CAR-T cells) have yielded unprecedented efficacy in refractory/relapsed B-cell acute lymphoblastic leukemia (B-ALL), especially in children and young adult. However, antigen loss relapse has been observed in approximately 14% of patients in anti-CD19 CAR-T cell therapy across institutions, which emerges as a challenge for the long-term disease control of this promising immunotherapy. Recently, CD19/CD20 and CD19/CD22 dual antigen targeting have been proposed to overcome antigen loss relapse after the administration of anti-CD19 CAR-T cells. This strategy may result in enhanced anti-tumor activity, while safety concern regarding the risk of cytokine release syndrome (CRS) due to significant CAR-T cell activation and cytokine release needs to be addressed.
Here, we conducted an open-label, single-center and single-arm pilot study of sequential infusion of anti-CD22 and anti-CD19 CAR-T cells. We aimed to evaluate its safety and efficacy in adult patients with refractory or relapsed B-ALL. This trial is registered with ChiCTR, number ChiCTR-OPN-16008526.
Between March 2016 and March 2017, 27 patients with refractory or relapsed B-ALL were enrolled in this clinical trial, with a median age of 30±12 years (range, 18-62 years). Thirteen patients (48.1%) had a history of at least two prior relapsed or primary refractory disease. Twenty-six patients received fludarabine and cyclophosphamide before the infusion of CAR-T cells. The median cell dosages of anti-CD22 and anti-CD19 CAR-T cells were 2.44 ± 1.02 × 106 /kg and 1.98 ± 1.05 × 106 /kg, respectively. 24/29 (88.9%) patients achieved CR or Cri, including 7 patients who received prior hematopoietic stem cell transplantation, and 13/27 (48.1%) patients achieved minimal residual disease negative (MRD-) CR accessed by flow cytometry. Sustained remission was achieved with a 6-month overall survival rate of 79% (95% CI, 66-97) and an event-free survival rate of 72% (95% CI, 55-95). 24/29 (88.9%) patients experienced CRS and 6/27 (22.2%) patients had reversible sever CRS (grade 3-4). And 3/27 (11.1%) patients developed neurotoxicity. Multi-color flow cytometry was used to screen and quantitate MRD in blood, bone marrow and cerebrospinal fluid. Antigen escape of CD19 and CD22 was not detected in any relapsed patient post-CAR-T cell therapy.
Our results indicated that sequential infusion of third generation Anti-CD22 and Anti-CD19 CAR-T cell therapy is feasible and safe for patients with refractory/relapsed B-ALL. Dual antigen targeting should be a promising approach for overcoming antigen escape relapse, while needs to be further determined in our clinical trial.

Disclosures
No relevant conflicts of interest to declare.
Genome Editing Strategies to Treat Beta-Hemoglobinopathies
Authors: Weiss Mitchell J 
Published: April 2021

Genetic forms of anemia caused by HBB gene mutations that impair beta globin production are extremely common worldwide. The resultant disorders, mainly sickle cell disease (SCD) and beta-thalassemia, cause substantial morbidity and early mortality. Treatments for these diseases include medical therapies and bone marrow transplantation (BMT), which can be curative. However, medical therapies are suboptimal and BMT is associated with serious toxicities, particularly because HLA-matched allogeneic sibling donors are not available for most patients. Thus, new therapies are urgently needed for millions of affected individuals. Gene therapy offers great promise to cure SCD and beta thalassemia and emerging genome editing technologies represent a new form of gene therapy. Approaches to cure SCD and beta-thalassemia via genome editing include: 1) Correction of HBB mutations by homology directed repair (HDR); 2) use of non-homologous end joining (NHEJ) to activate gamma globin production and raise fetal hemoglobin (HbF) levels; 3) NHEJ to disrupt alpha-globin genes (HBA1 or HBA2) and thereby alleviate globin chain imbalance in intermediately severe forms of beta thalassemia. Challenges for these approaches include selection of the most effective genome editing tools, optimizing their delivery to hematopoietic stem cells (HSCs), improving specificity and better understanding potential off target effects, particularly those that are biologically relevant. Technologies for genome editing are advancing rapidly and being tested in preclinical models for HBB-mutated disorders. Ultimately, however, the best strategies can only be identified in clinical trials. This will require close collaborations between basic/translational researchers who study genome editing, clinical hematologists and collaboration between experts in academia and the bio-pharmaceutical industry.

Disclosures
No relevant conflicts of interest to declare.
New Bone Marrow Failure Genes: DNAJC21 and ERCC6L2
Authors: Dokal Inderjeet 
Published: April 2021

A significant number of cases with bone marrow failure present with one or more extra-hematopoietic abnormality. This suggests a constitutional or genetic basis, and yet many of them remain uncharacterized. Through exome sequencing, we have recently identified two sub groups of these cases, one defined by germline biallelic mutations in DNAJC21 (DNAJ homolog subfamily C member 21) and the other in ERCC6L2 (excision repair cross complementing 6 like-2).
Patients with DNAJC21 mutations are characterized by global bone marrow failure in early childhood. They can also have a variable number of extra-hematopoietic abnormalities such as short stature and retinal dystrophy. The encoded protein associates with ribosomal RNA (rRNA) and plays a highly conserved role in the maturation of the 60S ribosomal subunit. Lymphoblastoid patient cells exhibit increased sensitivity to the transcriptional inhibitor actinomycin D and reduced levels of rRNA. Characterisation of mutations has revealed impairment in interactions with cofactors (PA2G4, HSPA8 and ZNF622) involved in 60S maturation. DNAJC21 deficiency results in cytoplasmic accumulation of the 60S nuclear export factor PA2G4, aberrant ribosome profiles and increased cell death. Collectively these findings demonstrate that biallelic mutations in DNAJC21 cause disease due to defects in early nuclear rRNA biogenesis and late cytoplasmic maturation of the 60S subunit.
Patients harbouring biallelic ERCC6L 2 mutations are characterized by bone marrow failure (in childhood or early adulthood) and one or more extra-hematopoietic abnormality such as microcephaly. Knockdown of ERCC6L2 in human cells significantly reduces their viability upon exposure to the DNA damaging agent irofulven but not etoposide and camptothecin suggesting a role in nucleotide excision repair. ERCC6L2 knockdown cells and patient cells harbouring biallelic ERCC6L2 mutations also display H2AX phosphorylation that significantly increases upon genotoxic stress, suggesting an early DNA damage response. ERCC6L2 is seen to translocate to mitochondria as well as the nucleus in response to DNA damage and its knockdown induces intracellular reactive oxygen species (ROS). Treatment with the ROS scavenger, N-acetyl-cysteine, attenuates the irofulven-induced cytotoxicity in ERCC6L2 knockdown cells and abolishes its traffic to mitochondria and nucleus in response to this DNA damaging agent. Collectively, these observations suggest that ERCC6L2has a pivotal rolein DNA repair and mitochondrial function.
In conclusion, ERCC6L2 and DNAJC21 have an important role in maintaining genomic stability and ribosome biogenesis, respectively. They bring into focus new biological connections/pathways whose constitutional disruption is associated with defective hematopoiesis since patients harbouring germline biallelic mutations in these genes uniformly have bone marrow failure.

Disclosures
No relevant conflicts of interest to declare.
Normal Plasma Cell Biology: Natural Achilles Heels as Targets in Myeloma
Authors: Georgopoulos Katia 
Published: April 2021

Abstract
Normal Plasma Cell Biology: Natural Achilles Heels as Targets in MyelomaÊ Primary exposure to antigen leads to affinity maturation, selection and terminal differentiation of mature B cells to antibody-secreting plasma cells. Long-lived high-affinity plasma cells and their immediate precursors reside in the bone marrow and are responsible for rapid recall reactions and a life-time production of high affinity antibodies. Members of the IKAROS gene family have been specifically implicated in the generation of long-lived plasma cells. Mice deficient for Aiolos, the B cell specific member of the IKAROS gene family fail to produce high affinity plasma cells in the bone marrow and to sustain serum antibody titers after both primary or secondary immunization with a range of hapten concentrations. Chimera reconstitutions have demonstrated that the bone marrow plasma cell defect is B cell intrinsic. However, lack of AIOLOS does not alter expression of any of the previously described factors required for B cell differentiation into the plasma cell stage. No defect in somatic hyper-mutation, the generation of memory B cells, or short-lived high affinity plasma cells in the spleen is observed upon challenge or re-challenge. Thus this IKAROS family member is critically required for high-affinity bone plasma cells possibly by regulating their interaction with the bone marrow microenvironment, a process that is likely critical for long-term survival. High-affinity bone marrow plasma cells are the normal counterpart of the devastating B cell malignancy multiple myeloma. Multiple myeloma is treatable with immune modulatory drugs (IMiD) such as lenalidomide. Recent studies have shown that IMiD alter the specificity of the CRL4-CEREBLON (CRL4CRBN) E3 ubiquitin ligase complex. Among the new targets for the CRL4CRBN complex are two of the IKAROS family members, AIOLOS and IKAROS, whose degradation adversely affects the cellular fitness of multiple myeloma cells. Recent studies in B cell precursors have implicated the IKAROS gene family in the regulation of bone marrow stromal interactions. IKAROS and AIOLOS activities balance self-renewal, survival, and pre-B cell differentiation by engaging epigenetic and transcriptional machineries through discrete lineage-specific superenhancers. Such AIOLOS and IKAROS-dependent regulatory pathways engaged in early B cell precursors may also be involved in controlling bone marrow stromal interactions with high affinity plasma cells and their malignant counterparts thereby contributing to long-term growth and survival. Further exploitation of IKAROS family-targeted pathways in bone marrow plasma cells and multiple myeloma is warranted.

Disclosures
No relevant conflicts of interest to declare.
Spatial matching on the urban labor market: estimates with unique micro data
Authors: Wozniak Marcin 
Published: April 2021

AbstractIn the paper, we investigate spatial relationship on the labor market of Poznań agglomeration (Poland) with unique data on job vacancies. We have developed spatial panel models to assess the search and matching process with a particular focus on spatial spillovers. In general, spatial models may provide different findings than regular panel models regarding returns to scale in matching technology. Moreover, we have identified global spillover effects as well as other factors that impact the job-worker matching. We underline the role of data on job vacancies: the data retrieved from commercial job portals produced much more reliable estimates than underestimated registered data.