bluuebunny/crossref_metadata_2025 huggingface dataset:
Physicians’ Hierarchy of Tumor Biomarkers for Optimizing Chemotherapy in Breast Cancer Care
Authors: Thannickal Halle H , Eltoum Noon , Henderson Nicole L , Wallner Lauren P , Wagner Lynne I , Wolff Antonio C , Rocque Gabrielle B
Published: July 2023

Background

Tumor biomarkers are regularly used to guide breast cancer treatment and clinical trial enrollment. However, there remains a lack of knowledge regarding physicians’ perspectives towards biomarkers and their role in treatment optimization, where treatment intensity is reduced to minimize toxicity.

Methods

Thirty-nine academic and community oncologists participated in semi-structured qualitative interviews, providing perspectives on optimization approaches to chemotherapy treatment. Interviews were audio-recorded, transcribed, and analyzed by 2 independent coders utilizing a constant comparative method in NVivo. Major themes and exemplary quotes were extracted. A framework outlining physicians’ conception of biomarkers, and their comfortability with their use in treatment optimization, was developed.

Results

In the hierarchal model of biomarkers, level 1 is comprised of standard-of-care (SoC) biomarkers, defined by a strong level of evidence, alignment with national guidelines, and widespread utilization. Level 2 includes SoC biomarkers used in alternative contexts, in which physicians expressed confidence, yet less certainty, due to a lack of data in certain subgroups. Level 3, or experimental, biomarkers created the most diverse concerns related to quality and quantity of evidence, with several additional modulators.

Conclusion

This study demonstrates that physicians conceptualize the use of biomarkers for treatment optimization in successive levels. This hierarchy can be used to guide trialists in the development of novel biomarkers and design of future trials.
CHROMATIN REMODELING 11-dependent nucleosome occupancy affects disease resistance in rice
Authors: Liu He , Li Jing , Wang Shuai , Hua Jian , Zou Baohong
Published: July 2023

Plant immune responses involve transcriptional reprograming of defense response genes, and chromatin remodeling is important for transcriptional regulation. However, nucleosome dynamics induced by pathogen infection and its association with gene transcription are largely unexplored in plants. Here, we investigated the role of the rice (Oryza sativa) gene CHROMATIN REMODELING 11 (OsCHR11) in nucleosome dynamics and disease resistance. Nucleosome profiling revealed that OsCHR11 is required for the maintaining of genome-wide nucleosome occupancy in rice. Nucleosome occupancy of 14% of the genome was regulated by OsCHR11. Infection of bacterial leaf blight Xoo (Xanthomonas oryzae pv. oryzae) repressed genome-wide nucleosome occupancy, and this process depended on OsCHR11 function. Furthermore, OsCHR11/Xoo-dependent chromatin accessibility correlated with gene transcript induction by Xoo. In addition, accompanied by increased resistance to Xoo, several defense response genes were differentially expressed in oschr11 after Xoo infection. Overall, this study reports the genome-wide effects of pathogen infection on nucleosome occupancy, its regulation, and its contribution to disease resistance in rice.
Associations of smartphone usage patterns with sleep and mental health symptoms in a clinical cohort receiving virtual behavioral medicine care: a retrospective study
Authors: Knights Jonathan , Shen Jacob , Mysliwiec Vincent , DuBois Holly
Published: July 2023

Study Objectives

We sought to develop behavioral sleep measures from passively sensed human-smartphone interactions and retrospectively evaluate their associations with sleep disturbance, anxiety, and depressive symptoms in a large cohort of real-world patients receiving virtual behavioral medicine care.

Methods

Behavioral sleep measures from smartphone data were developed: daily longest period of smartphone inactivity (inferred sleep period [ISP]); 30-day expected period of inactivity (expected sleep period [ESP]); regularity of the daily ISP compared to the ESP (overlap percentage); and smartphone usage during inferred sleep (disruptions, wakefulness during sleep period). These measures were compared to symptoms of sleep disturbance, anxiety, and depression using linear mixed-effects modeling. More than 2300 patients receiving standard-of-care virtual mental healthcare across more than 111 000 days were retrospectively analyzed.

Results

Mean ESP duration was 8.4 h (SD = 2.3), overlap percentage 75% (SD = 18%) and disrupted time windows 4.85 (SD = 3). There were significant associations between overlap percentage (p < 0.001) and disruptions (p < 0.001) with sleep disturbance symptoms after accounting for demographics. Overlap percentage and disruptions were similarly associated with anxiety and depression symptoms (all p < 0.001).

Conclusions

Smartphone behavioral measures appear useful to longitudinally monitor sleep and benchmark depressive and anxiety symptoms in patients receiving virtual behavioral medicine care. Patterns consistent with better sleep practices (i.e. greater regularity of ISP, fewer disruptions) were associated with lower levels of reported sleep disturbances, anxiety, and depression.
Elevated nutrient supply can exert worse effects on Norway spruce than drought, viewed through chemical defence against needle rust
Authors: Ganthaler Andrea , Guggenberger Andreas , Stöggl Wolfgang , Kranner Ilse , Mayr Stefan
Published: July 2023

Abiotic factors such as water and nutrient availability can exert a dominant influence on the susceptibility of plants to various pathogens. Effects of abiotic environmental factors on phenolic compound concentrations in the plant tissue may represent one of the major underlying mechanisms, as these compounds are known to play a substantial role in plant resistance to pests. In particular, this applies to conifer trees, in which a large range of phenolic compounds are produced constitutively and/or induced by pathogen attack. We subjected Norway spruce saplings to water limitation and elevated nutrient supply over 2 years and subsequently controlled infection with the needle rust Chrysomyxa rhododendri (DC.) de Bary and analysed both constitutive and inducible phenolic compound concentrations in the needles as well as the degree of infection. Compared with the control group, both drought and fertilization profoundly modified the constitutive and pathogen-induced profiles of phenolic compounds, but had little impact on the total phenolic content. Fertilization predominantly affected the inducible phenolic response and led to higher infection rates by C. rhododendri. Drought stress, in contrast, mainly shaped the phenolic profiles in healthy plant parts and had no consequences on the plant susceptibility. The results show that specific abiotic effects on individual compounds seem to be decisive for the infection success of C. rhododendri, whereby the impaired induced response in saplings subjected to nutrient supplementation was most critical. Although drought effects were minor, they varied depending on the time and length of water limitation. The results indicate that prolonged drought periods in the future may not significantly alter the foliar defence of Norway spruce against C. rhododendri, but fertilization, often propagated to increase tree growth and forest productivity, can be counterproductive in areas with high pathogen pressure.

Highlights
Lean Health Care Internships: A Novel Systems-Based Practice Education Program for Undergraduate Medical Students
Authors: Erdmann Marjorie A. , Paramel Ipe S. , Marshall Carolyn M.
Published: July 2023

Problem

Given the United States’ urgency for systemic-level improvements to care, advancing systems-based practice (SBP) competency among future physicians is crucial. However, SBP education is inadequate, lacks a unifying framework and faculty confidence in its teaching, and is taught late in the medical education journey.

Approach

The Oklahoma State University Center for Health Systems Innovation (CHSI) created an SBP program relying on Lean Health Care for a framework and targeted medical students before their second year began. Lean curricula were developed (lecture and simulation) and a partnership with a hospital was secured for work-based practice. The CHSI developed a skills assessment tool for preliminary evaluation of the program. In June 2022, 9 undergraduate medical students responded to a Lean Health Care Internship (LHCI) presentation.

Outcomes

Student SBP skills increased after training and again after work-based practice. All 9 students reported that their conceptualization of problems in health care changed “extraordinarily,” and they were “extraordinarily” confident in their ability to approach another health care problem by applying the Lean method. The LHCI fostered an awareness of physicians as interdependent systems citizens, a key goal of SBP competency. After the internship concluded, the Lean team recommendations generated a resident-led quality assurance performance improvement initiative for bed throughput.

Next Steps

The LHCI was effective in engaging students and building SBP skills among undergraduate medical education students. The levels of student enthusiasm and skill acquisition exceeded the Lean trainers’ expectations. The researchers will continue to measure LHCI’s effect on students’ rotation experiences to better evaluate the long-term benefit of introducing SBP concepts earlier in medical education. The program’s success has spurred enthusiasm for continued collaboration with hospital and residency programs. Program administrators are exploring how to broaden access.
Testosterone Therapy Is Associated With Increased Odds of Quadriceps Tendon Injury
Authors: Meghani Ozair , Albright J. Alex , Testa Edward J. , Arcand Michel A. , Daniels Alan H. , Owens Brett D.
Published: July 2023

Background

Anabolic steroid use at supraphysiologic doses has been associated with an increased risk of tendon injury. However, the musculoskeletal effects of testosterone therapy in the clinical setting are not well understood.

Questions/purposes

(1) Is prescription testosterone associated with a higher odds of subsequent quadriceps muscle or tendon injury? (2) Is prescription testosterone associated with a higher odds of surgical repair of the quadriceps tendon?

Methods

The PearlDiver Database, which contains data on Medicaid, Medicare, and commercially insured patients, allows for a large representative sample of the US population including both publicly and privately insured patients. The database was queried for all patients between 2011 and 2018 who filled a testosterone prescription. Additionally, all quadriceps injuries using ICD-9 and ICD-10 codes between 2011 and 2018 were queried. Propensity score matching based on age, sex, Charlson comorbidity index, and specific comorbidities allowed us to create matched control groups. We used the t-test and chi-square analysis to compare the unmatched and matched cohorts. A total of 151,797 patients (123,627 male patients and 28,170 female patients) with a history of filled testosterone prescriptions were included in the study after matching with the control group, which was of equal size and representation of age, male-female proportions, and comorbidities. Chi-square and logistic regression analyses were performed to compare odds of quadriceps injury and quadriceps tendon repair among the testosterone groups to that of their respective control groups by age and sex.

Results

Within 1 year of filling prescriptions for testosterone, 0.06% (97 of 151,797) of patients experienced a quadriceps injury compared with less than 0.01% (18 of 151,797) of patients in the control group (OR 5.4 [95% CI 3.4 to 9.2]; p < 0.001). Within the sex-specific matched groups, filling a testosterone prescription was associated with an increase in the odds of quadriceps injury in male patients within 1 year of the prescription (OR 5.8 [95% CI 3.5 to 10.3]; p < 0.001). Additionally, patients who filled a testosterone prescription were at increased risk of having quadriceps tendon repair within a year of the injury than were patients in the matched control group (OR 4.7 [95% CI 2.0 to 13.8]; p = 0.001).

Conclusion

Considering these findings, it is important for physicians to counsel patients receiving testosterone replacement therapy of the substantially increased odds of quadriceps tendon injury. Future investigations into the mechanisms of influence of exogenous anabolic steroids on tendon injury remains of interest.

Level of Evidence

Level III, therapeutic study.
Improvement of Global Longitudinal Strain and Myocardial Work in Type 2 Diabetes Patients on Sodium–Glucose Cotransporter 2 Inhibitors Therapy
Authors: Russo Vincenzo , Malvezzi Caracciolo D'Aquino Marco , Caturano Alfredo , Scognamiglio Gabriella , Pezzullo Enrica , Fabiani Dario , Del Giudice Carmen , Carbone Andreina , Bottino Roberta , Caso Valentina , Nigro Gerardo , Golino Paolo , Liccardo Biagio , D'Andrea Antonello
Published: July 2023

Sodium–glucose cotransporter 2 inhibitors (SGLT2-i) are a novel class of oral hypoglycemic agents currently used among patients with type 2 diabetes mellitus (T2DM). The effects of SGLT2-i inhibitors on cardiac structure and function are not fully understood. The aim of this study is to evaluate the echocardiographic changing among patients with well-controlled T2DM treated with SGLT2-i in real-world setting. Thirty-five well-controlled T2DM patients (65 ± 9 years, 43.7% male) with preserved left ventricular ejection fraction (LVEF) and 35 age and sex-matched controls were included. T2DM patients underwent clinical and laboratory evaluation; 12-lead surface electrocardiogram; 2-dimensional color Doppler echocardiography at enrolment, before SGLT2-i administration, and at 6 months follow-up after an uninterrupted 10 mg once daily of empagliflozin (n: 21) or dapagliflozin (n: 14). Standard echocardiographic measurements, LV global longitudinal strain (LV-GLS), global wasted work, and global work efficiency were calculated. T2DM patients showed higher E\E′ ratio (8.3 ± 2.5 vs. 6.3 ± 0.9; P < 0.0001) and lower LV-GLS (15.8 ± 8.1 vs. 22.1 ± 1.4%; P < 0.0001) and global myocardial work efficiency (91 ± 4 vs. 94 ± 3%; P: 0.0007) compared with age and sex-matched controls. At 6-month follow-up, T2DM patients showed a significant increase in LVEF (58.9 ± 3.2 vs. 62 ± 3.2; P < 0.0001), LV-GLS (16.2 ± 2.8 vs. 18.7 ± 2.4%; P = 0.003), and global work efficiency (90.3 ± 3.5 vs. 93.3 ± 3.2%; P = 0.0004) values; conversely, global wasted work values (161.2 ± 33.6 vs. 112.72 ± 37.3 mm Hg%; P < 0.0001) significantly decreased. Well-controlled T2DM patients with preserved LVEF who are treated with a SGLT2-i on top of the guidelines direct medical therapy showed a favorable cardiac remodeling, characterized by the improvement of LV-GLS and myocardial work efficiency.
The effect of postpartum lifestyle interventions on blood pressure: a systematic literature review
Authors: Murray Horwitz Mara E. , Tabani Alaina , Brédy G. Saradhja , Flynn David B. , Edwards Camille V. , Curran Nadia J. , Parikh Nisha I.
Published: July 2023

Postpartum lifestyle modification is recommended to hypertension risk. We conducted a systematic literature review to assess the evidence for postpartum lifestyle interventions to reduce blood pressure. We searched for relevant publications from 2010 through November 2022. Two authors independently conducted article screening and data extraction; a third resolved discrepancies. Ultimately, nine studies met inclusion criteria. Most were randomized controlled trials and had sample sizes <100. In all but one of the eight studies reporting race data, nearly all participants identified as White. None of the studies reported a significant intervention effect on blood pressure. However, most interventions were associated with improvements in other outcomes, such as physical activity. Overall, the evidence for postpartum lifestyle interventions to reduce blood pressure is limited to a handful of studies characterized by small sample sizes and a lack of racial diversity. Additional research with larger samples, more diverse populations, and intermediate outcomes is warranted.
Bacterial Infections and Clinical Outcomes Among Febrile Infants up to 90 Days Old With SARS-CoV-2 Infection: A Multicenter Cohort Study
Authors: Jacob Ron , Padeh Gabi , Kaplan Or , Koppel Jordanna H. , Porat Danit , Weiser Giora , Levy Nitai , Cohen Noy , Capua Tali , Schnapp Zeev , Friedman Nir
Published: July 2023

We present a large, multicenter, cohort study that aimed to assess bacterial infection rates among febrile infants up to 90 days old presenting to the pediatric emergency department with severe acute respiratory syndrome coronavirus 2 infection during 2021–2022 throughout successive variant waves. Overall, 417 febrile infants were included. Twenty-six infants (6.2%) had bacterial infections. All bacterial infections consisted of urinary tract infections, and there were no invasive bacterial infections. There was no mortality.
Economic and Clinical Outcomes of Pediatric Patients Under Two With Respiratory Syncytial Virus Infection in Thailand: A Real-world Retrospective Cohort Study
Authors: Tan Chia Jie , Patikorn Chanthawat , Techasaensiri Chonnamet , Pattanaprateep Oraluck , Chaiyakunapruk Nathorn
Published: July 2023

Background:

Respiratory syncytial virus (RSV) is a common cause of acute respiratory tract infection in children, including in Thailand. We conducted this study to evaluate the economic and clinical outcomes of patients <2 years old with RSV infection at a tertiary teaching hospital in Thailand.

Methods:

This was a retrospective cohort study during 2014–2021. To be eligible, patients had to report at least 1 positive RSV test and were <2 years old. Descriptive statistics were used to describe baseline characteristics, healthcare resource utilization, direct medical costs (1 US dollars [USD] = 31.98 Thai Baht) and clinical outcomes.

Results:

Among 1370 RSV-positive patients, 49.9% of the patients (n = 683) were hospitalized at or within 3 days of RSV diagnosis with a median length of stay of 6 days (interquartile range [IQR]: 4–9 days), 38.8% were diagnosed with RSV-related respiratory complications (n = 532) and 1.5% died during the hospitalization episode (n = 20). A total of 22.5% of hospitalized patients (n = 154) received critical care during the hospitalization episode. The median cost of each RSV episode was USD539 (IQR: USD167–USD2106) and was higher among hospitalized patients (median: USD2112; IQR: USD1379–USD3182) compared with nonhospitalized patients (median: USD167; IQR: USD112–USD276).

Conclusions:

RSV infection represents a potentially important contributor to healthcare resource use and medical costs among children <2 years old in Thailand. Coupled with epidemiologic data, findings from our study will be useful to illustrate the overall economic burden associated with RSV infection among children in Thailand.
Customized Nasal Prosthesis for a Jones Lacrimal Bypass Tube Using 3-Dimensional Planning and Printing Technology
Authors: Vandeurzen Jelle , Vander Poorten Vincent , de Jong Maarten , Mombaerts Ilse
Published: July 2023

A 35-year-old woman was treated for extensive squamous cell carcinoma of the nasal septal mucosa with total rhinectomy, including removal of the nasal septum, and chemoradiotherapy. A magnet-retained nasal prosthesis was fitted. She had developed right-sided epiphora from total proximal lacrimal canalicular obstruction, for which an angled Jones lacrimal bypass tube was inserted. The tube, however, intermittently rotated in the nasal cavity, causing recurrent epiphora and irritation at the caruncular site. With the aid of 3-dimensional technology, we designed a septum for the prosthesis that stabilized the tube within the nasal cavity. At the follow-up 2 years later, the patient was satisfied with the nasal prosthesis and lacrimal stent. To our knowledge, this report is the first to describe a patient-specific nasal prosthesis adapted for a Jones tube after total rhinectomy.
Accessory Muscles Associated With the Levator Palpebrae Superioris Muscle in 100 Cadavers
Authors: Nteli Chatzioglou Gkionoul , Kale Ayşin , Özbilen Kemal Turgay , Önal Vildan , Coşkun Osman , Gayretli Özcan
Published: July 2023

Purpose:

This study aimed to determine the variations of the levator palpebrae superioris muscle and to reveal its morphological features.

Methods:

This study conducted on 100 adult orbit cadavers in the Department of Anatomy, Istanbul University, used an exploratory, descriptive research design. The anatomical and morphological variations of the levator palpebrae superioris muscle and its relationship with the superior ophthalmic vein were evaluated.

Results:

Variations of levator palpebrae superioris muscle were discovered in 11 of 100 orbits. Single (9%), double (1%), and triple (1%) accessory muscle slips were observed. The origin of accessory muscle slips showed variation as the accessory muscle slips originated either from the proximal or distal half of the levator palpebrae superioris muscle. Also, the insertions of accessory muscle slips were variable, as they were inserted into levator aponeurosis, trochlea, lacrimal gland, lateral orbital wall, or the fascia of the superior ophthalmic vein.

Conclusions:

Accessory muscles associated with levator aponeurosis were found in a significant proportion of cadavers. These muscles may cause confusion in orbital surgery and should be taken into account during surgical planning and orientation in the superior orbit.
Chronic Traumatic Encephalopathy in Soccer Players: Review of 14 Cases
Authors: Hageman Gerard , Hageman Ivar , Nihom Jik
Published: July 2023

Objective:

Exposure to repetitive sports-related concussions or (sub)concussive head trauma may lead to chronic traumatic encephalopathy (CTE). Which impact (heading or concussion) poses the greatest risk of CTE development in soccer players?

Design:

Narrative review.

Setting:

Teaching hospital and University of Applied sciences.

Patients:

A literature search (PubMed) was conducted for neuropathologic studies in the period 2005-December 2022, investigating soccer players with dementia and a CTE diagnosis, limited to English language publications. 210 papers were selected for final inclusion, of which 7 papers described 14 soccer players.

Assessment:

Magnetic resonance imaging studies in soccer players show that lifetime estimates of heading numbers are inversely correlated with cortical thickness, grey matter volume, and density of the anterior temporal cortex. Using diffusion tensor imaging–magnetic resonance imaging, higher frequency of headings—particularly with rotational accelerations—are associated with impaired white matter integrity. Serum neurofilament light protein is elevated after heading.

Main Outcome Measures:

Chronic traumatic encephalopathy pathology, history of concussion, heading frequency.

Results:

In 10 of 14 soccer players, CTE was the primary diagnosis. In 4 cases, other dementia types formed the primary diagnosis and CTE pathology was a concomitant finding. Remarkably, 6 of the 14 cases had no history of concussion, suggesting that frequent heading may be a risk for CTE in patients without symptomatic concussion. Rule changes in heading duels, management of concussion during the game, and limiting the number of high force headers during training are discussed.

Conclusions:

Data suggest that heading frequency and concussions are associated with higher risk of developing CTE in (retired) soccer players. However based on this review of only 14 players, questions persist as to whether or not heading is a risk factor for CTE or long-term cognitive decline.
Exhaled breath analysis in interstitial lung disease
Authors: van der Sar Iris G. , Wijsenbeek Marlies S. , Moor Catharina C.
Published: July 2023

Purpose of review

There is a need for better noninvasive tools to diagnose interstitial lung disease (ILD) and predict disease course. Volatile organic compounds present in exhaled breath contain valuable information on a person's health and may be a novel biomarker in ILD. In this review, we will give an overview of the basic principles of breath analysis, summarize the available evidence in ILD, and discuss future perspectives.

Recent findings

An increasing number of studies on exhaled breath analysis were performed over the last decade in patients with ILD, using two methods for exhaled breath analysis: gas chromatography-mass spectrometry and electronic nose technology. Most studies showed high accuracy for diagnosis of ILD, but study design and methods widely varied. Studies investigating the potential of electronic nose technology to predict treatment response and disease behavior are ongoing.

The majority of studies using exhaled breath analysis in ILD show promising results for diagnostic purposes, but validation studies are lacking. Larger prospective longitudinal studies using standardized methods are needed to collect the evidence required for developing an approved diagnostic medical test.
Evaluation of Histopathologic Alterations in First-trimester COVID-19-positive Pregnancies Ending in Abortion
Authors: Adanaş Aydin Gültekin , Nalbant Melike , Ünal Serhat , Tosun Serkan
Published: July 2023

This study aims to evaluate histopathologic alterations and the presence of chronic histiocytic intervillositis in first-trimester coronavirus-2019 (COVID-19)-positive pregnancies ending in abortion, compared with those at a similar gestational week and undergoing curettage before the pandemic. This retrospective case-control study consisted of 9 patients who were infected with COVID-19 and undergoing curettage for abortion between April 2020 and January 2021. The control group consisted of 34 patients with a similar gestational age who underwent curettage for abortion before August 2019. Demographic and clinical data were recorded. A histopathologic examination of the placental specimens was performed. The CD68 immunostaining was performed to detect intravillous and intervillous histiocytes. At the time of diagnosis of COVID 19, 7 patients (77.8%) of COVID-19-positive women had symptoms with the most common symptoms of fatigue (66.7%) and cough (55.6%). Histopathologic examination revealed that the rate of intravillous and intervillous calcification, intervillous fibrinoid deposition, hydropic villi and acute lymphocytic villitis, and fetal and maternal thrombi was significantly higher in the COVID-19-positive patients than the control group (P=0.049, 0.002, 0.049, 0.014, 0.008, 0.001, and 0.014, respectively). There was a significant difference in the CD68 staining of the intravillous and intervillous histiocytes between the groups (P=0.001). This study showed a significant increase in the intervillous fibrinoid deposition, thrombi formation in the maternal and fetal vascular structures, acute lymphocytic villitis, and an increase of CD68+ stained histiocytes in the intravillous and intervillous spaces in women infected with COVID-19 during the first trimester of pregnancy.
Uterine Leiomyosarcoma With Osteoclast-like Giant Cells: Report of 2 Cases and Review of Literature
Authors: Chen Zhengshan , Ji Jianling , Yung Evan , Martin Sue Ellen , Walia Saloni
Published: July 2023

Leiomyosarcoma (LMS) with osteoclast-like giant cells (OLGCs) is a rare entity with only 18 reported cases thus far. It is not known whether these OLGCs are a reactive or malignant component of LMS. Herein we describe the clinical, histologic, and molecular characteristics of 2 cases of LMS with OLGCs and perform a brief literature review. In 2 of our cases, the OLGCs, marked with CD68, had a low proliferation index with Ki67 and did not show diffuse positivity for smooth muscle markers by immunohistochemistry. By next-generation sequencing, one case harbored a clinically significant TP53 mutation, which has been reported in a significant subset of conventional LMSs. In this case, based on immunohistochemistry, OLGCs showed different molecular alterations as compared with LMS. Although we did not show a distinct immunophenotype or molecular profile for LMS with OLGCs, this study provides additional data on this rare entity.
HER2/ERBB2 Immunohistochemical Expression and Copy Number Status in Ovarian Mucinous Tumors
Authors: Smithgall Marie C. , Yemelyanova Anna , Mathew Susan , Gogineni Swarna , He Bing , Zhang Taotao , Robinson Brian D. , Tu Jiangling J.
Published: July 2023

Primary mucinous ovarian carcinoma (MOC) is a rare ovarian epithelial cancer, which is often refractory to chemotherapy. HER2-targeting therapy is being increasingly considered in gynecologic malignancies. Although there have been limited studies examining the HER2 status of such tumors, the criteria for HER2 expression scoring have not been standardized for MOC as it has for other sites. This study aimed to survey immunohistochemical HER2 expression patterns in MOC and its precursor, mucinous borderline tumor in correlation with fluorescence in situ hybridization (FISH). Immunohistochemistry (IHC) for HER2 was performed on 12 cases of MOC and 15 mucinous borderline tumors, including 7 with intraepithelial carcinoma. HER2 expression was quantified using the gastric/gastroesophageal carcinoma protocol. Cases were considered 3+ if the tumor cells displayed strong complete or basolateral/lateral membranous staining in ≥10% of tumor cells. Cases (2+) had weak to moderate staining in ≥10% of tumor cells. Cases (1+) had faint staining in ≥10% of tumor cells. Cases considered 0 had no staining or faint staining in <10% of tumor cells. HER2 expression was also quantified with the endometrial serous carcinoma protocol, which uses a 30% tumor cell positivity cutoff. FISH for HER2 was performed on all 3+ and 2+ and a subset of 1+ cases. Of the MOC cases, 25% were 3+ and 1 mucinous borderline tumor with intraepithelial carcinoma had 3+ staining. All 3+ IHC MOC cases had >30% basolateral membranous staining. HER2 amplification was confirmed by FISH on all 3+ IHC cases and in one 2+ IHC case of MOC. Up to 25% of mucinous ovarian tumors showed HER2 IHC overexpression with an excellent correlation between IHC and FISH using the HER2 scoring protocol for either gastric/gastroesophageal carcinoma or uterine serous carcinoma.
Promotion of Para athlete well-being (the PROPEL studies): A cross-sectional study of sleep in Para athletes across two nations
Authors: Badenhorst Marelise , Brown James , Runciman Phoebe , Fliess Douer Osnat , Derman Wayne
Published: July 2023

Objectives

Limited research exists on the sleep profiles of South African Para athletes. The aim of this study was to describe sleep quality, day-time sleepiness and chronotype of South African Para athletes, and to compare the relationship between sleep-related outcomes and demographic factors to athletes from a higher resourced country.

Design

A descriptive, cross-sectional survey was conducted. Sleep-related characteristics were assessed with the Pittsburgh Sleep Quality Index, Epworth Sleepiness scale and Morningness-Eveningness Questionnaire. Multiple regression models were run with and without country as independent variable.

Results

124 South African athletes and 52 Israeli athletes were included. 30% of South African athletes presented with excessive daytime sleepiness, 35% slept 6 hours or less/night, and 52% reported poor sleep quality. 33% of Israeli athletes reported excessive daytime sleepiness, 29% slept 6 hours or less and 56% reported poor sleep quality. Chronotype was the only variable that differed significantly between countries (over-representation of morning types in South African athletes, and intermediate types in Israeli athletes). Intermediate chronotypes had significantly greater odds of excessive daytime sleepiness (p = 0.007) and poor sleep quality (p = 0.002) than morning types, irrespective of country.

Conclusion

The high prevalence of poor sleep among both South African and Israeli Para athletes warrants further investigation.
COMPARATIVE STUDY OF THE PAIN, FUNCTION AND BIOMARKERS OF JOINT DISEASE IN THE TRANSITION TO ADULTHOOD IN INDIVIDUALS WITH AND WITHOUT CEREBRAL PALSY
Authors: Hanaoka Chad , Gaebler-Spira Deborah , Pichika Rajeswari , Jayabalan Prakash
Published: July 2023

Background

Biomarkers have potential to identify early signs of joint disease. This study compared joint pain and function in adolescents and young adults with CP compared to individuals without.

Methods

Cross-sectional study compared individuals with CP(n = 20), aged 13-30 with Gross Motor Function Classification System (GMFCS) I-III and age-matched individuals without CP(n = 20). Knee and hip joint pain measured using Numeric Pain Rating Scale (NPRS) and Knee injury and Osteoarthritis Outcome Score (KOOS) and Hip dysfunction and Osteoarthritis Outcome Score (HOOS) surveys. Objective strength and function were also measured. Biomarkers for tissue turnover (serum COMP, urinary CTX-II) and cartilage degradation (serum MMP-1, MMP-3) were measured in blood and urinary samples.

Findings

Individuals with CP had increased knee and hip joint pain, reduced leg strength, reduced walking and standing speeds, and ability to carry out activities of daily living(p < 0.005) compared to controls. They also had higher serum MMP-1(p < 0.001) and urinary CTX-II levels(p < 0.05). Individuals with CP who were GMFCS I and II demonstrated reduced hip joint pain(p = 0.02) and higher MMP-1 levels (p = 0.02) compared to GMFCS III.

Interpretation

Individuals with CP with less severe mobility deficits had higher MMP-1 levels likely due to more prolonged exposure to abnormal joint loading forces but experienced less joint pain.
Functional Reconstruction of Arches of the Foot With Vascularized Fibula Flap
Authors: Zor Fatih , Bayram Yalcin , Kulahci Yalcin
Published: July 2023

The skeletal integrity of the foot is as important as the soft tissue coverage of the foot. In this article, we present reconstruction of arches of foot with free fibula flap. Three patients with composite foot defects underwent reconstruction a with vascularized fibula flap. Free fibula flap was used to reconstruct the transverse arch in 2 cases and longitudinal arch in 1 case. The mean follow-up period was 3.2 years. Functional outcome was evaluated with 3-dimensional motion analyses at 12 months postoperatively. No early or late complications were encountered, and all patients were satisfied with both cosmetic appearance and functional aspects of their foot. Fibular bone showed a very healthy course without any fracture, resorption, extrusion, or migration. Three-dimensional motion analyses revealed acceptable gait capability in all cases showing successful restoration of the foot arches. As a conclusion, osteocutaneous free fibula flap can provide functional and durable reconstruction of longitudinal and transverse arches of the foot, especially if preservation of the length or the width of the foot is desired.
INVESTIGATION INTO P2Y RECEPTOR FUNCTION IN PLATELETS FROM PATIENTS WITH SEPSIS
Authors: Arkless Kate L. , Fish Matthew , Jennings Aislinn , Page Clive P. , Shankar-Hari Manu , Pitchford Simon C.
Published: July 2023

Key underlying pathological mechanisms contributing to sepsis are hemostatic dysfunction and overwhelming inflammation. Platelet aggregation is required for hemostasis, and platelets are also separately involved in inflammatory responses that require different functional attributes. Nevertheless, P2Y receptor activation of platelets is required for this dichotomy of function. The aim of this study was to elucidate whether P2YR-dependent hemostatic and inflammatory functions were altered in platelets isolated from sepsis patients, compared with patients with mild sterile inflammation. Platelets from patients undergoing elective cardiac surgery (20 patients, 3 female) or experiencing sepsis after community-acquired pneumonia (10 patients, 4 female) were obtained through the IMMunE dysfunction and Recovery from SEpsis-related critical illness in adults (IMMERSE) Observational Clinical Trial. In vitro aggregation and chemotaxis assays were performed with platelets after stimulation with ADP and compared with platelets isolated from healthy control subjects (7 donors, 5 female). Cardiac surgery and sepsis both induced a robust inflammatory response with increases in circulating neutrophil counts with a trend toward decreased circulating platelet counts being observed. The ability of platelets to aggregate in response to ex vivo ADP stimulation was preserved in all groups. However, platelets isolated from patients with sepsis lost the ability to undergo chemotaxis toward N-formylmethionyl-leucyl-phenylalanine, and this suppression was evident at admission through to and including discharge from hospital. Our results suggest that P2Y1-dependent inflammatory function in platelets is lost in patients with sepsis resulting from community-acquired pneumonia. Further studies will need to be undertaken to determine whether this is due to localized recruitment to the lungs of a platelet responsive population or loss of function as a result of dysregulation of the immune response.
CHRONIC ETHANOL USE WORSENS GUT PERMEABILITY AND ALTERS TIGHT JUNCTION EXPRESSION IN A MURINE SEPSIS MODEL
Authors: Oami Takehiko , Yumoto Tetsuya , Shimazui Takashi , Sarmiento Sofia , Klingensmith Nathan J. , Chen Ching-Wen , Otani Shunsuke , Liang Zhe , Burd Eileen M. , Mahdi Zaid K. , Ford Mandy L. , Coopersmith Craig M.
Published: July 2023

Alcohol use disorder is associated with increased mortality in septic patients. Murine studies demonstrate that ethanol/sepsis is associated with changes in gut integrity. This study examined intestinal permeability after ethanol/sepsis and investigated mechanisms responsible for alterations in barrier function. Mice were randomized to drink either 20% ethanol or water for 12 weeks and then were subjected to either sham laparotomy or cecal ligation and puncture (CLP). Intestinal permeability was disproportionately increased in ethanol/septic mice via the pore, leak, and unrestricted pathways. Consistent with increased permeability in the leak pathway, jejunal myosin light chain (MLC) kinase (MLCK) expression and the ratio of phospho-MLC to total MLC were both increased in ethanol/CLP. Gut permeability was altered in MLCK−/− mice in water/CLP; however, permeability was not different between WT and MLCK−/− mice in ethanol/CLP. Similarly, jejunal IL-1β levels were decreased while systemic IL-6 levels were increased in MLCK−/− mice in water/CLP but no differences were identified in ethanol/CLP. While we have previously shown that mortality is improved in MLCK−/− mice after water/CLP, mortality was significantly worse in MLCK−/− mice after ethanol/CLP. Consistent with an increase in the pore pathway, claudin 4 levels were also selectively decreased in ethanol/CLP WT mice. Furthermore, mRNA expression of jejunal TNF and IFN-γ were both significantly increased in ethanol/CLP. The frequency of CD4+ cells expressing TNF and IL-17A and the frequency of CD8+ cells expressing IFN-γ in Peyer’s Patches were also increased in ethanol/CLP. Thus, there is an ethanol-specific worsening of gut barrier function after CLP that impacts all pathways of intestinal permeability, mediated, in part, via changes to the tight junction. Differences in the host response in the setting of chronic alcohol use may play a role in future precision medicine approaches toward the treatment of sepsis.
Event-related Potentials Corresponding to Decision-making Under Uncertain Conditions
Authors: Farrar Danielle C. , Killiany Ronald J. , Moss Mark B. , Fink Brandi , Budson Andrew E.
Published: July 2023

Background:

Decision-making is essential to human functioning, and resolving uncertainty is an essential part of decision-making. Impaired decision-making is present in many pathological conditions, and identifying markers of decision-making under uncertainty will provide a measure of clinical impact in future studies of therapeutic intervention for impaired decision-making.

Objective:

To describe EEG event-related potentials (ERPs) correlating with decision-making under uncertain conditions when compared with certain conditions.

Method:

We used a novel card-matching task based on the Wisconsin Card Sorting Test to describe the neural correlates of uncertainty, as measured by EEG, in a group of 27 neurotypical individuals. We evaluated 500-ms intervals in the 2 seconds after card presentation to identify ERPs that are associated with maximal uncertainty compared with maximal certainty.

Results:

After correcting for multiple comparisons, we identified an ERP in the 500–1000-ms time frame (certain > uncertain, max amplitude 12.73 µV, latency 914 ms) in the left posterior inferior region of the scalp. We also found a P300-like ERP in the left frontal and parietal regions in the 0–500-ms time frame when the individuals received correct versus incorrect feedback (incorrect feedback > correct feedback, max amplitude 1.625 µV, latency 339 ms).

Conclusion:

We identified an ERP in the 500–1000-ms time frame (certain > uncertain) that may reflect the resolution of uncertainty, as well as a P300-like ERP when feedback is presented (incorrect feedback > correct feedback). These findings can be used in future studies to improve decision-making and resolve uncertainty on the described markers.
Voltage-calibrated, finely tunable protein assembly
Authors: Lin Yin-Chen , Masquelier Eloise , Al Sabeh Yahya , Sepunaru Lior , Gordon Michael J. , Morse Daniel E.
Published: July 2023

Neuronally triggered phosphorylation drives the calibrated and cyclable assembly of the reflectin signal transducing proteins, resulting in their fine tuning of colours reflected from specialized skin cells in squid for camouflage and communication. In close parallel to this physiological behaviour, we demonstrate for the first time that electrochemical reduction of reflectin A1, used as a surrogate for charge neutralization by phosphorylation, triggers voltage-calibrated, proportional and cyclable control of the size of the protein's assembly. Electrochemically triggered condensation, folding and assembly were simultaneously analysed using
in situ
dynamic light scattering, circular dichroism and UV absorbance spectroscopies. The correlation of assembly size with applied potential is probably linked to reflectin's mechanism of dynamic arrest, which is controlled by the extent of neuronally triggered charge neutralization and the corresponding fine tuning of colour in the biological system. This work opens a new perspective on electrically controlling and simultaneously observing reflectin assembly and, more broadly, provides access to manipulate, observe and electrokinetically control the formation of intermediates and conformational dynamics of macromolecular systems.
Implications of different membrane compartmentalization models in particle-based
in silico
studies
Authors: Henning Philipp , Köster Till , Haack Fiete , Burrage Kevin , Uhrmacher Adelinde M.
Published: July 2023

Studying membrane dynamics is important to understand the cellular response to environmental stimuli. A decisive spatial characteristic of the plasma membrane is its compartmental structure created by the actin-based membrane-skeleton (fences) and anchored transmembrane proteins (pickets). Particle-based reaction–diffusion simulation of the membrane offers a suitable temporal and spatial resolution to analyse its spatially heterogeneous and stochastic dynamics. Fences have been modelled via hop probabilities, potentials or explicit picket fences. Our study analyses the different approaches’ constraints and their impact on simulation results and performance. Each of the methods comes with its own constraints; the picket fences require small timesteps, potential fences might induce a bias in diffusion in crowded systems, and probabilistic fences, in addition to carefully scaling the probability with the timesteps, induce higher computational costs for each propagation step.
The dynamic resilience of urban labour networks
Authors: Feng Xiangnan , Rutherford Alex
Published: July 2023

Both cities and markets are well understood as complex systems which are amenable to analysis using physically inspired methods. Cities have shown fascinating universality with size, while labour markets modelled as networks have considerable explanatory power. Labour markets are a particularly attractive domain of study in this context due to societal importance, the influx of high-resolution data as well as exogenous influence of automation. While much previous work has studied the economic characteristics of cities as a function of size and examined the exposure of urban economies to automation, this has often been from a static perspective. In this work, we examine the diffusive properties of labour markets and examine their variance across cities. More specifically, we identify the occupations which are most important in promoting the diffusion of beneficial or deleterious properties. To this end, we propose a new measure of node centrality empSI. We find that these properties of influence vary considerably with city size.
The effect of stent graft curvature on the hemodynamic displacement force after abdominal aortic aneurysm endovascular repair
Authors: Brand Moshe , Yoel Bar , Eichler Eran , Speter Chen , Halak Moshe , Marom Gil
Published: July 2023

Endovascular aortic aneurysm repair is a minimally invasive procedure with low mortality and morbidity. Clinical studies have revealed that a displacement force (DF) can cause stent graft (SG) migration in some circumstances requiring repeated intervention. This study aims to determine the relationship between the SG curvature and the calculated DF from four patient-specific computational fluid dynamics models. The SG's curvature was defined according to the centrelines of the implanted SG's branches. The centrelines were defined as either intersecting or separated lines. The centreline curvature (CLC) metrics were calculated based on the local curvature radii and the distances from the centrelines of idealized straight branches. The average CLC value and average variation were calculated to represent the entire graft's curvature. These CLC calculations were compared, and the method that gave the best correlation to the calculated DF was found. The optimal correlation is obtained from calculating the CLC average variation using separated centrelines and distance from straight lines, with an
R
2
= 0.89. Understanding the relationship between vascular morphology and DF can help identify at-risk patients before the procedure. In these cases, we can provide appropriate treatment and follow up with the patient to prevent future failure.
Evolutionary walks through flower colour space driven by gene expression inPetuniaand allies (Petunieae)
Authors: Wheeler Lucas C. , Dunbar-Wallis Amy , Schutz Kyle , Smith Stacey D.
Published: July 2023

The structure and function of biochemical and developmental pathways determine the range of accessible phenotypes, which are the substrate for evolutionary change. Accordingly, we expect that observed phenotypic variation across species is strongly influenced by pathway structure, with different phenotypes arising due to changes in activity along pathway branches. Here, we use flower colour as a model to investigate how the structure of pigment pathways shapes the evolution of phenotypic diversity. We focus on the phenotypically diverse Petunieae clade in the nightshade family, which containsca180 species ofPetuniaand related genera, as a model to understand how flavonoid pathway gene expression maps onto pigment production. We use multivariate comparative methods to estimate co-expression relationships between pathway enzymes and transcriptional regulators, and then assess how expression of these genes relates to the major axes of variation in floral pigmentation. Our results indicate that coordinated shifts in gene expression predict transitions in both total anthocyanin levels and pigment type, which, in turn, incur trade-offs with the production of UV-absorbing flavonol compounds. These findings demonstrate that the intrinsic structure of the flavonoid pathway and its regulatory architecture underlies the accessibility of pigment phenotypes and shapes evolutionary outcomes for floral pigment production.