bluuebunny/crossref_metadata_2025 huggingface dataset:
The value of next‐generation sequencing in routine diagnostics and management of patients with cytopenia
Authors: Breinholt Marie Fredslund , Nielsen Kåre , Schejbel Lone , Fassi Daniel El , Schöllkopf Claudia , Novotny Guy Wayne , Mortensen Bo Kok , Ahmad Azhar , Høgdall Estrid , Nørgaard Peter
Published: February 2022

Introduction

We performed a single‐center study of real‐world health data to investigate the direct clinical consequence of targeted next‐generation sequencing (NGS) results integrated in the clinicopathological evaluation of patients with cytopenia suspected of myelodysplastic syndrome (MDS).

Methods

The study included 87 newly referred patients, who had a bone marrow examination, which included targeted NGS analysis. NGS was requested at the discretion of either examining pathologist or hematologist. Data were collected retrospectively from patient files including pathology reports with integrated NGS results.

Results

The NGS results had a diagnostic impact in 67 cases (77%) when combining both histopathological and final clinical evaluation and provided prognostic value in 19 cases (22%). NGS supported a confident or tentative histopathological diagnosis in 52 cases (60%). Twenty cases (23%) had a final diagnosis of either Clonal Cytopenia of Undetermined Significance (CCUS) or Idiopathic Cytopenia of Undetermined Significance (ICUS). In 4 cases, NGS results affected the choice of principal treatment strategy, including considerations of allotransplantation. Twenty‐one patients (24%) could be discharged to primary care physician.

Conclusion

In a multidisciplinary clinicopathological real‐world setting, NGS analysis of bone marrow samples from selected patients contributed substantially to the diagnostic evaluation and management of patients with cytopenia suspected of MDS. Consequently, we have now included NGS analysis in most routine bone marrow examinations from patients with MDS or unexplained cytopenia.
Identification of peripheral blood CD26+ leukemic stem cells has a potential role in the rapid diagnosis of chronic myeloid leukemia
Authors: Sharma Praveen , Sachdeva Man Updesh Singh , Naseem Shano , Sreedharanunni Sreejesh , Das Reena , Malhotra Pankaj , Varma Neelam
Published: February 2022

Background

Chronic myeloid leukemia (CML) is a hematopoietic stem cell (SC) neoplasm diagnosed by the demonstration of t(9;22)(BCR‐ABL1) fusion gene. We performed a flow cytometric assay to identify CD26+ CML leukemic stem cells (LSCs) for its value as a standalone diagnostic investigation for CML and its utility for detection of residual disease in CML patients on therapy.

Methods

Patients with clinical suspicion of CML/CML on follow‐up were included, and peripheral (PB) and/or bone marrow (BM) samples were utilized for flow cytometric analysis. PB and/or BM of patients with diseases other than CML were used as controls. A pre‐titrated antibody cocktail containing CD45, CD34, CD38, and CD26 MoABs was used.

Results

A total of 104 samples (63 PB and 41 BM) from 64 patients [suspected CML (n = 30), CML on follow‐up (n = 15), and non‐CML (n = 19)] were tested. CD26+ LSCs were identified in all patients with a confirmed diagnosis of CML (median = 0.07 (range 0.002%–26.79%)). None of the patients in the control group (non‐CML) and follow‐up patients with negative reverse transcriptase‐polymerase chain reaction (RT‐PCR) results showed the presence of CD26+ LSCs. Also, there was a strong correlation between CD26+ CML LSCs in the PB and BM (r = .917).

Conclusion

Flow cytometric identification of CD26+ LSCs in the peripheral blood can be a cheap, rapid, robust, and potential diagnostic tool for the diagnosis of CML compared to available testing methods. It is irrespective of BCR‐ABL1 transcript type, and its role in residual disease monitoring needs thorough investigation.
Post‐prostate biopsy acute bacterial prostatitis and screening cultures using selective media: An overview
Authors: Acosta Herik , Sadahira Takuya , Sekito Takanori , Maruyama Yuki , Iwata Takehiro , Araki Motoo , Ogawa Kohei , Tsuboi Ichiro , Wada Koichiro
Published: February 2022

The development of several culture media and the availability to isolate and treat pathogens prior to a surgical procedure give us the ability to minimize treatment‐related complications, and ultimately results in better outcomes for patients and avoidance of unwanted post‐procedure inpatient admissions. In the last decade, an increasing incidence of multidrug‐resistant Escherichia coli, especially extended‐spectrum beta‐lactamase‐producing E. coli and fluoroquinolone‐resistant pathogens, has been reported. These resistant species frequently colonize the rectal flora and gain access to the systemic circulation via the rectal plexus following a prostate biopsy. The bacteria can eventually lead to life‐threatening complications, which is especially important in high‐risk patients with multiple co‐morbidities. Previously published studies have focused on the isolation of these pathogens with selective media before an invasive procedure and the potential benefits of incorporating the use of selective media as a mandatory pre‐operative step. This preventive measure will allow us to offer a tailored prophylactic treatment that benefits patients and reduces the economic burden for the hospital.
Staphylococcus aureus controls eicosanoid and specialized pro‐resolving mediator production via lipoteichoic acid
Authors: Miek Laura , Jordan Paul M. , Günther Kerstin , Pace Simona , Beyer Timo , Kowalak David , Hoerr Verena , Löffler Bettina , Tuchscherr Lorena , Serhan Charles N. , Gerstmeier Jana , Werz Oliver
Published: February 2022

Staphylococcus aureus causes severe infections associated with inflammation, such as sepsis or osteomyelitis. Inflammatory processes are regulated by distinct lipid mediators (LMs) but how their biosynthetic pathways are orchestrated in S. aureus infections is elusive. We show that S. aureus strikingly not only modulates pro‐inflammatory, but also inflammation‐resolving LM pathways in murine osteomyelitis and osteoclasts as well as in human monocyte‐derived macrophages (MDMs) with different phenotype. Targeted LM metabololipidomics using ultra‐performance liquid chromatography‐tandem mass spectrometry revealed massive generation of LM with distinct LM signature profiles in acute and chronic phases of S. aureus‐induced murine osteomyelitis in vivo. In human MDM, S. aureus elevated cyclooxygenase‐2 (COX‐2) and microsomal prostaglandin E2 synthase‐1 (mPGES‐1), but impaired the levels of 15‐lipoxygenase‐1 (15‐LOX‐1), with respective changes in LM signature profiles initiated by these enzymes, that is, elevated PGE2 and impaired specialized pro‐resolving mediators, along with reduced M2‐like phenotypic macrophage markers. The cell wall component, lipoteichoic acid (LTA), mimicked the impact of S. aureus elevating COX‐2/mPGES‐1 expression via NF‐κB and p38 MAPK signalling in MDM, while the impairment of 15‐LOX‐1 correlates with reduced expression of Lamtor1. In conclusion, S. aureus dictates LM pathways via LTA resulting in a shift from anti‐inflammatory M2‐like towards pro‐inflammatory M1‐like LM signature profiles.
Arthroscopic Anatomical Acromioclavicular Joint Reconstruction using a Button Device and a Semitendinosus Graft
Authors: Maia Dias Carlos , Leite Maria João , Ribeiro da Silva Manuel , Granate Pedro , Manuel Teixeira José
Published: February 2022

Objective

To report a new technique for anatomical acromioclavicular (AC) joint reconstruction.

Methods

In order to minimize such complications, the authors describe a new anatomical and biological AC joint repair. This technique aims to provide greater stability by using two anatomically placed clavicular tunnels and a combined construct with a double endobutton cortical fixation for primary stabilization, and to be biologically advantageous by using an autologous semitendinosus (ST) tendon graft. Additionally, the coracoclavicular ligament reconstruction is complemented with an AC joint cerclage and capsular reinforcement, which will protect the biological construction in its initial stage of healing.

Results

This technique provides adequate primary and secondary biomechanical stability by passing both a semitendinosus autogenous graft and a double endobutton device, through anatomically placed and small diameter clavicle holes, without the need for coracoid drilling. Our technique showed encouraging results regarding pain resolution, range of motion, and function. At final follow‐up we experienced excellent results with average pain score of 1.6, and average ROM of 159° of forward flexion, 160° of abduction, 68° of external rotation, and internal rotation level at T11. Postoperative function also showed great improvements with average ASES of 85 points, an average Constant Score of 87 and a Subjective Shoulder Value of 89 points. This technique also achieved perfectly acceptable radiographic results, with an average coracoclavicular distance increase of 0.8 mm. Regarding complications, our sample showed one case of AC join subluxation, two cases of internal saphenous nerve injury, and two partial graft tears at the suture‐button interface, with none of these requiring surgical revision.

Conclusion

This technique is advantageous in treatment of acromioclavicular joint dislocation and can be performed in both the subacute and chronic setting.
Genome‐wide identification and characterization of aquaporins in mangrove plant Kandelia obovata and its role in response to the intertidal environment
Authors: Guo Zejun , Ma Dongna , Li Jing , Wei Mingyue , Zhang Ludan , Zhou Lichun , Zhou Xiaoxuan , He Shanshan , Wang Lin , Shen Yingjia , Li Qingshun Quinn , Zheng Hai‐Lei
Published: February 2022

Aquaporins (AQPs) play important roles in plant growth, development and tolerance to environmental stresses. To understand the role of AQPs in the mangrove plant Kandelia obovata, which has the ability to acquire water from seawater, we identified 34 AQPs in the K. obovata genome and analysed their structural features. Phylogenetic analysis revealed that KoAQPs are homologous to AQPs of Populus and Arabidopsis, which are evolutionarily conserved. The key amino acid residues were used to assess water‐transport ability. Analysis of cis‐acting elements in the promoters indicated that KoAQPs may be stress‐ and hormone‐responsive. Subcellular localization of KoAQPs in yeast showed most KoAQPs function in the membrane system. That transgenic yeast with increased cell volume showed that some KoAQPs have significant water‐transport activity, and the substrate sensitivity assay indicates that some KoAQPs can transport H2O2. The transcriptome data were used to analyze the expression patterns of KoAQPs in different tissues and developing fruits of K. obovata. In addition, real‐time quantitative PCR analyses combined transcriptome data showed that KoAQPs have complex responses to environmental factors, including salinity, flooding and cold. Collectively, the transport of water and solutes by KoAQPs contributed to the adaptation of K. obovata to the coastal intertidal environment.
Desiccation of the leaf mesophyll and its implications for CO2 diffusion and light processing
Authors: Momayyezi Mina , Borsuk Aleca M. , Brodersen Craig R. , Gilbert Matthew E. , Théroux‐Rancourt Guillaume , Kluepfel Daniel A. , McElrone Andrew J.
Published: February 2022

Leaves balance CO2 and radiative absorption while maintaining water transport to maximise photosynthesis. Related species with contrasting leaf anatomy can provide insights into inherent and stress‐induced links between structure and function for commonly measured leaf traits for important crops. We used two walnut species with contrasting mesophyll anatomy to evaluate these integrated exchange processes under non‐stressed and drought conditions using a combination of light microscopy, X‐ray microCT, gas exchange, hydraulic conductance, and chlorophyll distribution profiles through leaves. Juglans regia had thicker palisade mesophyll, higher fluorescence in the palisade, and greater low‐mesophyll porosity that were associated with greater gas‐phase diffusion (gIAS), stomatal and mesophyll (gm) conductances and carboxylation capacity. More and highly‐packed mesophyll cells and bundle sheath extensions (BSEs) in Juglans microcarpa led to higher fluorescence in the spongy and in proximity to the BSEs. Both species exhibited drought‐induced reductions in mesophyll cell volume, yet the associated increases in porosity and gIAS were obscured by declines in biochemical activity that decreased gm. Inherent differences in leaf anatomy between the species were linked to differences in gas exchange, light absorption and photosynthetic capacity, and drought‐induced changes in leaf structure impacted performance via imposing species‐specific limitations to light absorption, gas exchange and hydraulics.
OsTGAL1 suppresses the resistance of rice to bacterial blight disease by regulating the expression of salicylic acid glucosyltransferase OsSGT1
Authors: Li Dongyue , Zhou Jie , Zheng Chao , Zheng Ersong , Liang Weifang , Tan Xiaojing , Xu Rumeng , Yan Chengqi , Yang Yong , Yi Keke , Liu Xiuli , Chen Jianping , Wang Xuming
Published: February 2022

Many TGA transcription factors participate in immune responses in the SA‐mediated signaling pathway in Arabidopsis. This study identified a transcription factor OsTGAL1, which is induced upon infection by Xoo. Overexpression of OsTGAL1 increased the susceptibility of rice to Xoo. Plants overexpressing OsTGAL1 could affect the expression of many SA signaling‐related genes. OsTGAL1 was able to interact with the promoter of OsSGT1, which encodes a key enzyme for SA metabolism. The transcript of OsSGT1 was induced by Xoo and this responsive expression was further increased in plants overexpressing OsTGAL1. OsSGT1 knockout lines had enhanced resistance to Xoo, and knocking out OsSGT1 in plants overexpressing OsTGAL1 blocked the susceptibility caused by OsTGAL1. Altered expression levels of several OsPRs in all the transgenic plants demonstrated that SA‐mediated signaling had been affected. Furthermore, we identified an oxidoreductase of CC‐type glutaredoxin, OsGRX17, which interacted with OsTGAL1. OsGRX17 reduced the regulation of OsTGAL1 on OsSGT1, and this may be due to its redox modulation. Thus, our results demonstrate that OsTGAL1 negatively regulates resistance to Xoo by its effects on SA metabolism via the activation of OsSGT1, which provides valuable targets for plant breeders in developing new cultivars that are resistant to Xoo.
Multiple brace root phenotypes promote anchorage and limit root lodging in maize
Authors: Hostetler Ashley N. , Erndwein Lindsay , Reneau Jonathan W. , Stager Adam , Tanner Herbert G. , Cook Douglas , Sparks Erin E.
Published: February 2022

Plant mechanical failure (lodging) causes global yield losses of 7%−66% in cereal crops. We have previously shown that the above‐ground nodal roots (brace roots) in maize are critical for anchorage. However, it is unknown how brace root phenotypes vary across genotypes and the functional consequence of this variation. This study quantifies the contribution of brace roots to anchorage, brace root traits, plant height, and root lodging susceptibility in 52 maize inbred lines. We show that the contribution of brace roots to anchorage and root lodging susceptibility varies among genotypes and this contribution can be explained by plant architectural variation. Additionally, supervised machine learning models were developed and show that multiple plant architectural phenotypes can predict the contribution of brace roots to anchorage and root lodging susceptibility. Together these data define the plant architectures that are important in lodging resistance and show that the contribution of brace roots to anchorage is a good proxy for root lodging susceptibility.
Managing medical equipment capacity with early spread of infection in a region
Authors: Jain Apurva , Rayal Swapnil
Published: February 2022

We develop a model for a regional decision‐maker to analyze the requirement of medical equipment capacity in the early stages of a spread of infections. We use the model to propose and evaluate ways to manage limited equipment capacity. Early‐stage infection growth is captured by a stochastic differential equation (SDE) and is part of a two‐period community spread and shutdown model. We use the running‐maximum process of a geometric Brownian motion to develop a performance metric, probability of breach, for a given capacity level. Decision‐maker estimates costs of economy versus health and the time till the availability of a cure; we develop a heuristic rule and an optimal formulation that use these estimates to determine the required medical equipment capacity. We connect the level of capacity to a menu of actions, including the level and timing of shutdown, shutdown effectiveness, and enforcement. Our results show how these actions can compensate for the limited medical equipment capacity in a region. We next address the sharing of medical equipment capacity across regions and its impact on the breach probability. In addition to traditional risk‐pooling, we identify a peak‐timing effect depending on when infections peak in different regions. We show that equipment sharing may not benefit the regions when capacity is tight. A coupled SDE model captures the messaging coordination and movement across regional borders. Numerical experiments on this model show that under certain conditions, such movement and coordination can synchronize the infection trajectories and bring the peaks closer, reducing the benefit of sharing capacity.
Explaining Why the Computer Says No: Algorithmic Transparency Affects the Perceived Trustworthiness of Automated Decision‐Making
Authors: Grimmelikhuijsen Stephan
Published: February 2022

Algorithms based on Artificial Intelligence technologies are slowly transforming street‐level bureaucracies, yet a lack of algorithmic transparency may jeopardize citizen trust. Based on procedural fairness theory, this article hypothesizes that two core elements of algorithmic transparency (accessibility and explainability) are crucial to strengthening the perceived trustworthiness of street‐level decision‐making. This is tested in one experimental scenario with low discretion (a denied visa application) and one scenario with high discretion (a suspicion of welfare fraud). The results show that: (1) explainability has a more pronounced effect on trust than the accessibility of the algorithm; (2) the effect of algorithmic transparency not only pertains to trust in the algorithm itself but also—partially—to trust in the human decision‐maker; (3) the effects of algorithmic transparency are not robust across decision context. These findings imply that transparency‐as‐accessibility is insufficient to foster citizen trust. Algorithmic explainability must be addressed to maintain and foster trustworthiness algorithmic decision‐making.
Effects of the COVID‐19 lockdowns on the management of coral restoration projects
Authors: Montano Simone , Dehnert Inga , Seveso Davide , Maggioni Davide , Montalbetti Enrico , Strona Giovanni , Siena Federica , Amir Hana , Antoine Athina , Marino‐Ramirez Camila , Saponari Luca , Shah Nirmal J. , Azcarate Molina Ruben , Alegria Ortega Angela , Galli Paolo , Montoya‐Maya Phanor H.
Published: February 2022

Coral restoration initiatives are gaining significant momentum in a global effort to enhance the recovery of degraded coral reefs. However, the implementation and upkeep of coral nurseries are particularly demanding, so that unforeseen breaks in maintenance operations might jeopardize well‐established projects. In the last 2 years, the COVID‐19 pandemic has resulted in a temporary yet prolonged abandonment of several coral gardening infrastructures worldwide, including remote localities. Here we provide a first assessment of the potential impacts of monitoring and maintenance breakdown in a suite of coral restoration projects (based on floating rope nurseries) in Colombia, Seychelles, and Maldives. Our study comprises nine nurseries from six locations, hosting a total of 3,554 fragments belonging to three coral genera, that were left unsupervised for a period spanning from 29 to 61 weeks. Floating nursery structures experienced various levels of damage, and total fragment survival spanned from 40 to 95% among projects, with Pocillopora showing the highest survival rate in all locations present. Overall, our study shows that, under certain conditions, abandoned coral nurseries can remain functional for several months without suffering critical failure from biofouling and hydrodynamism. Still, even where gardening infrastructures were only marginally affected, the unavoidable interruptions in data collection have slowed down ongoing project progress, diminishing previous investments and reducing future funding opportunities. These results highlight the need to increase the resilience and self‐sufficiency of coral restoration projects, so that the next global lockdown will not further shrink the increasing efforts to prevent coral reefs from disappearing.
Parents’ experiences of living with a child with Paediatric Feeding Disorder: An interview study in Sweden
Authors: Lamm Kajsa , Kristensson Hallström Inger , Landgren Kajsa
Published: February 2022

Introduction

Children affected by Paediatric Feeding Disorder (PFD) cannot consume enough nourishment by mouth. PFD is highly prevalent and can affect the child's growth and development as well as family life.

Aim

To illuminate Swedish parents’ experiences of living with a child with PFD.

Method

Semi‐structured interviews via telephone or video calls were conducted with 14 purposefully recruited mothers and six fathers. The interviews were analysed using content analysis. Ethics approval was obtained, and the parents all gave informed consent.

Results

Four overarching themes emerged: Living with stress; Advocating for the child; Adapting family life; and Gaining hope. Parents described fearing for their child's life and health, feeling pressure over meals and being emotionally affected. They told of experiencing a lack of understanding from healthcare professionals, friends and family. Parents expressed a struggle for help, the need for early interventions and more effective treatment, and developed strategies for coping with the demands of feeding and caring for their child, accepting their living reality. Finding support from a network helped, but the adaptation of daily life affected their family relations. They felt gratitude towards helpful professionals and relief and joy when their child was doing better.

Conclusions

A more cohesive chain of care is important for children with PFD, and guidelines and educational support for healthcare providers are needed. Parental experiences provide a base for knowledge for further development of early detection and intervention for children with PFD.
When does ownership matter? Parents’ reasoning about children's conflicts over possessions
Authors: Nancekivell Shaylene E. , Maurer Brian A.
Published: February 2022

In three studies (N = 854), including one pre‐registered study, we examined factors that might influence American parents’ decisions to side with owners versus promote prosociality or sharing when thinking about children's property conflicts. We found that parents’ thinking about property conflicts was affected by the relationships among the parents and their children. Namely, parents were most likely to side with owners when their child was described as transgressing upon another's property. Conversely, when the parents’ child was the owner, they were more likely to encourage sharing. Parents’ explanations revealed that their decisions were a reflection of their personal beliefs about the importance of personal rights and/or promoting prosociality. The findings also suggested that some parents were reasoning in nuanced ways about the importance of teaching children about consent and its link to ownership. The findings from these studies have bearing on the potential role of parental input in young children's appreciation of owners’ rights. These results suggest that parents may be providing children with some informative input regarding the nature of ownership rights such as when they matter most.
Mediating the claim? How ‘local ecosystems of support’ shape the operation and experience of UK social security
Authors: Edmiston Daniel , Robertshaw David , Young David , Ingold Jo , Gibbons Andrea , Summers Kate , Scullion Lisa , Geiger Ben Baumberg , de Vries Robert
Published: February 2022

Local state and third sector actors routinely provide support to help people navigate their right to social security and mediate their chequered relationship to it. COVID‐19 has not only underlined the significance of these actors in the claims‐making process, but also just how vulnerable those working within ‘local ecosystems of support’ are to external shocks and their own internal pressures. Drawing on qualitative fieldwork with organisations providing support to benefit claimants and those financially struggling during COVID‐19, this paper examines the increasingly situated nature of the claims‐making process across four local areas in the United Kingdom. We do so to consider what bearing ‘local ecosystems of support’ have on income adequacy, access and universality across social security systems. Our analysis demonstrates how local state and third sector actors risk amplifying inequalities that at best disadvantage, and at worst altogether exclude, particular social groups from adequate (financial) assistance. Rather than conceiving of social security as a unitary collection of social transfers, we argue that its operation needs to be understood as much more fragmented and contingent. Practitioners exhibit considerable professional autonomy and moral agency in their discretionary practice, arbitrating between competing organisational priorities, local disinvestment, and changing community needs. Our findings offer broader lessons for understanding the contemporary governance of social security across welfare states seeking to responsibilise low‐income households through the modernisation of public services, localism, and welfare reforms.
Substrate promiscuity of acyltransferases contributes to the diversity of hydroxycinnamic acid derivatives in purple coneflower
Authors: Fu Rao , Zhang Pingyu , Jin Ge , Wei Shuo , Chen Jiang , Pei Jin , Zhang Yang
Published: February 2022

Hydroxycinnamic acid derivatives (HADs) such as chicoric acid are the main active ingredients of purple coneflower (Echinacea purpurea (L.) Moench). Recently, the biosynthesis of chicoric acid catalyzed by both BAHD and serine carboxypeptidase‐like (SCPL) acyltransferases has been elucidated. However, the diversity of HADs in purple coneflower and their biosynthesis pathways remain unclear. Here, through an alignment of extract ion chromatograms of potential fragments, tentative HADs, such as phaselic acid and chicoric acid analogs (deoxy‐ and methyl‐), were found in purple coneflower. Phylogenetic analyses based on the full‐length transcriptome were conducted to explore additional BAHD and SCPL acyltransferases that might be involved in HAD biosynthesis. One BAHD, conserved among Echinacea species, showed weak hydroxycinnamoyl‐CoA:tartaric acid hydroxycinnamoyl transferase (HTT) activity. Further results indicated that this BAHD was hydroxycinnamoyl‐CoA:malic acid hydroxycinnamoyl transferase (HMT), which catalyzes the biosynthesis of phaselic acid. Although no potential isozyme was found for chicoric acid synthase (CAS), CAS itself showed acyl acceptor promiscuity and catalyzed the biosynthesis of deoxychicoric acid and methylchicoric acid. Overall, we identified additional HADs and depicted their biosynthesis network in purple coneflower. The substrate promiscuity of identified acyltransferases diversifies HADs, indicating the complexity of plant secondary metabolism.
How do I: Evaluate the safety and legitimacy of unproven cellular therapies?
Authors: Guleria Indira , de Los Angeles Muñiz Maria , Wilgo Matthew , Bapat Asawari , Cui Wanxing , Hsu Yen‐Michael Sheng , Jeyaraman Madhan , Muthu Sathish , Rodriguez Federico , Fesnak Andrew , Celluzzi Christina , Sesok‐Pizzini Deborah , Reich‐Slotky Ronit , Spitzer Thomas
Published: February 2022

Background

Unproven cellular therapies are being offered to patients for a variety of conditions and diseases for which other treatments have failed. The use of untested cellular therapies is a worldwide problem. Practitioners (e.g., physicians, scientists, QA/QI facility managers, and policy advocates) are perhaps unaware of the risks involved with such therapies. Therefore, a critical need exists to bring attention to the potential limitations and adverse effects of these therapies to inform and limit misinformation.

Study Design and Methods

We describe the extent of the unproven cellular therapy problem through a search of scientific literature and social media coverage. We also describe the regulatory framework that can be used by the practitioner to review and evaluate both proven and unproven cellular therapies.

Results

We report on the current state of unproven cellular therapies across the globe. A workflow to facilitate an understanding of the regulatory processes involved in the approval of cellular therapies is provided as well as a list of warnings required by regulatory agencies on various products. It is hoped that this article will serve as a tool kit to educate the practitioner on navigating the field of unproven cellular therapy products.

Discussion

Increasing awareness of the issues associated with unproven therapies through education is important to help in reducing misinformation and risks to patients.
Effects of physical activity as an adjunct treatment on healing outcomes and recurrence of venous leg ulcers: A scoping review
Authors: Qiu Yunjing , Osadnik Christian R. , Team Victoria , Weller Carolina D.
Published: February 2022

Healing time is protracted and ulcer recurrence is common in patients with venous leg ulcers. Although compression is the mainstay treatment, many patients do not heal timely. Physical activity may be a clinically effective adjunct treatment to compression to improve healing outcomes. This scoping review provides a broad overview of the effect of physical activity as an adjunct treatment to compression on wound healing and recurrence. We followed the six‐step framework developed by Arksey and O'Malley. We searched electronic databases and trial registration websites for relevant studies and ongoing trials. Two authors independently screened and selected articles. Findings were presented in a descriptive statistical narrative summary. We consulted and presented our findings to the wound consumer group to ensure the relevance of our study. Physical activity interventions in 12 out of the 16 eligible studies consisted of only one component, eight studies were resistance exercises, three studies reported ankle and/or foot range of motion exercises, and one study reported aerobic/walking exercises. The remaining four studies involved multicomponent exercise interventions. Resistance exercise combined with ankle and/or foot range of motion exercise minimised ulcer size on day 12 (intervention group: 4.55 ± 1.14 cm2 vs. control group: 7.43 ± 0.56 cm2) and improved calf muscle pump performance on day 8 (ejection fraction: 40%–65%; residual volume fraction: 56%–40%). We identified one study that reported ulcer recurrence rate with no clinical difference in the intervention group versus the control group (i.e., 12% in intervention vs. 5% in control). Our review identified that resistance exercise was the most common type of physical activity intervention trialled in the published literature. Resistance exercise combined with ankle and/or foot range of motion exercise appears to be effective adjunct treatments; however, the overall evidence is still relatively weak as most programmes had a short intervention period which limited clinical outcomes.
LUMPY SKIN DISEASE VIRUS: APPROACHES TO ATTENUATION FOR VACCINE DEVELOPMENT
Authors: Chervyakova O.V. , Sultankulova K.T. , Nissanova R.K. , Orynbayev M.B.
Published: February 2022

Lumpy skin disease (LSD) is a disease caused by the lumpy skin disease virus (LSDV) of the genus capripoxvirus. The disease is responsible for serious losses to the cattle industry globally. Vaccination is the most effective way of controlling LSDV. The currently available live attenuated vaccines are used in many countries and provide stable immunity. However, use of these vaccines can sometimes cause postvaccinal complications in animals. Attenuation of viruses by the classical method is associated with random mutations in the genome, and some vaccines can contain a mixture of viruses of different genotypes and virulence. Hence, there is a need to develop a safe immunogenic vaccine that will provide improved protection against LSDV. The most promising approach is gene modification to develop an attenuated capripoxvirus strain with high immunogenicity and protectivity. Sequencing and analysis of capripoxvirus DNA genomes has resulted in the identification of a number of genes whose protein products effectively stimulate antibody production in the host organism. These proteins are able to function both inside and outside the cell, neutralizing the complement factors, inhibiting apoptosis and synthesis of interferons, and reducing counter-inflammatory cytokines and chemokines. Here, we review the literature for instances of genetic manipulation of genes encoding the above proteins, resulting in capripoxvirus attenuation.
GENOTYPING OF DRUG-RESISTANT MYCOBACTERIUM TUBERCULOSIS ISOLATES FROM SOUTHERN KAZAKHSTAN
Authors: Tarlykov P. , Atavliyeva S. , Alenova A. , Zholdybayeva E. , Ramankulov Ye.
Published: February 2022

The incidence of drug-resistant tuberculosis in Kazakhstan has risen over the last decades, making it a serious threat. The purpose of this study was to characterize M. tuberculosis isolates circulating in the south of Kazakhstan, based on mutations of known association with multidrug-resistance and extensive drug resistance. A total of 58 clinical isolates of M. tuberculosis with drug resistance from southern Kazakhstan were selected. Seven genetic loci were sequenced, namely, rpoB (for resistance to RIF), katG, inhA (for resistance to INH), embB (for resistance to EMB), as well as the gyrA, gyrB (for resistance to CIP and OFX) and rrs (for resistance to KAN, AMK, and CPR). In addition, mutations in codon 315 of katG (n = 53; 91.4%), in codon 531 of the rpoB (n = 45; 77.6%), at the position of 1401 A/G of rrs (n = 33; 56.9%) and in the codon 94 of the gyrA were found to be prevalent in the samples. MIRU-VNTR typing showed that most isolates belong to the Beijing family (n = 53; 94.4%). Whole genome sequencing of a single M. tuberculosis strain from southern Kazakhstan was conducted. The emergence of drug-resistance is characteristic of the Beijing family, which may explain the increase in the incidence rates of resistant forms of tuberculosis in Kazakhstan.
STANDARDIZATION OF KI-67 AS A BIOMARKER OF CELL PROLIFERATION
Authors: Zhylkibayev A.A. , Sarina N.I. , Mun E.A. , Eskendirova S.Z.
Published: February 2022

Currently, the most informative, accessible, and common method for evaluating the level of cell proliferative activity is identification and quantification of Ki-67 protein as a universal proliferation biomarker. The Ki-67 antigen is a component of the nuclear matrix, and nuclear core localization changes are observed during the cell cycle. Ki-67 protein is mainly associated with the chromosomes and belongs to the family of perichromonucleic proteins that surround chromosomes during mitosis. Ki-67 is characterized as a large nuclear protein based on cloning and sequencing a cDNA library. It is subjected to conformational changes during the cell cycle. Ki-67 also undergoes post-translational modifications by phosphorylation, accompanied by redistribution from the nucleoplasm into the perichromosomal layer and back during mitosis. Accordingly, Ki-67 is a widely used biomarker for cancer cells, including for pathological diagnosis and monitoring treatment responses. In particular, determination of the expression level of Ki-67 plays an important role in distinguishing the molecular subtypes of breast cancer and is one of the main criteria for determining the appropriate scheme of chemotherapy. However, there is currently no standardization of evaluation methods for predicting the disease outcome and effectiveness of chemotherapy. Researchers have reported the high variability in the Ki-67 index between different laboratories, depending on the choice of primary antibodies, methods for conducting immunohistochemistry, and methods for quantifying expression.

The most appropriate threshold values of Ki-67 expression for clinical monitoring are continuously debated, and determination of a single cut-off point of Ki-67 was shown to not appropriately reflect the heterogeneous biology of the disease. In accordance with the latest recommendations of the St. Gallen conference of 2015,  low, medium, and high Ki-67 thresholds were identified to achieve a better response to therapy. Here, we discuss the structure and function of the protein, as well as progress toward achieving a standardized determination method of Ki-67.
Una metodología desde la teoría de redes para las redes culturales
Authors: Caparrini Fernando Sancho
Published: February 2022

Este documento presenta, desde un punto de vista introductorio y orientado a no expertos en teoría de redes, los fundamentos de grafos y redes que permiten proyectar información sobre redes culturales en un contexto formal. Asimismo, describe algunas de las medidas y herramientas más comunes para diseñar mecanismos cuantitativos para el análisis posterior de estas redes. Este artículo no pretende ser un curso ni un tutorial completo sobre teoría de redes, para eso el lector puede acudir a cualquiera de las referencias que se apuntan al final, más bien constituye una introducción orientada a recorrer, en un solo documento, algunos de los detalles que se consideran más importantes y que suelen quedar fuera de las explicaciones iniciales sobre el tema.
Redes Culturales Afro-Latinoamericanas. El caso del Primer Congreso de la Cultura Negra de las Américas
Authors: Arriaga Arango Eduard
Published: February 2022

El artículo estudia el Primer Congreso de la Cultura Negra de las Américas y su red cultural. A partir de una metodología de análisis de redes complejas, el texto explora cómo dicha red se conecta con la súper-red de representaciones artísticas y de activismo de lo afrolatinoamericano, y, a pesar de ser un nodo débil y tener conexiones débiles, logra alcanzar una posición central en las redes intelectuales y de activismo afrolatinoamericanas. Asimismo, el artículo discute los aportes de las redes culturales como metodología para alcanzar unas humanidades digitales críticas más centradas en la experiencia humana y de producción cultural en una era en la que los algoritmos parecen dirigir nuestra experiencia de la cultura.
Redes mercantiles e intercambio cultural en la ruta del Galeón de Manila, 1565-1600
Authors: Villamar Cuauhtémoc
Published: February 2022

El artículo presenta un análisis del Galeón de Manila, principal sistema comercial que mantuvo en comunicación a América y Asia, a través del océano Pacífico. Ha sido ampliamente reconocido que este sistema de comercio permitió la apertura del proceso de globalización de la temprana edad moderna. Sin embargo, esta investigación enfatiza en los intercambios culturales activados por el Galeón de Manila, concretamente, en la naturaleza social y cultural de una red de comerciantes instalados en Manila. Se concluye con una reflexión metodológica sobre las herramientas de investigación digital y los enfoques de la historia global y la microhistoria utilizados para comprender el proceso de globalización temprana.
A Novel Semiemperical Friction Coefficient Model Between Needle and Polyvinyl Alcohol Tissue Phantom and Its Validation by Using Computational Inverse Technique
Authors: Li Murong , Lei Yong , Hu Yingda , Du Shilun , Gao Dedong , Wang Zhen , Xu Tian
Published: February 2022

Needle–tissue interactive force is vital for developing a virtual simulation and planning system (SPS) and optimizing needle control strategy, wherein the friction coefficient is an important parameter but difficult to pre-determine. The existing studies on friction coefficient estimation were lack of qualitative analysis and did not consider the effect of normal pressure and interactive velocity, which may lead to the inaccuracy of the friction calculation. In this paper, we proposed a novel semiempirical friction coefficient model based on the modified classical elastic friction theory that constructs the relationship between the friction coefficient and parameters such as the normal pressure and velocity. The proposed friction coefficient model is validated by using the computational inverse technique based on coupled finite element material point (CFEMP) contact algorithm. The results show that the friction coefficient between the needle and polyvinyl alcohol (PVA) tissue phantom varies from 0.091 to 0.242 with different normal pressure (7.95–17.80 kPa) and insertion velocity (1–9 mm/s), which agrees well with the experimental data. The results of the paper can help to better understand the intrinsic characteristics of the needle–tissue interactions and optimal needle actuation strategies.
Acoustic detection of unmanned aerial vehicles using biologically inspired vision processing
Authors: Fang Jian , Finn Anthony , Wyber Ron , Brinkworth Russell S. A.
Published: February 2022

Robust detection of acoustically quiet, slow-moving, small unmanned aerial vehicles is challenging. A biologically inspired vision approach applied to the acoustic detection of unmanned aerial vehicles is proposed and demonstrated. The early vision system of insects significantly enhances signal-to-noise ratios in complex, cluttered, and low-light (noisy) scenes. Traditional time-frequency analysis allows acoustic signals to be visualized as images using spectrograms and correlograms. The signals of interest in these representations of acoustic signals, such as linearly related harmonics or broadband correlation peaks, essentially offer equivalence to meaningful image patterns immersed in noise. By applying a model of the photoreceptor stage of the hoverfly vision system, it is shown that the acoustic patterns can be enhanced and noise greatly suppressed. Compared with traditional narrowband and broadband techniques, the bio-inspired processing can extend the maximum detectable distance of the small and medium-sized unmanned aerial vehicles by between 30% and 50%, while simultaneously increasing the accuracy of flight parameter and trajectory estimations.
The effect of target and interferer frequency on across-frequency binaural interference of interaural-level-difference sensitivity
Authors: Rosen Beth , Goupell Matthew J.
Published: February 2022

Across-frequency binaural interference occurs when the sensitivity to changes in interaural differences in a target sound is decreased by a spectrally remote diotic interfering sound. For interaural time differences (ITDs), low-frequency (e.g., 0.5 kHz) interferers cause more interference on high-frequency (e.g., 4 kHz) targets than vice versa. For interaural level differences (ILDs), however, it is unclear if a frequency dependence exists. Therefore, ILD discrimination thresholds and across-frequency binaural interference were measured for target and interferer frequencies between 0.5 and 8 kHz (for tones) or 12 kHz (for narrowband noises). For tones, 8-kHz targets experienced the least interference and 8-kHz interferers produced the most interference, suggesting that higher-frequency ILDs are a more heavily weighted localization cue than lower-frequency ILDs. For narrowband noises, the frequency-dependent interference patterns increased in complexity in comparison to tones. Low-frequency ITD dominance (from randomly varying onset ITDs) and grouping cues (e.g., envelope modulations) might explain some of the complexity in the interference patterns for the noises. These data contribute to a better understanding of across-frequency ILD processing, which remains poorly understood.
Signal-to-noise ratio of diverging waves in multiscattering media: Effects of signal duration and divergence angle
Authors: Kumru Yasin , Köymen Hayrettin
Published: February 2022

In this paper, SNR maximization in coded diverging waves is studied, and experimental verification of the results is presented. Complementary Golay sequences and binary phase shift keying modulation are used to code the transmitted signal. The SNR in speckle and pin targets is maximized with respect to chip signal length. The maximum SNR is obtained in diverging wave transmission when the chip signal is as short a duration as the array permits. We determined the optimum diverging wave profile to confine the transmitted ultrasound energy in the imaging sector. The optimized profile also contributes to the SNR maximization. The SNR performances of the optimized coded diverging wave and conventional single-focused phased array imaging are compared on a single frame basis. The SNR of the optimized coded diverging wave is higher than that of the conventional single-focused phased array imaging at all depths and regions.
Spatial-CUT&Tag: Spatially resolved chromatin modification profiling at the cellular level
Authors: Deng Yanxiang , Bartosovic Marek , Kukanja Petra , Zhang Di , Liu Yang , Su Graham , Enninful Archibald , Bai Zhiliang , Castelo-Branco Gonçalo , Fan Rong
Published: February 2022

Spatial omics emerged as a new frontier of biological and biomedical research. Here, we present spatial-CUT&Tag for spatially resolved genome-wide profiling of histone modifications by combining in situ CUT&Tag chemistry, microfluidic deterministic barcoding, and next-generation sequencing. Spatially resolved chromatin states in mouse embryos revealed tissue-type-specific epigenetic regulations in concordance with ENCODE references and provide spatial information at tissue scale. Spatial-CUT&Tag revealed epigenetic control of the cortical layer development and spatial patterning of cell types determined by histone modification in mouse brain. Single-cell epigenomes can be derived in situ by identifying 20-micrometer pixels containing only one nucleus using immunofluorescence imaging. Spatial chromatin modification profiling in tissue may offer new opportunities to study epigenetic regulation, cell function, and fate decision in normal physiology and pathogenesis.
EU and US legislation seek to open up digital platform data
Authors: Nonnecke Brandie , Carlton Camille
Published: February 2022

Constraints on data access must be addressed to facilitate research
Induced giant piezoelectricity in centrosymmetric oxides
Authors: Park D.-S. , Hadad M. , Riemer L. M. , Ignatans R. , Spirito D. , Esposito V. , Tileli V. , Gauquelin N. , Chezganov D. , Jannis D. , Verbeeck J. , Gorfman S. , Pryds N. , Muralt P. , Damjanovic D.
Published: February 2022

Piezoelectrics are materials that linearly deform in response to an applied electric field. As a fundamental prerequisite, piezoelectric materials must have a noncentrosymmetric crystal structure. For more than a century, this has remained a major obstacle for finding piezoelectric materials. We circumvented this limitation by breaking the crystallographic symmetry and inducing large and sustainable piezoelectric effects in centrosymmetric materials by the electric field–induced rearrangement of oxygen vacancies. Our results show the generation of extraordinarily large piezoelectric responses [with piezoelectric strain coefficients (
d
33
) of ~200,000 picometers per volt at millihertz frequencies] in cubic fluorite gadolinium-doped CeO
2−

x

films, which are two orders of magnitude larger than the responses observed in the presently best-known lead-based piezoelectric relaxor–ferroelectric oxide at kilohertz frequencies. These findings provide opportunities to design piezoelectric materials from environmentally friendly centrosymmetric ones.
Caloric restriction has a new player
Authors: Rhoads Timothy W. , Anderson Rozalyn M.
Published: February 2022

Reverse translation of a human caloric restriction trial finds an immunometabolic regulator