bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of continuous infusion of dexmedetomidine on blood loss in orthognathic surgery: a retrospective study
Authors: Jin Chenyu , Lv Xiang , Sun Yu , Jiang Hong
Published: July 2021

Background

Patients with maxillofacial deformities require orthognathic surgeries to correct occlusion. The surgical procedure may lead to massive bleeding, which is associated with haematoma, respiratory obstruction, and asphyxia. Dexmedetomidine has been used in controlled hypotension and may reduce blood loss in orthognathic surgery. We conducted a retrospective cohort study to evaluate the effect of dexmedetomidine on blood loss in orthognathic surgeries.

Methods

The primary outcome examined was blood loss, and secondary outcomes were postoperative haemoglobin level; intraoperative heart rate and blood pressure (T1: at incision; T2: 30 min after incision; T3: 60 min after incision; T4: 120 min after incision); dosage of fentanyl, remifentanil, urapidil, and esmolol; operation time; and incidence of allogeneic blood transfusion.

Results

A total of 1247 patients were included in this study, and 540 patient pairs were matched via propensity score matching. There were significant decreases in mean blood loss, heart rate at T1–T4, blood pressure at T1, and remifentanil and esmolol dosage in the dexmedetomidine group compared with those in the control group. There was also a significant increase in the postoperative haemoglobin level of the dexmedetomidine group.

Conclusions

Continuous infusion of dexmedetomidine can decrease blood loss in orthognathic surgery.

Trial registration: ChiCTR1800018794 (retrospectively registered)

Name of registry: Chinese Clinical Trial Registry

Date of registration: 2018/10/09

URL: www.chictr.org.cn/showproj.aspx?proj=30612
Genetic pathogenesis of immunoglobulin light chain amyloidosis: basic characteristics and clinical applications
Authors: Xu Linchun , Su Yongzhong
Published: July 2021

Immunoglobulin light chain amyloidosis (AL) is an indolent plasma cell disorder characterized by free immunoglobulin light chain (FLC) misfolding and amyloid fibril deposition. The cytogenetic pattern of AL shows profound similarity with that of other plasma cell disorders but harbors distinct features. AL can be classified into two primary subtypes: non-hyperdiploidy and hyperdiploidy. Non-hyperdiploidy usually involves immunoglobulin heavy chain translocations, and t(11;14) is the hallmark of this disease. T(11;14) is associated with low plasma cell count but high FLC level and displays distinct response outcomes to different treatment modalities. Hyperdiploidy is associated with plasmacytosis and subclone formation, and it generally confers a neutral or inferior prognostic outcome. Other chromosome abnormalities and driver gene mutations are considered as secondary cytogenetic aberrations that occur during disease evolution. These genetic aberrations contribute to the proliferation of plasma cells, which secrete excess FLC for amyloid deposition. Other genetic factors, such as specific usage of immunoglobulin light chain germline genes and light chain somatic mutations, also play an essential role in amyloid fibril deposition in AL. This paper will propose a framework of AL classification based on genetic aberrations and discuss the amyloid formation of AL from a genetic aspect.
Vibrio vulnificus induces the death of a major bacterial species in the mouse gut via cyclo-Phe-Pro
Authors: Kim Jeong-A , Jang Bo-Ram , Kim Yu-Ra , Jung You-Chul , Kim Kun-Soo , Lee Kyu-Ho
Published: July 2021

Background

A foodborne pathogen, Vibrio vulnificus, encounters normal microflora inhabiting the gut environments prior to causing fatal septicemia or gastroenteritis and should overcome the barriers derived from the gut commensals for successful infection. Its interactions with gut commensals during the infection process, however, have not yet been understood. In the present study, the effect of V. vulnificus on the community structures of gut microbiota in mice was examined.

Results

Analyses of microbiota in the fecal samples of mice that died due to V. vulnificus infection revealed the decreased abundance of bacteria belonged to Bacteroidetes, notably, the species Bacteroides vulgatus. In vitro coculturing of the two bacterial species resulted in the decreased survival of B. vulgatus. The antagonistic effect of V. vulnificus against B. vulgatus was found to be mediated by cyclo-Phe-Pro (cFP), one of the major compounds secreted by V. vulnificus. cFP-treated B. vulgatus showed collapsed cellular morphology with an undulated cell surface, enlarged periplasmic space, and lysed membranes, suggesting the occurrence of membrane disruption. The degree of membrane disruption caused by cFP was dependent upon the cellular levels of ObgE in B. vulgatus. Recombinant ObgE exhibited a high affinity to cFP at a 1:1 ratio. When mice were orally injected with cFP, their feces contained significantly reduced B. vulgatus levels, and their susceptibility to V. vulnificus infection was considerably increased.

Conclusions

This study demonstrates that V. vulnificus-derived cFP modulates the abundance of the predominant species among gut commensals, which made V. vulnificus increase its pathogenicity in the hosts.
Implementation and implications for polygenic risk scores in healthcare
Authors: Slunecka John L. , van der Zee Matthijs D. , Beck Jeffrey J. , Johnson Brandon N. , Finnicum Casey T. , Pool René , Hottenga Jouke-Jan , de Geus Eco J. C. , Ehli Erik A.
Published: July 2021

Increasing amounts of genetic data have led to the development of polygenic risk scores (PRSs) for a variety of diseases. These scores, built from the summary statistics of genome-wide association studies (GWASs), are able to stratify individuals based on their genetic risk of developing various common diseases and could potentially be used to optimize the use of screening and preventative treatments and improve personalized care for patients. Many challenges are yet to be overcome, including PRS validation, healthcare professional and patient education, and healthcare systems integration. Ethical challenges are also present in how this information is used and the current lack of diverse populations with PRSs available. In this review, we discuss the topics above and cover the nature of PRSs, visualization schemes, and how PRSs can be improved. With these tools on the horizon for multiple diseases, scientists, clinicians, health systems, regulatory bodies, and the public should discuss the uses, benefits, and potential risks of PRSs.
Preventive behaviours and family inequalities during the COVID-19 pandemic: a cross-sectional study in China
Authors: Ye Yisheng , Wu Ruijun , Ge Yao , Wang Tao , Yao Xin , Yang Yao , Long Chengxu , Chen Fangfei , Tang Shangfeng , Huang Rui
Published: July 2021

Background

The coronavirus disease 2019 (COVID-19) pandemic is an international public health threat, and people's participation in disease-related preventive behaviours is the key to controlling infectious diseases. This study aimed to assess the differences in adopting preventive behaviours among populations to explore potential individual and household factors and inequalities within families.

Methods

This online survey was conducted in April 2020. The directional stratified convenient sampling method was used to select 4704 participants from eight provinces in eastern, central, and western China. The questionnaire included demographic information, household variables, and five target prevention behaviours. The chi-squared test, binary multilevel model, and Mantel–Haenszel hierarchical analysis were used for data analysis in the study.

Results

Approximately 71.2% of the participants had appropriate outdoor prevention, and 32.9% of the participants had indoor protection in place. Sharing behaviours (P < 0.001) and education level (P < 0.001) were positively associated with adopting preventive measures. The inhibiting effect of household crowding and stimulating effect of high household income on preventive behaviours were determined in this study. Household size was negatively associated with living area (β = -0.057, P < 0.05) and living style (β = -0.077, P < 0.05). Household income was positively associated with age (β = 0.023, P < 0.05), and relationship with friends (β = 0.053, P < 0.05). Vulnerable groups, such as older adults or women, are more likely to have inadequate preventive behaviours. Older adults (OR = 1.53, 95% CI 1.09–2.15), women (OR = 1.37, 95% CI 1.15–1.64), and those with more than 2 suspected symptoms (OR = 1.85, 95% CI 1.07–3.19) were more likely to be affected by the inhibiting effect of household crowding, while the stimulating effect of high household income was limited in these groups.

Conclusions

Inequalities in COVID-19 prevention behaviours exist between families and inadequate adoption of prevention by vulnerable groups are noteworthy. This study expands the research perspective by emphasizing the role of household factors in preventive behaviours and by focusing on family inequalities. The government should use traditional media as a platform to enhance residents’ public health knowledge. Targeted additional wage subsidies, investments in affordable housing, financial support for multigenerational households, and temporary relocation policies may deserve more attention. Communities could play a critical role in COVID-19 prevention.

Graphical abstract
Characterization of point-spread function specification error on Geometric Transfer Matrix partial volume correction in [11C]PiB amyloid imaging
Authors: Laymon Charles M. , Minhas Davneet S. , Royse Sarah K. , Aizenstein Howard J. , Cohen Ann D. , Tudorascu Dana L. , Klunk William E.
Published: July 2021

Purpose

Partial-volume correction (PVC) using the Geometric Transfer Matrix (GTM) method is used in positron emission tomography (PET) to compensate for the effects of spatial resolution on quantitation. We evaluate the effect of misspecification of scanner point-spread function (PSF) on GTM results in amyloid imaging, including the effect on amyloid status classification (positive or negative).

Methods

Twenty-nine subjects with Pittsburgh Compound B ([11C]PiB) PET and structural T1 MR imaging were analyzed. FreeSurfer 5.3 (FS) was used to parcellate MR images into regions-of-interest (ROIs) that were used to extract radioactivity concentration values from the PET images. GTM PVC was performed using our “standard” PSF parameterization [3D Gaussian, full-width at half-maximum (w) of approximately 5 mm]. Additional GTM PVC was performed with “incorrect” parameterizations, taken around the correct value. The result is a set of regional activity values for each of the GTM applications. For each case, activity values from various ROIs were combined and normalized to produce standardized uptake value ratios (SUVRs) for nine standard [11C]PiB quantitation ROIs and a global region. GTM operating-point characteristics were determined from the slope of apparent SUVR versus w curves.

Results

Errors in specification of w on the order of 1 mm (3D) mainly produce only modest errors of up to a few percent. An exception was the anterior ventral striatum in which fractional errors of up to 0.29 per millimeter (3D) of error in w were observed.

Conclusion

While this study does not address all the issues regarding the quantitative strengths and weakness of GTM PVC, we find that with reasonable caution, the unavoidable inaccuracies associated with PSF specification do not preclude its use in amyloid quantitation.
PTD-mediated delivery of α-globin chain into Κ-562 erythroleukemia cells and α-thalassemic (HBH) patients’ RBCs ex vivo in the frame of Protein Replacement Therapy
Authors: Miliotou Androulla N. , Papagiannopoulou Dionysia , Vlachaki Efthymia , Samiotaki Martina , Laspa Dimitra , Theodoridou Stamatia , Tsiftsoglou Asterios S. , Papadopoulou Lefkothea C.
Published: July 2021

Background

α-Thalassemia, a congenital hemoglobinopathy, is characterized by deficiency and/or reduced levels of α-globin chains in serious forms of α-thalassemia (HbH disease/Hb Bart’s). This research work deals with a Protein Replacement Therapy approach in order to manage α-thalassemia manifestations, caused by the excess of β-globin chain into HbH RBCs. The main goal was to produce the recombinant human α-globin chain in fusion with TAT, a Protein Transduction Domain, to ex vivo deliver it into HbH patients RBCs, to replace the endogenous missing α-globin chain.

Results

Cloning of the α-globin coding sequence, fused to the nucleotide sequence of TAT peptide was conducted and the human recombinant fusion proteins, 10xHis-XaSITE-α-globin-HA and 10xHis-XaSITE-TAT-α-globin-HA were produced. The ability of human recombinant 10xHis-XaSITE-α-globin-HA to interact in vitro with the previously produced 10xHis-XaSITE-TAT-β-globin-HA and form α-/β-globin heterodimers, was assessed and confirmed by size exclusion chromatography. The recombinant 10xHis-XaSITE-TAT-α-globin-HA was successfully delivered into human proerythroid K-562 cells, during the preliminary transduction evaluation experiments. Finally, the recombinant, TAT-fused α-globin was successfully transduced into RBCs, derived from HbH patients and reduced the formation of HbH-Inclusion Bodies, known to contain harmful β4-globin chain tetramers.

Conclusions

Our data confirm the successful ex vivo transduction of recombinant α-globin chains in HbH RBCs to replace the missing a-globin chain and reduce the HbH-inclusion bodies, seen in α-thalassemias. These findings broaden the possibility of applying a Protein Replacement Therapy approach to module sever forms of α-thalassemia, using recombinant α-globin chains, through PTD technology.
Biochemical and molecular characterization of Alternaria alternata isolates highly resistant to procymidone from broccoli and cabbage
Authors: Wang Bingran , Lou Tiancheng , Wei Lingling , Chen Wenchan , Huang Longbing , Ding Lei , Zhao Weicheng , Zhang Pengcheng , Sun Patrick , Chen Changjun , Wang Kai
Published: July 2021

Alternaria alternata, a causal agent of leaf blights and spots on a wide range of hosts, has a high risk of developing resistance to fungicides. Procymidone, a dicarboximide fungicide (DCF), has been widely used in controlling Alternaria leaf blights in China for decades. However, the resistance of A. alternata against DCFs has rarely been reported from crucifer plants. A total of 198 A. alternata isolates were collected from commercial fields of broccoli and cabbage during 2018–2019, and their sensitivities to procymidone were determined. Biochemical and molecular characteristics were subsequently compared between the high-level procymidone-resistant (ProHR) and procymidone-sensitive (ProS) isolates, and also between ProHR isolates from broccoli and cabbage. Compared with ProS isolates, the mycelial growth rate, sporulation capacity and virulence of most ProHR isolates were reduced; ProHR isolates displayed an increased sensitivity to osmotic stresses and a reduced sensitivity to sodium dodecyl sulfate (SDS); all ProHR isolates showed a reduced sensitivity to hydrogen peroxide (H2O2) except for the isolate B102. Correlation analysis revealed a positive cross-resistance between procymidone and iprodione, or fludioxonil. When treated with 10 μg/mL of procymidone, both mycelial intracellular glycerol accumulations (MIGAs) and relative expression of AaHK1 in ProS isolates were higher than those in ProHR isolates. Sequence alignment of AaHK1 from ten ProHR isolates demonstrated that five of them possessed a single-point mutation (P94A, V612L, E708K or Q924STOP), and four isolates had an insertion or a deletion in their coding regions. No significant difference in biochemical characteristics was observed among ProHR isolates from two different hosts, though mutations in AaHK1 of the cabbage-originated ProHR isolates were distinct from those of the broccoli-originated ProHR isolates.
Missed nursing care, non-nursing tasks, staffing adequacy, and job satisfaction among nurses in a teaching hospital in Egypt
Authors: Hammad Marwa , Guirguis Wafaa , Mosallam Rasha
Published: July 2021

Background

Missed nursing care (MNC) has been linked to patient harm in a growing body of literature. However, this issue is still not adequately investigated in developing countries. The aim of the study is to measure the extent of missed nursing care, to identify its types, and to determine factors contributing to missed nursing care.

Methods

A cross-sectional design was used. The study was conducted among 50 units at 1762-beds teaching Hospital in Alexandria that employs 1211 nurses in inpatient areas. A sample of 553 nurses were interviewed using the MISSCARE and the N4CAST survey. The MISSCARE survey measured the amount of missed nursing care (MNC) that was experienced on the last worked shift by each nurse. The N4CAST survey was used to collect data about level of non-nursing work carried out by nurses and the nurses’ job satisfaction.

Results

The overall mean score for the missed nursing care was 2.26 ± 0.96 out of 5, with highest mean score attributed to “Planning” and lowest mean score attributed to “Assessment and Vital Signs” (2.64 and 1.96, respectively). Missed nursing care was significantly associated with number of patients admitted and cared for in the last shift and perceived staffing adequacy. Almost all non-nursing care tasks and most of satisfaction elements showed negative weak correlation with overall missed nursing care.

Conclusion

Missed Nursing Care is common in study hospital which may endanger patient safety. MNC Missed Nursing Care is positively associated with nursing adequacy. There is no association between MNC and neither nurses’ job satisfaction nor non-nursing tasks. Nursing leaders should monitor missed nursing care and the environmental and staffing conditions associated with it in order to design strategies to reduce such phenomena.
Prevalence and risk factors of autism spectrum disorders in preschool children in Sharkia, Egypt: a community-based study
Authors: Yousef Amira Mohamed , Roshdy Eman H. , Abdel Fattah Nelly R. , Said Randa M. , Atia Maha M. , Hafez Elham M. , Mohamed Amany Elshabrawy
Published: July 2021

Background

Lateness in the diagnosis of autism spectrum disorders (ASD) results in significant disability and pressure on affected children and their families. We aimed to detect the preschool children who have high-risk criteria for ASD in Sharkia Governorate in Egypt and assess the prevalence and risk factors of ASD. A cross-sectional community-based study was done in 39 kindergartens throughout Sharkia Governorate, Egypt, using a multi-stage random sampling technique. The study included two phases, the screening phase, where 3722 preschool children were screened by Modified Check List for Toddlers/Revised (M-CHAT-R), and the diagnostic phase where the diagnosis of ASD among the high-risk children was made according to the research diagnostic criteria of Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5) of ASD administrated by experienced psychiatrists and the Childhood Autism Rating Scale (CARS).

Results

This study showed that 2.8% of children were at high risk for ASD. The prevalence of ASD in Sharkia Governorate was 5.4/1000. The significant risk factors for the disorder were the presence of factories near the house, first and middle child order, congenital anomalies, child medication during the first year of life, child chronic medical condition, child attachment to TV, a medical condition affecting mother during pregnancy, and psychiatric disorders history in the family.

Conclusion

Autism spectrum disorder is prevalent in preschool children in Sharkia, Egypt, and multiple risk factors contribute to this prevalence.
Meta-analysis of Gender Performance Gaps in Undergraduate Natural Science Courses
Authors: Odom Sara , Boso Halle , Bowling Scott , Brownell Sara , Cotner Sehoya , Creech Catherine , Drake Abby Grace , Eddy Sarah , Fagbodun Sheritta , Hebert Sadie , James Avis C. , Just Jan , St. Juliana Justin R. , Shuster Michele , Thompson Seth K. , Whittington Richard , Wills Bill D. , Wilson Alan E. , Zamudio Kelly R. , Zhong Min , Ballen Cissy J.
Published: July 2021

We investigated patterns of gender-based gaps in biology and chemistry through meta-analysis, reviewing data collected in 169 undergraduate biology courses. While we did not detect a significant gender gap in performance across all studies and unpublished data, we identified several factors that moderated performance differences.
Physiologic Frailty and Neurocognitive Decline Among Young-Adult Childhood Cancer Survivors: A Prospective Study From the St Jude Lifetime Cohort
Authors: Williams AnnaLynn M. , Krull Kevin R. , Howell Carrie R. , Banerjee Pia , Brinkman Tara M. , Kaste Sue C. , Partin Robyn E. , Srivastava Deokumar , Yasui Yutaka , Armstrong Gregory T. , Robison Leslie L. , Hudson Melissa M. , Ness Kirsten K.
Published: July 2021

PURPOSE

Eight percent of young-adult childhood cancer survivors meet criteria for frailty, an aging phenotype associated with poor health. In the elderly general population, frailty is associated with neurocognitive decline; this association has not been examined in adult survivors of childhood cancer.

METHODS

Childhood cancer survivors 18-45 years old (≥ 10 years from diagnosis) were clinically evaluated for prefrailty or frailty (respectively defined as ≥ 2 or ≥ 3 of: muscle wasting, muscle weakness, low energy expenditure, slow walking speed, and exhaustion [Fried criteria]) and completed neuropsychologic assessments at enrollment (January 2008-June 2013) and 5 years later. Weighted linear regression using inverse of sampling probability estimates as weights compared differences in neurocognitive decline in prefrail and frail survivors versus nonfrail survivors, adjusting for diagnosis age, sex, race, CNS–directed therapy (cranial radiation, intrathecal chemotherapy, and neurosurgery), and baseline neurocognitive performance.

RESULTS

Survivors were on average 30 years old and 22 years from diagnosis; 18% were prefrail and 6% frail at enrollment. Frail survivors declined an average of 0.54 standard deviation (95% CI, −0.93 to −0.15) in short-term verbal recall, whereas nonfrail survivors did not decline (β = .22; difference of βs = −.76; 95% CI, −1.19 to −0.33). Frail survivors declined more than nonfrail survivors on visual-motor processing speed (β = −.40; 95% CI, −0.67 to −0.12), cognitive flexibility (β = −.62; 95% CI, −1.02 to −0.22), and verbal fluency (β = −.23; 95% CI, −0.41 to −0.05). Prefrail and frail survivors experienced greater declines in focused attention (prefrail β = −.35; 95% CI, −0.53 to −0.17; frail β = −.48; 95% CI, −0.83 to −0.12) compared with nonfrail survivors.

CONCLUSION

Over approximately 5 years, prefrail and frail young-adult survivors had greater declines in cognitive domains associated with aging and dementia compared with nonfrail survivors. Interventions that have global impact, designed to target the mechanistic underpinnings of frailty, may also mitigate or prevent neurocognitive decline.
Obesity Is Strongly Associated With Low Testosterone and Reduced Penis Growth During Development
Authors: Mancini Mario , Pecori Giraldi Francesca , Andreassi Alice , Mantellassi Gianna , Salvioni Michela , Berra Cesare C , Manfrini Roberto , Banderali Giuseppe , Folli Franco
Published: July 2021

Context

Growth of male genitalia represents an important marker of sexual development. Testicle size is the primary measure and little is known regards penile length changes during puberty.

Objective

This work aims to assess penis growth and testosterone levels in obese vs normal-weight children and adolescents, to evaluate a possible influence of obesity on genital development in boys, and to establish a new method for measuring penis length that allows comparison of normal-weight and overweight boys.

Methods

We assessed anthropometric and genital development in 1130 boys from birth to age 20 years. Testosterone levels were also measured. A new method for penile length measurement was employed to minimize errors when comparing obese and nonobese children. Penis length was measured with a gentle, painless, straight positioning on a centimetric ruler without stretching, which is doable from the first years of life until the end of adolescence.

Results

Penis length and testosterone are strongly related in children during puberty. Penile length growth is significantly decreased (by about 10%) in obese boys when compared to normal-weight boys, with concomitantly reduced testosterone levels, across puberal phases.

Conclusion

Childhood obesity represents an important determinant of lower testosterone level and reduced penis development. A new method should be employed to improve penis measurement in normal-weight and overweight/obese boys. The possible significance of these observations for adult genital development and reproductive potential will require large longitudinal studies.
Patient Satisfaction Through an Immersive Experience Using a Mobile Phone–Based Head-Mounted Display During Arthroscopic Knee Surgery Under Spinal Anesthesia: A Randomized Clinical Trial
Authors: Tharion Joseph G. , Kale Suniti
Published: July 2021

BACKGROUND:

Patient satisfaction is an important element of high-quality health care. Virtual reality has been studied for its sedative and analgesic effects, as it immerses the patient into an artificial interactive environment. Deriving from this concept, we hypothesized that an immersive experience that engulfs the senses with noninteractive visual and auditory stimuli would have a positive effect on satisfaction and anxiety in patients undergoing spinal anesthesia.

METHODS:

We enrolled and randomized 90 patients undergoing spinal anesthesia for arthroscopic knee surgery into an immersive experience arm and an intravenous midazolam sedation arm. The immersive experience was provided through a mobile phone–based head-mounted display showing binocular monoscopic video and noise-canceling headphones playing audio. The primary outcome measure was postoperative satisfaction, measured using a visual analog scale and compared using the Mann-Whitney U test; secondary outcomes included anxiety score (measured using the 6-item State-Trait Anxiety Inventory), hemodynamic stability, and additional sedative requirement.

RESULTS:

The visual analog scale satisfaction score with immersive experience was significantly higher than with midazolam (median [interquartile range {IQR}] of 93 [82–98] and 80 [73–93], respectively, P = .004), with Hodges-Lehmann median difference estimate of 7 (95% confidence interval, 3–14). The change in anxiety scores from the preoperative to postoperative period between the groups was not significantly different (P = .08), with a Hodges-Lehmann median difference estimate of 3.3 (95% confidence interval, 0–6.7). All patients were hemodynamically stable, were without significant adverse events, and did not require additional sedatives.

CONCLUSIONS:

We have found that an immersive experience is an effective and acceptable intraoperative alternative to pharmacological sedation in patients undergoing arthroscopic knee surgery under spinal anesthesia, with higher satisfaction levels and no detected difference in preoperative to postoperative anxiolytic effect.
B1 lymphocytes develop independently of Notch signaling during mouse embryonic development
Authors: Azevedo Portilho Nathalia , Scarfò Rebecca , Bertesago Elisa , Ismailoglu Ismail , Kyba Michael , Kobayashi Michihiro , Ditadi Andrea , Yoshimoto Momoko
Published: July 2021

B1 lymphocytes are a small but unique component of the innate immune-like cells. However, their ontogenic origin is still a matter of debate. Although it is widely accepted that B1 cells originate early in fetal life, whether or not they arise from hematopoietic stem cells (HSCs) is still unclear. In order to shed light on the B1 cell origin, we set out to determine whether their lineage specification is dependent on Notch signaling, which is essential for the HSC generation and, therefore, all derivatives lineages. Using mouse embryonic stem cells (mESCs) to recapitulate murine embryonic development, we have studied the requirement for Notch signaling during the earliest B-cell lymphopoiesis and found that Rbpj-deficient mESCs are able to generate B1 cells. Their Notch independence was confirmed in ex vivo experiments using Rbpj-deficient embryos. In addition, we found that upregulation of Notch signaling induced the emergence of B2 lymphoid cells. Taken together, these findings indicate that control of Notch signaling dose is crucial for different B-cell lineage specification from endothelial cells and provides pivotal information for their in vitro generation from PSCs for therapeutic applications.

This article has an associated ‘The people behind the papers’ interview.
The multicellular interplay of microglia in health and disease: lessons from leukodystrophy
Authors: Berdowski Woutje M. , Sanderson Leslie E. , van Ham Tjakko J.
Published: July 2021

Microglia are highly dynamic cells crucial for developing and maintaining lifelong brain function and health through their many interactions with essentially all cellular components of the central nervous system. The frequent connection of microglia to leukodystrophies, genetic disorders of the white matter, has highlighted their involvement in the maintenance of white matter integrity. However, the mechanisms that underlie their putative roles in these processes remain largely uncharacterized. Microglia have also been gaining attention as possible therapeutic targets for many neurological conditions, increasing the demand to understand their broad spectrum of functions and the impact of their dysregulation. In this Review, we compare the pathological features of two groups of genetic leukodystrophies: those in which microglial dysfunction holds a central role, termed ‘microgliopathies’, and those in which lysosomal or peroxisomal defects are considered to be the primary driver. The latter are suspected to have notable microglia involvement, as some affected individuals benefit from microglia-replenishing therapy. Based on overlapping pathology, we discuss multiple ways through which aberrant microglia could lead to white matter defects and brain dysfunction. We propose that the study of leukodystrophies, and their extensively multicellular pathology, will benefit from complementing analyses of human patient material with the examination of cellular dynamics in vivo using animal models, such as zebrafish. Together, this will yield important insight into the cell biological mechanisms of microglial impact in the central nervous system, particularly in the development and maintenance of myelin, that will facilitate the development of new, and refinement of existing, therapeutic options for a range of brain diseases.
How to generate graded spinal cord injuries in swine – tools and procedures
Authors: Züchner Mark , Escalona Manuel J. , Teige Lena Hammerlund , Balafas Evangelos , Zhang Lili , Kostomitsopoulos Nikolaos , Boulland Jean-Luc
Published: July 2021

Spinal cord injury (SCI) is a medically, psychologically and socially disabling condition. A large body of our knowledge on the basic mechanisms of SCI has been gathered in rodents. For preclinical validation of promising therapies, the use of animal models that are closer to humans has several advantages. This has promoted the more-intensive development of large-animal models for SCI during the past decade. We recently developed a multimodal SCI apparatus for large animals that generated biomechanically reproducible impacts in vivo. It is composed of a spring-load impactor and support systems for the spinal cord and the vertebral column. We now present the functional outcome of farm pigs and minipigs injured with different lesion strengths. There was a correlation between the biomechanical characteristics of the impact, the functional outcome and the tissue damage observed several weeks after injury. We also provide a detailed description of the procedure to generate such a SCI in both farm pigs and minipigs, in the hope to ease the adoption of the swine model by other research groups.
Appetitive olfactory learning suffers in ants when octopamine or dopamine receptors are blocked
Authors: Wissink Maarten , Nehring Volker
Published: July 2021

Associative learning relies on the detection of coincidence between a stimulus and a reward or punishment. In the insect brain, this process is carried out in the mushroom bodies under the control of octopaminergic and dopaminergic neurons. It was assumed that appetitive learning is governed by octopaminergic neurons, while dopamine is required for aversive learning. This view has recently been challenged: both neurotransmitters are involved in both types of learning in bees and flies. Here, we tested which neurotransmitters are required for appetitive learning in ants. We trained Lasius niger workers to discriminate two mixtures of linear hydrocarbons and to associate one of them with a sucrose reward. We analysed the walking paths of the ants using machine learning and found that the ants spent more time near the rewarded odour than near the other, a preference that was stable for at least 24 h. We then treated the ants before learning with either epinastine, an octopamine receptor blocker, or flupentixol, a dopamine receptor blocker. Ants with blocked octopamine receptors did not prefer the rewarded odour. Octopamine signalling is thus necessary for appetitive learning of olfactory cues, probably because it signals information about odours or reward to the mushroom body. In contrast, ants with blocked dopamine receptors initially learned the rewarded odour but failed to retrieve this memory 24 h later. Dopamine is thus probably required for long-term memory consolidation, independent of short-term memory formation. Our results show that appetitive olfactory learning depends on both octopamine and dopamine signalling in ants.
Radiotherapy CT-based contouring atlas for non-malignant skeletal and soft tissue disorders: a practical proposal from Spanish experience
Authors: Alvarez Beatriz , Montero Angel , Hernando Ovidio , Ciervide Raquel , Garcia Juan , Lopez Mercedes , Garcia-Aranda Mariola , Chen Xin , Flores Ines , Sanchez Emilio , Valero Jeannette , Prado Alejandro , Alonso Rosa , Alonso Leyre , Fernandez-Leton Pedro , Rubio Carmen
Published: July 2021

Objective:

Interest in low-dose radiotherapy (LD-RT) for the symptomatic treatment of nonmalignant conditions, including inflammatory and degenerative disorders of the joints and para-articular soft tissues, has increased substantially in recent years. In the present document, we provide a CT-based contouring atlas to help identify and delineate the most common osteoarticular regions susceptible to LD-RT.

Methods:

The clinical efficacy of LD-RT is supported by a large body of evidence. However, there is no consensus on the parameters for contouring the planning target volume (PTV). Moreover, 3D simulation and planning should be the standard of care even for nonmalignant disorders. For this reason, the present guidelines were prepared to help guide PTV contouring based on CT images, with the same quality criteria for patient immobilization, treatment simulation, planning and delivery as those routinely applied for cancer radiotherapy.

Results:

PTV for radiotherapy requires precise identification of the target areas based on CT and other imaging techniques. Using a series of cases treated at our institution, we have defined the PTVs for each location on the simulation CT to establish the relationship between the image and the anatomical structures to be treated. We also specify the immobilization systems used to ensure treatment accuracy and reproducibility.

Conclusions:

This comprehensive atlas based on CT images may be of value to radiation oncologists who wish to use LD-RT for the symptomatic treatment of degenerative or inflammatory osteoarticular diseases.

Advances in knowledge:

The recommendations and contouring atlas described in this article provide an eminently practical tool for LD-RT in non-malignant conditions, based on the same quality criteria recommended for all modern radiotherapy treatments in Spain.
Two new species of Diplommatina Benson, 1849 (Gastropoda, Caenogastropoda: Diplommatinidae) from Borneo
Authors: Vermeulen Jaap J. , Khalik Mohd Zacaery
Published: July 2021

Two new species of Diplommatina from limestone hills on Borneo are described: D. heteropleura sp. nov., from Sarawak (Malaysia) and D. stenoacron sp. nov., from East Kalimantan (Indonesia). The first is uniquely identified among the Bornean Diplommatina by the arrangement of radial ribs: widely spaced on all whorls except the last 1.5, where they are closely spaced; the second belongs to a small group of species without radial ribs but is larger than any of them.
CODECHECK: an Open Science initiative for the independent execution of computations underlying research articles during peer review to improve reproducibility
Authors: Nüst Daniel , Eglen Stephen J.
Published: July 2021

The traditional scientific paper falls short of effectively communicating computational research.  To help improve this situation, we propose a system by which the computational workflows underlying research articles are checked. The CODECHECK system uses open infrastructure and tools and can be integrated into review and publication processes in multiple ways. We describe these integrations along multiple dimensions (importance, who, openness, when). In collaboration with academic publishers and conferences, we demonstrate CODECHECK with 25 reproductions of diverse scientific publications. These CODECHECKs show that asking for reproducible workflows during a collaborative review can effectively improve executability. While CODECHECK has clear limitations, it may represent a building block in Open Science and publishing ecosystems for improving the reproducibility, appreciation, and, potentially, the quality of non-textual research artefacts. The CODECHECK website can be accessed here: https://codecheck.org.uk/.
Towards recognizing the mechanisms of effects evoked in living organisms by static magnetic field. Numerically simulated effects of the static magnetic field upon simple inorganic molecules.
Authors: Ciesielski Wojciech , Girek Tomasz , Oszczęda Zdzisław , Soroka Jacek , Tomasik Piotr
Published: July 2021

Background: Recognizing effects of static magnetic field (SMF) of varying flux density on flora and fauna is attempted. For this purpose, the influence of static magnetic field upon molecules of water, nitrogen, ammonia, carbon dioxide, methane and molecular oxygen was studied.

Methods: Computations of the effect of SMF of 0.1, 1, 10 and 100T flux density were performed in a computer vacuum involving advanced computational methods.

Results: It was shown that SMF polarizes molecules depending on applied flux density but it neither ionizes nor breaks valence bonds. Three-molecular conglomerates of very dense packing form systems involving supramolecular orbitals. These orbitals deteriorate with an increase in the SMF flux density developing highly polarized structures. They are entirely different from these originally formed out of SMF.

Conclusions: Small inorganic molecules commonly present in living organisms of flora and fauna can substantially influence functioning of those organisms when exposed to SMF.
Cerebrospinal fluid neurofilament light levels in CLN2 disease patients treated with enzyme replacement therapy normalise after two years on treatment
Authors: Iwan Katharina , Patel Nina , Heslegrave Amanda , Borisova Mina , Lee Laura , Bower Rebecca , Mole Sara E. , Mills Philippa B. , Zetterberg Henrik , Mills Kevin , Gissen Paul , Heywood Wendy E.
Published: July 2021

Classic late infantile neuronal ceroid lipofuscinosis (CLN2 disease) is caused by a deficiency of tripeptidyl-peptidase-1. In 2017, the first CLN2 enzyme replacement therapy (ERT) cerliponase alfa (Brineura) was approved by the FDA and EMA. The CLN2 disease clinical rating scale (CLN2 CRS) was developed to monitor loss of motor function, language and vision as well as frequency of generalised tonic clonic seizures. Using CLN2 CRS in an open label clinical trial it was shown that Brineura slowed down the progression of CLN2 symptoms.

Neurofilament light chain (NfL) is a protein highly expressed in myelinated axons. An increase of cerebrospinal fluid (CSF) and blood NfL is found in a variety of neuroinflammatory, neurodegenerative, traumatic, and cerebrovascular diseases. We analysed CSF NfL in CLN2 patients treated with Brineura to establish whether it can be used as a possible biomarker of response to therapy. Newly diagnosed patients had CSF samples collected and analysed at first treatment dose and up to 12 weeks post-treatment to look at acute changes. Patients on a compassionate use programme who were already receiving ERT for approximately 1yr had CSF samples collected and NfL analysed over the following 1.3 years (2.3 years post-initiation of ERT) to look at long-term changes.

All newly diagnosed patients we investigated with classical late infantile phenotype had high NfL levels >2000 pg/ml at start of treatment. No significant change was observed in NfL up to 12 weeks post-treatment. After one year of ERT, two out of six patients still had high NfL levels, but all patients showed a continued decrease, and all had low NfL levels after two years on ERT. NfL levels appear to correspond and predict improved clinical status of patients on ERT and could be useful as a biomarker to monitor neurodegeneration and verify disease modification in CLN2 patients on ERT.
The relative incidence of COVID-19 in healthcare workers versus non-healthcare workers: evidence from a web-based survey of Facebook users in the United States
Authors: Flaxman Abraham D. , Henning Daniel J. , Duber Herbert C.
Published: July 2021

Background: Healthcare workers are at the forefront of the COVID-19 pandemic and it is essential to monitor the relative incidence rate of this group, as compared to workers in other occupations. This study aimed to produce estimates of the relative incidence ratio between healthcare workers and workers in non-healthcare occupations.

Methods: Analysis of cross-sectional data from a daily, web-based survey of 1,822,662 Facebook users from September 8, 2020 to October 20, 2020. Participants were Facebook users in the United States aged 18 and above who were tested for COVID-19 because of an employer or school requirement in the past 14 days. The exposure variable was a self-reported history of working in healthcare in the past four weeks and the main outcome was a self-reported positive test for COVID-19.

Results: On October 20, 2020, in the United States, there was a relative COVID-19 incidence ratio of 0.73 (95% UI 0.68 to 0.80) between healthcare workers and workers in non-healthcare occupations.

Conclusions: In fall of 2020, in the United States, healthcare workers likely had a lower COVID-19 incidence rate than workers in non-healthcare occupations.
Psychophysiological Aspects in the Clinical Picture of Disease in Patients Who Received Local Radiation Injury
Authors: Metlyaeva Nelya , Lartsev M. , Bushmanov A. , Galstyan I. , Ryabinina L. , Sukhova M. , Skorobogatykh E. , Kirilchev A. , Shcherbatykh O. , Torubarov F.
Published: July 2021

Purpose: To evaluate in dynamics the psychophysiological adaptation of a patient who received local radiation damage to the tissues of the left half of the chest IV (extremely severe) severity (23 years of observation).

Material and methods: Patient KTS, 66 years old, as the main diagnosis are the effects of local radiation damage to the skin and underlying tissues of the left half of the chest from external radiation (about 3 % of body surface area) IV extremely severe. Before receiving a radiation injury, she was able-bodied and socially adapted, worked as a nurse. In 1996, she was diagnosed with stage I left breast cancer T1N0M0 stage I, in connection with which she underwent a sectoral resection of the mammary gland. Then the patient underwent a course of radiation therapy. By retrospective assessment, the total dose of therapeutic effect before the incident was 10 Gy. At the time of the next session of radiation therapy in connection with the breakdown of the apparatus, a sharp uncontrolled increase in the dose of ionizing radiation (more than 100 Gy) occurred, causing serious injury. The patient was admitted to the Institute of Biophysics Clinic on the 5th day. Psychophysiological research was carried out with the use of automated software and methodic complex «Expert», designed to study the personal characteristics of a person, cognitive and intellectual personality characteristics in 2001 – 2017 years.

Results: The effects of local radiation damage to the skin and underlying tissues of the left half of the chest from external irradiation of IV (extremely severe) degree in the form of cicatricial-atrophic changes of the soft tissues, with no bone skeleton remain. Disorders of mental adaptation are expressed in the form of senesto-hypochondria disorders, autism of perception, demonstrativeness, apathetic depression and introversion. The most profound contribution to the reduction of the adaptation of the victim is brought about by the features of deep internal disharmony caused by contradictory combinations of demonstrativeness, schizoid traits, anxious depression and affective rigidity.

Conclusion: The data obtained indicate that impaired mental adaptation is an integral part of the clinical picture of local radiation injuries, and reveal the urgent need not only of specific treatment of radiation injury, but also of psychotropic pharmacotherapy and psychotherapy.
SPECT with 67Ga Citrate in the Diagnosis of Systemic Sarcoidosis
Authors: Zolotnitskaia V , Amosov I. , Baranova O. , Litvinov A. , Amosov V. , Speranskaia A. , Ratnikov V.
Published: July 2021

Purpose: To study the possibilities of using 67Ga-citrate in patients with systemic manifestations of sarcoidosis to identify foci of pathological accumulation of the drug and assess the degree of process activity. Material and methods: Radionulide study with 67Ga-citrate was performed in 140 patients with respiratory sarcoidosis and suspected extrapulmonary localization. In addition, all patients underwent X-ray examination of the lungs, MSCT of the organs of the chest and abdominal cavity, SPECT of the lungs with radiopharmaceutical macroaggregates of albumin, ultrasound of the abdomen, pelvis, MRI of the head was performed in 16 patients with suspected neurosarcoidosis. Results: Most patients (n = 125) showed changes in the lungs, manifested by a bright glow (yellow or purple) on the computer screen, which indicated a pronounced impaired function of lymphoid tissue. In 22 patients, the changes were recurrent. The results correlated with published data on damage to the nervous system (r = 0.96), musculoskeletal system (r = 0.97), parotid glands (r = 0.91), liver, spleen (r = 0.83) . At the same time, the results for eye damage (r = 0.23), ENT organs (r = 0.15), intestines (r = 0.48) were significantly different. In our study, no heart lesions were detected in any case. Conclusions: The use of positive scintigraphy with Ga-67 citrate, taking into account the whole body scan and SPECT of areas of interest of interest (chest cavity, abdominal cavity, head, pelvis) is effective for the diagnosis of systemic sarcoidosis and in determining the activity of the process. The study is recommended to be performed 72 hours after intravenous administration of the drug. The combination of CT, MRI and radionuclide studies allows you to obtain reliable information about the activity of the process, to identify the localization of increased metabolic activity, that is, the topography of active sarcoidosis.