bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preclinical and clinical evaluation of German-sourced ONC201 for the treatment of H3K27M-mutant diffuse intrinsic pontine glioma
Authors: Duchatel Ryan J , Mannan Abdul , Woldu Ameha S , Hawtrey Tom , Hindley Phoebe A , Douglas Alicia M , Jackson Evangeline R , Findlay Izac J , Germon Zacary P , Staudt Dilana , Kearney Padraic S , Smith Nathan D , Hindley Kate E , Cain Jason E , André Nicolas , La Madrid Andres Morales , Nixon Brett , De Iuliis Geoffry N , Nazarian Javad , Irish Kathleen , Alvaro Frank , Eisenstat David D , Beck Alexander , Vitanza Nicholas A , Mueller Sabine , Morris Jonathan C , Dun Matthew D 
Published: December 2021

Abstract

Background
Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood brainstem tumor for which radiation is the only treatment. Case studies report a clinical response to ONC201 for patients with H3K27M-mutant gliomas. Oncoceutics (ONC201) is only available in the United States and Japan; however, in Germany, DIPG patients can be prescribed and dispensed a locally produced compound—ONC201 German-sourced ONC201 (GsONC201). Pediatric oncologists face the dilemma of supporting the administration of GsONC201 as conjecture surrounds its authenticity. Therefore, we compared GsONC201 to original ONC201 manufactured by Oncoceutics Inc.

Methods
Authenticity of GsONC201 was determined by high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy. Biological activity was shown via assessment of on-target effects, in vitro growth, proliferation, and apoptosis analysis. Patient-derived xenograft mouse models were used to assess plasma and brain tissue pharmacokinetics, pharmacodynamics, and overall survival (OS). The clinical experience of 28 H3K27M+ mutant DIPG patients who received GsONC201 (2017–2020) was analyzed.

Results
GsONC201 harbored the authentic structure, however, was formulated as a free base rather than the dihydrochloride salt used in clinical trials. GsONC201 in vitro and in vivo efficacy and drug bioavailability studies showed no difference compared to Oncoceutics ONC201. Patients treated with GsONC201 (n = 28) showed a median OS of 18 months (P = .0007). GsONC201 patients who underwent reirradiation showed a median OS of 22 months compared to 12 months for GsONC201 patients who did not (P = .012).

Conclusions
This study confirms the biological activity of GsONC201 and documents the OS of patients who received the drug; however, GsONC201 was never used as a monotherapy.
Pharmacokinetic Evaluation of Cefazolin in the Cerebrospinal Fluid of Critically Ill Patients
Authors: Novak Alison R , Krsak Martin , Kiser Tyree H , Neumann Robert T , Cava Prado Luis , Molina Kyle C , Mueller Scott W 
Published: December 2021

Abstract

Background
The relative distribution of cefazolin into the cerebrospinal fluid (CSF) remains debated. Determining the distribution of cefazolin into the CSF in noninfected adults may allow for further treatment applications of cefazolin. This prospective pharmacokinetic study aimed to determine the pharmacokinetic parameters of cefazolin in serum and CSF from external ventricular drains (EVDs) in neurologically injured adults.

Methods
Blood and CSF were collected, using a biologic waste protocol, for cefazolin quantification and trapezoidal rule–based pharmacokinetic analysis in a total of 15 critically ill adults receiving 2000 mg intravenously every 8 hours or the renal dose equivalent for EVD prophylaxis.

Results
A median (range) of 3 (2–4) blood and 3 (2–5) CSF samples were collected for each patient. The most common admitting diagnosis was subarachnoid hemorrhage (66.7%). The median calculated cefazolin CSF Cmax and Cmin values (interquartile range [IQR]) were 2.97 (1.76–8.56) mg/L and 1.59 (0.77–2.17) mg/L, respectively. The median (IQR) CSF to serum area under the curve ratio was 6.7% (3.7%–10.6%), with time-matched estimates providing a similar estimate (8.4%). Of those receiving cefazolin every 8 hours, the median and minimum directly measured CSF cefazolin concentration ≥4 hours following administration were 1.87 and 0.78 mg/L, respectively.

Conclusions
Cefazolin dosed for EVD prophylaxis achieved CSF concentrations suggesting viability as a therapeutic option for patients with meningitis or ventriculitis due to susceptible bacteria such as methicillin-susceptible Staphylococcus aureus. Further clinical trials are required to confirm a role in therapy for cefazolin. Population-based pharmacokinetic–pharmacodynamic modeling may suggest an optimal cefazolin regimen for the treatment of central nervous system infections.
Moderate to Intense Physical Activity Is Associated With Improved Clinical, CD4/CD8 Ratio, and Immune Activation Status in HIV-Infected Patients on ART
Authors: Bernal Enrique , Martinez Monica , Campillo José Antonio , Puche Gabriel , Baguena Carlos , Tomás Cristina , Jimeno Amaya , Alcaraz Maria Jose , Alcaraz Antonia , Muñoz Angeles , Oliver Eva , de la Torre Alejandro , Marín Irene , Cano Alfredo , Minguela Alfredo 
Published: December 2021

Abstract

Background
Physical activity has anti-inflammatory effects and reduces morbidity and mortality in the general population, but its role in the clinical, CD4/CD8 ratio, and immune activation status of HIV-infected patients has been poorly studied.

Methods
A cross-sectional study was carried out in a cohort of 155 HIV-infected patients on stable antiretroviral therapy (ART) to compare clinical, biochemical, CD4/CD8 ratio, and immune activation status according to their physical activity in the last 2 years (sedentary/low vs moderate/intense) assessed by the iPAQ. A binary logistic regression and mixed analysis of variance were performed to evaluate the impact of levels of physical activity on CD4/CD8 ratio.

Results
In our series, 77 (49.7%) out of 155 patients were sedentary, and 78 (50.3%) practiced moderate/intense physical activity. Moderate/intense physical activity was associated with better metabolic control (lower body mass index, P = .024; glucose, P = .024; and triglyceride, P = .002) and CDC HIV stage (P = .046), lower CD8+ (P =  .018), CD4+CD8+ (P = .026), CD4+CD86+ (P = .045), CD4+HLA-DR+ (P = .011), CD8+HLA-DR+ (P = .048) T lymphocytes and CD16+HLA-DR+ natural killer cells (P = .026), and higher CD3+CD4+ T lymphocytes (P = .016) and CD4/CD8 ratio (P = .001). Sedentary lifestyle (odds ratio [OR], 2.12; P = .042), CD4 nadir (OR, 1.005; P &lt; .001), and CD8+CD38+ T cells (OR, 1.27; P = .006) were independently associated with low CD4/CD8 ratio (&lt;0.8). Earlier and more intense CD4/CD8 ratio recovery was observed in patients with higher physical activity in the 2-year follow-up with a significant interaction between these variables: F(2, 124) = 3.31; P = .049; partial η2 = 0.042.

Conclusions
Moderate to high physical activity is associated with beneficial health effects, improvement in metabolic profile, and reduction of chronic inflammation in patients with HIV. Although more studies and clinical trials are needed to confirm these findings, a healthy lifestyle including at least moderate physical activity should be recommended to HIV patients on stable ART.
Multiple endocrine neoplasia 2A presenting in a family with a history of Hirschprung’s disease
Authors: Johns Allison M , Vuong Angela H , Hassan Omer A , Randle Reese W , Gorris Matthew A 
Published: December 2021

ABSTRACT
Hirschprung’s disease co-occurs with multiple endocrine neoplasia type 2A infrequently but at a higher rate with certain RET mutations. We present a case of a patient evaluated for an adrenal incidentaloma with a history of familial Hirschprung’s. Our patient was found to have synchronous pheochromocytoma and medullary thyroid carcinoma illustrating the importance of genetic testing in these patients to determine appropriate screening for endocrine tumors.
Mind the Gap: An Analysis of Physical Therapist Earnings in the United States by Male/Female Sex
Authors: Chevan Julia , Chevan Albert 
Published: December 2021

Abstract

Objective
Earnings discrepancies between male and female health and medical professionals are well documented. The purpose of this study was to examine the distribution of physical therapist earnings using a quartile regression approach to determine the nature of the gender-based differences in earnings between male and female physical therapists in the United States, with “gender” as defined by the dataset as being male or female.

Methods
This observational study used data from the 2014 to 2018 American Community Survey 5-year public use microdata file. The file contained 12,123 physical therapist cases weighted to an estimate of the physical therapist active workforce of 238,221 (95% CI = 232,587 to 243,855). To analyze the influence of gender on earnings, a multivariable quantile regression approach was used in which physical therapist earnings were the dependent variable and the variables representing the geographic distribution, social characteristics, and employment characteristics were the independent variables.

Results
In 2018 dollars, the average annual earnings of a physical therapist were $73,444.98 (95% CI = $72,498.19 to $74,391.11), with a median value of $71,735.09. Differences in male and female earnings were evident in both the unadjusted bivariable and in the adjusted values produced by the quartile regression. The ratios of female-to-male earnings at each quartile were 0.89, 0.90, and 0.89. When age of the earner is accounted for, male physical therapists earned more than female therapists in both the 30-to-54-year age group and the ≥55-year age group. In the youngest age group of earners under 30 years of age, the differences were substantially smaller.

Conclusions
Gender differences in income persist across the distribution of earnings, resulting in female physical therapists earning approximately 10% less than their male counterparts. The differences are most distinct as physical therapists advance in their careers.

Impact
The etiology of the earnings gap is unknown, but gender equity has not been achieved yet for physical therapy.
Efficacy and safety of belimumab during maintenance therapy in patients with systemic lupus erythematosus
Authors: Miyazaki Yusuke , Nakayamada Shingo , Sonomoto Koshiro , Kawabe Akio , Inoue Yoshino , Okubo Naoaki , Iwata Shigeru , Hanami Kentaro , Tanaka Yoshiya 
Published: December 2021

Abstract

Objectives
The efficacy of belimumab (BEL) during maintenance therapy in patients with SLE remains unclear in the real-life clinical setting. This study investigated the efficacy and safety of BEL in patients with SLE during maintenance therapy.

Methods
In this retrospective observational study, maintenance therapy was defined as low-dose glucocorticoid (GC) therapy (prednisolone equivalent dose of ≤0.2 mg/kg/day) in patients with a Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) score &lt;10. Participants comprised patients with SLE on HCQ or MMF [standard-of-care (SoC) group: n = 103] and those on BEL plus SoC (BEL+SoC group: n = 100). Selection bias was minimized using propensity score-based inverse probability of treatment weighting (IPTW). GC dose trajectories were modelled using growth mixture modelling (GMM). The primary end point was GC dose at 52 weeks.

Results
No significant difference was observed in patient characteristics between the two groups after IPTW adjustment. The BEL+SoC group exhibited a significant decrease in GC dose. GC dose at 52 weeks and relapse rate were significantly lower in the BEL+SoC group than in the SoC group. The proportion of patients in one of four groups defined by GMM for which GC dose was tapered to 0 mg within 52 weeks (GC tapering-discontinuation group) was significantly higher in the BEL+SoC group than in the SoC group. In the BEL+SoC group, low SELENA-SLEDAI score and low GC dose at baseline were associated with being GC dose-tapering discontinuation.

Conclusion
The present study suggests that BEL is suitable for patients with SLE during maintenance therapy.
Objective sleep profile in LGI1/CASPR2 autoimmunity
Authors: Devine Michelle F , Feemster John C , Lieske Elizabeth A , McCarter Stuart J , Sandness David J , Steele Tyler , Timm Paul C , Mandrekar Jay , Boeve Bradley F , Silber Michael H , Dubey Divyanshu , McKeon Andrew , St. Louis Erik K 
Published: December 2021

AbstractStudy ObjectivesRapid eye movement (REM) sleep behavior disorder (RBD) and other sleep disturbances are frequent in leucine-rich, glioma inactivated protein 1-IgG (LGI1) and contactin-associated protein 2-IgG (CASPR2) autoimmunity, yet polysomnographic analyses of these disorders remain limited. We aimed to characterize clinical presentations and analyze polysomnographic manifestations, especially quantitative REM sleep without atonia (RSWA) in LGI1/CASPR2-IgG seropositive (LGI/CASPR2+) patients.MethodsWe retrospectively analyzed clinical and polysomnographic features and quantitative RSWA between LGI1+/CASPR2+ patients and age-sex matched controls. Groups were compared with Wilcoxon rank-sum and chi-square tests. Combined submentalis and anterior tibialis (SM + AT) RSWA was the primary outcome.ResultsAmong 11 (LGI1+, n = 9; CASPR2+, n = 2) patients, Morvan syndrome sleep features were present in seven (63.6%) LGI1+/CASPR2+ patients, with simultaneous insomnia and dream enactment behavior (DEB) in three (27.3%), and the most common presenting sleep disturbances were DEB (n = 5), insomnia (n = 5), and sleep apnea (n = 8; median apnea-hypopnea index = 15/hour). Median Epworth Sleepiness Scale was nine (range 3–24; n = 10), with hypersomnia in four (36.4%). LGI1+/CASPR2+ patients had increased N1 sleep (p = .02), decreased REM sleep (p = .001), and higher levels of SM + AT any RSWA (p &lt; .001). Eight of nine (89%) LGI1+ exceeded RBD RSWA thresholds (DEB, n = 5; isolated RSWA, n = 3). RSWA was greater in AT than SM. All 10 LGI1+/CASPR2+ patients treated with immunotherapy benefitted, and 5/10 had improved sleep disturbances.ConclusionsLGI1/CASPR2-IgG autoimmunity is associated with prominent dream enactment, insomnia, RSWA, sleep apnea, and shallower sleep. Polysomnography provides objective disease markers in LGI1+/CASPR2+ autoimmunity and immunotherapy may benefit associated sleep disturbances.
Tox-GAN: An Artificial Intelligence Approach Alternative to Animal Studies—A Case Study With Toxicogenomics
Authors: Chen Xi , Roberts Ruth , Tong Weida , Liu Zhichao 
Published: December 2021

Abstract
Animal studies are a critical component in biomedical research, pharmaceutical product development, and regulatory submissions. There is a worldwide effort in toxicology toward “reducing, refining, and replacing” animal use. Here, we proposed a deep generative adversarial network (GAN)-based framework capable of deriving new animal results from existing animal studies without additional experiments. To prove the concept, we employed this Tox-GAN framework to generate both gene activities and expression profiles for multiple doses and treatment durations in toxicogenomics (TGx). Using the pre-existing rat liver TGx data from the Open Toxicogenomics Project-Genomics-Assisted Toxicity Evaluation System (Open TG-GATES), we generated Tox-GAN transcriptomic profiles with high similarity (0.997 ± 0.002 in intensity and 0.740 ± 0.082 in fold change) to the corresponding real gene expression profiles. Consequently, Tox-GAN showed an outstanding performance in 2 critical TGx applications, gaining a molecular understanding of underlying toxicological mechanisms and gene expression-based biomarker development. For the former, over 87% agreement in Gene Ontology was found between Tox-GAN results and real gene expression data. For the latter, the concordance of biomarkers between real and generated data was high in both predictive performance and biomarker genes. We also demonstrated that the Tox-GAN models constructed with the Open TG-GATES data were capable of generating transcriptomic profiles reported in DrugMatrix. Finally, we demonstrated potential utility for Tox-GAN in aiding chemical-based read-across. To the best of our knowledge, the proposed Tox-GAN model is novel in its ability to generate in vivo transcriptomic profiles at different treatment conditions from chemical structures. Overall, Tox-GAN holds great promise for generating high-quality toxicogenomic profiles without animal experimentation.
Leech anticoagulants are ancestral and likely to be multifunctional
Authors: Iwama Rafael Eiji , Tessler Michael , Kvist Sebastian 
Published: December 2021

AbstractBloodfeeding leeches have powerful anticoagulants that allow them to feed for extended periods. However, many leech species are predatory rather than bloodfeeding. It is not known whether they express these proteins and whether the proteins are co-opted for other purposes. Little is known about salivary secretions of the sister groups of leeches, where blood is not part of the diet. We screened the transcriptomes of four non-bloodfeeding leeches and four leech relatives to identify major lineages of anticoagulant genes, helping to determine their evolutionary origin and maintenance. We estimated selection regimes that are expected after a change in feeding behaviour. We found widespread presence of putative anticoagulants, although our results also indicate that several of these are members of multicopy gene families. Our analyses suggest that homologues to leech anticoagulants were already present before the origin of bloodfeeding in leeches and that negative selection is the major driver of evolutionary rates even in non-bloodfeeding taxa. These results point to the retention of the original function by these molecules in non-bloodfeeding species. Ultimately, the proteins might not be involved in bloodfeeding or it seems likely that their putative pleiotropic effects are of great importance.
Outcomes of Patients With Large Versus Small Bone Defects in Open Tibia Fractures Treated With an Intramedullary Nail: A Descriptive Analysis of a Multicenter Retrospective Study
Authors: Obremskey William T. , Tornetta Paul , Luly Jason , Morshed Saam , O'Toole Robert V. , Hsu Joseph R. , Mitchell Stuart L. , Mackenzie Ellen J. , Frey Katherine P. , Castillo Renan C. , Bosse Michael J. , Scharfstein Daniel O. ,   on behalf of METRC
Published: December 2021

Objectives:
To compare outcomes in patients with open tibia shaft fractures based on defect size.

Design:
Retrospective review.

Setting:
Eighteen trauma centers.

Population:
The study included 132 patients with diaphyseal tibia bone defects >1 cm and ≥50% cortical loss treated with intramedullary nail.

Outcomes:
The primary outcome was number of secondary surgeries to promote healing (bone graft, revision fixation, or bone transport). Additional outcomes included occurrence of secondary surgeries (bone graft, infection, amputation, and flap failure) and proportion healed at one year. Results are compared by “radiographic apparent bone gap” of <2.5 or ≥2.5 cm.

Results:
The estimated conditional probability of bone grafting within one year given graft-free at 90 days was 44% and 47% in the <2.5 cm and ≥2.5 cm groups, respectively. An estimated infection risk of 14% was observed in both groups [adjusted hazard ratio (HR) 0.98, 95% confidence interval (CI): 0.33–2.92], estimated amputation risk was 9% (<2.5 cm) and 4% (≥2.5 cm) (unadjusted HR 0.66, 95% CI: 0.13–3.29), and estimated flap failure risk (among those with flaps) was 10% and 13%, respectively (unadjusted HR 1.71, 95% CI: 0.24–12.25). There was no appreciable difference in the proportion healed at one year between defect sizes [adjusted HR: 1.07 (95% CI, 0.63–1.82)].

Conclusions:
Larger size bone defects were not associated with higher number of secondary procedures to promote healing or a lower overall one-year healing rate.

Level of Evidence:
Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
Reported COVID-19 Incidence in Indoor Winter Sports Among US High-School Athletes
Authors: Watson Andrew M. , Haraldsdottir Kristin , Biese Kevin , Goodavish Leslie , Stevens Bethany , McGuine Timothy 
Published: December 2021

Objective:
To evaluate the association between COVID-19 incidence among high-school athletes participating in different indoor winter sports and attending schools with in-person versus virtual instructional delivery.

Design:
Cross-sectional survey.

Setting:
US high schools.

Participants:
High-school athletic directors.

Independent Variables:
Indoor winter sports, school instructional delivery method, and state COVID-19 incidence.

Main Outcome Measures:
Surveys were distributed to high-school athletic directors throughout the United States regarding sport reinitiation and COVID-19 cases in winter 2020 to 2021. Separate mixed effects Poisson regression models were developed to evaluate the associations between reported COVID-19 incidence and (1) different sports and (2) school instructional delivery method, while adjusting for the background, state COVID-19 incidence.

Results:
Four hundred thirty schools had restarted fall sports, representing 31 274 athletes on 1404 teams from 14 states. One thousand four hundred sixty cases of COVID-19 were reported, representing a case rate of 4668 cases per 100 000 athletes and an incidence rate of 58.7 cases per 100 000 player-days. Reported COVID-19 incidence was greatest among girls' hockey (82.1 cases per 100 000 player-days (95% CI, 56.8-115) and boys' hockey [76.7 (61.8-94.2)] and lowest among swimming [39.0 (31.1-48.2)] and gymnastics [28.5 (13.1-54.2)]. No difference in reported COVID-19 incidence was identified among athletes attending schools with virtual versus in-person instruction [incidence rate ratio = 0.86 (0.52-1.4)].

Conclusions:
In this nationwide survey of US high-school athletic directors regarding indoor winter sports, reported COVID-19 incidence was lower in noncontact sports but unrelated to school instructional delivery method. This information may help guide decision-making regarding high-school sport participation during the COVID-19 pandemic.