bluuebunny/crossref_metadata_2025 huggingface dataset:
Program Evaluation in Health Professions Education: An Innovative Approach Guided by Principles
Authors: Balmer Dorene F. , Anderson Hannah , West Daniel C.
Published: October 2022

Problem

Program evaluation approaches that center the achievement of specific, measurable, achievable, realistic, and time-bound goals are common in health professions education (HPE) but can be challenging to articulate when evaluating emergent programs. Principles-focused evaluation is an alternative approach to program evaluation that centers on adherence to guiding principles, not achievement of goals. The authors describe their innovative application of principles-focused evaluation to an emergent HPE program.

Approach

The authors applied principles-focused evaluation to the Children’s Hospital of Philadelphia Medical Education Collaboratory, a works-in-progress program for HPE scholarship. In September 2019, the authors drafted 3 guiding principles. In May 2021, they used feedback from Collaboratory attendees to revise the guiding principles: Advance Excellence, Build Bridges, and Cultivate Learning.

Outcomes

In July 2021, the authors queried participants about the extent to which their experience with the Collaboratory adhered to the revised guiding principles. Twenty of the 38 Collaboratory participants (53%) responded to the survey. Regarding the guiding principle Advance Excellence, 9 respondents (45%) reported that the Collaboratory facilitated engagement in scholarly conversation only by a small extent, and 8 (40%) reported it facilitated professional growth only by a small extent. Although some respondents expressed positive regard for the high degree of rigor promoted by the Collaboratory, others felt discouraged because this degree of rigor seemed unachievable. Regarding the guiding principle Build Bridges, 19 (95%) reported the Collaboratory welcomed perspectives within the group. Regarding the guiding principle Cultivate Learning, 19 (95%) indicated the Collaboratory welcomed perspectives within the group and across disciplines, and garnered collaboration.

Next Steps

Next steps include improving adherence to the principle of Advancing Excellence, fostering a shared mental model of the Collaboratory’s guiding principles, and applying a principles-focused approach to the evaluation of multi-site HPE programs.
Philanthropic Foundations' Discourse and Nursing's Future: Part II
Authors: Kneipp Shawn M. , Canales Mary K. , Drevdahl Denise J.
Published: October 2022

Critical social scholarship highlights the power philanthropic foundations wield on the collective agency of groups, yet analyses specific to nursing are absent in the literature. In this second of a 2-part series, we employed critical discourse analysis to examine how control of enunciative privilege in Robert Wood Johnson Foundation's (RWJF) 2010 and 2020-2030 Future of Nursing (FON) initiatives challenge nursing's ability to enact its collective agency, particularly through professional nursing organizations. Findings are discussed within the context of nursing's self-regulatory privileges, history, and agentic obligations that are bestowed on the discipline by the greater public for the public good.
LOC554202 contributes to chordoma progression by sponging miR-377-3p and up-regulating SMAD3
Authors: Xu Guang , Liu Jingnan , He Jun , He Haibo , Su Xiaotao , Gui Qianhuan
Published: October 2022

Chordoma is a rare malignant bone tumor originating from the remnants of the notochord. Here, the role of long noncoding LOC554202 in chordoma progression and its associated mechanism were explored. Cell proliferation was analyzed by 3-(4, 5-dimethylthiazol-2-yl)-2, 5 diphenyltetrazolium bromide and colony formation assays. Flow cytometry was conducted to analyze cell apoptosis rate. The migration and invasion of chordoma cells were analyzed by transwell migration and invasion assays and wound healing assays. A xenograft tumor model was established in nude mice to explore the role of LOC554202 in regulating tumor growth in vivo. The interaction between microRNA-377-3p (miR-377-3p) and LOC554202 or sekelsky mothers against d PP (SMAD) family member 3 (SMAD3) was verified by dual-luciferase reporter and RNA immunoprecipitation assays. The glycolytic rate of chordoma cells was analyzed using glucose assay kit, lactic acid kit and ApoSENSOR ADP/ATP ratio assay kit. LOC554202 expression was upregulated in chordoma tissues and cell lines. LOC554202 silencing suppressed the proliferation, migration and invasion and induced the apoptosis of chordoma cells. LOC554202 knockdown restrained xenograft tumor growth in vivo. miR-377-3p was confirmed as a target of LOC554202, and miR-377-3p silencing largely overturned LOC554202 knockdown-mediated anti-tumor effects in chordoma cells. miR-377-3p interacted with the 3′ untranslated region (3′UTR) of SMAD3 and miR-377-3p overexpression-mediated antitumor effects in chordoma cells were largely attenuated by SMAD3 overexpression. LOC554202 could positively regulate SMAD3 expression by sponging miR-377-3p in chordoma cells. LOC554202 contributed to the glycolysis of chordoma cells by targeting binding to miR-377-3p/SMAD3 axis. LOC554202 facilitated the proliferation, migration, invasion and glycolysis and inhibited the apoptosis of chordoma cells by mediating miR-377-3p/SMAD3 axis.
Remarkable response to gemcitabine rechallenge in advanced urothelial carcinoma: a case report
Authors: Merler Sara , Pafumi Sarah , Zampiva Ilaria , Zacchi Francesca , Manduca Stefano , Fantinel Emanuela , Zivi Andrea , Milella Michele
Published: October 2022

Therapeutic alternatives in advanced urothelial carcinoma are limited, especially in advanced lines, with only a few drugs having demonstrated relevant clinical benefit. This article discusses about a young patient with significant cardiovascular comorbidities, already treated with recommended first- and second-line drugs, and suffering from liver metastases. Despite the known poor prognosis of this disease and the few supporting data, given his peculiar clinical history, we opted to treat him with a third-line gemcitabine rechallenge with a notable response on his liver lesions. We present an intriguing case, both in terms of the therapeutic sequence and the disease course.
Pretreatment platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio as a predictor of pathological complete response to neoadjuvant chemotherapy in patients with breast cancer: single center experience from Turkey
Authors: Acikgoz Ozgur , Yildiz Anil , Bilici Ahmet , Olmez Omer Fatih , Basim Pelin , Cakir Asli
Published: October 2022

The aim of this study was to investigate the predictive value of PLR and NLR as an indicator of pathological complete response (pCR) in patients with breast cancer after NACT. One hundred thirty-nine patients with early or LABC and candidates to NACT were retrospectively analyzed. The prognostic significance of PLR and NLR was analyzed. In addition, predictive indicators of pCR to NACT were also evaluated. pCR was obtained in 48.9% of patients. Significant difference was detected between pCR and PLR, tumor grade, clinical lymph node status and molecular subgroup. The higher rate of pCR was significantly achieved for patients with PLRlow (<181.7) compared with those with PLRhigh (>181.7) (68.6% vs. 33.4%; P < 0.001). PLR, tumor grade and pCR to NACT for disease-free survival (DFS), and PLR, NLR, tumor grade and pCR to NACT for overall survival were detected to be prognostic factors by univariate analysis. On the other hand, a logistic regression analysis indicated that PLR and NLR were found to be an independent factors for predicting pCR to NACT (P < 0.001; OR, 0.07; 95% CI, 0.02–0.25 and P = 0.016; OR, 4.66; 95% CI, 1.33–16.2, respectively), as were molecular subtypes (P = 0.001; OR, 0.23; 95% CI, 0.09–0.56). Our results showed that PLRlow and NLRlow before NACT are readily feasible and simple and also inexpensive biomarkers predicting pCR to NACT for patients with LABC.
circUBAP2 inhibits cisplatin resistance in gastric cancer via miR-300/KAT6B axis
Authors: Cheng Weicai , Luan Pengbo , Jin Xiao
Published: October 2022

Circular RNAs play an important role in regulating cisplatin (CDDP) resistance in gastric cancer (GC). The aim of this study was to examine the role and downstream regulation mechanisms of circUBAP2 in CDDP resistance of GC. The expression of circUBAP2 in GC and its correlation with the prognosis of GC patients were analyzed using qRT-PCR and the Kaplan–Meier plotter database. The effects of circUBAP2 on cell viability and apoptosis were investigated by Cell Counting Kit 8 assay and flow cytometry. The expressions of drug-resistance-related proteins, P-gp and MRP1, were detected by Western blot. The interaction between circUBAP2 and miR-300 was confirmed using RNA pulldown and immunoprecipitation assays. The correlation between miR-300 and KAT6B was assessed using dual-luciferase reporter assay and TCGA database. CircUBAP2 was downregulated in GC tissues and cell lines, and correlated with the poor prognosis of GC. In addition, circUBAP2 enhanced apoptosis but inhibited cell viability and the CDDP resistance of GC cells in vitro. CircUBAP2 acted as a sponge of microRNA-300 (miR-300) and was negatively correlated with miR-300. Moreover, the upregulation of miR-300 partially removed the effects of circUBAP2 on cell viability, apoptosis and CDDP resistance in GC cells. MiR-300 directly targeted to lysine acetyltransferase 6B (KAT6B), and KAT6B overexpression showed an inhibitory effect on cell viability and CDDP resistance of GC cells. Our data suggested that the circUBAP2/miR-300/KAT6B axis was involved in the inhibition of CDDP resistance in GC, which might provide a novel focus for potential GC therapy.
Identification and validation of RB1 as an immune-related prognostic signature based on tumor mutation burdens in bladder cancer
Authors: Liu Ning , Wu Tiange , Ma Yuexian , Cheng Hong , Li Wenchao , Chen Ming
Published: October 2022

Bladder cancer (BCa) is one of the most common malignant tumors in the urinary system. Developing effective prognostic gene and exploring the immune cells that affect the prognosis of tumor are required. Full transcriptome data (n = 433), clinical information (n = 581) and mutation sequencing (n = 412) were obtained from The Cancer Genome Atlas and independent mutation sequencing data of 101 samples were acquired from International Cancer Genome Consortium. Statistical processing was conducted using R packages. Gene biologically functional research was performed with gene set enrichment analysis based on Kyoto Encyclopedia of Genes and Genomes database. Twenty-two types of immune cell infiltration were assessed and calculated in 398 samples of BCa. Furthermore, the expression of immune-related prognostic signature was verified. The relationship between prognostic gene and immune cells was explored preliminarily. Tumor mutation burdens of mutant-type groups were higher than wild-type groups of 19 genes, except for FGFR3 and CREBBP. Kaplan–Meier analysis showed that high frequency of retinoblastomal 1 (RB1) mutation led to poor prognosis of BCa patients and was an independent prognostic factor (P = 0.004; HR = 1.776). Proportions and correlation of 22 types of immune cells in 433 samples were determined. We found that RB1 expression decreased in BCa validated through quantitative PCR and immunohistochemistry. In addition, regulatory T cells (Tregs) were detected as a negatively correlated type of immune cell to mutation of RB1, whereas fluorescence costaining showed that Foxp3 expression of Tregs infiltration was negatively related to the expression of RB1. Mutation of RB1 can be identified as an independent prognostic predictor of BCa, and it may suppress the infiltration of Tregs in BCa tissues, increasing the incidence of tumor immune escape.
Pemetrexed long-term maintenance therapy for advanced severe lung cancer with long-term progression-free survival: a case report
Authors: Zhao Weichao , Zhu Minli , Wang Ruijuan , Tong Zhaohui
Published: October 2022

It is relatively rare to achieve a median progression-free survival (PFS) of 40 months with pemetrexed monotherapy maintenance, especially in patients with advanced and severe lung cancer. Here, we reported a case of advanced severe lung adenocarcinoma treated with pemetrexed monotherapy maintenance achieving long survival with a median PFS of 46 months. A 52-year-old female diagnosed with stage IV lung adenocarcinoma was tested for no targeted drug benefit in the driver gene. The patient was financially disadvantaged and could not afford and refused immune checkpoint inhibitor drugs but was in the favor of platinum-based double-drug chemotherapy. After six cycles of effective administration of cisplatin in combination with pemetrexed, pemetrexed monotherapy was given for long-term maintenance treatment to date, with a median PFS of 46 months, with a treatment effect close to complete response and tolerable side effects.
Palbociclib enhances the effect of doxorubicin-induced apoptosis in activated B-cell–like diffuse large B-cell lymphoma cells
Authors: Yi Liuying , Hu Linhui , Huang Keke , Li Qian , Wang Yangyang , Wang Jiyu , Zhai Zhimin
Published: October 2022

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma around the world. While R-CHOP has significantly improved patient outcomes, a subset of patients still has poor outcome. Here, the oncogenic roles of cyclin dependent kinase 4/6 (CDK4/6)-Cyclin D (CCND) signaling axis in DLBCL and its potential mechanism were investigated to explore the possibility of targeting CDK4/6-CCND signaling axis for DLBCL therapy. The transcription levels, functional enrichment analysis, mutation analysis, and prognostic values were performed via the Oncomine, GEPIA, UALCAN, cBioPortal, and Metascape and GenomicScape databases. Expression of CDK4/6-CCND signaling axis in DLBCL patients and DLBCL cell lines was evaluated by qRT-PCR. Additionally, the impact of CDK4/6-CCND signaling axis on cell viability and apoptosis in DLBCL cell lines were evaluated in vitro. The transcription levels of CDK4/6-CCND signaling were increased in DLBCL patients. Meanwhile, in Gene Expression Omnibus dataset, the expression of CDK4 and CCND2 was higher in ABC-DLBCL, whereas the expression of CCND1 and CCND3 was higher in GCB-DLBCL. Moreover, according to the results of qRT-PCR, the expression of CDK4/6-CCND signaling axis in ABC-DLBCL cell line is higher than that in GCB-DLBCL cell lines. Prognostic analysis indicated that upregulation of CDK4, CCND2, and CCND3 was significantly associated with poor survival. Cell function experiments showed that palbociclib could enhance the apoptosis-promoting and cell viability-inhibiting effects of doxorubicin on ABC-DLBCL (SU-DHL-2) cells. Doxorubicin accumulation experiment showed that palbociclib promoted doxorubicin accumulation in ABC-DLBCL cells. Additionally, Western blot analysis demonstrated that palbociclib prevented antiapoptotic protein BCL2 expression in ABC-DLBCL cell line. Our study provides novel insights into targeted therapies for ABC-DLBCL patients.
Local Recurrence Rates of Extramammary Paget Disease Are Lower After Mohs Micrographic Surgery Compared With Wide Local Excision: A Systematic Review and Meta-Analysis
Authors: Kim Grace Y. , Campbell Elliott H. , Brewer Jerry D.
Published: October 2022

BACKGROUND

Extramammary Paget disease (EMPD) is a rare, slow growing neoplasm that presents most commonly in the anogenital region of older adults.

OBJECTIVE

To analyze the difference in local recurrence rates of EMPD in patients treated with wide local excision (WLE) versus Mohs micrographic surgery (MMS).

MATERIALS AND METHODS

A systematic review of the literature and meta-analysis were performed. Inclusion criteria were adults greater than 18 years of age with a diagnosis of EMPD who have undergone surgical intervention and had follow-up data. Studies were independently reviewed by 2 coinvestigators with discrepancies resolved by the principal investigator.

RESULTS

Twenty-seven studies met the inclusion criteria. Patients had a 2.67 times higher chance of local recurrence after WLE than MMS (95% confidence interval [CI]:1.47, 4.85; p = .001). Meta-analysis of single-arm studies revealed a 7.3% local recurrence rate after MMS (95% CI: 0.039, 0.107; p < .001) versus a 26.3% recurrence rate after WLE (95% CI: 0.149, 0.376; p < .001). After excluding recurrent tumors, the odds ratio for recurrence in WLE versus MMS was 2.3 (95% CI: 0.285, 18.43, p = .435).

CONCLUSION

There is a clinically and statistically increased risk of local recurrence of EMPD after WLE compared with MMS.
Nonpalmar Endoscopic versus Open Trigger Finger Release: Results from a Prospective Trial
Authors: Brown Ashley M. , Tanabe Kylie L. , DellaMaggiora Ryan J. , Tsai Eugene Y. , Kuschner Stuart H. , Kulber David A.
Published: October 2022

Background:

The most common complaint after open surgical release for trigger finger is of pain and scarring at the surgical site. We hypothesized that use of a new nonpalmar endoscopic approach for release of the A1 pulley through an incision at the proximal digital crease would result in decreased scarring and faster recovery compared to those treated with standard open release.

Methods:

Patients with trigger finger were prospectively enrolled and treated with a nonpalmar endoscopic versus open surgical technique. Outcome measures included scar assessment based on the Patient and Observer Scar Assessment Scale (POSAS) administered 1 week, 1 month, and 6 months postoperatively, time before return to work, occupational therapy visits, and overall satisfaction. Additional outcomes included pain medication use, operative time, and complication and recurrence rates.

Results:

POSAS scores were better in the endoscopic treatment group than in the open group at all time points with a statistically significant difference seen at 1 week and 1 month postoperatively. The endoscopic group returned to work sooner, required fewer occupational therapy visits, and had better overall satisfaction compared to the open group, but the differences were not statistically significant. Complication and recurrence rates did not differ significantly between groups.

Conclusions:

Patients treated for trigger finger with a nonpalmar endoscopic release through an incision at the proximal digital crease demonstrate significantly better scarring in the early postoperative period compared to patients treated with the open surgical approach. Treatment for trigger finger with this technique is as effective as the standard open technique.
Reproducibility of sequential ambulatory blood pressure and pulse wave velocity measurements in normotensive and hypertensive individuals
Authors: Keehn Louise , Hall Wendy L. , Berry Sarah E. , Sanders Thomas A.B. , Chowienczyk Phil , Floyd Christopher N.
Published: October 2022

Objective:

Errors in blood pressure (BP) measurement account for a large proportion of misclassified hypertension diagnoses. Ambulatory blood pressure monitoring (ABPM) is often considered to be the gold standard for measurement of BP, but uncertainty remains regarding the degree of measurement error. The aim of this study was to determine reproducibility of sequential ABPM in a population of normotensive and well controlled hypertensive individuals.

Methods:

Individual participant data from three randomized controlled trials, which had recorded ABPM and carotid-femoral pulse wave velocity (PWV) at least twice were combined (n = 501). We calculated within-individual variability of daytime and night-time BP and compared the variability between normotensive (n = 324) and hypertensive (n = 177) individuals. As a secondary analysis, variability of PWV measurements was also calculated, and multivariable linear regression was used to assess characteristics associated with blood pressure variability (BPV).

Results:

Within-individual coefficient of variation (CoV) for systolic BP was 5.4% (day) and 7.0% (night). Equivalent values for diastolic BP were 6.1% and 8.4%, respectively. No statistically significant difference in CoV was demonstrated between measurements for normotensive and hypertensive individuals. Within-individual CoV for PWV exceeded that of BP measurements (10.7%). BPV was associated with mean pressures, and BMI for night-time measurements. PWV was not independently associated with BPV.

Conclusion:

The variability of single ABPM measurements will still yield considerable uncertainty regarding true average pressures, potentially resulting in misclassification of hypertensive status and incorrect treatment regimes. Repeated ABPM may be necessary to refine antihypertensive therapy.
Development of epilepsy after recovery from posterior reversible encephalopathy syndrome in children with renal disease
Authors: Takahashi Masaki , Kamei Koichi , Hayakawa Itaru , Abe Yuichi , Sato Mai , Ogura Masao , Ishikura Kenji , Ito Shuichi
Published: October 2022

Rationale:

Posterior reversible encephalopathy syndrome (PRES) generally shows complete recovery of clinical and imaging findings within several weeks, although a few cases show neurological sequelae, such as developmental delay and epilepsy after recovery from PRES.

Patient concerns:

We report 4 pediatric patients with renal diseases (nephrotic syndrome in 3 and renovascular hypertension in 1) who developed epilepsy after recovery from PRES. None of the patients had epilepsy before PRES. Case 1 developed focal-onset bilateral tonic-clonic seizures at 32 months after PRES. Case 2 developed focal impaired-awareness seizures with nausea and deviation of the eyes to the left at 62 months after PRES. Case 3 developed focal impaired-awareness seizures with vomiting at 85 months after PRES. Case 4 developed focal impaired-awareness seizures at 2 months after PRES. Three patients developed epilepsy more than 2 years later in the remote stage.

Diagnosis:

All cases developed recurrent seizures and electroencephalograms of 3 cases except case 3 were abnormal.

Intervention:

Three patients required anticonvulsants and 1 did not require any medication.

Outcomes:

Case 1 was treated with multiple anticonvulsants and became seizure free 2 years later. He was free from anticonvulsants finally at the age of 11 years and developed intellectual disability with severe behavioral problems. Case 2 was seizure free with levetiracetam treatment for more than 2 years. Case 3 maintained seizure freedom with carbamazepine treatment for more than a year. Case 4 had no seizures for more than 2 years without taking any medication. There was no complication in the follow-up period in these 3 cases.

Lessons:

Although the prognosis of PRES is relatively favorable, neurological sequelae may develop in few cases. Some patients may develop epilepsy in the remote stage even if they show no neurological sequelae. It is necessary for children who develop PRES to receive long-term observation, regardless of their neurological symptoms.
Fracture of the epidural catheter tip during epidural anesthesia
Authors: Abu-jajeh Ra’ed K. , Abu Seif Badie M. , Abu Serhan Hashem , Farooq Nudrat , Abdul Fatir Chaudhary , Tahir Muhammad Junaid , Abbasher Hussien Mohamed Ahmed Khabab , Al-Tarawneh Shatha Atef , Yousaf Zohaib
Published: October 2022

Introduction:

Epidural anesthesia is a neuraxial technique that is widely used for surgical, obstetric, and chronic pain management. It involves injecting an anesthetic material into the epidural space through the intervertebral space using an epidural needle. Epidural anesthesia may result in complications including epidural hematoma, epidural abscess, and shearing of the epidural catheter. Breakage of the tip of the epidural catheter is a rare complication.

Patient concerns:

A 27-year-old primigravid woman, previously well, was admitted for normal vaginal delivery, for which she received epidural analgesia. After delivery, the epidural catheter was removed and the tip was missing.

Diagnoses:

A neurosurgical consultation requested magnetic resonance imaging of the lumbar spine with intravenous contrast. Magnetic resonance imaging failed to reveal any missing part.

Interventions:

A multidisciplinary team deferred surgical removal of the tip and followed-up with the patient.

Outcomes:

Weekly follow-up of 3 months showed no symptoms or neurological sequelae.

Conclusions:

Breakage of the epidural catheter tip is an infrequent complication of epidural anesthesia. An expert physician should insert or remove the epidural catheters. The decision between conservative and surgical management should be case-based, with open discussion with the patient.
Florid cemento-osseous dysplasia associated with multiple impacted teeth in a Japanese female
Authors: Ishikawa Jun , Suzuki Shusuke , Uchiyama Yumiko , Toyama Naoto , Nambu Kazuya , Sugimoto Keisuke , Fujimoto Takehiro
Published: October 2022

Rationale:

Florid cemento-osseous dysplasia (FCOD) is a rare, benign, multifocal fibro-osseous dysplastic process affecting the tooth-bearing areas of the jaw. Although FCOD is often symmetrically located in various regions of the jaw, cases associated with impacted teeth are very rare. FCOD most commonly affects females in the fourth and fifth decades of life, and is seen less frequently in Asian populations.

Patient concerns:

A 39-year-old Japanese female was referred to our department with dull pain in region 28. Intraoral examination revealed that all third molars were completely impacted. Imaging findings revealed multiple periapical sclerotic areas surrounded by radiolucent zones in regions 28, 38, and 48.

Diagnosis:

Histological appearance was compatible with a diagnosis of FCOD.

Interventions:

Under general anesthesia, we performed the extraction of the lesions with the impacted third molars. The lesions were gritty and reddish brown, continuous to the roots of 28, 38, and 48.

Outcomes:

The patient had no complications during the 2-year follow-up period.

Lessons:

Although FCOD has sex and racial ubiquity, it may occur in the opposite sex and other races. Appropriate treatment should be selected depending on the presence or absence of symptoms.
Global perspectives on cellular therapy for children with sickle cell disease
Authors: John Tami D. , Namazzi Ruth , Chirande Lulu , Tubman Venée N.
Published: October 2022

Purpose of review

Low-income and middle-income countries (LMICs), primarily in sub-Saharan Africa (SSA), predominantly experience the burden of sickle cell disease (SCD). High frequency of acute and chronic complications leads to increased utilization of healthcare, which burdens fragile health systems. Mortality for children with limited healthcare access remains alarmingly high. Cellular based therapies such as allogeneic hematopoietic stem cell transplant (HSCT) are increasingly used in resource-rich settings as curative therapy for SCD. Broad access to curative therapies for SCD in SSA would dramatically alter the global impact of the disease.

Recent findings

Currently, application of cellular based therapies in LMICs is limited by cost, personnel, and availability of HSCT-specific technologies and supportive care. Despite the challenges, HSCT for SCD is moving forward in LMICs. Highly anticipated gene modification therapies have recently proven well tolerated and feasible in clinical trials in resource-rich countries, but access remains extremely limited.

Translation of curative cellular based therapies for SCD should be prioritized to LMICs where the disease burden and cost of noncurative treatments is high, and long-term quality of life is poor. Focus on thoughtful modifications of current and future therapies to meet the need in LMICs, especially in SSA, will be especially impactful.
Comprehensive Molecular Profiling of Sinonasal Teratocarcinosarcoma Highlights Recurrent SMARCA4 Inactivation and CTNNB1 Mutations
Authors: Rooper Lisa M. , Agaimy Abbas , Gagan Jeffrey , Simpson Roderick H.W. , Thompson Lester D.R. , Trzcinska Anna M. , Ud Din Nasir , Bishop Justin A.
Published: October 2022

Sinonasal teratocarcinosarcoma (TCS) is a rare tumor defined by intermixed neuroepithelial, mesenchymal, and epithelial elements. While its etiology was historically ambiguous, we recently reported frequent SMARCA4 loss by immunohistochemistry, suggesting that TCS might be related to SMARCA4-deficient sinonasal carcinomas. However, other molecular alterations including CTNNB1 mutation have been reported in TCS, and its full genetic underpinnings are unclear. Here, we performed the first comprehensive molecular analysis of sinonasal TCS to better understand its pathogenesis and classification. We collected 30 TCS including 22 cases from our initial study. Immunohistochemical loss of SMARCA4 was seen in 22 cases (73%), with total loss in 18 cases (60%). β-catenin showed nuclear localization in 14 cases (64%) of the subset tested. We selected 17 TCS for next-generation sequencing with enrichment for partial or intact SMARCA4 immunoexpression. We identified inactivating SMARCA4 mutations in 11 cases (65%) and activating CTNNB1 mutations in 6 cases (35%), including 5 cases with both. Of 5 cases that lacked SMARCA4 or CTNNB1 mutation, 2 harbored other SWI/SNF complex and Wnt pathway alterations, including 1 with SMARCB1 inactivation and 1 with concomitant APC and ARID1A mutations, and 3 had other findings, including DICER1 hotspot mutation. These findings confirm that SMARCA4 inactivation is the dominant genetic event in sinonasal TCS with frequent simultaneous CTNNB1 mutations. They further underscore a possible relationship between TCS and sinonasal carcinomas with neuroendocrine/neuroectodermal differentiation. However, while SMARCA4 and β-catenin immunohistochemistry may help confirm a challenging diagnosis, TCS should not be regarded as a molecularly defined entity.
“Long-term aesthetic and functional evaluation of intramuscular augmentation gluteoplasty with implants.”
Authors: de Andrade Gustavo M , Aboudib José H , Serra Fernando
Published: October 2022

Introduction:

The insertion of gluteal silicone implants by intramuscular technique leads patients to develop gluteus maximus muscle atrophy. The objective of the present study was to correlate the muscular atrophy of the gluteus maximus proportional to the volume of the silicone implants used. The secondary objectives were to assess volumetry of the gluteus maximus muscle in the late follow-up, positioning of the implants and to verify association between volumetric muscle recovery and practice of physical exercise.

Methods:

This is a prospective study. The sample was composed of 22 patients who were operated and followed up on an outpatient basis and through gluteus computed tomography in 3 different moments: pre-operative, 12-month post-operative and late post-operative (≥ 96 months).

Results:

Computed Tomography 3D reconstruction and volumetric analysis showed a median atrophy of 6.68% of the gluteus maximus muscle volume in 12 months and 7.47% in the late post-operative period. The correlation between relative volume of the implant and atrophy percentage of the gluteus maximus didn’t present statistically significant results. There was an association between the practice of physical exercise and volumetry recovery of the gluteus maximus. No patient presented gluteal implant rotation.

Conclusion:

There isn’t correlation between proportional volume of implants and atrophy percentage of gluteus maximus muscle, when using implants up to 400cm3. The gluteus maximus muscle presents atrophy in the late follow-up of augmentation gluteoplasty with implants surgery. There is recovery of muscle volumetry on the patients that practice physical activities. Intramuscular plane implants demonstrated stability in their long-term positioning.
Adipose-derived stem cells attenuate skin fibrosis and improve fat retention of localized scleroderma mouse model
Authors: Wang Hayson Chenyu , Sun Elliot Tianyu , Zhao Robert Chunhua , Chen Bo , Han Qin , Li Na , Long Xiao , Wang Xiaojun
Published: October 2022

Background:

Though autologous fat grafting is a feasible surgical technique to improve facial deformity in patients with localized scleroderma, its success is limited by the low graft retention induced by the local inflammatory environment.

Objective:

To investigate the potential effect of adipose-derived stem cells (ASCs) on skin fibrosis and fat retention in localized scleroderma mouse model.

Methods:

BALB/C nude mice which were induced by bleomycin to establish localized scleroderma model were randomly divided into five groups: blank control, fat grafting, low, moderate, and high dose of ASCs-assisted fat grafting. The mice's backs were subcutaneously injected with phosphate-buffered saline, or fat, or fat with low, moderate and high doses of ASCs (1×105/ml, 5 ×105/ml and 25×105/ml), respectively. The skin fibrosis and fat retention were analyzed after one month or three months, respectively.

Results:

Compared to disease model group, fat grafting group, as well as low, and moderate doses of ASCs-enriched groups, high-dose ASCs significantly attenuated skin fibrosis, inhibited the production of type III collagen and TGF-β1, increased fat graft retention, enhanced the expression of angiogenesis-related cytokines and angiogenesis, and increased the expression of adipogenesis-related cytokines.

Conclusions:

The results demonstrated that high-dose ASCs attenuated skin fibrosis and improved fat retention in localized scleroderma model by reducing inflammation as well as promoting angiogenesis and adipogenesis. We further demonstrated that ASCs enhanced adipogenesis through AKT/ERK signaling pathway.
Gut microbiota and plasma metabolites associated with bone mineral density in women with or at risk of HIV infection
Authors: Mei Zhendong , Yin Michael T. , Sharma Anjali , Wang Zheng , Peters Brandilyn A. , Chandran Aruna , Weber Kathleen M. , Ross Ryan D. , Gustafson Deborah , Zheng Yan , Kaplan Robert C. , Burk Robert D. , Qi Qibin
Published: October 2022

Objective:

To evaluate gut microbiota (GMB) alterations and metabolite profile perturbations associated with bone mineral density (BMD) in the context of HIV infection.

Design:

Cross-sectional studies of 58 women with chronic HIV infection receiving antiretroviral therapy and 33 women without HIV infection.

Methods:

We examined associations of GMB and metabolites with BMD among 91 women. BMD was measured by dual-energy X-ray absorptiometry (DXA), and T-scores of lumbar spine or total hip less than −1 defined low BMD. GMB was measured by 16S rRNA V4 region sequencing on fecal samples, and plasma metabolites were measured by liquid chromatography–tandem mass spectrometry. Associations of GMB with plasma metabolites were assessed in a larger sample (418 women; 280 HIV+ and 138 HIV−).

Results:

Relative abundances of five predominant bacterial genera (Dorea, Megasphaera, unclassified Lachnospiraceae, Ruminococcus, and Mitsuokella) were higher in women with low BMD compared with those with normal BMD (all linear discriminant analysis (LDA) scores >2.0). A distinct plasma metabolite profile was identified in women with low BMD, featuring lower levels of several metabolites belonging to amino acids, carnitines, caffeine, fatty acids, pyridines, and retinoids, compared with those with normal BMD. BMD-associated bacterial genera, especially Megasphaera, were inversely associated with several BMD-related metabolites (e.g. 4-pyridoxic acid, C4 carnitine, creatinine, and dimethylglycine). The inverse association of Megasphaera with dimethylglycine was more pronounced in women with HIV infection compared with those without HIV infection (P for interaction = 0.016).

Conclusion:

Among women with and at risk of HIV infection, we identified altered GMB and plasma metabolite profiles associated with low BMD.
Pediatric Traumatic Hemorrhagic Shock Consensus Conference Research Priorities
Authors: Russell Robert T. , Bembea Melania M. , Borgman Matthew A. , Burd Randall S. , Gaines Barbara A. , Jafri Mubeen , Josephson Cassandra D. , Leeper Christine M. , Leonard Julie C. , Muszynski Jennifer A. , Nicol Kathleen K. , Nishijima Daniel K. , Stricker Paul A. , Vogel Adam M. , Wong Trisha E. , Spinella Philip C.
Published: October 2022

Background

Traumatic injury is the leading cause of death in children and adolescents. Hemorrhagic shock remains a common and preventable cause of death in the pediatric trauma patients. A paucity of high-quality evidence is available to guide specific aspects of hemorrhage control in this population. We sought to identify high priority research topics for the care of pediatric trauma patients in hemorrhagic shock.

Methods

A panel of 16 consensus multidisciplinary committee members from the Pediatric Traumatic Hemorrhagic Shock Consensus Conference developed research priorities for addressing knowledge gaps in the care of injured children and adolescents in hemorrhagic shock. These ideas were informed by a systematic review of topics in this area and a discussion of these areas in the consensus conference. Research priorities were synthesized along themes and prioritized by anonymous voting.

Results

Eleven research priorities were identified by the consensus committee that warrant additional investigation. Areas of proposed study included well-designed clinical trials and evaluations, including increasing the speed and accuracy of identifying and treating hemorrhagic shock, defining the role of whole blood and tranexamic acid use, and assessment of the utility and appropriate use of viscoelastic techniques during early resuscitation. The committee recommended the need to standardize essential definitions, data elements, and data collection to facilitate research in this area.

Conclusions

Research gaps remain in many areas related to the care of hemorrhagic shock after pediatric injury. Addressing these gaps is needed to develop improved evidence-based recommendations for the care of pediatric trauma patients in hemorrhagic shock.

Level of Evidence

N/A
Development of a novel Macaque-Tropic HIV-1 adapted to cynomolgus macaques
Authors: Ode Hirotaka , Saito Akatsuki , Washizaki Ayaka , Seki Yohei , Yoshida Takeshi , Harada Shigeyoshi , Ishii Hiroshi , Shioda Tatsuo , Yasutomi Yasuhiro , Matano Tetsuro , Miura Tomoyuki , Akari Hirofumi , Iwatani Yasumasa
Published: October 2022

Macaque-tropic HIV-1 (HIV-1mt) variants have been developed to establish preferable primate models that are advantageous in understanding HIV-1 infection pathogenesis and in assessing the preclinical efficacy of novel prevention/treatment strategies. We previously reported that a CXCR4-tropic HIV-1mt, MN4Rh-3, efficiently replicates in peripheral blood mononuclear cells (PBMCs) of cynomolgus macaques homozygous for TRIMCyp (CMsTC). However, the CMsTC challenged with MN4Rh-3 displayed low viral loads during the acute infection phase and subsequently exhibited short-term viremia. These virological phenotypes in vivo differed from those observed in most HIV-1-infected people. Therefore, further development of the HIV-1mt variant was needed. In this study, we first reconstructed the MN4Rh-3 clone to produce a CCR5-tropic HIV-1mt, AS38. In addition, serial in vivo passages allowed us to produce a highly adapted AS38-derived virus that exhibits high viral loads (up to approximately 106 copies ml−1) during the acute infection phase and prolonged periods of persistent viremia (lasting approximately 16 weeks postinfection) upon infection of CMsTC. Whole-genome sequencing of the viral genomes demonstrated that the emergence of a unique 15-nt deletion within the vif gene was associated with in vivo adaptation. The deletion resulted in a significant increase in Vpr protein expression but did not affect Vif-mediated antagonism of antiretroviral APOBEC3s, suggesting that Vpr is important for HIV-1mt adaptation to CMsTC. In summary, we developed a novel CCR5-tropic HIV-1mt that can induce high peak viral loads and long-term viremia and exhibits increased Vpr expression in CMsTC.
Early Growth Assessment of Treculia africana Seedlings Influenced by Different Light Intensities and Mycorrhizal Inoculation
Authors: Ayomide Oyefara , Yisau Juliet
Published: October 2022

Light is essential for plant growth. The rate at which a plant grows depends on the light it receives. This study was carried out to observe the growth of Treculia africana seedlings under different light intensities (100%, 75%, 50%, and 25%) and mycorrhiza inoculation (Ectomycorrhiza, Endomycorrhiza, and topsoil {control}) with five replicates in each treatment. The experiment was laid out in a 3×4 factorial in CRD, and data were collected fortnightly for twelve (12) weeks. Data were subjected to analysis of variance in SAS, and the significant mean was separated using Fisher’s LSD. The result showed that the seedlings inoculated with ectomycorrhizal had the highest plant height (15.08), leaf area (26.90), number of leaves (5.75), collar diameter (2.61), fresh shoot weight (3.86), root weight (3.86), fresh weight (7.44), dry root weight (1.53), dry weight (2.87), absolute growth rate (0.34) and relative growth rate (0.39) which was significantly different from other treatment. Seedlings exposed to 75% and 25% light intensity had the highest performances compared to seedlings exposed to different light intensities. There was no significant difference (P>0.05) in the seedlings’ physiological variables assessed under the interaction of different light intensities and mycorrhiza inoculation. The seedlings inoculated with ectomycorrhizal and raised in 25% light intensity had the overall highest performance in all the growth variables assessed. Therefore, this study recommends raising Treculia africana seedlings with the inoculation of ectomycorrhizal and under shade to enhance early growth and massive nursery production.
Octopamine metabolically reprograms astrocytes to confer neuroprotection against α-synuclein
Authors: Shum Andrew , Zaichick Sofia , McElroy Gregory S. , D’Alessandro Karis , Novakovic Michaela , Peng Wesley , Chung Daayun , Flanagan Margaret E. , Smith Roger , Morales Alejandro , Stumpf Laetitia , McGrath Kaitlyn , Krainc Dimitri , Mendillo Marc L. , Prakriya Murali , Chandel Navdeep S. , Caraveo Gabriela
Published: October 2022

Octopamine is a well-established invertebrate neurotransmitter involved in fight-or-flight responses. In mammals, its function was replaced by norepinephrine. Nevertheless, it is present at trace amounts and can modulate the release of monoamine neurotransmitters by a yet unidentified mechanism. Here, through a multidisciplinary approach utilizingin vitroandin vivomodels of α-synucleinopathy, we uncovered an unprecedented role for octopamine in driving the conversion from toxic to neuroprotective astrocytes in the cerebral cortex by fostering aerobic glycolysis. Physiological levels of neuron-derived octopamine act on astrocytes via a TAAR1-Orai1-Ca2+-calcineurin-mediated signaling pathway to stimulate lactate secretion. Lactate uptake in neurons via the MCT2-calcineurin-dependent pathway increases ATP and prevents neurodegeneration. Pathological increases of octopamine caused by α-synuclein halts lactate production in astrocytes and short-circuits the metabolic communication to neurons. Our work provides a novel function of octopamine as a modulator of astrocyte metabolism and subsequent neuroprotection with implications to α-synucleinopathies.
SBT-272 improves TDP-43 pathology in the ALS motor cortex by modulating mitochondrial integrity, motility, and function
Authors: Gautam Mukesh , Genç Barış , Helmold Benjamin , Ahrens Angela , Kuka Janis , Makrecka-Kuka Marina , Günay Aksu , Koçak Nuran , Aguilar-Wickings Izaak R. , Keefe Dennis , Zheng Guozhu , Swaminathan Suchitra , Redmon Martin , Zariwala Hatim A. , Özdinler P. Hande
Published: October 2022

Mitochondrial defects are one of the common underlying causes of neuronal vulnerability in motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), and TDP-43 pathology is the most common proteinopathy in ALS. Disrupted inner mitochondrial membrane (IMM) reported in the upper motor neurons (UMNs) of ALS patients with TDP-43 pathology is recapitulated in the UMNs of well-characterized mutant hTDP-43 mouse models of ALS. The construct validity, such as common cellular pathology in mice and human, offers a unique opportunity to test treatment strategies that may translate. SBT-272 is a well-tolerated brain-penetrant small molecule that stabilizes cardiolipin, a phospholipid found in IMM, thereby restoring mitochondrial structure and respiratory function. We investigated whether SBT-272 can improve IMM structure and health in UMNs diseased with TDP-43 pathology in our well-characterized UMN reporter line for ALS. We found that SBT-272 significantly improved mitochondrial structural integrity and restored mitochondrial motility and function. This led to improved health of diseased UMNsin vitro.In comparison to edaravone and AMX0035, SBT-272 appeared more effective in restoring health of diseased UMNs. Chronic treatment of SBT-272 for sixty days starting at an early symptomatic stage of the diseasein vivoled to a reduction in astrogliosis, microgliosis, and retention of UMN degeneration in the ALS motor cortex. Our results underscore the therapeutic potential of SBT-272, especially within the context of TDP-43 pathology and mitochondrial dysfunction.

Highlights

Early and progressive upper motor neuron (UMN) degeneration defines ALS pathology

Mitochondrial defects are prominent and common in UMNs with TDP-43 pathology

SBT-272 treatment improves mitochondrial stability, mobility and function

SBT-272 treatment reduces astrogliosis, microgliosis and improves UMN health
Cortical-wide impairment of “The Glymphatic system” after focal brain injury
Authors: Azuma M. , Lee H. , Shinzaki K. , Yamane R. , Morita M.
Published: October 2022

In peripheral tissues, cells are maintained in the interstitial fluid that flows from capillaries to lymph system. However, the brain has no lymphatic capillaries, and the actual state of the interstitial fluid has long been unknown. Recently, a glymphatic system has been proposed in which part of the cerebrospinal fluid flowing on the surface of brain tissue enters the brain parenchyma via the peri-arterial space, becomes interstitial fluid, and then flows out again from the peri-venous space. Brain injury due to head contusion or stroke is thought to impair the intracerebral circulation and aggravate the extracellular environment, but the actual situation is unknown. Therefore, in this study, we examined the effects of focal brain tissue damage on intracerebral circulation using the light-injured mouse, an originally developed closed head injury model. In light-injured mice, the injury-making process does not affect intracerebral circulation because the cranium is maintained. However, this method has quantitative problems, so we developed a method to image cerebrospinal fluid and blood vessels from the surface of the cerebral cortex. After examining different injury sites and different time periods after injury, it was found that intracerebral circulation was reduced to the same extent on the ipsilateral and contralateral sides of the injury at one-week post-injury. This intracerebral circulatory deficit was still partially present at four-weeks post-injury. These results indicate that the intracerebral circulation is extensively impaired by local injury and neurodegenerative diseases.