bluuebunny/crossref_metadata_2025 huggingface dataset:
P13.23 Study of migration characteristics of human glioma cells in vitro
Authors: Pavlova G , Pavlova S , Drozd S , Savchenko E , Zakharova L , Shamadykova D , Golbin D , Potapov A , Revishchin A
Published: September 2021

BACKGROUND

Gliomas are still one of the most aggressive human cancers, and even despite modern therapeutic approaches, the prognosis for patients with this disease is not favorable. It is known that glioma cells are capable of local invasiveness, when glioma cells migrate into healthy brain tissue. A lack of any definite markers, characterizing migrating glioma cells and allowing them to be distinguished from healthy brain cells, requires a thorough investigation. In case it would be possible to characterize invasive glioma cells, then a development of targeted therapy could be feasible.

MATERIAL AND METHODS

Cell cultures of human gliomas Gr II, III and IV were developed with 5 cultures for each Grade. MTT, RT-PCR, Western and Nosern blot, transcriptome analysis were applied.

RESULTS

Three cultures of human gliomas had a high degree of migration, within the range of 6% - 14%. These cultures were developed from gliomas of Grade III and Grade IV, and with IDH1- (minus) phenotype. Moreover, cell cultures with IDH1 + (plus) phenotype had a low migration rate within 1%. An intensity of migration correlated with the degree of malignancy, and an average rate decreased with a decrease of the Grade. Moreover, an analysis of the proliferative activity of cell cultures of human gliomas of various degrees of malignancy did not reveal a relationship with a migratory properties of cultures. A number of actively proliferating cultures did not show high migration, while cultures with medium proliferative activity could show a high level of migration. The low level of proliferation of cultures of gliomas of Grade II and I at the beginning of cultivation, in some cases, subsequently increased, but an inherent low migration activity did not change. In actively migrating cultures, a significant decrease in the expression of Sox2 and Nestin is detected. A positive correlation was found between migration abilities of human glioma cell culture cells and the marker Ki67, GFAP, Sox2, and Oct4. The difference was statistically significant by the one-sided Mann-Whitney test.

CONCLUSION

Conclusions: Cell cultures derived from glioma tumor tissue can be used to predict invasive properties of the tumor. High tumor invasiveness is characteristic for Grade III and Grade IV, and with IDH1- (minus) phenotype, and it also correlates with elevated expression of GFAP, Sox2 and Oct4The reported study was funded by RFBR according to the research project № 18-29-01012 and by the Ministry of Science and Higher Education of the Russian Federation, grant number 075-15-2020-809 (13.1902.21.0030).
P14.11 Severe treatment-induced myelosuppression is more frequent in female malignant glioma patients and associated with reduced overall survival
Authors: Zeiner P S , Filipski K , Forster M , Voss M , Fokas E , Herrlinger U , Harter P N , Steinbach J P , Ronellenfitsch M W
Published: September 2021

BACKGROUND

An association of treatment-related myelotoxicity with female gender has been previously suggested. However, a systematic analysis of the prognostic relevance of radiochemotherapy-related cytopenia involving the different blood cell lineages is lacking.

MATERIAL AND METHODS

We retrospectively analyzed cytopenia during temozolomide-based concomitant radiochemotherapy (RCT) in 493 glioma patients. Histological grading, molecular pathology, surgical procedures and median overall survival (OS) were recorded. The extent of cytopenia was correlated with gender and outcome.

RESULTS

Treatment-induced severe cytopenia (leuko-, lympho-, neutro- and thrombocytopenia) occurred much more often in female than in male glioma patients (40.8 vs. 13.9%, p-value <0.0001). In female patients with IDH-wildtype high-grade astrocytomas there was a negative correlation of severe leuko-, lympho- and thrombocytopenia during temozolomide RCT with OS (36 vs. 54, 37 vs. 54 and 36 vs. 57 weeks, respectively; all p-values <0.05). In male patients there was also a trend for this unfavorable effect. Additionally, severe cytopenia correlated with reduced temozolomide dose exposure during RCT (all p-values <0.05 in total cohort) and reduced dose exposure was independently associated with worse OS (p-values <0.05 in the total and female cohort).

CONCLUSION

Our data confirm that women are at higher risk for treatment-induced cytopenia during RCT which is associated with a significant decrease in OS. From our data, it appears plausible that reduced temozolomide dose exposure during RCT is at least in part responsible for this finding. Immunosuppression of patients with severe cytopenia may be an independent contributor to adverse outcome.
P14.58 Efficacy and safety of lomustine versus fotemustine as first and second line treament in relapsed glioblastoma patients
Authors: Domènech M , Fabregat C , Hernández A , del Barco S , Panciroli C , Garcia-Illescas D , Vieito M , Vilariño N , Mesia C , Balañà C
Published: September 2021

BACKGROUND

Glioblastoma (GB) is the most aggressive primary brain tumour. Despite the survival benefit associated with adjuvant therapy, most of patients (pts) relapse after initial therapy. Nitrosoureas (NU) are the standard treatment at relapse in Europe. Both fotemustine (FM) (Addeo schema) and lomustine (LM) (administered orally every 6 weeks) are used in this context.

MATERIAL AND METHODS

This retrospective cohort study included pts diagnosed with GB treated with NU at relapse in four Catalonia hospitals from 2010 to 2020. Clinical and pathological data were collected from medical records. We analysed 6months-progression-free survival (6m-PFS), progression-free survival (PFS) and overall survival (OS) from the start of NU to progression or death respectively. Differences in toxicity grade using CTCAE v5.0 were analysed globally as ‘non-toxicity’, ‘mild toxicity (grade 1 or 2)’ and ‘high toxicity (grade 3 or 4)’.

RESULTS

We identified 236 GB pts with a median age of 58 years old. 29% of the pts presented MGMT promotor methylation and only 3%(n=7) had IDH mutation. After a median follow-up of 20 months, 94% of the pts were dead at the time of the analyses. At first line, 83 pts were treated with FM and 18 with LM. Pts treated with FM had better performance status (PS) than those treated with LM (p=.010). Median PFS was 2 months and 6m-PFS was 12% vs 6% in FM and LM group respectively (p=.87). Median OS was 3 months with LM vs 6 months with FM, with no statistically significant differences even adjusted for prognostic factors (p=.79 HR:0.9 CI 95% 0.41–1.96).At second line, 78 were treated with FM and 24 with LM, no differences between groups. Median PFS was 2 months in both groups and median OS was 3 vs 5 months for pts treated with LM vs FM respectively, with no significant differences. 6m-PFS was 13% for LM vs 0% for the FM group (p=.39).Pts received a mean of 1.7 cycles (every 6 weeks) and 4.1 cycles (every 2 weeks) in LM and FM group, respectively. Thrombocytopenia was the most common serious side-effect, with a higher proportion of grade 1–2 toxicity in the FM group (p=.03) that also required more treatment delays (p=.01).

CONCLUSION

Despite being retrospective study and a few pts were treated with LM, there were no differences neither in PFS nor in OS in pts treated with LM vs FM at first or second line. Higher G1-2 thrombocytopenia was shown in the FM group probably due to a higher number of hematology samples collected.
P14.64 PriCoTTF Trial: A phase I/II trial of TTFields prior and concomitant to radiotherapy in newly diagnosed glioblastoma
Authors: Kebir S , Pierscianek D , Proescholdt M , Hau P , Grosu A , Krex D , Sure U , Scheffler B , Stuschke M , Glas M
Published: September 2021

BACKGROUND

TTFields therapy is applied at 200 kHz by arrays that are placed at the patients’ scalp. In the phase 3 EF-14 trial, survival rates were significantly improved when adding tumor-treating fields (TTFields) to adjuvant temozolomide-based chemotherapy in patients with newly diagnosed glioblastoma (nGBM). In preclinical studies, the combination of TTFields and radiotherapy synergistically impaired proliferation and growth of glioblastoma cells. Here, we present the PriCoTTF trial, which is enrolling nGBM patients and will assess the safety and efficacy of TTFields initiated prior and concomitant to radiochemotherapy.

MATERIAL AND METHODS

Following surgery and complete wound-healing, TTFields therapy is initiated in adult nGBM patients. TTFields therapy continues throughout radiochemotherapy and adjuvant chemotherapy for a total of approximately 9 months. During radiotherapy, the arrays - through which TTFields is delivered - remain on the patients’ scalp. Totally, thirty-three patients are planned to be enrolled in two treatment arms. In arm A, 20 patients receive normo-fractionated radiotherapy, whereas in the elderly arm, arm B, 13 patients receive hypo-fractionated radiotherapy. Concomitant and adjuvant chemotherapy follow institutional standards and interdisciplinary tumor conference recommendations.

RESULTS

The primary endpoint of this trial is safety and tolerance that will be gauged by a set of pre-specified treatment-limiting toxicities. Secondary endpoints include the frequency of adverse events, progression-free survival (PFS), and overall survival (OS). The trial is currently enrolling patients at four sites in Germany. At the time of abstract submission, 9 patients enrolled in Arm B. Patient recruitment for arm A has been completed with 20 patients enrolled. We will present initial practical experiences as well as preliminary safety and tolerance data.

CONCLUSION

There is a biological rationale for combining TTFields and radiotherapy to further improve survival of GBM patients. In the presented phase I/II trial, the safety and efficacy of TTFields initiated prior and concomitant to RT in nGBM will be assessed. In addition, initial efficacy data (phase II) may serve as a rationale for a putative randomized phase III trial.
P14.86 Predictive value of MGMT promoter (pMGMT) methylation status on pseudoprogression (PsP) and survival analysis in Glioblastoma (GBM) patients: a retrospective single institutional analysis
Authors: Interno’ V , De Santis P , Stucci L , Porta C
Published: September 2021

BACKGROUND

Glioblastoma is the most common and aggressive primary brain tumor. Conventional therapies, such as maximal extension of surgery followed by radiotherapy (RT) and chemotherapy with Temozolomide (TMZ) have not resulted in major improvements in terms of patients’ outcome, overall survival (OS) still remaining poor. In this context, radiological response assessment after radiotherapy remains challenging due to the potential effect of radionecrosis, often mimicking tumor progression. Differentiation between PsP and true progression is required to avoid further unnecessary surgeries, or the premature discontinuation of TMZ. It is known that pMGMT methylated patients respond better to chemotherapy than unmethylated counterpart, so, tumor cells necrosis can be enhanced in this setting. The aim of the study is to observe the correlation between pMGMT methylation status with the incidence of PsP in GBM patients at the first radiological evaluation after RT.

MATERIALS AND METHODS

Patients with histologically diagnosis of GBM from 2017 to 2021 and availability of pMGMT methylation status were enrolled. PsP was radiologically defined at first brain MRI after RT in case of increasing size of the enhancing component and of peritumoral oedema that remain stable or decrease after antioedema therapy, such as a clinical improvement was observed.

RESULTS

We analysed 55 GBM patients, 35 (64%) displayed pMGMT methylation whereas 20 (36%) resulted pMGMT unmethylated. PsP was evident in 29 patients (53%), all of them showed methylation of pMGMT. In our analysis, none of pMGMT unmethylated patients experienced PsP. Regarding survival outcome for pMGMT methylated patients, our analysis shows a mPFS of 8.7 (95% CI: 5–10) months versus 9.3 (95%CI: 4.6–12.3) months in methylated and unmethylated respectively (p=0.87).

CONCLUSIONS

Methylation status of pMGMT showed to be predictor of PsP in GBM patients. If validated, this information could be very useful to guide clinicians in differentiating PsP from true progression. To date, our survival analysis regarding PFS showed no statistical difference among methylated patients with respect to the presence or absence of PsP. Thus, PsP seems not to be a marker of responsiveness to common treatment. Further data are needed to validate our results.
P15.02 Loss of Williams Syndrome Transcription Factor (WSTF) leads to improved temozolomide sensitivity in human glioblastoma cells irrespective of MGMT expression
Authors: Sarnow K , Schwab S G , Rio O , Mukherjee J , Bjerkvig R , Johannessen T A
Published: September 2021

BACKGROUND

The prognosis for newly diagnosed adult glioblastoma multiforme (GBM) patients is poor even after standard therapy with a median survival of approximately 14–15 months. The DNA repair protein O 6 -methylguanine-DNA methyltransferase (MGMT) efficiently counteracts formation of the most lethal DNA adducts by temozolomide (TMZ) chemotherapy, and is thus associated with poor outcome in GBM patients. Williams Syndrome Transcription Factor (WSTF) has previously been suggested to regulate the DNA damage response pathway (DDR) in both an indirect (through chromatin remodeling together with SMARCA5 in the WICH complex) and direct manner (by phosphorylating H2AX at Tyr142). However, whether WSTF has any role in the development of resistance against chemotherapy through its ability to regulate the DDR in GBMs, is so far not known. In this study, we investigated whether loss of WSTF sensitizes different MGMT-proficient and -deficient GBM cell lines to TMZ treatment.

MATERIAL AND METHODS

We generated WSTF knockout clones from both MGMT-proficient (LN18, T98G) and -deficient GBM cell lines (U-251) using CRISPR/Cas9 gene-editing technology with lentiviral vectors. The PCR-based screening results combined with the T7 endonuclease mismatch assay for bi-allelic monoclonal knockouts were verified via sequencing and immunoblotting to identify candidate knockout clones. For each cell line, three knockout clones were chosen for further investigation. Colony formation assays were performed to determine the survival ability in response to TMZ treatment. Statistical analysis was performed using two-way ANOVA.

RESULTS

WSTF knockout clones showed a significant decrease in colony formation after TMZ-treatment compared to the corresponding WSTF-expressing control groups (non-target single guide RNA) (LN18: Clone 59 vs control: p= 0.0456, T98G: All three studied clones vs control: p <0.0001, U-251: Clone 7/35.1/70.2 vs control: p <0.0001/p= 0.0107/p= 0.0119). Furthermore, two out of three clones of T98G and U-251 (T98G Clone 13 and 128 vs control, p <0.0001, U-251 Clone 7 vs control, p= 0.0062; clone 70.2, p= 0.0052) showed significantly reduced plating efficiency compared to control cells.

CONCLUSION

WSTF is an important factor in both MGMT de- and proficient GBM cell lines for response against TMZ chemotherapy. The loss of WSTF leads to a significantly increased TMZ sensitivity in clinically relevant concentrations for all the studied cell lines. Ongoing studies are investigating the underlying mechanisms and potential alterations in the DDR pathway caused by WSTF loss.
P16.05 Implementation of a novel ex-vivo brain slice model to study human glioblastoma and glioma-associated microglia
Authors: Flüh C , Nanvuma C , Huang Y , Motta E , Kuhrt L , Yuan Y , Xia P , Lubas M , Schnauss M , Hu F , Synowitz M , Kettenmann H
Published: September 2021

BACKGROUND

Glioblastoma multiforme is a highly malignant brain tumor with a devastating prognosis. Resection followed by radio-chemotherapy leads to an overall survival of only 15 months. Up to 40% of the tumor mass consist of tumor-associated microglia and macrophages (TAMs). These cells were shown to promote tumor growth and invasiveness in many murine glioma models. The interaction between TAMs and tumor cells is crucial for tumor progression and includes several known pathways. Still, murine glioma models only partially mirror the human tumor microenvironment. Several known genes, which are highly upregulated in human glioma and TAMs are only expressed in human tissue and not in mice. To further investigate some of these genes, we aimed at establishing a humanized ex-vivo brain slice model, in which human TAMs and human glioma cells can be studied in a standardized manner.

MATERIAL AND METHODS

We used 250 micrometer thick murine brain slices, which were depleted of intrinsic microglia by applying clodoronated liposomes. Next, we inoculated human glioma cells (originating from the cell lines mCherryU87, mCherryU251MG, mCherryLN229 and several patient derived cells lines) with or without human microglia derived from induced pluripotent stem cells (iPSCs). Slices were cultivated for 7 to 14 days. Next, we performed a detailed analysis of microglia morphology (sphericity, cell body volume, process length and branching pattern) and tumor volume.

RESULTS

Clodronation efficacy was high, depending on duration of treatment and length of cultivation. iPSCs and tumor cells integrated into the slice very well. The presence of tumor cells led to an increased sphericity of iPSC-dervied microglia and to an increased cell body volume. Branching pattern and process length did not differ between both conditions. Tumor volume was significantly larger when iPSC-derived microglia were present. This was found in various glioma cells lines and also in patient derived cells.

CONCLUSION

The newly established humanized ex-vivo brain slice system was shown to be feasible. The method successfully allows to study the interaction between human TAMs and tumor cells. Microglia foster tumor growth not only in murine glioma models, but also in a human paradigm. The humanized ex-vivo brain slice model therefore is the optimal basis to study the role human-specific genes in TAM-glioma interaction.
Discourse, Language, and Grand Strategy
Authors: Kornprobst Markus , Traistaru Corina-Ioana
Published: September 2021

This chapter discusses linguistic approaches to grand strategy. Although hints of the importance of language abound in the existing literature, rationalist contributions very much included, an explicitly linguistic perspective addressing grand strategy is relatively new. Yet it makes three important contributions: First, it reminds is that grand strategy—linkages across representations of environment, identity, interest, and means—are intersubjective categories that do not exist independently from language. Second, all kinds of actors can be holders of grand strategy. States are not the only ones. Third, actors make, remake, and unmake convergences on grand strategies in communicative encounters. Processes of justification feature prominently. Since linguistic approaches are still newcomers to the study of grand strategy, many research avenues await further exploration. These pertain to comparing grand strategies held by different (kinds of) actors, exploring productive overlaps of linguistic and other perspectives, and addressing the inescapable normative side of studying grand strategy in responsible fashion.
Rhetoric, Legitimation, and Grand Strategy
Authors: Goddard Stacie E.
Published: September 2021

Scholars associated with diverse research traditions have increasingly agreed that legitimacy is significant in the formulation and operation of grand strategy. Despite the field’s embrace of legitimacy, scholars of international relations have shown less interest in the role of legitimation—the public justification of policy—in creating and sustaining grand strategies. This oversight is puzzling. Grand strategy only becomes legitimate when leaders articulate the reasons why policies are justifiable, and only if audiences accept those claims. Empirically, moreover, leaders devote substantial time, energy, and resources to justifying their strategy to audiences at home and abroad. To overlook legitimation is to overlook much of global politics. This chapter makes the case for treating legitimation as central to the study of grand strategy. It explains what legitimation is, why it matters, and how it drives grand strategy at every stage, from the articulation of national interest, to the interpretation of threat, to the selection of instruments. The essay concludes with challenges to the legitimation of grand strategy in contemporary international politics.
Diplomacy and Grand Strategy
Authors: Sending Ole Jacob
Published: September 2021

Grand strategy can be said to reflect a certain agentic hubris, as if states operate in an environment that is known and controllable. Diplomacy, by contrast, is typically associated with a set of tasks—negotiation, communication, representation—that reflect agentic constraints. Building on the editors’ reflection on grand strategy as an unattainable yet regulative ideal for the conduct of foreign policy, I discuss how grand strategy is integral to states’ presentation of themselves as sovereign—as having a level of control over their environment. The argument falls in three parts: part one introduces grand strategy and diplomacy as core terms. Part two discuss how diplomacy and grand strategy is defined and discussed, highlighting different readings of grand strategy, and introducing an institutional perspective on diplomacy. Part three moves on to reflect on whether grand strategy is a necessary illusion for states to uphold to demonstrate agency vis-à-vis internal and external audiences, and how particular elements of “grand strategy” live on as informal yet defining features of a state’s diplomacy.
The Grand Strategies of Small States
Authors: Wivel Anders
Published: September 2021

This article discusses the nature, opportunities and limitations of small state grand strategy. It identifies the similarities and differences between the grand strategies of small states and great powers and unpacks the nature of traditional defensive small state grand strategies hiding and shelter-seeking as well as more recent offensive, influence-seeking small state grand strategies under the heading of smart state strategy. The article argues that while small state grand strategy remains tied to national security and is formulated in the shadow of great power interests, a changing security environment creates both the need and opportunity for small states to use their weakness instrumentally for maximizing interests. The likelihood of success depends on a pragmatic political culture and the willingness and ability to prioritize goals and means to utilize their nonthreatening small state status in “smart” or “entrepreneurial” policies.
City States in the Later Medieval Mediterranean World
Authors: Lantschner Patrick
Published: September 2021

This article offers a comparative study of city states in the Christian and Islamic spheres of the later medieval Mediterranean world, with a particular focus on Italy, Syria and al-Andalus. Medieval city states are not usually associated with the Islamic world, but rather with a narrative that has foregrounded the exceptional nature of European cities in world history, especially the famous city republics in Northern and Central Italy, and the role that city states played in the formation of European states. Yet city states were a phenomenon that could be observed across urbanized regions of the Mediterranean world where cities turned into important political arenas in the context of sustained political fragmentation. City states are best approached as political systems that were characterized by brittle regimes and experienced high levels of political volatility: they often lacked a clear boundary between the ‘inside’ and ‘outside’ of city states and were characterized by the multiple political organizations that crystallized in, and fought hard to control, urban political space. The most commonly shared type of political organization in city states was the urban lordship, but city-based lords usually found themselves in intense competition with elite-based collective associations, families and factions, and popular political organizations.
Private Equity and the Resolution of Financial Distress
Authors: Hotchkiss Edith S , Smith David C , Strömberg Per
Published: September 2021

We examine the role private equity (PE) sponsors play in the resolution of financial distress of portfolio companies. PE-backed firms have higher leverage and default at higher rates than other companies borrowing in leveraged loan markets. But, PE-backed firms restructure more quickly, avoid bankruptcy court more often, and liquidate less often compared to other highly leveraged firms experiencing financial distress. PE owners are also more likely to retain control post-restructuring, often by infusing capital as firms approach distress. While default frequencies are higher among PE-backed firms, PE investors appear to manage financial distress at lower cost compared to other owners. (JEL G23, G32, G33)
Calcium pyrophosphate crystal deposition in a cohort of 57 patients with Gitelman syndrome
Authors: Chotard Emilie , Blanchard Anne , Ostertag Agnès , Latourte Augustin , Gailly Gilles , Frochot Vincent , Lioté Frédéric , Bousson Valérie , Richette Pascal , Bardin Thomas , Vargas-Poussou Rosa , Ea Hang Korng
Published: September 2021

Objective

Gitelman syndrome (GS) is the most frequent salt-wasting genetic tubulopathy and a source of hypokalaemia and hypomagnesemia. Chondrocalcinosis (CC) is a frequent feature of GS. The aim of our study was to determine the prevalence, distribution patterns, clinical phenotypes and risk factors for CC in GS.

Methods

This prospective study of a cohort of 57 patients with GS included a systematic screening for CC by peripheral joint radiography, cervical spine CT and joint US. The prevalence of cervical C1–C2 CC by CT was compared between 33 GS patients and sex- and age-matched controls. Clinical and biochemical features were analysed to identify factors associated with CC.

Results

Mean (s.d.) age of patients was 46.5 (12.4) years, 66.7% were women and 93.0% carried SLC12A3 mutations. Mean serum magnesium level was 0.60 (0.30) mmol/l. CC was observed in 79% of patients, with the highest prevalence at the cervical spine (81.8%) followed by the knee (52.6%), wrist (50.9%), ankle (38.6%), TM joint (36.4%), shoulder (33.3%), hip (22.8%), elbow (14.0%) and sclerochoroid (12.1%). Prevalence of CC at the C1–C2 level was higher in the GS cohort than control group (72.7% vs 9.1%) (adjusted odds ratio 21.0, 95% CI 2.8, 156.1, P = 0.003). Independent factors associated with CC were low serum magnesium level and age.

Conclusion

GS was associated with widespread CC, favoured by aging and hypomagnesemia. The C1–C2 level was the most affected site. Follow-up of this unique cohort will help understanding the clinical consequences of CC, especially the precise characterization of pyrophosphate arthropathy.
Plasma exchange therapy in refractory inflammatory myopathy with anti-signal recognition particle antibody: a case series
Authors: Zhang Hao , Sun Yue , Liu Honglei , Cheng Xiaobing , Ye Junna , Hu Qiongyi , Jia Jinchao , Wang Mengyan , Liu Tingting , Zhou Zhuochao , Yang Chengde , Chi Huihui , Teng Jialin , Su Yutong
Published: September 2021

Objectives

To explore the efficacy of plasma exchange (PE) therapy in refractory idiopathic inflammatory myopathy (IIM) patients with positive anti-signal recognition particle (SRP) antibody.

Methods

Nine refractory IIM patients with positive anti-SRP antibody were enrolled, who received PE therapy at Ruijin Hospital from October 2017 to December 2020. The clinical manifestations, laboratory tests, chest CT and lower extremity MRI images before and after PE therapy were compared. The treatment response was evaluated by the 2016 ACR/EULAR myositis response criteria.

Results

A total of 88.9% (8/9) of subjects had achieved improvement by 3 weeks after PE therapy, with 55.6% (5/9) minimal improvement and 33.3% (3/9) moderate improvement. There were statistically significant improvements between baseline and after PE therapy at 3 weeks on the core set measures: physician global activity, patient global activity, HAQ, manual muscle testing (MMT), extramuscular disease activity, and muscle enzymes activity including creatine kinase (CK), lactate dehydrogenase (LDH), aspartate transaminase (AST), except for alanine transaminase (ALT). Moreover, the chest CT showed regression of ground glass opacities and irregular linear opacities after PE therapy in four patients with interstitial lung disease. The MRI images of lower extremity in four patients showed reduction of muscle oedema after the therapy.

Conclusion

PE therapy is effective for refractory IIM patients with positive anti-SRP antibody. It should be considered as an alternative treatment for those patients who are resistant to the combined therapy of glucocorticoids and immunosuppressive agents.
New developments in osteoarthritis pharmacological therapies
Authors: Ghouri Asim , Quicke Jonathan G. , Conaghan Philip G.
Published: September 2021

OA is an increasingly common, painful condition with complex aetiology and limited therapies. Approaches to expanding our therapeutic armamentarium have included repurposing existing therapies used for other rheumatological conditions, modifying existing OA preparations to enhance their benefits, and identifying new therapeutics. HCQ and low-dose MTX have been unsuccessful in improving hand OA pain or reducing structural progression. Anti-IL-6 and anti-GM-CSF also did not improve symptoms in hand OA trials, but IL-1 remains an intriguing target for large-joint OA, based on reduced joint replacements in a post hoc analysis from a large cardiovascular disease trial. The peripheral nociceptive pathway appears an attractive target, with mAbs to nerve growth factor and IA capsaicin demonstrating efficacy; tropomyosin receptor kinase A inhibitors are at an earlier stage of development. Limited evidence suggests pharmacological therapies can modify cartilage and bone structural progression, though evidence of synchronous symptom benefits are lacking.
Heart rate variability as a potential biomarker of pediatric obstructive sleep apnea resolution
Authors: Martín-Montero Adrián , Gutiérrez-Tobal Gonzalo C , Kheirandish-Gozal Leila , Vaquerizo-Villar Fernando , Álvarez Daniel , del Campo Félix , Gozal David , Hornero Roberto
Published: September 2021

Study Objectives

Pediatric obstructive sleep apnea (OSA) affects cardiac autonomic regulation, altering heart rate variability (HRV). Although changes in classical HRV parameters occur after OSA treatment, they have not been evaluated as reporters of OSA resolution. Specific frequency bands (named BW1, BW2, and BWRes) have been recently identified in OSA. We hypothesized that changes with treatment in these spectral bands can reliably identify changes in OSA severity and reflect OSA resolution.

Methods

Four hundred and four OSA children (5–9.9 years) from the prospective Childhood Adenotonsillectomy Trial were included; 206 underwent early adenotonsillectomy (eAT), while 198 underwent watchful waiting with supportive care (WWSC). HRV changes from baseline to follow-up were computed for classical and OSA-related frequency bands. Causal mediation analysis was conducted to evaluate how treatment influences HRV through mediators such as OSA resolution and changes in disease severity. Disease resolution was initially assessed by considering only obstructive events, and was followed by adding central apneas to the analyses.

Results

Treatment, regardless of eAT or WWSC, affects HRV activity, mainly in the specific frequency band BW2 (0.028–0.074 Hz). Furthermore, only changes in BW2 were specifically attributable to all OSA resolution mediators. HRV activity in BW2 also showed statistically significant differences between resolved and non-resolved OSA.

Conclusions

OSA treatment affects HRV activity in terms of change in severity and disease resolution, especially in OSA-related BW2 frequency band. This band allowed to differentiate HRV activity between children with and without resolution, so we propose BW2 as potential biomarker of pediatric OSA resolution.

Clinical Trial Registration

Childhood Adenotonsillectomy Trial, NCT00560859, https://sleepdata.org/datasets/chat.
Genome-wide identification of lncRNAs, miRNAs, mRNAs and their regulatory networks involved in tapping panel dryness in rubber tree (Hevea brasiliensis)
Authors: Liu Hui , Hu Yiyu , Yuan Kun , Feng Chengtian , He Qiguang , Sun Liang , Wang Zhenhui
Published: September 2021

Noncoding RNAs (ncRNAs) play pivotal roles in various biological processes in plants. However, the role of ncRNAs in tapping panel dryness (TPD) of rubber tree (Hevea brasiliensis Muell. Arg.) is largely unknown. Here, the whole transcriptome analyses of bark tissues from healthy and TPD trees were performed to identify differentially expressed long ncRNAs (DELs), microRNAs/miRNAs (DEMs), genes (DEGs) and their regulatory networks involved in TPD. A total of 263 DELs, 174 DEMs and 1574 DEGs were identified in the bark of TPD tree compared with that of healthy tree. Kyoto Encyclopedia of Genes and Genomes analysis revealed that most of the DEGs and targets of DELs and DEMs were mainly enriched in metabolic pathways, biosynthesis of secondary metabolites and plant hormone signal transduction. Additionally, the majority of DEGs and DELs related to rubber biosynthesis were downregulated in TPD trees. Furthermore, 98 DEGs and 44 DELs were targeted by 54 DEMs, 190 DEGs were identified as putative targets of 56 DELs, and 2 and 44 DELs were predicted as precursors and endogenous target mimics of 2 and 6 DEMs, respectively. Based on these, the DEL–DEM–DEG regulatory network involved in TPD was constructed, and 13 hub DELs, 3 hub DEMs and 2 hub DEGs were identified. The results provide novel insights into the regulatory roles of ncRNAs underlying TPD and lay a foundation for future functional characterization of long ncRNAs, miRNAs and genes involved in TPD in rubber tree.
The Use of Medical Scribes in Primary Care Settings
Authors: Ziemann Margaret , Erikson Clese , Krips Maddie
Published: September 2021

Background:

Clerical burdens have strained primary care providers already facing a shifting health care landscape and workforce shortages. These pressures may cause burnout and job dissatisfaction, with negative implications for patient care. Medical scribes, who perform real-time electronic health record documentation, have been posited as a solution to relieve clerical burdens, thus improving provider satisfaction and other outcomes.

Objective:

The purpose of this study is to identify and synthesize the published research on medical scribe utilization in primary care and safety net settings.

Research Design:

We conducted a review of the literature to identify outcomes studies published between 2010 and 2020 assessing medical scribe utilization in primary care settings. Searches were conducted in PubMed and supplemented by a review of the gray literature. Articles for inclusion were reviewed by the study authors and synthesized based on study characteristics, medical scribe tasks, and reported outcomes.

Results:

We identified 21 publications for inclusion, including 5 that examined scribes in health care safety net settings. Scribe utilization was consistently reported as being associated with improved productivity and efficiency, provider experience, and documentation quality. Findings for patient experience were mixed.

Conclusions:

Published studies indicate scribe utilization in primary care may improve productivity, clinic and provider efficiencies, and provider experience without diminishing the patient experience. Further large-scale research is needed to validate the reliability of study findings and assess additional outcomes, including how scribes enhance providers’ ability to advance health equity.
Disparities in heart and lung transplantation
Authors: Tsuang Wayne , Khedraki Rola , Hsich Eileen
Published: September 2021

Purpose of review

Cardiothoracic transplantation is the definitive therapy for end-stage heart and lung disease. In service to this population, disparities in access and care must be simultaneously understood and addressed.

Recent findings

There are sex, race, geographic, age, and underlying disease disparities in both heart and lung transplantation. Women have reduced waitlist survival but improved posttransplant survival when compared with men for both heart and lung transplantation. Black patients have worse outcome compared with other races postheart transplant. Geographic disparities impact the likelihood of receiving heart or lung transplant and the growing number of patients with advanced age seeking transplant complicates discussions on survival benefit. Finally, underlying disease has affected outcomes for both heart and lung transplant and now are incorporated into the allocation system.

Though heart and lung transplantation have several existing disparities, it remains to be seen how advancements in medical technology, changes in donor organ allocation policies, and growing experience in patient selection will impact these concerns.
Physician–Nurse and Nurse–Nurse Collaboration From the Perspective of Nurses
Authors: Şahin Ebru , Çatıker Aslıhan , Özdil Kamuran
Published: September 2021

The study aims to determine the physician–nurse and nurse–nurse collaboration levels of nurses and effective factors. A cross-sectional study was conducted with a sample of 477 nurses from five hospitals using a questionnaire. It was determined that the characteristics of working life explained 10% of the Nurse–Nurse Collaboration Scale and the regression model between variables and the Jefferson Scale of Attitudes Toward Physician–Nurse Collaboration was not statistically significant. Physician–nurse and nurse–nurse collaboration are affected by a variety of factors.
The Prognostic Values of HPV Genotypes and Tumor PD-L1 Expression in Patients With HPV-associated Endocervical Adenocarcinoma
Authors: Zhou Feng , Chen Hao , Li Meiping , Strickland Amanda L. , Zheng Wenxin , Zhang Xiaofei
Published: September 2021

Despite the well-established pathogenic effect of high-risk human papillomavirus (hrHPV) genotypes on endocervical adenocarcinomas (ECAs), the prognostic values of hrHPV genotypes and their association with other prognostic variables have not been established. We categorized 120 usual-type human papillomavirus–associated (HPVA) ECA cases into 3 species groups (HPV16+, HPV18/45+, and other genotypes+) based on the hrHPV status. The clinical-stage, invasion patterns (Silva), and programmed death ligand-1 (PD-L1) expression were compared among genotype groups. In addition, log-rank test and Kaplan-Meier survival curves were used to compare progression-free survival (PFS) among different patient groups. A total of 120 ECA cases with positive hrHPV tests were included in this study. Among them, 51 (42.5%) were positive for HPV16, 50 (41.7%) were positive for HPV18 or 18/45, 9 (7.5%) were positive for other hrHPV genotypes (not including HPV16/18/45). Our data showed patients had no significant difference in clinical stages (P=0.51), invasion patterns (P=0.55), and PFS (P=0.59) across genotype groups. Overall, a relatively high prevalence of PD-L1 expression was observed in HPVA ECAs (25% by tumor proportion score [TPS] and 55% by a combined positive score [CPS]). Using TPS, 19.6% (10/51) HPV16+ cases, 32.0% (16/50) cases of HPV18 or 18/45+ cases, and 22.2% (2/9) cases of other genotypes+ cases demonstrated PD-L1 positivity. No significant difference in PD-L1 expression was seen across genotype groups (P=0.35). PD-L1 expression in tumors with patterns B and C was significantly higher than in those with pattern A (P=0.00002). Patients with PD-L1-positive tumors by either CPS or TPS showed significantly poorer PFS than those with PD-L1-negative tumors (CPS, P=0.025; TPS, P=0.001). Our data support that HPV genotypes have no prognostic value in HPVA ECAs, while PD-L1 expression serves as a negative prognostic marker in HPVA ECAs and implies an unfavorable outcome.
SARS-CoV-2 mRNA Vaccination-Associated Myocarditis in Children Ages 12-17: A Stratified National Database Analysis
Authors: Høeg Tracy Beth , Krug Allison , Stevenson Josh , Mandrola John
Published: September 2021

Objectives

Establishing the rate of post-vaccination cardiac myocarditis in the 12-15 and 16-17-year-old population in the context of their COVID-19 hospitalization risk is critical for developing a vaccination recommendation framework that balances harms with benefits for this patient demographic.

Design, Setting and Participants

Using the Vaccine Adverse Event Reporting System (VAERS), this retrospective epidemiological assessment reviewed reports filed between January 1, 2021, and June 18, 2021, among adolescents ages 12-17 who received mRNA vaccination against COVID-19. Symptom search criteria included the words chest pain, myocarditis, pericarditis and myopericarditis to identify children with evidence of cardiac injury. The word troponin was a required element in the laboratory findings. Inclusion criteria were aligned with the CDC working case definition for probable myocarditis. Stratified cardiac adverse event (CAE) rates were reported for age, sex and vaccination dose number. A harm-benefit analysis was conducted using existing literature on COVID-19-related hospitalization risks in this demographic.

Main outcome measures

1) Stratified rates of mRNA vaccine-related myocarditis in adolescents age 12-15 and 16-17; and 2) harm-benefit analysis of vaccine-related CAEs in relation to COVID-19 hospitalization risk.

Results

A total of 253 CAEs were identified. Rates per million following dose 2 among males were 162.2 (ages 12-15) and 93.0 (ages 16-17); among females, rates were 13.0 and 12.5 per million, respectively. For boys 12-15 without medical comorbidities receiving their second mRNA vaccination dose, the rate of CAE is 2.6 to 4.3 times higher than their 120-day COVID-19 hospitalization risk even at times of peak incidence such as during the delta wave (7-day hospitalizations 2.1/100k population). For boys 16-17 without medical comorbidities, the rate of CAE is 1.5 to 2.5 times higher at times of high weekly COVID-19 hospitalization.

Conclusions

Post-vaccination CAE rate was highest in young boys aged 12-15 following dose two. For boys 12-17 without medical comorbidities, the likelihood of post vaccination dose two CAE is 162.2 and 93.0/million respectively. This incidence exceeds their expected 120-day COVID-19 hospitalization rate at both moderate and high COVID-19 hospitalization incidence. Further research into the severity and long-term sequelae of post-vaccination CAE is warranted. Quantification of the benefits of the second vaccination dose and vaccination in addition to natural immunity in this demographic may be indicated to minimize harm.
RNA-Seq analysis and transcriptome assembly of Salicornia neei reveals a powerful system for ammonium detoxification
Authors: Díaz-Silva Mónica , Maldonado Jonathan , Veloso Pamela , Delgado Nicol , Silva Herman , Gallardo José A.
Published: September 2021

Background

Salicornia neei is a halophyte plant that has been proposed for use in the phytoremediation of the saline wastewater generated by land-based aquaculture, which usually contains elevated concentrations of ammonium resulting from protein metabolism. To identify the molecular mechanisms related to ammonium response, we analyzed the transcriptome of S. neei in response to growth in saline water containing 3 mM ammonium and the Michaelis–Menten ammonium removal biokinetics.

Results

The RNA sequencing generated a total of 14,680,108 paired-end reads from the control and stressed conditions. De novo assembly using the CLC Genomic Workbench produced 86,020 transcripts and a reference transcriptome with an N50 of 683 bp.

A total of 45,327 genes were annotated, representing 51.2% of the contig predicted from de novo assembly. As regards DEGs, a total of 9,140 genes were differentially expressed in response to ammonium in saline water; of these, 7,396 could be annotated against functional databases. The upregulated genes were mainly involved in cell wall biosynthesis, transmembrane transport and antiporter activities, including biological KEGG pathways linked to the biosynthesis of secondary metabolites, plant hormone signal transduction, autophagy, and nitrogen metabolism. In addiction, a set of 72 genes was directly involved in ammonium metabolism, including glutamine synthetase 1 (GLN1), glutamate synthase 1 (GLT1), and ferredoxin-dependent glutamate synthase chloroplastic (Fd-GOGAT). Finally, we observed that the ammonium uptake rate increased with increasing ammonium concentrations, and tended toward saturation in the range of 3 to 4 mM.

Conclusion

Our results support the hypothesis that an ammonium detoxification system mediated by glutamine and glutamate synthase was activated in S. neei when exposed to ammonium and saline water. The present transcriptome profiling method could be useful when investigating the response of halophyte plants to saline wastewater from land-based aquaculture.
Dynamic analysis and control of a rice-pest system under transcritical bifurcations
Authors: Mandal Sajib , Oberst Sebastian , Biswas Md. Haider Ali , Islam Md. Sirajul
Published: September 2021

Cultural methods were widely applied at an early stage of agricultural pest management but then replaced over time through pesticides with adverse effects on crop quality and the environment due to extensive and long-term use. In this study, we have reformulated a rice-pest-control model by first modelling a rice-pest system rigorously to then extend it to become an optimal control problem. We consider both, cultural methods and pesticides, and minimize thereby the density of agricultural pests, to increase the production of rice and to reduce gross annual losses. Pesticides have been applied only in an emergency scenario, which reduces environmental pollution and damage to nearby ecosystems. For the emergency case, we have developed a decision model to mitigate potential risks. The formulated models are verified by stability analysis at equilibrium points and investigated through transcritical bifurcations. Moreover, we have extensively confirmed our main results by numerical investigations and discussed the biological implications in more detail.
eQTLs are key players in the integration of genomic and transcriptomic data for phenotype prediction
Authors: Wade Abdou Rahmane , Duruflé Harold , Sanchez Leopoldo , Segura Vincent
Published: September 2021

Multi-omics represent a promising link between phenotypes and genome variation. Few studies yet address their integration to understand genetic architecture and improve predictability. Our study used 241 poplar genotypes, phenotyped in two common gardens, with their xylem and cambium RNA sequenced at one site, yielding large phenotypic, genomic and transcriptomic datasets. For each trait, prediction models were built with genotypic or transcriptomic data and compared to concatenation integrating both omics. The advantage of integration varied across traits and, to understand such differences, we made an eQTL analysis to characterize the interplay between the genome and the transcriptome and classify the predicting features into CIS or TRANS relationships. A strong and significant negative correlation was found between the change in predictability and the change in predictor importance for eQTLs (both TRANS and CIS effects) and CIS regulated transcripts, and mostly for traits showing beneficial integration and evaluated in the site of transcriptomic sampling. Consequently, beneficial integration happens when redundancy of predictors is decreased, leaving the stage to other less prominent but complementary predictors. An additional GO enrichment analysis appeared to corroborate such statistical output. To our knowledge, this is a novel finding delineating a promising way to explore data integration.

One-sentence summary

Successful multi-omics integration when predicting phenotypes makes redundant the predictors that are linked to ubiquitous connections between the omics, according to biological and statistical approaches