bluuebunny/crossref_metadata_2025 huggingface dataset:
RTHP-34. IMPROVED SURVIVAL IN CNS LYMPHOMA WITH SALVAGE LOW-DOSE WHOLE-BRAIN RADIOTHERAPY WITH FOCAL BOOST AND CONCURRENT TEMOZOLOMIDE
Authors: Selwa Katherine , Laucis Anna , Lawrence Theodore , Junck Larry , Cuneo Kyle , Kim Michelle , Wahl Daniel , Umemura Yoshie
Published: November 2019

OBJECTIVE

There is no standard salvage radiotherapy (RT) regimen, nor a consensus on the concurrent chemotherapy use in CNS lymphoma. We assessed the efficacy of low-dose whole-brain radiotherapy (WBRT) with focal-boost to the area of disease and concurrent temozolomide for the salvage treatment of CNS lymphoma.

METHODS

A single center retrospective study of CNS lymphoma patients seen between 01/2004 and 02/2019. The inclusion criteria were: diagnosis of CNS lymphoma, age > 18 years at diagnosis, radiation treatment to the brain, and formulation of plan at University of Michigan with at least one follow-up. Overall survival (OS) was determined by Kaplan Meier method.

RESULTS

Out of 93 patients (median age 58, 45% female), 73% were diagnosed with primary CNS lymphoma (n=68), and the remainder with secondary CNS lymphoma. Radiation modalities were WBRT alone (n=52), low-dose WBRT + focal boost (n=33) and focal RT alone (n=8). Twenty-six patients (28%) received concurrent temozolomide with radiation. Those who received WBRT+boost achieved complete response at a significantly higher rate than those who received WBRT alone (36% vs 17% respectively, p=0.047). The median OS among all groups was 45 months. There was a significant improvement in OS in patients receiving low-dose WBRT+boost compared to WBRT alone (median 65 vs 14 months respectively, p=0.016). OS was significantly longer in patients who received concurrent temozolomide than in those who did not (median 86 vs 23 months respectively, p=0.0287).

CONCLUSIONS

In CNS lymphoma salvage RT, a longer survival was observed with low-dose WBRT with focal-boost compared to WBRT alone, as well as with concurrent temozolomide. This result is limited by the selection bias to each of the treatment groups; however, the low-dose WBRT with focal-boost and concurrent temozolomide is a useful salvage alternative to standard WBRT as it may reduce long-term neurocognitive toxicity.
RTHP-39. SPINAL CORD DELINEATION BASED ON CT MYELOGRAM VERSUS T2 MRI IN SPINE SBRT CASES
Authors: Hammoudeh Lubna , Young Lee Ho , Guenette Jeffrey , Balboni Tracy
Published: November 2019

PURPOSE/OBJECTIVE(S)

Spinal cord (SC) delineation is critical in spine SBRT. While underestimating cord can lead to myelitis, overestimating SC may compromise PTV coverage, resulting in higher rates of tumor recurrence. CT myelogram as part of CT simulation is a radiological means of better visualizing the SC and minimizing MRI fusion error. The aim of this study is to compare SC contours based on CT simulation with myelogram and with fused MRI.

MATERIALS/METHODS

Eight patients with 9 spinal metastases treated with spine SBRT were evaluated. All patients had spinal MRI and myelogram performed prior to CT simulation. The spinal MRI was fused and the SC volume was contoured from the superior to the inferior endplate of the target vertebral body volume based on the (1) CT myelogram images and (2) fused T2 MRI images. Comparing MRI to myelogram-defined SC, centroid deviations (deviations in the center point of the cord) were assessed at every slice through the VB target volume, and maximum deviations of the cord were assessed; all are reported with descriptive statistics. The SC cc volume based on CT myelogram and MRI were compared using paired t-test.

RESULTS

Between MRI- versus myelogram- defined SC volumes, average deviations of the centroid point cord contours was 0.06cm, ranging from 0.01-0.1cm; average deviation of the outmost aspect of the contours were on average between 0.07-0.11cm. Finally, the volume of the cord was significantly smaller when defined on MRI as compared to myelogram - 2.778cc (SD=0.98) vs. 3.44cc (SD=1.43), p=0.03 - respectively There was only one case that had a SC volume based on T2 MRI that was bigger than that based on myelogram (3.5cc vs. 2.9cc).

CONCLUSIONS

These data suggest average deviations on MRI of approximately 0.1cm, largely undercontouring the SC volume based on MRI as compared to CT simulation with myelogram.
RTHP-40. EFFECT OF RIND-BASED DOSIMETRIC TECHNIQUES FOR SCALP DOSE REDUCTION IN BRAIN IRRADIATION
Authors: No Diana , Julie Diana , Knisely Jonathan
Published: November 2019

OBJECTIVE

Radiation-induced alopecia is an unwanted side effect causing permanent cosmetic distress if hair regrowth does not occur. Rind-based techniques can effectively control dosimetric spread. We evaluated this technique to reduce scalp dose and alopecia while maintaining tumor coverage.

METHODS

Ten consecutive brain tumor plans were retrospectively evaluated. All planning tumor volume (PTV) margins were ≤ 15.0mm from the skin surface. Departmental guidelines for fractionation were followed, with minimum 95% PTV coverage receiving 100% dose. Fractionation variation was accounted for with biologically effective dose calculation (alpha/beta=2). Rind structures encompassed 5mm depth from scalp surface; upper dose limits were customized to minimum values without PTV coverage compromise. Standard comparative plans using identical criteria, without rind structures, were calculated. Scalp dose evaluation was defined for tissue from skin to 5mm depth. Paired T-tests were used for comparative evaluation.

RESULTS

Median age: 58 (range 27–85); 70% female (n=7). Histologies included gliomas (n=7) and meningiomas (n=3). Median PTV distance to skin surface: 13.5mm (range 8.0–15.0). Median PTV minimum and mean dose for rind-based plans: 88.63% (range 73.14–95.2) and 104.39% (range 102.07–107.38) of prescription and 90.90% (range 68.64–98.21) and 103.02% (range 101.91–107.04) for standard plans, respectively. Statistically significant reduction in scalp maximum and mean dose of 19.65% (p=2.72E-06) and 0.48% (p=0.007), respectively, was seen with rind-based planning. Scalp volume receiving 1000cGy-equivalent increased 6.7cc using rind-based techniques, although insignificant (p=0.33). Volume receiving 1500cGy-equivalent was significantly reduced 3.88cc (p=0.03) using rind-based techniques. With median 28.5 day follow-up, of 5 patients treated using rind-based techniques, 40% (n=2) exhibited acute alopecia compared to 100% of those treated with standard plans.

CONCLUSION

Rind-based dosimetric techniques exhibit significant reduction of scalp dose in brain irradiation. 60% of patients treated using this technique experienced no alopecia, versus 0% receiving standard treatment. Further investigation is warranted to better evaluate correlation.
RBTT-12. A PHASE I STUDY OF EGFRVIII-DIRECTED CAR T CELLS COMBINED WITH PD-1 INHIBITION IN PATIENTS WITH NEWLY, DIAGNOSED, MGMT-UNMETHYLATED GLIOBLASTOMA: TRIAL IN PROGRESS
Authors: Bagley Stephen , Desai Arati , Binder Zev , Nasrallah MacLean , Hwang Wei-Ting , Maloney-Wilensky Eileen , Prior Timothy , Brem Steven , O’Rourke Donald
Published: November 2019

BACKGROUND

This study builds on the results of the University of Pennsylvania sponsored phase I study of a single peripheral infusion of chimeric antigen receptor (CAR) T cells targeting epidermal growth factor receptor variant III (EGFRvIII) in recurrent glioblastoma (GBM) (NCT02209376). A dose of 5x108 CART-EGFRvIII cells was safe, and the cells were able to expand in the host and reach the GBM tumor in the brain. In addition, there was no cross-reactivity of CART-EGFRvIII cells with wild-type EGFR normally expressed by human tissues. Some patients required tumor resection after CAR T cell infusion. In situ evaluation of the tumor microenvironment demonstrated increased and robust expression of inhibitory molecules, such as programmed death-ligand 1 (PD-L1), compared to pre–CART-EGFRvIII tumor specimens. Therefore, we hypothesized that using a combination of CART-EGFRvIII cells and a PD-1 inhibitor would improve the outcome of the treatment.

METHODS

This single-center study (NCT03726515) has a single-arm, open-label, phase 1 design and will enroll 7 patients with newly diagnosed, O6-methylguanine-methyltransferase (MGMT)-unmethylated, EGFRvIII+ GBM. Following maximal safe tumor resection, patients receive a short course of adjuvant radiation with a total dose of 40 Gy administered in 15 fractions. Peripheral IV infusions of 2x108 CART-EGFRvIII cells and 200mg pembrolizumab begin 2–3 weeks after completing radiation therapy. Thereafter, subjects receive CART-EGFRvIII cells + pembrolizumab in 3-week cycles for up to 3 infusions of CART-EGFRvIII cells and 4 infusions of pembrolizumab. The primary endpoint of the study is the safety and tolerability of administering multiple infusions of CART-EGFRvIII cells in combination with pembrolizumab, as measured by the occurrence of study-related adverse events. Secondary endpoints include overall survival, progression-free survival, and objective response rate. PROGRESS: At 5 June 2019, 2 patients have been enrolled and treated on study.
RARE-19. ASSOCIATION BETWEEN METHOTREXATE TOXICITY AND GENETIC VARIANTS OF METHIONINE AND FOLATE METABOLISM RELATED GENES IN PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA PATIENTS
Authors: Ho Ka-wai , Wu Synphen , Baser Raymond , Orlow Irene , Correa Denise
Published: November 2019

BACKGROUND

Methotrexate (MTX) is the backbone of therapy for primary central nervous system lymphoma (PCNSL). There have been conflicting results over whether polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) and transcobalamin 2 (TCN2) genes modulate MTX-associated toxicity.

METHODS

This is a retrospective study involving patients who underwent MTX-based chemotherapy for PCNSL and were genotyped for polymorphisms in the MTHFR (Ala222Val, C >T; Glu429Ala, A >C) and TCN (Arg259Pro, C >T) genes as part of a separate study investigating the association of genetic risk factors for treatment-related cognitive dysfunction. Renal, hepatic, and bone marrow toxicities were graded according to CTCAEv5.0, and only toxicities grade 3 or higher were considered clinically significant. MRIs of the brain during and after MTX treatment were rated for white matter changes (WMC) and cortical atrophy (CA). Genotypes were cross-tabulated with toxicities and worsening of WMC and CA. Associations were tested using Fisher’s exact tests.

RESULTS

We identified 35 PCNSL patients treated with MTX and had available genotyping data. 18 patients (51%) carried one or more MTHFR-T (c.222 Val) alleles, 16 patients (46%) had one or more MTHFR- C (c.429 Ala) alleles, and 30 patients (86%) had one or more TCN-G (c. 259 Pro) alleles. Bivariate analysis revealed that the MTHFR-T (c.222Val) allele was associated with increased hepatotoxicity (p=0.03). None of the polymorphisms tested were associated with renal or bone marrow toxicity. Though changes in CA were observed, the association of polymorphisms with WMC or CA did not reach statistical significance, potentially confounded by small sample size and limited sensitivity of rating scales.

CONCLUSION

These preliminary observations suggest that the Val on codon 222 of the MTHFR gene might be involved in the modulation of toxicity, however a larger study is required to assess whether variants involved in methionine metabolism may influence MTX-associated hepatotoxicity in PCNSL patients.
RARE-23. HIGH DOSE METHOTREXATE WITH OR WITHOUT VINCRISTINE FOR PRIMARY CNS LYMPHOMA, THE OHIO STATE UNIVERSITY EXPERIENCE
Authors: Freeman Tracelyn , Legasto Carlo , Schickli Alex , McLaughlin Eric , Giglio Pierre , Puduvalli Vinay , Gonzalez Javier
Published: November 2019

OBJECTIVES

1) Determine the response rate (RR) after chemotherapy with high-dose methotrexate with or without vincristine in patients with primary CNS lymphoma. 2) Determine the difference in adverse effects with the use of vincristine. 3) Determine the difference in progression-free survival (PFS) and overall survival (OS) between the 2 groups.

METHODS

Retrospective study in patients 18–89 years with primary CNS lymphoma that received chemotherapy with rituximab (R), methotrexate (M), procarbazine (P), and vincristine (V) R-MPV, R-MV, R-MP, or R-M between 2010 and 2018 at The Ohio State University. Response rate by cycle 7 was compared with odds ratio. Kaplan-Meier curves were used to compare OS and PFS.

RESULTS

29 patients were included: 16 (55%) received vincristine. 14/16 patients treated with vincristine and 4/13 in the other group also had procarbazine. 12/29 patients had a complete response after a maximum of 7 cycles. The odds of complete response were 24% higher in patients treated with vincristine but the difference did not reach statistical significance. Side effects were higher in the vincristine arm. The most common was peripheral neuropathy (75% vs 8% - all grades). Median PFS was 60.7 months for the vincristine group and 23.7 months for the non-vincristine group. Median OS was 85.3 months for the vincristine group and 67.1 months for the non-vincristine group. OS and PFS curves did not differ significantly.

CONCLUSIONS

The use of vincristine in high-dose methotrexate chemotherapy regimens for CNS lymphoma was not associated with a statistically significant difference in RR. Patients who received vincristine had more side effects and there were no significant differences in OS and PFS. The sample size and rate of procarbazine use may be confounding factors. Further studies are necessary to determine the effect of vincristine in RR and OS in these patients.
RARE-32. POLYMORPHOUS LOW-GRADE NEUROEPITHELIAL TUMOR OF THE YOUNG (PLNTY): GENETIC ANALYSIS CONFIRMS FREQUENT MAPK PATHWAY ACTIVATION
Authors: Ida Cristiane , Johnson Derek , Kollmeyer Thomas , Kim DongKun , Kaufmann Timothy , Kipp Benjamin , Jenkins Robert , Giannini Caterina
Published: November 2019

Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently described epileptogenic tumor characterized by oligodendroglioma-like components, aberrant CD34 expression, and genetic MAPK pathway activation through alterations such as BRAF V600E mutation, and FGFR2-KIAA1598/CTNNA3 and FGFR3-TACC3 fusions. We report the molecular profiling of PLNTY in 9 patients, 7 female: 2 male, median age at diagnosis of 16 years (range, 5–34). All tumors were supratentorial with diagnostic morphological features of PLNTY including oligodendroglioma-like areas and strong diffuse CD34 immunostaining. Four (of 9; 44%) tumors were positive for BRAF V600E immunostain, indicating the presence of a BRAF V600E mutation. The 6 cases evaluated for IDH status were negative by IDH1-R132H immunostain (n=5; 3 BRAF V600E-negative and 2 BRAF V600E-positive) or by NGS (n=1; BRAF V600E-negative). Oncoscan chromosomal microarray performed in 5 BRAF V600E-negative tumors showed recurrent copy number changes including gain of whole chromosomes 5, 7, 8, 9, 12, 18, 19, 20, 21 and X, and loss of chromosomes 1, 2, 10q, 13, 22 and Xq. The 10q losses (n=2) were highly suggestive of an FGFR2-KIAA1598 and of a potentially novel FGFR2 underlying fusion event in one case each. Custom targeted neuro-oncology DNA and RNA NGS panel performed in 2 cases revealed a fusion similar to fusions previously reported in pilocytic astrocytoma: one with a KIAA1549-BRAF (exon 15-exon 9) fusion associated with a 7q34 ~785 kilobase deletion rather than the characteristic ~2 megabase duplication seen in pilocytic astrocytoma, and another with a QKI-NTRK2 (exon 6-exon 15) fusion associated with a 9q21 ~191 kilobase duplication disrupting NTRK2. The KIAA1549-BRAF fusion-positive case also had a TP53 mutation with loss of whole chromosome 17, suggesting TP53 complete inactivation. This study confirms that PLNTY is a low-grade neuroepithelial tumor with frequent MAPK pathway activation and expands the spectrum of MAPK activating alterations observed in PLNTY.
RARE-36. BORTEZOMIB WOKE UP A PATIENT WITH ANTI-NMDA RECEPTOR ENCEPHALITIS REFRACTORY TO STANDARD THERAPY AND LONG TERM FOLLOW-UP
Authors: Xiao-Tang Kong , Groysman Leonid , Dastur Cyrus , Fu Beverly , Bota Daniela
Published: November 2019

OBJECTIVE

To report a case with refractory NMDA encephalitis in comatose for 18 months, who was treated successfully with bortezomib.

BACKGROUND

Anti-NMDA encephalitis is a rare autoimmune encephalitis. Standard therapy include corticosteroid, IVIG or plasma exchange, cyclophosphamide, rituximab, and tumor removal. Refractory cases are very severe and often stay in ICU on ventilation for several months to years. Bortezomib for the treatment of refractory anti-NMDA receptor encephalitis was reported. We have applied the treatment to our refractory case and successfully woke up the patient. And we have followed up the patient for 3 years.

METHODS

Case report.

RESULTS

A 40 yo male was diagnosed as anti-NMDA encephalitis. Standard therapy was applied. After stabilization, the patient was eventually discharged to ICU at a long term care subacute hospital. The patient was brought back for more Rituxan or steroid or IVIG therapy. The condition had not improved at all. Eighteen months in comatose, the patient had worsening NMDA titer in CSF to 1:640. Decision was made to start bortezumib as reported with modification: 1.3 mg/m2 bortezomib were administered on days 1, 8, 11 and 14 and allowed two weeks off therapy. After first cycle, the patent started to talk first word “hurt.” After 6 cycles, the patient sat up and started riding bicycles for physical therapy. The NMDA titer in CSF was reduced to 1:40 at the end of 6 cycles. One year later, the patent stood up and ambulated with a walker. One and half year later, the patient walks without assistance and his speech and cognition have significantly improved with good communication with family members and staff.

CONCLUSIONS

Proteasome inhibitor bortezomib might be considered to be the third line therapy as early as possible if the first line and second line are ineffective to treat anti-NMDA receptor encephalitis.
STEM-20. RADIO-SENSITIZING GLIOBLASTOMA CANCER STEM CELLS BY INHIBITION OF FACT
Authors: Montgomery Miranda , Zalenski Abigail , Deighen Amanda , Mortach Sherry , Grubb Treg , Venere Monica
Published: November 2019

Glioblastoma (GBM) has a particularly high rate of recurrence with a 5-year overall survival rate of approximately 5%. This is in part due to a sub-population of cancer stem cells (CSC), which are both radioresistant and chemotherapeutically resistant to conventional treatments. Here we investigated CBL0137, a small molecule form of curaxin, in combination with radiotherapy as a means to radiosensitize CSCs. CBL0137 sequesters FACT (facilitates chromatin transcription) complex to chromatin, which leads to activation of p53 and inhibition of NF-κB. This sequestering of FACT results in cytotoxicity especially within tumor cells and prevents FACT from performing its primary role as a histone chaperone, as well as inhibits its part in the DNA damage response pathway. We show that when combined with radiotherapy, CBL0137 administration limited the ability of CSCs to identify and repair damaged DNA. CSCs treated in vitro with CBL0137 and irradiation showed an increased inhibition of cancer cell growth and decreased viability compared to irradiation or drug alone. Combination therapy also showed more DNA damage in the CSCs than with either agent alone. Based on our in vitro evidence for the efficacy of combination therapy to target CSCs, we moved forward to test the treatment in vivo. Using a subcutaneous model, we show that the amount of CD133+ cells (a marker for GMB CSCs) was reduced in irradiation plus CBL0137 compared to either treatment alone. Survival studies demonstrated that irradiation plus CBL0137 compared to irradiation alone or CBL0137 alone increase lifespan. Here we show the ability of CBL0137, in combination with irradiation, to target patient GBM CSCs both in vitro and in vivo. This work establishes a new treatment paradigm for GBM that inclusively targets CSCs and may ultimately reduce tumor recurrence.
Disruptive Behavior in Siblings Discordant for Exposure to Maternal Smoking During Pregnancy: A Multi-rater Approach
Authors: Ekblad Mikael O , Rolan Emily , Marceau Kristine , Palmer Rohan , Todorov Alexandre , Heath Andrew C , Knopik Valerie S
Published: November 2019

Introduction

Maternal smoking during pregnancy (SDP) is associated with disruptive behavior. However, there is debate whether the SDP-disruptive behavior association is a potentially causal pathway or rather a spurious effect confounded by shared genetic and environmental factors.

Aims and Methods

The Missouri Mothers and Their Children Study is a sibling comparison study that includes families (n = 173) selected for sibling pairs (aged 7–16 years) discordant for SDP. Critically, the sibling comparison design is used to disentangle the effects of SDP from familial confounds on disruptive behavior. An SDP severity score was created for each child using a combination of SDP indicators (timing, duration, and amount of SDP). Multiple informants (parents and teachers) reported on disruptive behavior (i.e., DSM-IV semi-structured interview, the Child Behavior Checklist, and Teacher Report Form).

Results

The variability in disruptive behavior was primarily a function of within-family differences (66%–100%). Consistent with prior genetically informed approaches, the SDP–disruptive behavior association was primarily explained by familial confounds (genetic and environmental). However, when using a multi-rater approach (parents and teachers), results suggest a potentially causal effect of SDP on disruptive behavior (b = 0.09, SE = 0.04, p = 0.03). The potentially causal effect of SDP remained significant in sensitivity analyses.

Discussion

These findings suggest that familial confounding likely plays a complex role in the SDP–disruptive behavior association when examining both parent and teacher reports of behavior. Importantly, the current study highlights the importance of multiple raters, reflecting a more comprehensive measure of complex behaviors (e.g., disruptive behavior) to examine the teratogenic effects of SDP.

Implications

Our study provides additional evidence that controlling for genetic and family factors is essential when examining the effect of SDP on later behavioral problems, as it explains a portion of the association between SDP and later behavioral problems. However, we found a significant association between SDP and disruptive behavior when using a multi-rater approach that capitalizes on both parent and teacher report, suggesting that parent and teacher ratings capture a unique perspective that is important to consider when examining SDP–behavior associations.
Exploring Patients’ Experiences of Internet-Based Self-Management Support for Low Back Pain in Primary Care
Authors: Geraghty Adam W A , Roberts Lisa C , Stanford Rosie , Hill Jonathan C , Yoganantham Dinesh , Little Paul , Foster Nadine E , Hay Elaine M , Yardley Lucy
Published: November 2019

Objective

We explored patients’ experiences of using Internet-based self-management support for low back pain (LBP) in primary care, with and without physiotherapist telephone guidance.

Design

Exploratory descriptive qualitative study using thematic analysis, nested within a randomized feasibility trial.

Methods

Patients with LBP who participated in a feasibility trial of the SupportBack Internet intervention (ISRCTN: 31034004) were invited to take part in semistructured telephone interviews after the three-month intervention period (a convenience sample from within the trial population). Fifteen participants took part (age range = 36–87 years, 66.7% female, characteristics representative of the trial population). Data were analyzed thematically.

Results

Analysis resulted in the development of six themes (subthemes in parentheses): Perceptions of SupportBack’s design (Clarity and ease of use, Variety and range of information provided, Need for specificity and flexibility), Engaging with the SupportBack intervention, Promoting positive thought processes (Reassurance, Awareness of self-management), Managing behavior with SupportBack (Motivation and goal setting, Using activity as a pain management strategy, Preferences for walking or gentle back exercises), Feeling supported by telephone physiotherapists (Provision of reassurances and clarity, Physiotherapists are motivating), Severity and comorbidity as barriers (Preexisting condition or severity acting as a barrier, Less useful for mild low back pain).

Conclusions

The Internet intervention SupportBack appeared to feasibly support self-management of LBP. Reassurance and ongoing support to implement behavioral changes were central to reported benefits. The addition of physiotherapist telephone support further enhanced the patient experience and the potential utility of the intervention.
Renormalon structure in compactified spacetime
Authors: Ishikawa Kosuke , Morikawa Okuto , Shibata Kazuya , Suzuki Hiroshi , Takaura Hiromasa
Published: November 2019

We point out that the location of renormalon singularities in theory on a circle-compactified spacetime $\mathbb{R}^{d-1} \times S^1$ (with a small radius $R \Lambda \ll 1$) can differ from that on the non-compactified spacetime $\mathbb{R}^d$. We argue this under the following assumptions, which are often realized in large-$N$ theories with twisted boundary conditions: (i) a loop integrand of a renormalon diagram is volume independent, i.e. it is not modified by the compactification, and (ii) the loop momentum variable along the $S^1$ direction is not associated with the twisted boundary conditions and takes the values $n/R$ with integer $n$. We find that the Borel singularity is generally shifted by $-1/2$ in the Borel $u$-plane, where the renormalon ambiguity of $\mathcal{O}(\Lambda^k)$ is changed to $\mathcal{O}(\Lambda^{k-1}/R)$ due to the circle compactification $\mathbb{R}^d \to \mathbb{R}^{d-1} \times S^1$. The result is general for any dimension $d$ and is independent of details of the quantities under consideration. As an example, we study the $\mathbb{C} P^{N-1}$ model on $\mathbb{R} \times S^1$ with $\mathbb{Z}_N$ twisted boundary conditions in the large-$N$ limit.
Utilizing Telepresence Robots for Multiple Patient Scenarios in an Online Nurse Practitioner Program
Authors: Mudd Shawna S. , McIltrot Kimberly S. , Brown Kristen M.
Published: November 2019

Simulation has been utilized widely in nurse practitioner programs for competency development and training. With the growing number of online educational programs, innovative solutions need to be developed to assess student competency for a variety of clinical situations and scenarios. An innovative method is the implementation of telepresence robots for multiple patient scenarios in a simulated environment. This article demonstrates the use of multiple patient scenarios using telepresence robots in an online post master’s acute care pediatric nurse practitioner program.
Information Integration and Mesoscopic Cortical Connectivity during Propofol Anesthesia
Authors: Liang Zhenhu , Cheng Lei , Shao Shuai , Jin Xing , Yu Tao , Sleigh Jamie W. , Li Xiaoli
Published: November 2019

Background

The neurophysiologic mechanisms of propofol-induced loss of consciousness have been studied in detail at the macro (scalp electroencephalogram) and micro (spiking or local field potential) scales. However, the changes in information integration and cortical connectivity during propofol anesthesia at the mesoscopic level (the cortical scale) are less clear.

Methods

The authors analyzed electrocorticogram data recorded from surgical patients during propofol-induced unconsciousness (n = 9). A new information measure, genuine permutation cross mutual information, was used to analyze how electrocorticogram cross-electrode coupling changed with electrode-distances in different brain areas (within the frontal, parietal, and temporal regions, as well as between the temporal and parietal regions). The changes in cortical networks during anesthesia—at nodal and global levels—were investigated using clustering coefficient, path length, and nodal efficiency measures.

Results

In all cortical regions, and in both wakeful and unconscious states (early and late), the genuine permutation cross mutual information and the percentage of genuine connections decreased with increasing distance, especially up to about 3 cm. The nodal cortical network metrics (the nodal clustering coefficients and nodal efficiency) decreased from wakefulness to unconscious state in the cortical regions we analyzed. In contrast, the global cortical network metrics slightly increased in the early unconscious state (the time span from loss of consciousness to 200 s after loss of consciousness), as compared with wakefulness (normalized average clustering coefficient: 1.05 ± 0.01 vs. 1.06 ± 0.03, P = 0.037; normalized average path length: 1.02 ± 0.01 vs. 1.04 ± 0.01, P = 0.021).

Conclusions

The genuine permutation cross mutual information reflected propofol-induced coupling changes measured at a cortical scale. Loss of consciousness was associated with a redistribution of the pattern of information integration; losing efficient global information transmission capacity but increasing local functional segregation in the cortical network.

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Effect of Home-Based Cardiac Rehabilitation in a Lower-Middle Income Country
Authors: Uddin Jamal , Joshi Vicky L. , Moniruzzaman Mohammad , Karim Rezaul , Uddin Jalal , Siraj Masoom , Rashid Mohammad Abdur , Rossau Henriette Knold , Taylor Rod S. , Zwisler Ann-Dorthe
Published: November 2019

Purpose:

Cardiovascular disease is the leading cause of mortality and morbidity in lower-middle income countries (LMICs), including Bangladesh. Cardiac rehabilitation (CR) as part of secondary prevention of cardiovascular disease has been shown to reduce mortality and morbidity and improve quality of life and exercise capacity. However, to date, very few controlled trials of CR have been conducted in LMICs.

Methods:

A quasi-randomized controlled trial comparing home-based CR plus usual care with usual care alone was undertaken with patients following coronary artery bypass graft surgery. Participants in the CR group received an in-hospital CR class and were introduced to a locally developed educational booklet with details of a home-based exercise program and then received monthly telephone calls for 12 mo. Primary outcomes were coronary heart disease (CHD) risk factors, health-related quality of life (HRQOL), and mental well-being. Maximal oxygen uptake as a measure of exercise capacity was a secondary outcome.

Results:

In total, 142 of 148 eligible participants took part in the trial (96%); 71 in each group. At 12-mo follow-up, 61 patients (86%) in the CR group and 40 (56%) in the usual care group provided complete outcome data. Greater reductions in CHD risk factors and improvements in HRQOL, mental well-being, and exercise capacity were seen for the CR group compared with the usual care group.

Conclusions:

In the context of a single-center LMIC setting, this study demonstrated the feasibility of home-based CR programs and offers a model of service delivery that could be replicated on a larger scale.
Acquisition and Development of the Extremely Preterm Infant Microbiota Across Multiple Anatomical Sites
Authors: Young Gregory R. , van der Gast Christopher J. , Smith Darren L. , Berrington Janet E. , Embleton Nicholas D. , Lanyon Clare
Published: November 2019

Objectives:

Microbial communities influencing health and disease are being increasingly studied in preterm neonates. There exists little data, however, detailing longitudinal microbial acquisition, especially in the most extremely preterm (<26 weeks’ gestation). This study aims to characterize the development of the microbiota in this previously under‐represented cohort.

Methods:

Seven extremely preterm infant‐mother dyads (mean gestation 23.6 weeks) were recruited from a single neonatal intensive care unit. Oral and endotracheal secretions, stool, and breast milk (n = 157 total), were collected over the first 60 days of life. Targeted 16S rRNA gene sequencing identified bacterial communities present.

Results:

Microbiota of all body sites were most similar immediately following birth and diverged longitudinally. Throughout the sampling period Escherichia, Enterococcus, Staphylococcus, and an Enterobacteriaceae were dominant and well dispersed across all sites. Temporal divergence of the stool from other microbiota was driven by decreasing diversity and significantly greater proportional abundance of Bifidobacteriaceae compared to other sites.

Conclusions:

Four taxa dominated all anatomical sampling sites. Rare taxa promoted dissimilarity. Cross‐seeding between upstream communities and the stool was demonstrated, possibly relating to buccal colostrum/breast milk exposure and indwelling tubes. Given the importance of dysbiosis in health and disease of extremely preterm infants, better understanding of microbial acquisition within this context may be of clinical benefit.
Reduced Time to Suppression Among Neonates With HIV Initiating Antiretroviral Therapy Within 7 Days After Birth
Authors: Domínguez-Rodríguez Sara , Tagarro Alfredo , Palma Paolo , Foster Caroline , Puthanakit Thanyawee , Jupimai Thidarat , Cotugno Nicola , Ananworanich Jintanat , Zangari Paola , Nastouli Eleni , Muñoz-Fernández María Ángeles , Navarro María Luisa , Giaquinto Carlo , Rossi Paolo , Kuhn Louise , Rojo Pablo ,   on behalf of the EPIICAL Consortium
Published: November 2019

There are limited data on infants with HIV starting antiretroviral therapy (ART) in the neonatal period. We investigated the association between the timing of ART initiation and time-to-suppression among infants who tested HIV-positive and initiated ART within the first 28 days of life. The effect was estimated using cumulative probability flexible parametric spline models and a multivariable generalized additive mixed model was performed to test nonlinear associations. Forty-four neonates were included. Nineteen (43.2%) initiated ART within 7 days of life and 25 (56.8%) from 8 to 28 days. Infants treated within 7 days were 4-fold more likely to suppress earlier than those treated after 7 days [Hazard ratio (HR) 4.01 (1.7–9.5)]. For each week the ART initiation was delayed, the probability of suppression decreased by 35% (HR 0.65 [0.46–0.92]). Age at ART start was linearly associated with time-to-suppression. However, a linear association with normally distributed residuals was not found between baseline viral load and time-to-suppression, with no association found when baseline viral loads were ≤5 log(10) copies/mL, but with exponential increase in time-to-suppression with > log5 copies/mL at baseline. Starting ART within 7 days of life led to 4-fold faster time to viral suppression, in comparison to initiation from 8 to 28 days.
Heterogeneous 68Ga–Prostate-Specific Membrane Antigen Uptake in the Left Upper Abdomen
Authors: Arçay Ayça , Aydin Funda , Kutlu Ömer , Ocak Güzide Ayşe , Güngör Firat
Published: November 2019

A 50-year-old man with recently diagnosed prostate adenocarcinoma was referred for whole-body 68Ga–prostate-specific membrane antigen (PSMA) PET/CT scan for staging. Apart from some nonspecific findings, 68Ga-PSMA PET/CT revealed large soft tissue mass in the left upper abdomen showing heterogeneous tracer uptake. Histological examination of the mass was interpreted as gastrointestinal/extragastrointestinal stromal tumor by pathologists. Prostate-specific membrane antigen is considered specific for prostate cancer cells, although PSMA activity has been described in many other benign or malign conditions. That is why PSMA uptake in uncommon locations for prostate cancer metastasis must be considered for second malignancies or other benign conditions.
A Quick and Reliable Method to Decellularize a Gracilis Flap
Authors: Sabbagh M. Diya , Roh Si-Gyun , Liu Junting , Morsy Mohamed , Abu-Ghname Amjed , Zhao Chunfeng , Carlsen Brian T.
Published: November 2019

Introduction

Tissue loss as a consequence of congenital anomalies, trauma, malignancy, or gangrene represents a major health care problem in the United States. Because younger individuals are disproportionately affected, the costs are magnified over time and the resultant individual and societal effects are tremendous. The currently available options to restore soft tissue defects are associated with donor site morbidities. Vascularized composite allotransplantation may provide form, function, and esthetics without a donor site; however, it comes with the significant risk associated with toxic immunosuppression (Biomaterials. 2015;61:246-256, Ann Plast Surg. 2015;75(1):112-116, Transplantation. 2009;88(2):203-210). Engineered tissues offer promise in finding viable alternatives to allograft and autologous tissues. In this study, we present our simple and quick method to decellularize a muscle without disrupting the vascular network integrity or the extracellular matrix. Optimizing the decellularization process is a crucial step toward creating an “off-the-shelf” flap that can be used for soft tissue reconstruction.

Methods

The superficial gracilis muscle of 20 rats were harvested on their circulation and decellularized using perfusion with Krebs-Henseleit buffer and sodium dodecyl sulfate for 6 hours. These flaps were evaluated by gross morphology, histology, DNA quantification, integrity of the vascular network, scanning electron microscopy, and transmission electron microscopy.

Results

All samples were decellularized successfully as determined by DNA content and histological analysis for cellular content. The vascular network was preserved in all samples.

Conclusions

We present a quick, simple, and affordable method to decellularize a muscle flap through the vascular network. Our proposed method is efficient and can be completed in a significantly shorter time when compared with other methods. It is also safe and does not affect integrity of tissue, and this is essential for a reliable recellularization.
Total Nasal Reconstruction With Prefabricated and Prelaminated Free Flap
Authors: Cavadas Pedro C. , Torres Asia
Published: November 2019

Nasal reconstruction is a complex staged procedure. When optimal donor areas are unavailable, flap prefabrication and prelamination techniques can be used for total nasal reconstruction. A technique of total nasal reconstruction using neovascularization of the supraclavicular skin from a skin free flap used for internal lining, along with prelamination of the cartilage framework and surgical delays, is described in 2 patients with adverse anatomical conditions.
Adeno-associated virus packaged TRPC5 gene therapy alleviated spinal cord ischemic reperfusion injury in rats
Authors: Shen Nana , Wang Lin , Wu Yiling , Liu Yanlin , Pei Haitao , Xiang Hongfei
Published: November 2019

Spinal cord injury (SCI) is a devastating disease with few effective treatments. This study mainly explored the mechanism of TRPC5 gene in the treatment of spinal cord ischemia reperfusion injury from the perspective of angiogenesis. Western blot, immunohistochemistry, hematoxylin and eosin, ELISA, and reverse transcription-PCR (RT-PCR) were used to detect the expression levels of related angiogenic proteins such as von Willebrend factor (vWF), vascular endothelial growth factor (VEGF), CD31, and HIF-1α. The results showed that compared with the IR group, the Basso, Beattie, and Bresnahan scores of IR + adeno-associated virus (AAV) + TRPC5 group were higher with significant difference. And compared with ischemia/reperfusion (I/R) group, RT-PCR and ELISA results showed that inflammatory factors such as IL-6, IL-1β, and TNF-α were significantly reduced in IR + AAV + TRPC5 group. In addition, the expression of vascular related proteins such as vWF, VEGF, and CD31 in spinal cord tissue were all increased. Taken together the results, we suggest that TRPC5 could significantly increase the expression of angiogenic protein and slow down the occurrence of inflammatory response to repair the SCI.
Monopole–antimonopole: interaction, scattering and creation
Authors: Saurabh Ayush , Vachaspati Tanmay
Published: November 2019

The interaction of a magnetic monopole–antimonopole pair depends on their separation as well as on a second ‘twist’ degree of freedom. This novel interaction leads to a non-trivial bound state solution known as a sphaleron and to scattering in which the monopole–antimonopoles bounce off each other and do not annihilate. The twist degree of freedom also plays a role in numerical experiments in which gauge waves collide and create monopole–antimonopole pairs. Similar gauge wavepacket scatterings in the Abelian–Higgs model lead to the production of string loops that may be relevant to superconductors. Ongoing numerical experiments to study the production of electroweak sphalerons that result in changes in the Chern–Simons number, and hence baryon number, are also described but have not yet met with success.

This article is part of a discussion meeting issue ‘Topological avatars of new physics’.
Machine learning techniques for detecting topological avatars of new physics
Authors: Bevan A. J.
Published: November 2019

The search for highly ionizing particles in nuclear track detectors (NTDs) traditionally requires experts to manually search through samples in order to identify regions of interest that could be a hint of physics beyond the standard model of particle physics. The advent of automated image acquisition and modern data science, including machine learning-based processing of data presents an opportunity to accelerate the process of searching for anomalies in NTDs that could be a hint of a new physics avatar. The potential for modern data science applied to this topic in the context of the MoEDAL experiment at the large Hadron collider at the European Centre for Nuclear Research, CERN, is discussed.

This article is part of a discussion meeting issue ‘Topological avatars of new physics’.
Transcranial random noise stimulation for the acute treatment of depression: a randomized controlled trial
Authors: Nikolin Stevan , Alonzo Angelo , Martin Donel , Gálvez Veronica , Buten Sara , Taylor Rohan , Goldstein James , Oxley Cristal , Hadzi-Pavlovic Dusan , Loo Colleen K.
Published: November 2019

Background

Transcranial electrical stimulation has broad potential as a treatment for depression. Transcranial random noise stimulation (tRNS), which delivers randomly fluctuating current intensities, may have greater cortical excitatory effects compared to other forms of transcranial electrical stimulation. We therefore aimed to investigate the antidepressant efficacy of tRNS.

Methods

Depressed participants were randomly assigned by computer number generator to receive 20 sessions of either active or sham tRNS over four weeks in a double-blinded, parallel group randomized-controlled trial. tRNS was delivered for 30mins with a direct current offset of 2mA and a random noise range of 2mA. Primary analyses assessed changes in depression severity using the Montgomery-Asperg Depression Rating Scale (MADRS). Neuroplasticity, neuropsychological, and safety outcomes were analysed as secondary measures.

Results

69 participants were randomised, of which three discontinued treatment early leaving 66 (sham n = 34, active n = 32) for per-protocol analysis. Depression severity scores reduced in both groups (MADRS reduction in sham = 7.0 [95%CI 5.0-8.9]; and active = 5.2 [95%CI 3.2-7.3]). However, there were no differences between active and sham groups in the reduction of depressive symptoms, or the number of participants meeting response (sham = 14.7%; active = 3.1%) and remission criteria (sham = 5.9%; active = 0%). Erythema, paraesthesia, fatigue, and dizziness/light-headedness occurred more frequently in the active tRNS group. Neuroplasticity, neuropsychological and acute cognitive effects were comparable between groups.

Conclusion

Our results do not support the use of tRNS with the current stimulation parameters as a therapeutic intervention for the treatment of depression.

Clinical trial registration at clinicaltrials.gov/NCT01792414.

Significance Statement

This is the first randomized sham-controlled clinical trial of a four-week course of transcranial random noise stimulation (tRNS) for the treatment of depression. tRNS is a relatively novel form of non-invasive electrical stimulation that uses mild, randomly fluctuating currents to constrain homeostatic mechanisms and increase brain excitability. We investigated effects across multiple validated mood outcomes and comprehensively assessed cognitive, neurophysiological, and physical side effects to examine the safety of tRNS. We found no differences between active and sham conditions for all mood outcomes, and are thus unable to lend support for tRNS as an effective treatment for depression. We found tRNS to be well-tolerated with no adverse acute cognitive, neuropsychological or severe phyisical side effects, suggesting a course of 20 repeated sessions can be delivered safely.
Somatic evolution in non-neoplastic IBD-affected colon
Authors: Olafsson Sigurgeir , McIntyre Rebecca E. , Coorens Tim , Butler Timothy , Jung Hyunchul , Robinson Philip , Lee-Six Henry , Sanders Mathijs A. , Arestang Kenneth , Dawson Claire , Tripathi Monika , Strongili Konstantina , Hooks Yvette , Stratton Michael R. , Parkes Miles , Martincorena Inigo , Raine Tim , Campbell Peter J. , Anderson Carl A.
Published: November 2019

Summary paragraph

Inflammatory bowel disease (IBD) is a chronic inflammatory disease associated with increased risk of gastrointestinal cancers. Here, we whole-genome sequenced 447 colonic crypts from 46 IBD patients, and compared these to 412 crypts from 41 non-IBD controls. The average mutation rate of affected colonic epithelial cells is 2.4-fold that of healthy colon and this increase is mostly driven by acceleration of mutational processes ubiquitously observed in normal colon. In contrast to the normal colon, where clonal expansions outside the confines of the crypt are rare, we observed widespread millimeter-scale clonal expansions. We discovered non-synonymous mutations inARID1A, FBXW7, PIGR and ZC3H12A,and genes in the interleukin 17 and Toll-like receptor pathways, under positive selection in IBD. These results suggest distinct selection mechanisms in the colitis-affected colon and that somatic mutations potentially play a causal role in IBD pathogenesis.