bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Mg ii interstellar medium absorption on near-ultraviolet exoplanet transit measurements
Authors: Sreejith A G , Fossati L , Cubillos P E , Ambily S , France K
Published: December 2022

Ultraviolet (UV) transmission spectroscopy probes atmospheric escape, which has a significant impact on planetary atmospheric evolution. If unaccounted for, interstellar medium absorption (ISM) at the position of specific UV lines might bias transit depth measurements, and thus potentially affect the (non-)detection of features in transmission spectra. Ultimately, this is connected to the so called ‘resolution-linked bias’ effect. We present a parametric study quantifying the impact of unresolved or unconsidered ISM absorption in transit depth measurements at the position of the Mg ii h&k resonance lines (i.e. 2802.705 Å and 2795.528 Å, respectively) in the near-ultraviolet spectral range. We consider main-sequence stars of different spectral types and vary the shape and amount of chromospheric emission, ISM absorption, and planetary absorption, as well as their relative velocities. We also evaluate the role played by integration bin and spectral resolution. We present an open-source tool enabling one to quantify the impact of unresolved or unconsidered Mg ii ISM absorption in transit depth measurements. We further apply this tool to a few already or soon to be observed systems. On average, we find that ignoring ISM absorption leads to biases in the Mg ii transit depth measurements comparable to the uncertainties obtained from the observations published to date. However, considering the bias induced by ISM absorption might become necessary when analysing observations obtained with the next generation space telescopes with UV coverage (e.g. LUVOIR, HABEX), which will provide transmission spectra with significantly smaller uncertainties compared to what obtained with current facilities (e.g. HST).
chronostar – II. Kinematic age and substructure of the Scorpius–Centaurus OB2 association
Authors: Žerjal Maruša , Ireland Michael J , Crundall Timothy D , Krumholz Mark R , Rains Adam D
Published: December 2022

The nearest region of massive star formation – the Scorpius–Centaurus OB2 association (Sco–Cen) – is a local laboratory ideally suited to the study of a wide range of astrophysical phenomena. Precision astrometry from the Gaia mission has expanded the census of this region by an order of magnitude. However, Sco–Cen’s vastness and complex substructure make kinematic analysis of its traditional three regions, Upper Scorpius, Upper Centaurus-Lupus, and Lower Centaurus-Crux, challenging. Here, we use chronostar, a Bayesian tool for kinematic age determination, to carry out a new kinematic decomposition of Sco–Cen using full six-dimensional kinematic data. Our model identifies eight kinematically distinct components consisting of 8185 stars distributed in dense and diffuse groups, each with an independently fit kinematic age; we verify that these kinematic estimates are consistent with isochronal ages for K dwarfs. Both Upper Centaurus-Lupus and Lower Centaurus-Crux are split into two parts. The kinematic age of the component that includes PDS 70, one of the most well-studied systems currently forming planets, is 15 ± 3 Myr.
The obscured nucleus and shocked environment of VV 114E revealed by JWST/MIRI spectroscopy
Authors: Donnan F R , García-Bernete I , Rigopoulou D , Pereira-Santaella M , Alonso-Herrero A , Roche P F , Hernán-Caballero A , Spoon H W W
Published: December 2022

Compact Obscured Nuclei (CONs) potentially hide extreme supermassive black hole (SMBH) growth behind large column densities of gas/dust. We present a spectroscopic analysis of the heavily obscured nucleus and the surrounding environment of the eastern region of the nearby (z = 0.02007) interacting galaxy VV 114 with the JWST Mid-InfraRed Instrument (MIRI). We model the spectrum from 4.9 to 28 μm to extract polycyclic aromatic hydrocarbon (PAH) emission and the underlying obscured continuum. We find that the NE nucleus (A) is highly obscured where the low PAH equivalent width (EW) ratio, EW(12.7)/EW(11.3), reveals a dust enshrouded continuum source. This is confirmed by decomposing the continuum into nuclear and star-forming where the nuclear component is found to be typical of CONs. The 11.3/6.2 PAH flux ratio is consistent with originating in star-forming regions rather than typical AGN. The second nucleus (B) is much less obscured, with PAH flux ratios also typical of star-forming regions. We do not detect any high ionization lines such as [Ne v] or [Ne vi] which suggests that if an AGN is present it must be highly obscured. Additionally, we detect a shock front south of the secondary nucleus (B) in the [Fe ii] (5.34 μm) line and in warm molecular hydrogen. The 6.2 PAH emission does not spatially coincide with the low-J transitions of H2 but rather appears strong at the shock front which may suggest destruction of the ionized PAHs in the post-shock gas behind the shock front.
Refractory PR3-positive ANCA-associated vasculitis with eosinophilia requiring anti-IL-5 therapy: A case report
Authors: Anderson Elizabeth , Friedman Marcia A
Published: December 2022

This report describes a highly unusual and refractory case of proteinase-3–positive antineutrophil cytoplasmic autoantibody–associated vasculitis, which was associated with marked eosinophilia and only achieved remission after interleukin-5 blockade was added to maximal induction therapy. The patient was a healthy 18-year-old woman who presented with scleritis, otitis, constitutional symptoms, skin and mucosal lesions, and diffuse alveolar haemorrhage and found to have refractory eosinophilia of unclear aetiology. The case did not meet classification criteria for a diagnosis of granulomatosis with polyangiitis or eosinophilic granulomatosis with polyangiitis. Despite induction therapy with glucocorticoids, cyclophosphamide, and rituximab, she did not achieve remission or normalisation of eosinophilia until the addition of mepolizumab, which corresponded to the suppression of peripheral blood eosinophils and clinical remission. This case highlights the limitations of classification criteria and success of interleukin-5 in a multimodal treatment of severe vasculitis with eosinophilia.
Alternative lengthening of telomeres (ALT) in pediatric high-grade gliomas can occur without ATRX mutation and is enriched in patients with pathogenic germline mismatch repair (MMR) variants
Authors: Stundon Jennifer L , Ijaz Heba , Gaonkar Krutika S , Kaufman Rebecca S , Jin Run , Karras Anastasios , Vaksman Zalman , Kim Jung , Corbett Ryan J , Lueder Matthew R , Miller Daniel P , Guo Yiran , Santi Mariarita , Li Marilyn , Lopez Gonzalo , Storm Phillip B , Resnick Adam C , Waanders Angela J , MacFarland Suzanne P , Stewart Douglas R , Diskin Sharon J , Rokita Jo Lynne , Cole Kristina A
Published: December 2022

Background

To achieve replicative immortality, most cancers develop a telomere maintenance mechanism, such as reactivation of telomerase or alternative lengthening of telomeres (ALT). There are limited data on the prevalence and clinical significance of ALT in pediatric brain tumors, and ALT-directed therapy is not available.

Methods

We performed C-circle analysis (CCA) on 579 pediatric brain tumors that had corresponding tumor/normal whole genome sequencing through the Open Pediatric Brain Tumor Atlas (OpenPBTA). We detected ALT in 6.9% (n = 40/579) of these tumors and completed additional validation by ultrabright telomeric foci in situ on a subset of these tumors. We used CCA to validate TelomereHunter for computational prediction of ALT status and focus subsequent analyses on pediatric high-grade gliomas (pHGGs) Finally, we examined whether ALT is associated with recurrent somatic or germline alterations.

Results

ALT is common in pHGGs (n = 24/63, 38.1%), but occurs infrequently in other pediatric brain tumors (<3%). Somatic ATRX mutations occur in 50% of ALT+ pHGGs and in 30% of ALT− pHGGs. Rare pathogenic germline variants in mismatch repair (MMR) genes are significantly associated with an increased occurrence of ALT.

Conclusions

We demonstrate that ATRX is mutated in only a subset of ALT+ pHGGs, suggesting other mechanisms of ATRX loss of function or alterations in other genes may be associated with the development of ALT in these patients. We show that germline variants in MMR are associated with the development of ALT in patients with pHGG.
Duration of Chemotherapy-induced Nausea and Vomiting (CINV) as a Predictor of Recurrent CINV in Later Cycles
Authors: Navari Rudolph , Binder Gary , Molasiotis Alex , Herrstedt Jørn , Roeland Eric J , Ruddy Kathryn J , LeBlanc Thomas W , Kloth Dwight D , Klute Kelsey A , Papademetriou Eros , Schmerold Luke , Schwartzberg Lee
Published: December 2022

Background

The relationship between CINV duration and recurrence in subsequent cycles is largely unstudied. Our objective was to determine if patients experiencing CINV in their first cycle of chemotherapy (C1) would face increased risk of CINV in later cycles and whether the duration of the CINV would predict increased risk of recurrence.

Patients and Methods

Using data from a previously reported phase III trial, we assessed patients’ recurrence of breakthrough CINV after antiemetic prophylaxis for anthracycline+cyclophosphamide (AC) for breast cancer, comparing C1 short CINV vs. extended CINV as a secondary analysis. Complete response (CR) and CINV duration were primary and secondary endpoints, respectively. CR was considered prophylaxis success; lack of CR was considered treatment failure (TF).

Results

Among 402 female patients, 99 (24.6%) had TF in C1 (TF1). The remaining 303 patients (CR1) had ≥93% CR rates in each subsequent cycle, while the 99 patients with TF1 had TF rates of 49.8% for cycles 2-4 (P < .001). The 51 patients with extended TF (≥3 days) in C1 had recurrent TF in 73/105 later cycles (69.5%, P < .001), while the 48 patients with short TF (1-2 days) in C1 had recurrent TF in 33/108 later cycles (30.6%). The relative risk of recurrence after C1 extended TF was 2.28 (CI 1.67-3.11; P < .001) compared to short TF.

Conclusions

Prophylaxis success in C1 led to >90% repeat success across cycles of AC-based chemotherapy. For patients with breakthrough CINV, extended duration strongly predicted recurrent CINV. The duration of CINV should be closely monitored, and augmenting antiemetic prophylaxis considered for future cycles when extended CINV occurs.
Hip Hop Dance and Injury Prevention
Authors: Ingram Tony
Published: December 2022

This chapter reviews the fundamentals of dance injury prevention with special emphasis on its application to breaking. Elements of training such as how to practice, exercise, warm up, and stretch safely and effectively are reviewed. The information is based on the research done on dance and sports sciences up until 2015. Advances in injury prevention from sports science are discussed, and the limitations of applying such research to b-boys and b-girls are considered. Similarly, limitations of the existing dance-injury prevention literature are discussed given that research typically investigates classically trained dancers. Because research typically involves group averages, an important discussion concerns how to personalize training to meet the specific needs of individual dancers. Finally, topics of further inquiry for those planning research on this unique population of dancers are suggested
The Phenomenological Turn in Romanian Spectralism
Authors: Hayes Aaron
Published: December 2022

This chapter approaches the music of Romanian composers Ana Maria Avram and Iancu Dumitrescu from a phenomenological perspective that moves away from a reliance on science and technology characteristic much of French spectralism. These composers have expressed their interest in a shift away from the scientific analysis of timbre and sound toward certain post-Husserlian ideas, and this change in focus coincides with recent work in transformational analysis, studies of embodiment and expression, and the ontology of music. Employing a number of concepts from these fields, including the work of Gilbert Simondon, this article focuses especially on Avram’s concept of transformation, and proposes that her music initiates a phenomenology of musical stability that corrects the simplified reification of musical objects: not simply by opposing stable and unstable, but by also employing multistability and metastability in music.
Reconstructing the Creative Process
Authors: Everist Mark
Published: December 2022

Music for the stage involves many more cultural artifacts than are evoked by such terms as “opera.” Considering a broader span of works than just continuous or through-composed opera brings into consideration such genres as opéra comique, Syngestykker, and Posse mit Gesang. With this change of perspective comes the possibility of reflecting on a wider variety of agents (in the terms of the sociologist Howard Becker) than the traditional librettist-composer paradigm permits. These basic principles are explored through two examples. The comédie-vaudeville: Le quaker et la danseuse, with its generic use of borrowed material, throws down a challenge to conventional views of authorship, and in doing so extends the array of agents under consideration. This study is juxtaposed with an examination of Wagner’s Tristan und Isolde, where the broader context of the work’s immediate reception reveals an equally broad range of agents engaged in the projection of the work.
The Evolving Ideas of Beethoven’s Creative Process
Authors: Kinderman William , Sallis Friedemann
Published: December 2022

The primary goal of this article is to examine some of the contexts within which critics and scholars have studied Beethoven’s Tempest Sonata, op. 31 no. 2, as well as the creative process pertaining to it. It will show that the diversity of analytical and interpretative outcomes is a consequence of the answers being sought and of the historical contexts within which the questions were posed. In so doing, it sheds light on the complex relationships that entangle the reception of Beethoven’s music, on the one hand, and the development of scholarship on compositional technique and the creative process, on the other.
Watershed memory amplified the Oroville rain-on-snow flood of February 2017
Authors: Haleakala Kayden , Brandt W Tyler , Hatchett Benjamin J , Li Dongyue , Lettenmaier Dennis P , Gebremichael Mekonnen
Published: December 2022

Mountain snowpacks are transitioning to experience less snowfall and more rainfall as the climate warms, creating more persistent low- to no-snow conditions. This precipitation shift also invites more high-impact rain-on-snow (ROS) events, which have historically yielded many of the largest and most damaging floods in the western United States. One such sequence of events preceded the evacuation of 188,000 residents below the already-damaged Oroville Dam spillway in February 2017 in California’s Sierra Nevada. Prior studies have suggested that snowmelt during ROS dramatically amplified reservoir inflows. However, we present evidence that snowmelt may have played a smaller role than previously documented (augmenting terrestrial water inputs by 21%). A series of hydrologic model experiments and subdaily snow, soil, streamflow, and hydrometeorological measurements demonstrate that direct, “passive” routing of rainfall through snow, and increasingly efficient runoff driven by gradually wetter soils can alternatively explain the extreme runoff totals. Our analysis reveals a crucial link between frequent winter storms and a basin’s hydrologic response—emphasizing the role of soil moisture “memory” of within-season storms in priming impactful flood responses. Given the breadth in plausible ROS flood mechanisms, this case study underscores a need for more detailed measurements of soil moisture along with in-storm changes to snowpack structure, extent, energy balance, and precipitation phase to address ROS knowledge gaps associated with current observational limits. Sharpening our conceptual understanding of basin-scale ROS better equips water managers moving forward to appropriately classify threat levels, which are projected to increase throughout the mid-21st century.
Topical SCD-153, a 4-methyl itaconate prodrug, for the treatment of alopecia areata
Authors: Tsai Jerry , Gori Sadakatali , Alt Jesse , Tiwari Sandhya , Iyer Jitesh , Talwar Rashmi , Hinsu Denish , Ahirwar Kailash , Mohanty Swayam , Khunt Chintan , Sutariya Brijesh , Jani Kaushal , Venkatasubbaiah Venkatesha , Patel Ashok , Meghapara Jasmin , Joshi Kaushal , Sahu Rajanikanta , Rana Vijay , Nigade Prashant , Talluri Ravi S , Murty Kadiyala V S N , Joshi Kiritkumar , Ramanathan Vikram , Li Ang , Islam Nasif , Snajdr Ivan , Majer Pavel , Rais Rana , Slusher Barbara S , Garza Luis A
Published: December 2022

Alopecia areata is a chronic hair loss disorder that involves autoimmune disruption of hair follicles by CD8+  T cells. Most patients present with patchy hair loss on the scalp that improves spontaneously or with topical and intralesional steroids, topical minoxidil, or topical immunotherapy. However, recurrence of hair loss is common, and patients with extensive disease may require treatment with oral corticosteroids or oral Janus kinase (JAK) inhibitors, both of which may cause systemic toxicities with long-term use. Itaconate is an endogenous molecule synthesized in macrophages that exerts anti-inflammatory effects. To investigate the use of itaconate derivatives for treating alopecia areata, we designed a prodrug of 4-methyl itaconate (4-MI), termed SCD-153, with increased lipophilicity compared to 4-MI (CLogP 1.159 vs. 0.1442) to enhance skin and cell penetration. Topical SCD-153 formed 4-MI upon penetrating the stratum corneum in C57BL/6 mice and showed low systemic absorption. When added to human epidermal keratinocytes stimulated with polyinosinic-polycytidylic acid (poly I:C) or interferon (IFN)γ, SCD-153 significantly attenuated poly I:C-induced interleukin (IL)-6, Toll-like receptor 3, IL-1β, and IFNβ expression, as well as IFNγ-induced IL-6 expression. Topical application of SCD-153 to C57BL/6 mice in the resting (telogen) phase of the hair cycle induced significant hair growth that was statistically superior to vehicle (dimethyl sulfoxide), the less cell-permeable itaconate analogues 4-MI and dimethyl itaconate, and the JAK inhibitor tofacitinib. Our results suggest that SCD-153 is a promising topical candidate for treating alopecia areata.
A machine learning approach reveals features related to clinicians’ diagnosis of clinically relevant knee osteoarthritis
Authors: Wang Qiuke , Runhaar Jos , Kloppenburg Margreet , Boers Maarten , Bijlsma Johannes W J , Bacardit Jaume , Bierma-Zeinstra Sita M A ,   The CREDO Experts Group, Aerts-Lankhorst N E , Agricola R , Bastick A N , van Bentveld R D W , van den Berg P J , Bijsterbosch J , de Boer A , Boers M , Bohnen A M , Boonen A E R C H , Bos P K , Boymans T A E J , Breedveldt-Boer H P , Brouwer R W , Colaris J W , Damen J , Elshout G , Emans P J , Enthoven W T M , Frölke E J M , Glijsteen R , van der Heide H J C , Huisman A M , van Ingen R D , Jacobs M L , Janssen R P A , Kevenaar P M , van Koningsbrugge M A , Krastman P , Kuchuk N O , Landsmeer M L A , Lems W F , van der Linden H M J , van Linschoten R , Mahler E A M , van Meer B L , Meuffels D E , Noort-van der Laan W H , van Ochten J M , van Oldenrijk J , Pols G H J , Piscaer T M , Rijkels-Otters J B M , Riyazi N , Schellingerhout J M , Schers H J , Schouten B W V , Snijders G F , van Spil W E , Stitzinger S A G , Tolk J J , van Trier Y D M , Vis M , Voorbrood V M I , de Vos B C , de Vries A
Published: December 2022

Objectives

To identify highly ranked features related to clinicians’ diagnosis of clinically relevant knee OA.

Methods

General practitioners (GPs) and secondary care physicians (SPs) were recruited to evaluate 5–10 years follow-up clinical and radiographic data of knees from the CHECK cohort for the presence of clinically relevant OA. GPs and SPs were gathered in pairs; each pair consisted of one GP and one SP, and the paired clinicians independently evaluated the same subset of knees. A diagnosis was made for each knee by the GP and SP before and after viewing radiographic data. Nested 5-fold cross-validation enhanced random forest models were built to identify the top 10 features related to the diagnosis.

Results

Seventeen clinician pairs evaluated 1106 knees with 139 clinical and 36 radiographic features. GPs diagnosed clinically relevant OA in 42% and 43% knees, before and after viewing radiographic data, respectively. SPs diagnosed in 43% and 51% knees, respectively. Models containing top 10 features had good performance for explaining clinicians’ diagnosis with area under the curve ranging from 0.76–0.83. Before viewing radiographic data, quantitative symptomatic features (i.e. WOMAC scores) were the most important ones related to the diagnosis of both GPs and SPs; after viewing radiographic data, radiographic features appeared in the top lists for both, but seemed to be more important for SPs than GPs.

Conclusions

Random forest models presented good performance in explaining clinicians’ diagnosis, which helped to reveal typical features of patients recognized as clinically relevant knee OA by clinicians from two different care settings.
2,3,7,8-Tetrachlorodibenzo-p-dioxin induces liver lipid metabolism disorder via the ROS/AMPK/CD36 signaling pathway
Authors: Cong Yewen , Hong Yujing , Wang Dandan , Cheng Pei , Wang Zhisheng , Xing Changming , Sun Wenxing , Xu Guangfei
Published: December 2022

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is widely considered as the most toxic and common carcinogen in the world. Exposure to TCDD causes liver lipid metabolism disorder and steatosis. However, the molecular mechanism of TCDD-induced liver lipid accumulation is not completely clear. Here, we found that a 5 μg/kg TCDD exposure for 3 weeks induced hepatocyte lipid deposition, increased CD36 expression, and promoted AMP-activated protein kinase (AMPK) ɑ phosphorylation in the liver of C57BL/6J mice. Furthermore, sulfo-N-succinimidyl oleate, a CD36 inhibiter, blunted TCDD-induced lipid deposition in Huh7 cells, confirming the critical role of CD36 in TCDD-induced hepatic steatosis. In terms of molecular mechanisms, we found that TCDD exposure increased reactive oxygen species (ROS) levels in Huh7 cells, which activated AMPK. Moreover, the activated AMPK upregulated CD36 expression. Therefore, we can see that the increase in CD36 expression induced by TCDD was regulated by ROS/AMPK/CD36 signaling pathway. Our results help to clarify the molecular mechanism of TCDD-induced hepatic steatosis.
Treatment of Lentigines: A Systematic Review
Authors: Mukovozov Ilya , Roesler Jordanna , Kashetsky Nadia , Gregory Allison
Published: December 2022

BACKGROUND

Treatments for solar lentigines include topical and physical therapies, including chemical peels, lasers, intense pulsed light, and cryotherapy. A direct comparison of treatment methods and their efficacy is lacking.

OBJECTIVE

To compare treatment efficacy and adverse events for different treatment modalities for lentigines.

METHODS

Cochrane, MEDLINE, and Embase databases were searched on August 25, 2021. Studies were included if they met our predetermined population, intervention, comparator, outcomes, study design framework. Results are presented in narrative form.

RESULTS

Forty-eight articles met the inclusion criteria, representing a total of 1,763 patients. Overall, combination-based treatments showed the greatest frequency of cases with complete response (65%, n = 299/458), followed by laser-based treatments (43%, n = 395/910), topical retinoids (21%, n = 12/57), cryotherapy (15%, n = 25/169), and peels (6%, n = 8/125). Adverse events occurred most commonly while using topical retinoids (82%, n = 23/28), followed by combination-based treatments (39%, n = 184/466), cryotherapy (33%, n = 47/144), laser-based treatments (23%, n = 173/738), and peels (19%, n = 21/110).

CONCLUSION

Despite heterogeneity of included study designs, patient populations, treatment regimens, and outcome measures, our results suggest that combination-based treatments and laser-based treatments were the most efficacious treatment modalities. Although cryotherapy was previously considered first-line, our results show that it has substantially lower pooled response rates compared with other treatment modalities.
Recurrent Lisch Epithelial Corneal Dystrophy Treated With 5-Fluorouracil: A Case Report and Review of the Literature
Authors: Amer Mona M. , Arze Karen , Galor Anat , Sayegh Yoseph , Dubovy Sander S. , Karp Carol L.
Published: December 2022

Purpose:

The aim of the study was to describe a case of Lisch epithelial corneal dystrophy (LECD), review its clinical and histopathological features and diagnostic imaging, and introduce a novel treatment approach using topical 5-fluorouracil (5-FU).

Methods:

A 65-year-old woman presented with a recurrent left-sided corneal lesion consistent with LECD. The lesion was evaluated clinically, with high-resolution optical coherence tomography (HR-OCT), and histologically. The lesion was successfully treated with two 1-week cycles of topical 5-FU.

Results:

Slit-lamp examination showed an opalescent, whorl-shaped corneal lesion. HR-OCT revealed a trapezoidal area of normal thickness epithelial hyperreflectivity. Histopathology demonstrated a mucosal epithelium with foamy cytoplasm and increased cell size consistent with LECD. Treatment with topical 5-FU resulted in marked clearance of the corneal lesion on slit-lamp examination and HR-OCT.

Conclusions:

5-FU may be considered as a treatment option for LECD.
Test-Retest Reliability and Criterion Validity of the Spanish Version of Two Motor Imagery Questionnaires in People With Parkinson Disease
Authors: Moreno-Verdú Marcos , Ferreira-Sánchez María del Rosario , Martín-Casas Patricia , Atín-Arratibel María de los Ángeles
Published: December 2022

Background and purpose:

The Kinesthetic and Visual Imagery Questionnaire (KVIQ) and the Movement Imagery Questionnaire-Revised Second Version (MIQ-RS) are measurement instruments that assess motor imagery vividness. The aim of this study was to examine the validity and reliability of the Spanish KVIQ and MIQ-RS in people with Parkinson disease (PD).

Methods:

A longitudinal descriptive study was conducted following the COSMIN standards. Thirty-five people with idiopathic PD were evaluated twice (7-15 days apart) with the Spanish KVIQ and MIQ-RS. Structural validity, internal consistency, test-retest reliability (ICC), standard error of measurement (SEM), smallest detectable change (SDC), and criterion validity of the MIQ-RS and KVIQ long (KVIQ-20), short (KVIQ-10), and extended (KVIQ-34) versions and their subscales (if pertinent) were tested.

Results:

Factor analysis was satisfactory for the MIQ-RS, KVIQ-20, and KVIQ-10, providing evidence of their 2-dimensional structure. Evidence of the structural validity of the KVIQ-34 was not confirmed and thus was analyzed as an overall score. Revelle's ω > 0.9 showed excellent internal consistency. Test-retest reliability was moderate (ICC = 0.58-0.75) and higher for all visual subscales. SEM and SDC were up to 14.39% and 39.89% of the scores, respectively. Criterion validity between questionnaires and subscales was strong (Spearman's r > 0.7).

Discussion and Conclusions:

The results provide evidence for the validity and reliability of the Spanish MIQ-RS, KVIQ-20, and KVIQ-10 to assess motor imagery vividness in people with PD, whereas the KVIQ-34 should only be interpreted as an overall score. Psychometric, procedural, and practical features of the questionnaires should be considered when applying into clinical practice.

Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A401).
“We’ve Got This”: Middle-Aged and Older Couples’ Satisfying Relationships and We-Talk Promote Better Physiological, Relational, and Emotional Responses to Conflict
Authors: Shrout M. Rosie , Wilson Stephanie J. , Renna Megan E. , Madison Annelise A. , Kiecolt-Glaser Janice K.
Published: December 2022

Objective

Conflict poses multiple relational and health risks. Dyadic stress theories suggest satisfaction and communication alter cardiovascular and autonomic function, key pathways from troubled relationships to poor health. However, “we-talk,” a positive communication pattern, can strengthen relationships and promote health. We examined how each spouse’s satisfaction and we-talk were related to conflict’s physiological, relational, and emotional toll.

Methods

Married couples (n = 107 couples, 214 individuals, ages 40–87 years) who were mostly White, highly educated, and higher-income Americans in different-gender relationships engaged in 20-minute conflict discussions while wearing monitors to assess heart rate variability (HRV). Spouses rated their closeness immediately after conflict and their conflict rumination 2 hours later. Conflict transcriptions measured we-talk, or the proportion of first-person plural pronouns (we, us, our).

Results

Satisfied spouses or those in mutually satisfying relationships had higher HRV during conflict (b = 0.0001, p = .049), felt closer immediately after conflict (b = 0.07, p < .001), and ruminated less about the conflict 2 hours later (b = −0.26, p = .026). Spouses’ HRV was highest (b = 0.0002, p = .002) and rumination was lowest (b = −0.49, p = .019) when they or their partners were satisfied and used we-talk more often. Women’s HRV (b = 0.0001, p = .035) and rumination (b = −0.01, p = .02) benefited when both spouses were satisfied, as did closeness when women were satisfied (b = 0.10, p < .001). Men’s closeness benefited when they (b = 0.04, p = .003) or their wives (b = 0.04, p = .002) were satisfied.

Conclusions

The combination of mutually satisfying relationships and we-talk was associated with better relational and health outcomes after conflict. These findings are important for middle-aged and older couples whose relationships are central to their health.
Hemihamate Arthroplasty Revisited
Authors: Doucet Véronique M. , Clark Tod A. , Giuffre Jennifer L.
Published: December 2022

Purpose

Proximal interphalangeal joint (PIPJ) fracture dislocations are complex injuries that can result in persistent pain, stiffness, and angulation. Hemihamate arthroplasty (HHA) can be used to reconstruct the base of the middle phalanx in cases of unstable PIPJ fracture dislocations. Despite previous case series describing good outcomes with HHA, it has not gained widespread use. The purpose of this study is to describe our straightforward, reproducible technique and to demonstrate the benefit in motion after the procedure in chronic unstable PIPJ fracture dislocations.

Methods

All patients with chronic, unstable PIPJ fracture dislocations requiring joint resurfacing of greater than 40% of the base of the middle phalanx treated with HHA were retrospectively reviewed. Patient demographics, injury features, surgical technique, preoperative and postoperative PIPJ range of motion and arc of motion, time to surgery, and complications were reviewed. Any fracture amenable to fixation or cases with radiographic evidence of arthritis or injury to the head of the proximal phalanx were excluded.

Results

Eleven cases were reviewed. The mean patient age was 35 years. The mean time from injury to surgery was 6 months. The mean joint surface involved was 64%. The mean PIPJ arc of motion was 17 degrees preoperatively and 63 degrees postoperatively. The mean bone block size required was 8 × 8 × 8 mm. The mean follow-up was 26 months. Postoperative pain at the PIPJ on the visual analog scale was 0.4 (scale of 0 to 10). Complications included 2 patients requiring tenolysis.

Conclusions

Despite the lack of a perfect geometric recreation of the base of the middle phalanx with the hamate, patients recover acceptable PIPJ motion and have minimal pain. Hemihamate arthroplasty is a good option for any patient with minimal motion of their PIPJ and a chronic, unstable fracture dislocation.
An update to the critical appraisal of Milwaukee protocol
Authors: Arslan Ferhat , Vahaboglu Haluk
Published: December 2022

Rabies is a highly fatal encephalitis. Currently, there is no approved treatment. Inducing therapeutic coma during the first week of symptomatic rabies patient, called Milwaukee protocol, had been suggested as promising. However, recent evidence failed to support the use of the Milwaukee protocol. This mini-review analyzed the reports of patients managed with therapeutic coma since 2014 to provide an update for the critical appraisal of this protocol.
Profile-Wise Analysis: A profile likelihood-based workflow for identifiability analysis, estimation, and prediction with mechanistic mathematical models
Authors: Simpson Matthew J. , Maclaren Oliver J.
Published: December 2022

Interpreting data using mechanistic mathematical models provides a foundation for discovery and decision-making in all areas of science and engineering. Developing mechanistic insight by combining mathematical models and experimental data is especially critical in mathematical biology as new data and new types of data are collected and reported. Key steps in using mechanistic mathematical models to interpret data include: (i) identifiability analysis; (ii) parameter estimation; and (iii) model prediction. Here we present a systematic, computationally-efficient workflow we callProfile-Wise Analysis(PWA) that addresses all three steps in a unified way. Recently-developed methods for constructing ‘profile-wise’ prediction intervals enable this workflow and provide the central linkage between different workflow components. These methods propagate profile-likelihood-based confidence sets for model parameters to predictions in a way that isolates how different parameter combinations affect model predictions. We show how to extend these profile-wise prediction intervals to two-dimensional interest parameters. We then demonstrate how to combine profile-wise prediction confidence sets to give an overall prediction confidence set that approximates the full likelihood-based prediction confidence set well. Our three case studies illustrate practical aspects of the workflow, focusing on ordinary differential equation (ODE) mechanistic models with both Gaussian and non-Gaussian noise models. While the case studies focus on ODE-based models, the workflow applies to other classes of mathematical models, including partial differential equations and simulation-based stochastic models. Open-source software on GitHub can be used to replicate the case studies.
Cell Tree Rings: the structure of somatic evolution as a human aging timer
Authors: Csordas Attila , Sipos Botond , Kurucova Terezia , Volfova Andrea , Zamola Frantisek , Tichy Boris , Hicks Damien G
Published: December 2022

Biological age is typically estimated using biomarkers whose states have been observed to correlate with chronological age. A persistent limitation of such aging clocks is that it is difficult to establish how the biomarker states are related to the mechanisms of aging. Somatic mutations could potentially form the basis for a more fundamental aging clock since the mutations are both markers and drivers of aging and have a natural timescale. Cell lineage trees inferred from these mutations reflect the somatic evolutionary process and thus, it has been conjectured, the aging status of the body. Such a timer has been impractical thus far, however, because detection of somatic variants in single cells presents a significant technological challenge. Here we show that somatic mutations detected using single-cell RNA sequencing (scRNA-seq) from thousands of cells can be used to construct a cell lineage tree whose structure correlates with chronological age. De novo single-nucleotide variants (SNVs) are detected in human peripheral blood mononuclear cells using a modified protocol. A default model based on penalized multiple regression of chronological age on 31 metrics characterizing the phylogenetic tree gives a Pearson correlation of 0.81 and a median absolute error of ∼4 years between predicted and chronological age. Testing of the model on a public scRNA-seq dataset yields a Pearson correlation of 0.85. In addition, cell tree age predictions are found to be better predictors of certain clinical biomarkers than age alone, for instance glucose, albumin levels and leukocyte count. The geometry of the cell lineage tree records the structure of somatic evolution in the individual and represents a new modality of aging timer. In addition to providing a numerical estimate of ‘Cell Tree Age’, it unveils a temporal history of the aging process, revealing how clonal structure evolves over life span. Cell Tree Rings complements existing aging clocks and may help reduce the current uncertainty in the assessment of geroprotective trials.
Cellular and Fibrillar Collagen Analyses in an Animal Model of Retinal Detachment-Related Proliferative Vitreoretinopathy Reveals a Defined Transition to Chronic Fibrosis
Authors: Peterson Cornelia , Santiago Clayton P. , Lu Yuchen , Price Antoinette , McNally Minda M. , Schubert William , Blackshaw Seth , Eberhart Charles G. , Singh Mandeep S.
Published: December 2022

Purpose

Proliferative vitreoretinopathy (PVR) is the most common cause of failure of surgically repaired rhegmatogenous retinal detachment (RRD). Chemically-induced and cell-injection PVR models do not fully simulate the clinical characteristics of PVR in the post-RRD context. There is an unmet need for translational models in which to study mechanisms and treatments specific to RRD-PVR.

Methods

RRD-PVR was induced in adult Dutch Belted rabbits. Posterior segments of enucleated globes were fixed or processed for RNA-Seq at 6 hours and 2, 7, 14, and 35 days post-induction. Histochemical staining and immunolabeling for glial fibrillary acidic protein (GFAP), alpha smooth muscle actin (αSMA), vascular endothelial growth factor receptor 2 (VEGFR2), CD68, and retinal pigment epithelium 65 kDa protein (RPE65) were performed, and labeling intensity was scored. Single cell RNA sequencing was performed.

Results

Acute histopathologic changes included intravitreal and intraretinal hemorrhage, leukocytic vitritis, chorioretinitis, and retinal rarefaction. Chronic lesions showed retinal atrophy, gliosis, fibrotic subretinal membranes, and epiretinal fibrovascular proliferation. Fibrillar collagen was present in the fibrocellular and fibrovascular membranes in chronic lesions. Moderate to strong labeling of glia and vasculature was detected in chronic lesions. At day 14, most cells profiled by single cell sequencing were identified as Müller glia and microglia, consistent with immunolabeling. Expression of several fibrillar collagen genes were upregulated in chronic lesions.

Conclusions

Histologic and transcriptional features of this rabbit model simulate important features of human RRD-PVR, including the transition to chronic intra and periretinal fibrosis. This high-fidelityin vivomodel of RRD-PVR will enable further research on targeted treatment interventions.
Bayesian methods for optimizing deep brain stimulation to enhance cognitive control
Authors: Nagrale Sumedh S , Yousefi Ali , Netoff Theoden I , Widge Alik S
Published: December 2022

Objective

Deep brain stimulation (DBS) of the ventral internal capsule/striatum (VCVS) is a potentially effective treatment for several mental health disorders when conventional therapeutics fail. Its effectiveness, however, depends on correct programming to engage VCVS sub-circuits. VCVS programming is currently an iterative, time-consuming process, with weeks between setting changes and reliance on noisy, subjective self-reports. An objective measure of circuit engagement might allow individual settings to be tested in seconds to minutes, reducing the time to response and increasing patient and clinician confidence in the chosen settings. Here, we present an approach to measuring and optimizing that circuit engagement.

Approach

We leverage prior results showing that effective VCVS DBS engages circuits of cognitive control, that this engagement depends primarily on which contact(s) are activated, and that circuit engagement can be tracked through a state space modeling framework. We combine this framework with an adaptive optimizer to perform a principled exploration of electrode contacts and identify the contacts that maximally improve cognitive control.

Main results

Using behavioral simulations directly derived from patient data, we show that an Upper Confidence Bound (UCB1) algorithm outperforms other optimizers (roughly 80% probability of convergence to a global optimum).

Significance

We show that the optimization can converge even with lag between stimulation and effect, and that a complete optimization can be done in a clinically feasible timespan (a few hours). Further, the approach requires no specialized recording or imaging hardware, and thus could be a scalable path to expand the use of DBS in psychiatric and other non-motor applications.
Improving theCOIDNA barcoding library for Neotropical phlebotomine sand flies (Diptera, Psychodidae)
Authors: Posada-López Laura , Rodrigues Bruno Leite , Velez Ivan Dario , Uribe Sandra
Published: December 2022

A fragment of the mitochondrialcytochrome c oxidase subunit I(COI) gene was used to generate 156 new barcode sequences for sand flies from different countries of the Neotropical region, mainly Colombia, which had been identified morphologically as 43 species. The sequencing of theCOIgene allowed the detection of cryptic diversity within species and correctly associated isomorphic females with males identified by morphology. The maximum intraspecific genetic distances ranged from 0 to 8.32% and 0 to 8.92% using uncorrectedpdistances and the K2P model, respectively. The minimum interspecific distance (nearest neighbor) for each species ranged from 1.5 to 14.14% and 1.51 to 15.7% using p and K2P distances, respectively. Three species had more than 3% maximum intraspecific distance:Psychodopygus panamensis, Micropygomyia cayennensis cayennensis, andPintomyia evansi. They also were splitted into at least two MOTUs each, using different species delimitation algorithms. Regarding interspecific genetic distances, the species of the generaNyssomyiaandTrichophoromyiagenerated values lower than 3% (exceptNy. ylephiletorandNy. trapidoi). However, the maximum intraspecific distances did not exceed these values, indicating the presence of a barcode gap despite their proximity. Also, nine sand fly species were DNA barcoded for the first time:Evandromyia georgii, Lutzomyia sherlocki, Ny. ylephiletor, Ny. yuilli pajoti, Psathyromyia punctigeniculata, Sciopemyia preclara, Trichopygomyia triramula, Trichophoromyia howardi, andTh. velezbernali. Thus, theCOIDNA barcode analysis allowed the correct delimitation of several Neotropical sand fly species from South and Central America and raised questions about the presence of cryptic species for some taxa, which should be further assessed.
Combination drug screen targeting glioblastoma core vulnerabilities reveals pharmacological synergisms
Authors: Ariey-Bonnet Jérémy , Berges Raphael , Montero Marie-Pierre , Mouysset Baptiste , Piris Patricia , Muller Kevin , Pinna Guillaume , Failes Tim W. , Arndt Greg M. , Baeza-Kallee Nathalie , Colin Carole , Chinot Olivier , Braguer Diane , Morelli Xavier , André Nicolas , Carré Manon , Tabouret Emeline , Figarella-Branger Dominique , Grand Marion Le , Pasquier Eddy
Published: December 2022

Synergistic drug combinations are an attractive anticancer strategy but prove challenging to identify. Here we present a stepwise approach consisting in revealing core cancer vulnerabilities and exploiting them through drug combination screen to uncover synergistic treatments for glioblastoma patients.

Methods

We established an innovative method, based on high-throughput screening, target deconvolution and functional genomics, to reveal core vulnerabilities in glioblastoma. Combination drug screen targeting these vulnerabilities was then designed to unveil synergistic associations. The therapeutic potential of the top drug combination was validated in two different clinically-relevant models: an organotypicex vivomodel and a syngeneic orthotopic mouse model of glioblastoma.

Results

Large-scale monotherapy drug screening identified 83 potent anti-glioblastoma compounds. Target deconvolution using public chemoinformatic databases uncovered 1,100 targets and interactors of the hit compounds. Screening of a focused siRNA library targeting the top 292 drug interactors revealed 22 targetable vulnerabilities, 9 of which were confirmed as core glioblastoma vulnerabilities by mining the CRISPR screen cohort data from the online Cancer Dependency Map portal. Six selective inhibitors of the core vulnerabilities were then screened in combination with a custom-made library of 88 compounds and synergies amongst the 528 tested pairwise combinations were predicted. The combinations of CHK1 / MEK and AURKA / BET inhibitors were highlighted and validated in 3D tumor spheroids. Using an organotypicex vivomodel and a syngeneic orthotopic mouse model, we definitively ascertained the efficacy of dual AURKA / BET inhibition in glioblastoma.

Conclusions

Collectively, we uncovered that dual inhibition of BET proteins and aurora kinase A is highly synergistic against GBM. Moreover, our study indicates that our approach to exploit drug poly-pharmacology for the rational design of drug combination screens represent a valuable strategy to discover synergistic treatments against refractory cancers.
The necessity of considering enzymes as compartments in constraint-based genome-scale metabolic models
Authors: Yang Xue , Mao Zhitao , Huang Jianfeng , Wang Ruoyu , Dong Huaming , Zhang Yanfei , Ma Hongwu
Published: December 2022

As the most widespread and practical digital representations of living cells, metabolic network models have become increasingly precise and accurate. By integrating cellular resources and abiotic constraints, the prediction functions were significantly expanded in recent years. However, we found that if unreasonable modeling methods were adopted due to the lack of consideration of biological knowledge, the conflicts between stoichiometric and other constraints, such as thermodynamic feasibility and enzyme resource availability, would lead to distorted predictions. In this work, we investigated a prediction anomaly of EcoETM, a constraints-based metabolic network model, and introduced the idea of enzyme compartmentalization into the analysis process. Through rational combination of reactions, we avoid the false prediction of pathway feasibility caused by the unrealistic assumption of free intermediate metabolites. This allowed us to correct the pathway structures of L-serine and L-tryptophan. Specific analysis explains the application method of EcoETM-like model, demonstrating its potential and value in correcting the prediction results in pathway structure by resolving the conflict between different constraints and incorporating the evolved roles of enzymes as reaction compartments. Notably, this work also reveals the trade-off between product yield and thermodynamic feasibility. Finally, we provide a preliminary comparison of the thermodynamic feasibility of ammonia and glutamine as amino donors, which revealed that the direct utilization of ammonia does not have a decisive impact on the thermodynamic feasibility of the anthranilate pathway. Our work is of great value for the structural improvement of constraints-based models.