bluuebunny/crossref_metadata_2025 huggingface dataset:
The COVID-19 Pandemic Significantly Impacts Pregnancy Planning and Mental Health of Women With Inflammatory Bowel Disease
Authors: Tandon Parul , O’Connor Katie , Nguyen Geoffrey , Maxwell Cynthia , Huang Vivian
Published: January 2022

Background and Goals:

The coronavirus disease 2019 (COVID-19) pandemic has significantly impacted daily life, particularly in those with inflammatory bowel disease (IBD). We aimed to determine the impact of the pandemic on the pregnancy planning and mental health of women with IBD.

Methods:

Women with IBD (age 18 to 45 y) were asked to complete anonymous surveys on the impact of the COVID-19 pandemic on pregnancy planning and mental health symptoms such as stress (Perceived Stress Scale), depression (Patient Health Questionnaire-9), and anxiety (Generalized Anxiety Disorder-7). Univariate and multivariable analyses were conducted to identify risk factors associated with stress, depression, and anxiety during the pandemic.

Results:

Seventy-three women with IBD were included (mean age: 32.1). Of 39 patients who were preconception, 20 (51.3%) reported a significant impact of the pandemic on pregnancy planning, with common reasons for not planning conception being fear of transmission of the virus to the fetus, lack of social supports, and no desire to be in hospital during pregnancy. Over half of all women reported an increase in stress and depression symptoms during the pandemic, with over half also reporting symptoms of anxiety. On multivariable linear regression analyses, increased anxiety levels were a significant predictor of increased stress and depression symptoms during the pandemic. Urban residence and younger age were significant predictors of increased anxiety symptoms during the pandemic.

Conclusion:

A significant proportion of women with IBD experienced an impact of the COVID-19 pandemic on pregnancy planning and mental health illnesses such as stress, depression, and anxiety.
Crossed cerebellar diaschisis in Alzheimer’s disease
Authors: Tripathi Shailendra Mohan , Murray Alison D. , Wischik Claude M. , Schelter Bjoern
Published: January 2022

Background

Crossed cerebellar diaschisis (CCD) is characterized by hypometabolism and hypoperfusion on molecular imaging in the cerebellum due to a supratentorial lesion on the contralateral side. CCD is a well-established phenomenon in acute or subacute conditions such as infarction but it has been less well described in chronic conditions such as neurodegenerative dementias. Here, we investigate CCD in a large sample of 830 people meeting research criteria for Alzheimer’s disease (AD) using [18F]fluorodeoxyglucose-positron emission tomography (FDG-PET).

Materials and methods

This study is based on FDG-PET data collected at baseline as part of two large-scale Phase III clinical trials of a novel tau aggregation inhibitor medication, methylthioninium in mild to moderate AD participants. Quantification of FDG-PET hypometabolism was carried out using standardized uptake value ratio (SUVR), with the pons as the comparison region. SUVR was compared in different regions of interest between the right and left hemispheres of the brain and cerebellum in people with mild AD (Mini-Mental State Examination score ≥ 20).

Results

Comparison of SUVR in different brain regions demonstrated significant differences in the temporal, occipital and cerebellar cortices. Right and left asymmetry was noted with lower SUVR in the left temporal and occipital regions, whereas SUVR was lower in the right side of the cerebellum.

Conclusion

Here, we found robust evidence of CCD in a large sample of people with AD, a chronic neurodegenerative condition. The presence of this phenomenon in AD opens up a new avenue of research in AD pathogenesis and has the potential to change future diagnostic and therapeutic strategies.
Comparison of reprojected bone SPECT/CT and planar bone scintigraphy for the detection of bone metastases in breast and prostate cancer
Authors: Arvola Samuli , Seppänen Marko , Malaspina Simona , Mätzke Sorjo , Raiko Juho , Timonen Kirsi L. , Ettala Otto , Jambor Ivan , Anttinen Mikael , Kuisma Anna , Löyttyniemi Eliisa , Boström Peter J. , Sohlberg Antti , Noponen Tommi
Published: January 2022

Objective

The aim of this study was to compare reprojected bone SPECT/CT (RBS) against planar bone scintigraphy (BS) in the detection of bone metastases in breast and prostate cancer patients.

Methods

Twenty-six breast and 105 prostate cancer patients with high risk for bone metastases underwent 99mTc-HMDP BS and whole-body SPECT/CT, 1.5-T whole-body diffusion-weighted MRI and 18F-NaF or 18F-PSMA-1007 PET/CT within two prospective clinical trials (NCT01339780 and NCT03537391). Consensus reading of all imaging modalities and follow-up data were used to define the reference standard diagnosis. The SPECT/CT data were reprojected into anterior and posterior views to produce RBS images. Both BS and RBS images were independently double read by two pairs of experienced nuclear medicine physicians. The findings were validated against the reference standard diagnosis and compared between BS and RBS on the patient, region and lesion levels.

Results

All metastatic patients detected by BS were also detected by RBS. In addition, three metastatic patients were missed by BS but detected by RBS. The average patient-level sensitivity of two readers for metastases was 75% for BS and 87% for RBS, and the corresponding specificity was 79% for BS and 39% for RBS. The average region-level sensitivity of two readers was 64% for BS and 69% for RBS, and the corresponding specificity was 96% for BS and 87% for RBS.

Conclusion

Whole-body bone SPECT/CT can be reprojected into more familiar anterior and posterior planar images with excellent sensitivity for bone metastases, making additional acquisition of planar BS unnecessary.
Test–retest repeatability and interobserver variation of healthy tissue metabolism using 18F-FDG PET/CT of the thorax among lung cancer patients
Authors: Malaih Afnan A. , Dunn Joel T. , Nygård Lotte , Kovacs David G. , Andersen Flemming L. , Barrington Sally F. , Fischer Barbara M.
Published: January 2022

Objectives

The aim of this study was to assess the test–retest repeatability and interobserver variation in healthy tissue (HT) metabolism using 2-deoxy-2-[18F]fluoro-d-glucose (18F-FDG) PET/computed tomography (PET/CT) of the thorax in lung cancer patients.

Methods

A retrospective analysis was conducted in 22 patients with non-small cell lung cancer who had two PET/CT scans of the thorax performed 3 days apart with no interval treatment. The maximum, mean and peak standardized uptake values (SUVs) in different HTs were measured by a single observer for the test–retest analysis and two observers for interobserver variation. Bland–Altman plots were used to assess the repeatability and interobserver variation. Intrasubject variability was evaluated using within-subject coefficients of variation (wCV).

Results

The wCV of test–retest SUVmean measurements in mediastinal blood pool, bone marrow, skeletal muscles and lungs was less than 20%. The left ventricle (LV) showed higher wCV (>60%) in all SUV parameters with wide limits of repeatability. High interobserver agreement was found with wCV of less than 10% in SUVmean of all HT, but up to 22% was noted in the LV.

Conclusion

HT metabolism is stable in a test–retest scenario and has high interobserver agreement. SUVmean was the most stable metric in organs with low FDG uptake and SUVpeak in HTs with moderate uptake. Test–retest measurements in LV were highly variable irrespective of the SUV parameters used for measurements.
Polyarteritis nodosa
Authors: Bilginer Yelda , Ozen Seza
Published: January 2022

Purpose of review

The aim is to review recent reports on childhood polyarteritis nodosa, including recent reports on treatment and outcome. Recently deficiency of adenosine deaminase-2 (ADA2), which may present as a polyarteritis nodosa-mimic, is becoming an important part of our practice. We also aim to highlight differences of childhood polyarteritis nodosa with deficiency of ADA2 as well as adult-onset disease.

Recent findings

The few recent childhood series confirm the systemic nature of this vasculitis with predominantly medium-vessel involvement. American College of Rheumatology Vasculitis foundation has suggested recommendations for the management of this vasculitis. Unfortunately, we lack large patient numbers to provide us high evidence for the treatment of these patients. However, for induction mycophenolate mofetil or shorter courses of cyclophosphamide can be considered.

Deficiency of ADA2 is now in the differential diagnosis of polyarteritis nodosa patients presenting with a family history and/or stroke with hematological and/or immunological abnormalities.

We need collaborative work to define management and treatment strategies for childhood polyarteritis nodosa. Distinguishing deficiency of ADA2 is important because the treatment is different.
Galactagogues and Lactation
Authors: Balkam Jane J.
Published: January 2022

Development of a milk supply is a complex process that is not always understood by women who are breastfeeding. Galactagogues are substances commonly used by breastfeeding women who perceive that they have an insufficient milk supply. They can be herbal substances or pharmaceuticals. Herbal galactagogues are advertised and sold to women as capsules, cookies, milk shakes, and teas, as well as other forms of herbal supplements. Herbal galactagogues are classified as dietary supplements and not reviewed or regulated by the U.S. Food and Drug Administration. There are limited data on their safety and efficacy. Women experiencing problems with their milk supply should receive a thorough and thoughtful assessment of the situation. There are many factors that should be considered when counseling breastfeeding women about use of galactagogues. The physiology of lactation, process of milk supply development, and the evidence for use of galactagogues are reviewed to add to the knowledge of nurses and other health care providers working with women who are breastfeeding.
Prevalence of and Theoretical Explanation for Type 2 Benign Paroxysmal Positional Vertigo
Authors: Harmat Kinga , Tamás László T. , Schubert Michael C. , Gerlinger Imre , Komoly Sámuel , Büki Béla
Published: January 2022

Background and Purpose:

A variant of benign paroxysmal positional vertigo (BPPV) involves the subjective report of vertigo without the coinciding nystagmus. This presentation includes truncal retropulsion when sitting up from the ipsilesional provocative test (ie, Dix-Hallpike), which we term type 2 BPPV. The primary objective of this study is to prospectively determine the prevalence and describe the clinical course of type 2 BPPV. We offer a theoretical explanation for the absence of nystagmus.

Methods:

Prospective, observational study carried out in 2 tertiary hospitals. One hundred eighty patients (134 women, 46 men) met the inclusion criteria and were included between January 10, 2018, and October 30, 2019. Efficacy of physical therapy maneuvers was determined at 1-week follow-up. Three-dimensional reconstructions of the planes of the semicircular canal cupula from histological preparations are offered as evidence for the theoretical explanation.

Results:

One-third of the patients met the criteria for type 2 BPPV; the remainder had typical posterior or horizontal semicircular canal involvement. Symptoms from type 2 BPPV were longer in duration yet responded favorably to physical therapy maneuvers. Upon repeat testing, 19 patients treated for posterior canalithiasis developed a slight, persistent positional downbeat nystagmus in the Dix-Hallpike position that we propose as evidence the otoconia entered the short arm of the posterior semicircular canal.

Discussion and Conclusions:

Our data and 3-dimensional rendering suggest the report of vertigo, yet absent nystagmus in type 2 BPPV is from otoconia aligning with the gravitoinertial vector during provocative testing that precludes cupular stimulation. Type 2 BPPV appears to be a common and treatable form of vertigo.

Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1 available at: http://links.lww.com/JNPT/A372).
0.45% Versus 0.9% Saline in 5% Dextrose as Maintenance Fluids in Children Admitted With Acute Illness
Authors: Ratnjeet Kumar , Pallavi Pallavi , Jhamb Urmila , Saxena Romit
Published: January 2022

Background

The safety of giving intravenous (IV) maintenance fluids according to Holliday and Segar's recommendations of 1957 has recently been questioned after reports of complications caused by iatrogenic hyponatremia in children receiving hypotonic fluids. However, the current practice of choice of maintenance IV fluids for hospitalized children varies worldwide. This study was planned to compare 0.45% and 0.9% saline in 5% dextrose at standard maintenance rates in hospitalized children aged 3 months to 12 years.

Objective

Primary objective was to study change in serum sodium level at 24 hours in children receiving total IV fluid maintenance therapy as 0.45% or 0.9% normal saline in 5% dextrose. Secondary objectives of this study were to estimate change in serum sodium levels from the baseline to 48 or 72 hours, if IV fluids were continued, and to find incidence of hyponatremia and hypernatremia after administering these 2 types of maintenance fluids.

Methods

This study was an open-label, randomized control trial conducted at the Department of Pediatrics of a tertiary care hospital from July 22, 2019, to October 28, 2019. Two hundred children aged 3 months to 12 years admitted in pediatric emergency and requiring IV maintenance fluid were randomized into 2 groups (group A received 0.45% saline in 5% dextrose, group B received 0.9% normal saline in 5% dextrose) with 100 in each group.

Results

Both groups were comparable for baseline characteristics. Fall in mean serum sodium from baseline was more with increasing duration of IV fluids until 24 hours in 0.45% saline group as compared with 0.9% saline group, which was statistically significant (P < 0.001). The incidence of mild and moderate hyponatremia was significantly more in hypotonic group at 12 hours (P < 0.001) and 24 hours (P < 0.001). However, there was no significant difference at 48 hours.

Conclusions

The fall in serum sodium values was significant, and there was significant risk of hyponatremia with the use of hypotonic fluids at 12 and 24 hours. Hence, the use of isotonic fluids seems to be more appropriate among the hospitalized children.

Trial Registration: CTRI/2019/10/021791.
Endoscopic Approach in the Diagnosis of Gastrointestinal Acute Graft Versus Host Disease in Children
Authors: Faraci Maura , Giardino Stefano , Madeo Annalisa , Coccia Cristina , Arrigo Serena , Pierri Filomena , Gandullia Paolo
Published: January 2022

Objectives:

The objectives of this study were to describe clinical, histological, and endoscopic findings in children undergoing gastrointestinal (GI) endoscopy for symptoms of digestive acute graft-versus-host disease (a-GvHD), to evaluate the rate of steroid-resistant GvHD and transplant-related mortality, and to describe the feasibility and safety of the endoscopic procedure.

Methods:

This was a retrospective study conducted, at the IRCSS Istituto G. Gaslini in Genova, Italy, in 26 children undergoing upper or lower GI endoscopy after allogeneic hematopoietic stem cell transplantation between 2000 and 2017.

Results:

Histology confirmed a diagnosis of a-GvHD in 73% of patients; it was frequently associated with steroid-resistant a-GvHD (P = 0.001) and with an increased transplant-related mortality. Additionally, one patient developed duodenal hematoma after endoscopy for a high-grade GI a-GvHD.

Conclusions:

In our experience, the endoscopic approach in the diagnosis of GI a-GvHD in children was feasible and safe. Furthermore, the histological diagnosis of GI a-GvHD was associated with an increased risk of steroid-resistant GvHD and with high transplant-related mortality.
Dual Biologic Therapy in an Adolescent With Camurati-Engelmann Disease and Crohn Disease
Authors: Sami Ahmad Salah , Rosh Joel R.
Published: January 2022

Camurati-Engelmann disease (CED) is a rare disorder caused by activating mutations in the TGF-β1 gene and characterized by hyperostosis of long bones and bone dysplasia. We describe a case of an adolescent with CED and moderate-severe Crohn Disease (CD). Infliximab improved gastrointestinal symptoms but was associated with worsening CED-associated bone pain. Clinical remission was successfully achieved with dual biologic therapy that included vedolizumab and ustekinumab. Possible reasons for this patient’s clinical response are advanced and include speculation about the complex role of TGF-β1 signaling in the etiology of both CED and CD.
Rapunzel Syndrome Complicated by Escherichia coli Sepsis, Bowel Perforation, and Pancreatitis in an 11-year-old Malnourished Female
Authors: Daniel Rhea , Arbuthnot Mary , Ramireddy Srinivas , Nair Supriya
Published: January 2022

The most common presenting symptoms of Rapunzel syndrome include abdominal pain (37%), nausea and vomiting (33.3%), obstruction (25.9%), and peritonitis (18.3%). Less commonly, patients may present with weight loss (7.4%) or intussusception (7.4%). Exceedingly rare complications of Rapunzel syndrome include gastric ulceration, obstructive jaundice, and acute pancreatitis as well as other malabsorptive-related complications including protein-losing enteropathy, iron deficiency, and megaloblastic anemia. This report details the case of an 11-year-old female with Rapunzel syndrome complicated by sepsis, a rare complication reported in only 2% of patients.
Are Perforators Reliable as Recipient Arteries in Lower Extremity Reconstruction? Analysis of 423 Free Perforator Flaps
Authors: Power Hollie A. , Cho Jeongmok , Kwon Jin Geun , Abdelfattah Usama , Pak Changsik John , Suh Hyunsuk Peter , Hong Joon Pio
Published: January 2022

Background:

Perforator flaps have revolutionized lower limb reconstruction by offering single-stage thin, pliable coverage with an excellent aesthetic match. Although anastomosis of the flap to a major artery remains the gold standard, perforator-to-perforator anastomosis has several advantages, including expedient recipient dissection and increased recipient options in vessel-depleted extremities. The aim of this study was to compare flap survival when a perforator or major artery was used as a recipient vessel.

Methods:

A retrospective cohort of free perforator flaps for lower limb reconstruction was reviewed. Demographics, comorbidities, vascular status, defect characteristics, operative details, and complications were recorded. Outcomes for perforator and major artery recipients were compared.

Results:

Four hundred twenty-three flaps were performed for various reasons using perforator flaps. The total limb salvage rate was 98.8 percent. Total and partial flap failure rates were 6.1 percent and 9.0 percent, respectively. Comparing perforator recipients [n = 109 (25.8 percent)] to major artery recipients [n = 314 (74.2 percent)], there was no significant difference in total (p = 0.746) or partial flap failure (p = 0.212). Significant factors between the groups included larger flap size with major artery recipients (p = 0.001) and shorter operative time when using a perforator recipient (p = 0.012)

Conclusions:

Perforator-to-perforator anastomosis is a reliable option that affords equivalent rates of flap success compared to major artery anastomosis in lower extremity reconstruction. The authors advocate using a major artery recipient in defects where the axial vessels are easily accessible. A perforator recipient is a viable alternative in defects where access to the axial vessels is inconvenient and in patients with limited recipient options.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, III.
68Ga-DOTA-FAPI-04 Uptake of Accessory Breast in a Patient With Breast Cancer
Authors: Xu Tingting , Wang Wei , Yang Chuan , Cai Liang , Chen Yue
Published: January 2022

68Ga-DOTA-FAPI-04 is a promising PET agent for tumor imaging. However, some nonneoplastic lesions can also show increased FAPI uptake. Herein, we presented a case of a patient with left breast cancer who showed a right accessory breast with increased tracer uptake on 68Ga-DOTA-FAPI-04 PET/CT. Final histopathology confirmed there were no malignant components in the accessory breast.
Factors Associated With Mortality Among Patients Managed for Large Volume Hemorrhage in a Medical Intensive Care Unit
Authors: Dettmer Matthew , Morrison James , Bari Vase , Krishnan Sudhir , Wang Xiaofeng , Li Manshi , Duggal Abhijit , Adams Gregory , Hite Duncan
Published: January 2022

Purpose:

Our goal was to describe resuscitation practices in critically ill medical patients with active hemorrhage requiring large volume resuscitation and identify factors associated with poor outcomes.

Patients and Methods:

This was a single center retrospective observational cohort study. Patients admitted to the medical intensive care unit from 2011 to 2017 who received ≥5 units of packed red blood cells (pRBCs) within 24 h were included. Data including volume of blood products and crystalloid administered, baseline sequential organ failure assessment (SOFA) scores, and outcomes were abstracted. Univariate and multivariate analyses were performed to determine clinical factors associated with hospital mortality.

Results:

Two hundred forty-six patients were identified. Mean volumes of 2,448 mL of pRBCs and 3.9L of crystalloid were transfused over 24 h. Inpatient mortality for the entire cohort was 48%. Multivariable analysis identified factors associated with hospital mortality; higher BMI (OR 1.047, 95% CI 1.013–1.083), higher ratio of fresh frozen plasma (FFP) to pRBCs (OR 2.744, 95% CI 1.1–6.844), and higher baseline SOFA scores (OR 1.3, 95% CI 1.175–1.437).

Conclusion:

In a cohort of critically ill medical patients undergoing resuscitation for hemorrhage, higher BMI, increased ratio of FFP to pRBCs, and higher SOFA scores were associated with increased mortality. Further studies are needed to clarify resuscitation practices associated with outcomes in this population.
Informing Simulation Design: A Qualitative Phenomenological Study of the Experiences of Bereaved Parents and Actors
Authors: Vemuri Sidharth , O'Neill Jenny , Hynson Jenny , Gillam Lynn
Published: January 2022

Introduction

Simulations, which represent reality, are effective in pediatric healthcare communication skills education and training. Parents are increasingly engaged in simulation development, particularly for authentic character development, to help achieve greater psychological fidelity. For simulated encounters related to a child's end-of-life, involvement of bereaved parents would make sense. However, this is challenging because there is limited research to guide their inclusion and significant responsibility for any approach to be thoughtful and psychologically safe for participating parents. This study explores the impact and experiences of bereaved parents and actors who participated in simulation design.

Methods

This qualitative phenomenological study involved five bereaved parents and two actors who participated in a full-day workshop to design and develop characters for use in a simulation. Individual semistructured interviews were conducted up to four weeks after the workshop. Data collected from these telephone interviews were analyzed using inductive content analysis.

Results

Bereaved parents found the workshop emotionally challenging but positive, worthwhile, and beneficial. Similarly, actors found the workshop helpful in character development and, although it was an intense experience for them, it validated the importance of their work. Key elements of our research findings could inform future such activities.

Conclusions

Involving bereaved parents in simulation design can be psychologically safe and beneficial for both parents and actors. Ongoing involvement of bereaved parents may lead to higher-quality simulated experiences, allowing clinicians to practice skills to enhance care provided at a child's end-of-life.
Hepatectomy Versus Sorafenib in Advanced Nonmetastatic Hepatocellular Carcinoma
Authors: Famularo Simone , Donadon Matteo , Cipriani Federica , Giuliante Felice , Ferri Silvia , Celsa Ciro , Ferrero Alessandro , Foschi Francesco Giuseppe , Baiocchi Gian Luca , Biasini Elisabetta , Campani Claudia , Valle Raffaele Dalla , Pelizzaro Filippo , Baroni Gianluca Svegliati , Raimondo Giovanni , Mega Andrea , Chiarelli Marco , Maestri Marcello , Gasbarrini Antonio , Jovine Elio , Grazi Gian Luca , Rapaccini Gian Ludovico , Ruzzenente Andrea , Morisco Filomena , Sacco Rodolfo , Memeo Riccardo , Crespi Michele , Antonucci Adelmo , Bernasconi Davide P. , Romano Fabrizio , Griseri Guido , Aldrighetti Luca , Torzilli Guido , Trevisani Franco ,   on behalf of ITA.LI.CA Group and HE.RC.O.LE.S. Group
Published: January 2022

Objective:

The aim of the study was to compare SURG vs SOR regarding the OS and progression-free survival (PFS) in a real-world clinical scenario.

Background data:

The treatment for advanced nonmetastatic HCC belonging to the Barcelona Clinic Liver Cancer stage C (BCLC C) is still controversial.

Methods:

BCLC C patients without extrahepatic spread and tumoral invasion of the main portal trunk were considered. Surgical patients were obtained from the HE.RC.O.LE.S. Register, whereas sorafenib patients were obtained from the ITA.LI.CA register The inverse probability weighting (IPW) method was adopted to balance the confounders between the 2 groups.

Results:

Between 2008 and 2019, 478 patients were enrolled: 303 in SURG and 175 in SOR group. Eastern Cooperative Oncological Group Performance Status (ECOG-PS), presence of cirrhosis, steatosis, Child-Pugh grade, hepatitis B virus and hepatitis C virus, alcohol intake, collateral veins, bilobar disease, localization of the tumor thrombus, number of nodules, alpha-fetoprotein, age, and Charlson Comorbidity index were weighted by IPW to create two balanced pseudo-populations: SURG = 374 and SOR = 263. After IPW, 1–3–5 years OS was 83.6%, 68.1%, 55.9% for SURG, and 42.3%, 17.8%, 12.8% for SOR (P < 0.001). Similar trends were observed after subgrouping patients by ECOG-PS = 0 and ECOG-PS >0, and by the intrahepatic location of portal vein invasion. At Cox regression, sorafenib treatment (hazard ratio 4.436; 95% confidence interval 3.19–6.15; P < 0.001) and Charlson Index (hazard ratio 1.162; 95% confidence interval 1.06–1.27; P = 0.010) were the only independent predictors of mortality. PFS at 1–3–5 years were 65.9%, 40.3%, 24.3% for SURG and 21.6%, 3.5%, 2.9% for SOR (P = 0.007).

Conclusions:

In BCLC C patients without extrahepatic spread but with intrahepatic portal invasion, liver resection, if feasible, was followed by better OS and PFS compared with sorafenib.
Donor-derived Cell-free DNA Complements De Novo Class II DSA in Detecting Late Alloimmune Injury Post Kidney Transplantation
Authors: Butiu Maria , Obrisca Bogdan , Sibulesky Lena , Bakthavatsalam Ramasamy , Smith Kelly D. , Gimferrer Idoia , Warner Paul , Ismail Gener , Leca Nicolae
Published: January 2022

Background.

We sought to evaluate the association between de novo donor-specific antibodies (dnDSAs) class and their mean fluorescence intensity (MFI) with donor-derived cell-free DNA (dd-cfDNA), aiming to further clarify the biomarker utility of these noninvasive tests in relation to renal allograft function and histology.

Methods.

The study included kidney transplant recipients (n = 171) who underwent surveillance testing with DSA and dd-cfDNA as part of their clinical care between September 2017 and December 2019 at our center.

Results.

We identified dnDSA in 43 patients (25%) at a median of 4.63 y (IQR, 1.5–7) posttransplant. The presence of DSA with MFI >2500 was associated with a median dd-cfDNA of 0.96% (IQR, 0.26–2.95) significantly higher than in patients with DSA MFI <2500 (0.28%; IQR, 0.19–0.39) or without detectable DSA (0.22%; IQR, 0.17–0.37; P < 0.001). Class II dnDSAs were the most prevalent dnDSA (88.3%), the majority with MFI >2500 (82.9%). Patients with DQ-dnDSAs (47.4%) had higher MFI and dd-cfDNA levels than other class II dnDSAs. By comparison, all patients that developed only class I DSAs had MFI <2500 and a low dd-cfDNA. In addition, the serum creatinine was 1.55 ± 0.48 mg/dL in those dnDSA-negative, 1.15 ± 0.37 mg/dL in those with dnDSA MFI <2500, and 1.53 ± 0.66 mg/dL in those with dnDSA MFI >2500 (P = 0.05). After multivariate adjustment, an elevated dd-cfDNA was independently associated with the presence of dnDSA with MFI ≥2500. We identified that both dd-cfDNA and dnDSAs were strongly associated with antibody-mediated rejection, whereas for individual Banff histological lesions, DSA MFIs ≥2500 had the strongest association with C4d staining score and dd-cfDNA >1% with microvascular inflammation.

Conclusions.

Our study identifies class II dnDSA as being strongly associated with late alloimmune injury post kidney transplant independent of allograft dysfunction and shows that dd-cfDNA may complement the clinical significance of dnDSAs.
Early-life experience shapes patterns of senescence in a food-caching passerine
Authors: Sorensen Marjorie C. , Strickland Dan , Freeman Nikole E. , Fuirst Matthew , Sutton Alex O. , Norris D. Ryan
Published: January 2022

For many species, breeding performance increases through early adulthood followed by declines later in life. Although patterns of age-specific decline have been shown to vary between individuals, the factors that lead to this individual variation in the intensity of reproductive senescence are yet to be fully understood. We investigated whether early-life social status influenced age-related trends in the breeding performance of male Canada jays (Perisoreus canadensis), year-round residents of North America's boreal and sub-alpine forests. Shortly after young become nutritionally independent, intra-brood dominance struggles lead to one juvenile (Dominant Juvenile) remaining on the natal territory after expelling its subordinate siblings (Ejectees). First, we show via radio tracking that in our declining range-edge population Ejectees either join an unrelated pair (67%), form a breeding pair with another bird (28%) or occupy a territory alone (5%). Second, using 39 years of breeding data, we demonstrate that Ejectee males advanced laying dates and increased the annual number of nestlings until 6 years of age before declining, whereas Dominant Juvenile males advanced laying dates until 11 years and increased annual number of nestlings until 12 years of age before declining. This study documents clear variation in ageing patterns between dominant and expelled young, with implications for the role of early-life experiences and phenotypic quality in determining patterns of ageing.
Cluster mean-field theory accurately predicts statistical properties of large-scale DNA methylation patterns
Authors: Kerr Lyndsay , Sproul Duncan , Grima Ramon
Published: January 2022

The accurate establishment and maintenance of DNA methylation patterns is vital for mammalian development and disruption to these processes causes human disease. Our understanding of DNA methylation mechanisms has been facilitated by mathematical modelling, particularly stochastic simulations. Megabase-scale variation in DNA methylation patterns is observed in development, cancer and ageing and the mechanisms generating these patterns are little understood. However, the computational cost of stochastic simulations prevents them from modelling such large genomic regions. Here, we test the utility of three different mean-field models to predict summary statistics associated with large-scale DNA methylation patterns. By comparison to stochastic simulations, we show that a cluster mean-field model accurately predicts the statistical properties of steady-state DNA methylation patterns, including the mean and variance of methylation levels calculated across a system of CpG sites, as well as the covariance and correlation of methylation levels between neighbouring sites. We also demonstrate that a cluster mean-field model can be used within an approximate Bayesian computation framework to accurately infer model parameters from data. As mean-field models can be solved numerically in a few seconds, our work demonstrates their utility for understanding the processes underpinning large-scale DNA methylation patterns.
Application of an organotypic ocular perfusion model to assess intravitreal drug distribution in human and animal eyes
Authors: Chan D. , Won G. J. , Read A. T. , Ethier C. R. , Thackaberry E. , Crowell S. R. , Booler H. , Bantseev V. , Sivak J. M.
Published: January 2022

Intravitreal (ITV) drug delivery is a new cornerstone for retinal therapeutics. Yet, predicting the disposition of formulations in the human eye remains a major translational hurdle. A prominent, but poorly understood, issue in pre-clinical ITV toxicity studies is unintended particle movements to the anterior chamber (AC). These particles can accumulate in the AC to dangerously raise intraocular pressure. Yet, anatomical differences, and the inability to obtain equivalent human data, make investigating this issue extremely challenging. We have developed an organotypic perfusion strategy to re-establish intraocular fluid flow, while maintaining homeostatic pressure and pH. Here, we used this approach with suitably sized microbeads to profile anterior and posterior ITV particle movements in live versus perfused porcine eyes, and in human donor eyes. Small-molecule suspensions were then tested with the system after exhibiting differing behaviours
in vivo
. Aggregate particle size is supported as an important determinant of particle movements in the human eye, and we note these data are consistent with a poroelastic model of bidirectional vitreous transport. Together, this approach uses ocular fluid dynamics to permit, to our knowledge, the first direct comparisons between particle behaviours from human ITV injections and animal models, with potential to speed pre-clinical development of retinal therapeutics.
Dynamic Boolean modelling reveals the influence of energy supply on bacterial efflux pump expression
Authors: Kerr Ryan , Jabbari Sara , Blair Jessica M. A. , Johnston Iain G.
Published: January 2022

Antimicrobial resistance (AMR) is a global health issue. One key factor contributing to AMR is the ability of bacteria to export drugs through efflux pumps, which relies on the ATP-dependent expression and interaction of several controlling genes. Recent studies have shown that significant cell-to-cell ATP variability exists within clonal bacterial populations, but the contribution of intrinsic cell-to-cell ATP heterogeneity is generally overlooked in understanding efflux pumps. Here, we consider how ATP variability influences gene regulatory networks controlling expression of efflux pump genes in two bacterial species. We develop and apply a generalizable Boolean modelling framework, developed to incorporate the dependence of gene expression dynamics on available cellular energy supply. Theoretical results show that differences in energy availability can cause pronounced downstream heterogeneity in efflux gene expression. Cells with higher energy availability have a superior response to stressors. Furthermore, in the absence of stress, model bacteria develop heterogeneous pulses of efflux pump gene expression which contribute to a sustained sub-population of cells with increased efflux expression activity, potentially conferring a continuous pool of intrinsically resistant bacteria. This modelling approach thus reveals an important source of heterogeneity in cell responses to antimicrobials and sheds light on potentially targetable aspects of efflux pump-related antimicrobial resistance.
A mathematical model for phenotypic heterogeneity in breast cancer with implications for therapeutic strategies
Authors: Li Xin , Thirumalai D.
Published: January 2022

Inevitably, almost all cancer patients develop resistance to targeted therapy. Intratumour heterogeneity is a major cause of drug resistance. Mathematical models that explain experiments quantitatively are useful in understanding the origin of intratumour heterogeneity, which then could be used to explore scenarios for efficacious therapy. Here, we develop a mathematical model to investigate intratumour heterogeneity in breast cancer by exploiting the observation that HER2+ and HER2− cells could divide symmetrically or asymmetrically. Our predictions for the evolution of cell fractions are in quantitative agreement with single-cell experiments. Remarkably, the colony size of HER2+ cells emerging from a single HER2− cell (or vice versa), which occurs in about four cell doublings, also agrees with experimental results, without tweaking any parameter in the model. The theory explains experimental data on the responses of breast tumours under different treatment protocols. We then used the model to predict that, not only the order of two drugs, but also the treatment period for each drug and the tumour cell plasticity could be manipulated to improve the treatment efficacy. Mathematical models, when integrated with data on patients, make possible exploration of a broad range of parameters readily, which might provide insights in devising effective therapies.
A hydraulic resistance model for interstitial fluid flow in the brain
Authors: Schreder Helena E. , Liu Jia , Kelley Douglas H. , Thomas John H. , Boster Kimberly A. S.
Published: January 2022

Metabolic wastes may be cleared from the brain by the flow of interstitial fluid (ISF) through extracellular spaces in the parenchyma, as proposed in the glymphatic model. Owing to the difficulty of obtaining experimental measurements, fluid-dynamic models are employed to better understand parenchymal flow. Here we use an analytical solution for Darcy flow in a porous medium with line sources (representing penetrating arterioles) and line sinks (representing ascending venules) to model the flow and calculate the hydraulic resistance as a function of parenchymal permeability and ISF viscosity for various arrangements of the vessels. We calculate how the resistance varies with experimentally determined arrangements of arterioles and venules in mouse and primate brains. Based on experimental measurements of the relative numbers of arterioles and venules and their spacing, we propose idealized configurations for mouse and primate brains, consisting of regularly repeating patterns of arterioles and venules with even spacing. We explore how the number of vessels, vessel density, arteriole-to-venule ratio, and arteriole and venule distribution affect the hydraulic resistance. Quantifying how the geometry affects the resistance of brain parenchyma could help future modelling efforts characterize and predict brain waste clearance, with relevance to diseases such as Alzheimer’s and Parkinson’s.
The ‘Stronsay Beast’: testimony, evidence and authority in early nineteenth-century natural history
Authors: Jenkins Bill
Published: January 2022

When an unknown sea creature was washed ashore on the Orkney Islands in September 1808, the Edinburgh anatomist John Barclay declared that this was the first solid scientific evidence for the existence of the ‘great sea snake’. The testimony of witnesses along with some of its preserved body parts were examined by both the Wernerian Natural History Society in Edinburgh and the surgeon and anatomist Everard Home in London. Contradicting Barclay's opinion, Home identified the creature as a decomposing basking shark. While Barclay took the testimony of the local witnesses largely on trust and accepted their interpretation of the Beast, Home discounted it and instead asserted his own expert authority to correctly interpret the evidence. Both made use of the preserved physical remains of parts of the creature in strikingly different ways: Barclay to support the accounts of the witnesses, Home to undermine them. The debate between the two anatomists has much to tell us about the uses of evidence and testimony in early nineteenth-century natural history, but also has broader resonances for the roles of evidence and authority in science that still remain relevant today.
Cranial volume and palate length of cats,
Felis
spp., under domestication, hybridization and in wild populations
Authors: Lesch Raffaela , Kitchener Andrew C. , Hantke Georg , Kotrschal Kurt , Fitch W. Tecumseh
Published: January 2022

Reduced brain size, compared with wild individuals, is argued to be a key characteristic of domesticated mammal species, and often cited as a key component of a putative ‘domestication syndrome’. However, brain size comparisons are often based on old, inaccessible literature and in some cases drew comparisons between domestic animals and wild species that are no longer thought to represent the true progenitor species of the domestic species in question. Here we replicate studies on cranial volumes in domestic cats that were published in the 1960s and 1970s, comparing wildcats, domestic cats and their hybrids. Our data indicate that domestic cats indeed, have smaller cranial volumes (implying smaller brains) relative to both European wildcats (
Felis silvestris
) and the wild ancestors of domestic cats, the African wildcats (
Felis lybica
), verifying older results. We further found that hybrids of domestic cats and European wildcats have cranial volumes that cluster between those of the two parent species. Apart from replicating these studies, we also present new data on palate length in
Felis
cat skulls, showing that domestic cat palates are shorter than those of European wildcats but longer than those of African wildcats. Our data are relevant to current discussions of the causes and consequences of the ‘domestication syndrome’ in domesticated mammals.
Darwin's small and medium ground finches might have taste preferences, but not for human foods
Authors: Lever D. , Rush L. V. , Thorogood R. , Gotanda K. M.
Published: January 2022

Urbanization is rapidly changing ecological niches. On the inhabited Galapagos Islands, Darwin's finches consume human-introduced foods preferentially; however, it remains unclear why. Here, we presented pastry with flavour profiles typical of human foods (oily, salty and sweet) to small ground finches (
Geospiza fuliginosa
) and medium ground finches (
Geospiza fortis
) to test if latent taste preferences might drive the selection of human foods. If human food flavours were consumed more than a neutral or bitter control only at sites with human foods, then we predicted tastes were acquired after urbanization; however, if no site differences were found then this would indicate latent taste preferences. Contrary to both predictions, we found little evidence that human food flavours were preferred compared with control flavours at any site. Instead, finches showed a weak aversion to oily foods, but only at remote (no human foods present) sites. This was further supported by behavioural responses, with beak-wiping occurring more often at remote sites after finches tasted flavours associated with human foods. Our results suggest, therefore, that while Darwin's finches regularly exposed to human foods might have acquired a tolerance to human food flavours, latent taste preferences are unlikely to have played a major role in their dietary response to increased urbanization.
The formation of political discussion networks
Authors: Hâncean Marian-Gabriel , Perc Matjaž , Gheorghiță Adrian , Vega Yon George G. , Mihăilă Bianca-Elena
Published: January 2022

Dialogues among politicians provide a window into political landscapes and relations among parties and nations. Existing research has focused on the outcomes of such dialogues and on the structure of social networks on which they take place. Little is known, however, about how political discussion networks form and which are the main driving forces behind their formation. We study a collection of ego-networks from 30 randomly sampled Romanian politicians to reveal fundamental processes behind the formation of political discussion networks. We show that ties in such networks tend to be strong and balanced, and that their organization is not affected by sex, age or education homophily. We use the exponential family of random graph models for small networks to assess likely closure mechanisms and possible homophily effects, but we note that further research and additional data are needed to fully understand the impact of context and political affiliations on the generalization of our findings.
Geometrical dynamics of edge-driven accretive surface growth
Authors: Nadir Kaplan C. , Mahadevan L.
Published: January 2022

Accretion of mineralized thin wall-like structures via localized growth along their edges is observed in physical and biological systems ranging from molluscan and brachiopod shells to carbonate–silica composite precipitates. To understand the shape of these mineralized structures, we develop a mathematical framework that treats the thin-walled shells as a smooth surface left in the wake of the growth front that can be described as an evolving space curve. Our theory then takes an explicit geometric form for the prescription of the velocity of the growth front curve, along with compatibility relations and a closure equation related to the nature of surface curling. Solutions of these equations capture a range of geometric precipitate patterns seen in abiotic and biotic forms across scales. In addition to providing a framework for the growth and form of these thin-walled morphologies, our theory suggests a new class of dynamical systems involving moving space curves that are compatible with non-Euclidean embeddings of surfaces.
Flow around topological defects in active nematic films
Authors: Rønning Jonas , Marchetti Cristina M. , Bowick Mark J. , Angheluta Luiza
Published: January 2022

We study the active flow around isolated defects and the self-propulsion velocity of+1/2defects in an active nematic film with both viscous dissipation (with viscosityη) and frictional dampingΓwith a substrate. The interplay between these two dissipation mechanisms is controlled by the hydrodynamic dissipation lengthℓd=η/Γthat screens the flows. For an isolated defect, in the absence of screening from other defects, the size of the shear vorticity around the defect is controlled by the system sizeR. In the presence of friction that leads to a finite value ofℓd, the vorticity field decays to zero on the lengthscales larger thanℓd. We show that the self-propulsion velocity of+1/2defects grows withRin small systems whereR<ℓd, while in the infinite system limit or whenR≫ℓd, it approaches a constant value determined byℓd.
Flexible group cohesion and coordination, but robust leader–follower roles, in a wild social primate using urban space
Authors: Bracken Anna M. , Christensen Charlotte , O'Riain M. Justin , Fürtbauer Ines , King Andrew J.
Published: January 2022

Collective behaviour has a critical influence on group social structure and organization, individual fitness and social evolution, but we know little about whether and how it changes in anthropogenic environments. Here, we show multiple and varying effects of urban space-use upon group-level processes in a primate generalist—the chacma baboon (Papio ursinus)—within a managed wild population living at the urban edge in the City of Cape Town, South Africa. In natural space, we observe baboon-typical patterns of collective behaviour. By contrast, in urban space (where there are increased risks, but increased potential for high-quality food rewards), baboons show extreme flexibility in collective behaviour, with changes in spatial cohesion and association networks, travel speeds and group coordination. However, leader–follower roles remain robust across natural and urban space, with adult males having a disproportionate influence on the movement of group members. Their important role in the group's collective behaviour complements existing research and supports the management tactic employed by field rangers of curbing the movements of adult males, which indirectly deters the majority of the group from urban space. Our findings highlight both flexibility and robustness in collective behaviour when groups are presented with novel resources and heightened risks.