bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of fermented corn protein and its effects in either high or low branch chain amino acid to leucine ratio diets on nursery pig performance and feed intake preference
Authors: Stas Ethan B , Chance Jenna A , Goodband Robert D , Tokach Mike D , Woodworth Jason C , DeRouchey Joel M , Gebhardt Jordan T
Published: September 2022

Three experiments were conducted to evaluate fermented corn protein (FCP) in nursery pig diets. The removal of non-fermentable components before fermentation of DDGS results in high protein dried distillers grains (HPDDGs). Fermented corn protein is produced when protein and yeast fraction syrup from ethanol production is added back to HPDDGs resulting in a product with up to 50% CP and 2% Lys. In Exp. 1, 350 barrows, initially 6.0 kg, were used to evaluate FCP as a replacement to enzymatically treated soybean meal. Treatments were arranged in a 2 × 2 + 1 factorial with main effects of specialty protein source (FCP or enzymatically treated soybean meal) and level (5 or 10%) or a control diet without any specialty protein source. There were 5 pigs per pen and 14 replications per treatment. From d 0 to 31, pigs fed enzymatically treated soybean meal had improved (P < 0.05) ADG and feed efficiency (G:F) compared to pigs fed FCP. In Exp. 2, 350 pigs, initially 12.1 kg, were used to determine the effects of FCP with high or low Ile and Val (Ile + Val):Leu ratio on growth performance. Treatments were arranged in a 2 × 2 + 1 factorial with main effects of FCP level (10 or 20%) and Ile + Val:Leu ratio (low or high) in addition to a corn-soybean meal control diet with 5 pigs per pen and 14 replications per treatment. From d 0 to 21, ADG, ADFI, and G:F worsened (linear, P < 0.001) as FCP increased. High Ile + Val:Leu improved (P < 0.05) G:F compared to low Ile + Val:Leu. In Exp. 3, 180 pigs, initially 7.7 kg, were used in a feed intake preference trial evaluating various FCP fractions. A total of 6 diet comparisons with 5 pigs per pen and 6 replications per comparison were used. Corn protein sources and fractions used included: FCP, HPDDGs, whole stillage solids (approximately 2/3 of FCP), and thin stillage solids (approximately 1/3 of FCP), and a control diet. Pigs preferred (P < 0.001) the control diet by consuming 82.5% of their intake compared with a diet containing FCP. There was no difference (P > 0.05) in feed consumption of diets containing whole stillage solids compared to FCP. Pigs preferred (P = 0.001) the diet containing thin stillage solids by consuming 75.8% of their intake with this diet compared to the diet containing FCP. In conclusion, feeding FCP decreased growth performance in nursery pigs, but increasing Ile + Val:Leu improved G:F. Diet preference comparisons suggest that whole stillage solids are the component of FCP that leads to reduced feed intake.
A New Approach Methodology (NAM) Based Assessment of Butylated hydroxytoluene (BHT) for Endocrine Disruption Potential
Authors: De Abrew K Nadira , Natoli Ted , Lester Cathy C , Wang Xiaohong , Shobair Mahmoud , Subramanian Arvind , Daston George P
Published: September 2022

Butylated hydroxytoluene (BHT) is a synthetic antioxidant widely used in many industrial sectors. BHT is a well-studied compound for which there are many favorable regulatory decisions. However, a recent opinion by the French Agency for Food, Environmental and Occupational Health and Safety (ANSES) hypothesizes a role for BHT in endocrine disruption (ANSES (2021). This opinion is based on observations in mostly rat studies where changes to thyroid physiology are observed. Enzymatic induction of Cytochrome P450-mediated thyroid hormone catabolism has been proposed as a mechanism for these observations, however, a causal relationship has not been proven. Other evidence proposed in the document includes a read across argument to butylated hydroxyanisole (BHA), another Community Rolling Action Plan (CoRAP)-listed substance with endocrine disruption concerns. We tested the hypothesis that BHT is an endocrine disruptor by using a Next Generation Risk Assessment (NGRA) method. Four different cell lines: A549, HCC1428, HepG2, and MCF7 were treated with BHT and a series of BHT analogs at 5 different concentrations, RNA was isolated from cell extracts and run on the L1000 gene array platform. A toxicogenomics-based assessment was performed by comparing BHT’s unique genomic signature to a large external database containing signatures of other compounds (including many known endocrine disruptors) to identify if any endocrine disruption-related modes of action (MoAs) are prevalent among BHT and other compounds with similar genomic signatures. In addition, we performed a toxicogenomics-based structure activity relationship (SAR) assessment of BHT and a series of structurally similar analogs to understand if endocrine disruption is a relevant MoA for chemicals that are considered suitable analogs to BHT using the P&G read across framework (Wu et al., 2010). Neither BHT nor any of its analogs connected to compounds that had endocrine activity for estrogens, androgens, thyroid, or steroidogenesis.
Machine learning and artificial intelligence in physiologically based pharmacokinetic modeling
Authors: Chou Wei-Chun , Lin Zhoumeng
Published: September 2022

Physiologically based pharmacokinetic (PBPK) models are useful tools in drug development and risk assessment of environmental chemicals. PBPK model development requires the collection of species-specific physiological, and chemical-specific absorption, distribution, metabolism, and excretion (ADME) parameters, which can be a time-consuming and expensive process. This raises a need to create computational models capable of predicting input parameter values for PBPK models, especially for new compounds. In this review, we summarize an emerging paradigm for integrating PBPK modeling with machine learning (ML) or artificial intelligence (AI)-based computational methods. This paradigm includes 3 steps (1) obtain time-concentration PK data and/or ADME parameters from publicly available databases, (2) develop ML/AI-based approaches to predict ADME parameters, and (3) incorporate the ML/AI models into PBPK models to predict PK summary statistics (eg, area under the curve and maximum plasma concentration). We also discuss a neural network architecture “neural ordinary differential equation (Neural-ODE)” that is capable of providing better predictive capabilities than other ML methods when used to directly predict time-series PK profiles. In order to support applications of ML/AI methods for PBPK model development, several challenges should be addressed (1) as more data become available, it is important to expand the training set by including the structural diversity of compounds to improve the prediction accuracy of ML/AI models; (2) due to the black box nature of many ML models, lack of sufficient interpretability is a limitation; (3) Neural-ODE has great potential to be used to generate time-series PK profiles for new compounds with limited ADME information, but its application remains to be explored. Despite existing challenges, ML/AI approaches will continue to facilitate the efficient development of robust PBPK models for a large number of chemicals.
Assessment of Intraoperative Rotational Alignment of Closed Locked Intramedullary Nailing for Humerus Fractures
Authors: Boothby Benjamin , Haase Lucas , Wetzel Robert
Published: September 2022

Intramedullary nailing of humerus fractures has evolved over the past half century and has grown in popularity especially for the polytraumatized patient. The importance of restoring appropriate rotational alignment is equivalent to that of restoring sagittal and coronal alignment to decrease the risk of shoulder degenerative changes and limit range of motion discrepancy from the contralateral limb. This technique is designed to introduce an intraoperative fluoroscopic method to obtain adequate rotational alignment of humeral shaft fractures treated with closed antegrade humeral locked nailing.
Novel biomarkers identifying hypertrophic cardiomyopathy and its obstructive variant based on targeted amino acid metabolomics
Authors: Guo Lanyan , Wang Bo , Zhang Fuyang , Gao Chao , Hu Guangyu , Zhou Mengyao , Wang Rutao , Zhao Hang , Yan Wenjun , Zhang Ling , Ma Zhiling , Yang Weiping , Guo Xiong , Huang Chong , Cui Zhe , Sun Fangfang , Song Dandan , Liu Liwen , Tao Ling
Published: September 2022

Background:

Hypertrophic cardiomyopathy (HCM) is an underdiagnosed genetic heart disease worldwide. The management and prognosis of obstructive HCM (HOCM) and non-obstructive HCM (HNCM) are quite different, but it also remains challenging to discriminate these two subtypes. HCM is characterized by dysmetabolism, and myocardial amino acid (AA) metabolism is robustly changed. The present study aimed to delineate plasma AA and derivatives profiles, and identify potential biomarkers for HCM.

Methods:

Plasma samples from 166 participants, including 57 cases of HOCM, 52 cases of HNCM, and 57 normal controls (NCs), who first visited the International Cooperation Center for HCM, Xijing Hospital between December 2019 and September 2020, were collected and analyzed by high-performance liquid chromatography–mass spectrometry based on targeted AA metabolomics. Three separate classification algorithms, including random forest, support vector machine, and logistic regression, were applied for the identification of specific AA and derivatives compositions for HCM and the development of screening models to discriminate HCM from NC as well as HOCM from HNCM.

Results:

The univariate analysis showed that the serine, glycine, proline, citrulline, glutamine, cystine, creatinine, cysteine, choline, and aminoadipic acid levels in the HCM group were significantly different from those in the NC group. Four AAs and derivatives (Panel A; proline, glycine, cysteine, and choline) were screened out by multiple feature selection algorithms for discriminating HCM patients from NCs. The receiver operating characteristic (ROC) analysis in Panel A yielded an area under the ROC curve (AUC) of 0.83 (0.75–0.91) in the training set and 0.79 (0.65–0.94) in the validation set. Moreover, among 10 AAs and derivatives (arginine, phenylalanine, tyrosine, proline, alanine, asparagine, creatine, tryptophan, ornithine, and choline) with statistical significance between HOCM and HNCM, 3 AAs (Panel B; arginine, proline, and ornithine) were selected to differentiate the two subgroups. The AUC values in the training and validation sets for Panel B were 0.83 (0.74–0.93) and 0.82 (0.66–0.98), respectively.

Conclusions:

The plasma AA and derivatives profiles were distinct between the HCM and NC groups. Based on the differential profiles, the two established screening models have potential value in assisting HCM screening and identifying whether it is obstructive.
COVID-19 and the Integrated Plastic Surgery Match: An Update on Match Trends by Applicant Location
Authors: Kebede Sara , Marxen Troy , Om Anjali , Bakayoko Ngafla , Losken Albert
Published: September 2022

Background:

COVID-19 significantly impacted the residency match process. Away rotations and in-person interviews were canceled in 2021, resulting in a geographic shift in integrated plastic surgery match results. Although several of these limitations were lifted during the 2022 cycle, the resulting geographic outcomes have yet to be described. This study aims to determine whether the changes seen during the previous cycle persisted despite loosened restrictions.

Methods:

Integrated plastic surgery match results and applicants’ home institutions from the 2022 match cycle were determined using publicly available data. Geographic data from this cycle were then compared with pre-COVID-19 match cycles (2016–2020) and the COVID-19-affected 2021 match cycle.

Results:

Eighty percent (n = 68) of US integrated plastic surgery programs were included in this study. In 2022, 18.42% of applicants matched at their home institution compared with 25.12% in 2021. There was no significant difference in home, state, or regional match rates between 2022 and the five cycles preceding the pandemic (2016–2020). Combining these data to reflect the non-COVID-19-affected cycles (2016–2020 and 2022) and comparing to the COVID-19-affected cycle (2021), a significant difference in rates of home matches (P = 0.0395) was identified.

Conclusions:

A significant increase in home institution match rates was not noted during the 2022 cycle. This return to pre-COVID-19 rates is likely attributed to the loosening of restrictions and more opportunities for interaction between applicants and programs outside of their home institution.
Proposed Solutions for Improving Maternal Health Care in Rural America
Authors: Garcia Kelly K. , Hunter Stephen K.
Published: September 2022

Increasing hospital and labor & delivery (L&D) closures have led to declining access to hospital obstetric care in rural areas across the country. These closures increase the burden on women and families living in rural communities, who often must drive long distances for prenatal visits and delivery. The lack of maternal health care in rural America can also result in several adverse maternal and infant outcomes including premature birth, low birth weight, out of hospital births, maternal and infant morbidity and mortality, and increased risk of postpartum depression. The reasons for these closures are multifactorial, and include, workforce shortages, financial viability, low volume of patients, concerns over maintaining the knowledge base and skill sets of the obstetrical health care team required to provide high quality and safe care, as well as medical-legal concerns. The problems of providing and accessing quality maternal and obstetrical care in rural America have not happened overnight, Likewise, the solutions to these problems will also not occur overnight and must also address the multifactorial nature of the problem. However, there are several opportunities to improve access to maternal health care in rural communities. Programs, policies, and funding need to be designed and provided to make these opportunities a reality.
Meniscus-Shaped Stromal Lenticule Addition Keratoplasty for Corneal Regularization and Thickening in Advanced Keratoconus
Authors: Pedrotti Emilio , Bonacci Erika , Fasolo Adriano , Fraccaroli Sebastiano , Anastasi Marco , Vinciguerra Riccardo , Vinciguerra Paolo , Giorgio Marchini
Published: September 2022

Purpose:

The aim of this study was to investigate the outcome of the meniscus-shaped stromal lenticule addition keratoplasty (MS-SLAK) in corneal regularization and thickness.

Methods:

Patients waiting for deep anterior lamellar keratoplasty for advanced keratoconus with an intolerance to contact lenses (CLs) underwent the MS-SLAK procedure by FSL 80 kHz ablation (VICTUS, Technolas Perfect Vision, DE). Customized positive meniscus-shaped stromal lenticules were obtained and implanted. Examination was performed at baseline and at 3-, 6-, and 12-month follow-up and included corrected distance visual acuity both with spectacles and CLs (spectacle CDVA and CL-CDVA), manifest refraction spherical equivalent, slit-lamp examination, anterior segment optical coherence tomography, corneal topography, and in vivo confocal microscopy.

Results:

Fifteen patients completed the study. Statistical increases in corneal thickness values were found from the first follow-up (P < 0.001). Improvement in the Surface Asymmetry Index (P = 0.04), Symmetry Index (P = 0.02), spherical aberration (P < 0.001), coma (P= 0.18), high-order aberration (P = 0.37), and anterior asphericity index (Q) (P = 0.31) were found at 12 months. At the 12-month follow-up, no improvement were found in spectacle CDVA (P = 0.23); however, all patients reported CL wearing tolerance recovery, and significant improvement in CL-CDVA (P = 0.002) was found. The confocal microscopy at 12 months showed a significant increase in keratocyte density within the lenticule and absence of fibrotic reactions in both anterior and posterior interfaces.

Conclusions:

MS-SLAK seems to be effective in regularizing the corneal surface as showed by the significant improvement in topographic symmetry indices, coma, and high-order aberration. The corneal regularization is also confirmed by the results in anterior Q and the recovery of the CL wearing tolerance.
Association between prescribed opioid dose and risk of motor vehicle crashes
Authors: Quinn Patrick D. , Chang Zheng , Pujol Toyya A. , Bair Matthew J. , Gibbons Robert D. , Kroenke Kurt , D'Onofrio Brian M.
Published: September 2022

Opioid-involved motor vehicle traffic fatalities have increased over the past 2 decades. However, the extent to which prescribed opioids increase the risk of motor vehicle crashes remains uncertain. This study used real-world healthcare claims data to examine the association between prescription opioid dose and motor vehicle crash risk. Using nationwide US commercial insurance claims data for 2010 to 2018, we identified 772,404 adults who received incident, noncancer opioid therapy. We examined associations between daily prescription opioid dose, calculated in morphine milligram equivalents (MME) from filled prescription claims, and risk of motor vehicle crashes, assessed as diagnoses of motor vehicle injuries in claims for emergency visits, inpatient hospitalizations, and ambulance transportation. We estimated associations using a within-individual design, which ruled out all time-stable confounding. We complemented the design with time-varying statistical adjustment for other pharmacotherapies and a negative control pain pharmacotherapy analysis (with incident cyclic antidepressant prescriptions). During 2,150,009 person-years of follow-up, there were 12,123 motor vehicle crashes (5.64 crashes per 1000 person-years). In within-individual comparisons, crash risk was greater during opioid prescription periods involving doses ≤60 MME/day (odds ratio [OR], 3.86; 95% confidence interval [CI], 3.54, 4.21), >60 to 120 MME/day (OR, 5.46; 95% CI, 4.44, 6.73), and >120 MME/day (OR, 3.45; 95% CI, 2.31, 5.15) than during off-treatment periods. The negative control analysis supported the specificity of the results to opioids rather than to other processes associated with pharmacologic pain management. These findings suggest that the receipt of prescription opioids, even at doses ≤60 MME/day, is associated with an increased risk of motor vehicle crashes.
Stage M Infantile Neuroblastoma With Involvement of Falx Cerebri: Case Report and Literature Review
Authors: Sai Miyu , Moriya Kunihiko , Kaino Akira , Suzuki Tasuku , Katayama Saori , Aoki Hidekazu , Sasahara Yoji
Published: September 2022

Neuroblastoma is the most common extracranial solid tumor in children. When metastasis to the falx cerebri is present, it is classified as stage M; however, its behavior has not been well characterized. Here we present a case of stage M infantile neuroblastoma (NB) with involvement of the falx cerebri, and also summarize the clinical profiles of previously reported cases. Notably, all of the tumors resolved with low-dose chemotherapy alone. Although further study is needed to distinguish NBs presenting at these different intracranial locations, NB with metastasis to the falx cerebri may be categorized as MS when diagnosed at less than 18 months of age.
Efficacy of Cytomegalovirus Specific Immunoglobulins to Reduce CMV Reactivation in Pediatric Hematopoietic Stem Cell Transplant Recipients
Authors: Geurten Claire , Ghinai Rosanna , Munford Haydn , Lawson Sarah
Published: September 2022

Cytomegalovirus (CMV) infection is a serious complication of pediatric hematopoietic stem cell transplant (HSCT). To date, antiviral therapy has been the mainstay of prophylaxis, with conflicting results regarding the benefits of CMV-specific immunoglobulins (CMV-Ig). After introducing prophylactic CMV-Ig to HSCT recipients at risk (seropositive recipient and/or donor), we conducted a single-center retrospective study comparing the incidence and severity of CMV infection with and without CMV-Ig. We identified 49 ‘at risk’ recipients from 76 consecutive HSCTs over 3.5 years, in addition to standard antiviral prophylaxis, 10 patients received CMV-Ig and 39 did not. There was no significant difference in donor type, cell source, conditioning, or CMV status between the groups. We observed a potential trend toward reduction of incidence of CMV reactivation in patients exposed to CMV-Ig (30%) compared with those who weren’t (38.4%). Besides, no symptomatic or lethal infection was observed in the CMV-Ig group, and time to recovery seemed shorter (21 [±7] vs 51.4 [±55] days) and peak titers lower (4578 [±4788] vs 24131 [±49257]) with CMV-Ig. No adverse events were noted. The statistical significance of the results was limited by the small sample size. These data raise interest in prophylactic CMV-Ig as a safe way of potentially reducing the severity and duration of CMV reactivation in HSCT.
Older Adults' Behavioral Intentions Toward Advance Care Planning Based on Theory of Reasoned Action
Authors: Ke Li-Shan , Cheng Hui-Chuan , Ku Yu-Chen , Lee Ming-Ju , Chang Su-Yu , Huang Hsiu-Ying , Lin Yin-Ling
Published: September 2022

This study aimed to explore the factors affecting the behavioral intentions of older adults toward advance care planning (ACP). A questionnaire survey was conducted at 2 medical wards and a senior activity center in northern Taiwan. Four hundred one participants were older adults aged over 65 years, comprising hospitalized patients, their caregivers, and members of a senior activity center. The regression model revealed that participant type (patient, caregiver, or community resident); financial support; discussion of ACP with family; and knowledge, attitudes, and subjective norms accounted for 46.3% of the variance in behavioral intentions. The behavioral intention of caregivers was higher than that of patients. The behavioral intention of participants who were financially dependent on the family was lower than that of pensioners. Regarding discussing ACP with family, older adults in the contemplation and preparation stages score higher on behavioral intention than those in the precontemplation stage. This study supports the theory of reasoned action. Older adults' ACP knowledge and attitudes need to be enhanced through education. Caregivers' behavioral intentions tend to perform ACP. Sharing their caring experiences may be a strategy for promoting ACP. Older adults' financial status affects their behavioral intentions. Therefore, financial planning should be performed early and should incorporate ACP.
Palliative Care for Patients With Multiple Sclerosis
Authors: Wilder Carolyn Ann
Published: September 2022

Multiple sclerosis (MS) affects more than 2.8 million people worldwide and is an incurable, heterogeneous, chronic, degenerative, demyelinating, immune-mediated neurological disease of the central nervous system. It affects the physical, mental, psychosocial, financial, and spiritual dimensions of patients and their families. Given this illness trajectory and the multiple complex symptoms associated with MS, palliative care services would improve the quality of life for MS patients. Palliative care is a human right for all patients with a life-limiting, progressive disease. The goal of palliative care is the prevention and relief of suffering by means of assessment and treatment that holistically addresses symptoms and suffering. Thus, this article argues for the early integration of palliative care for persons given a diagnosis of MS. This argument is underscored by the analysis of a case study of a typical patient with MS who would have benefited from conjunctive palliative care.
Targeting Epidermal Growth Factor Receptor in Head and Neck Cancer
Authors: Bhatia Aarti
Published: September 2022

Head and neck squamous cell carcinomas are rising in incidence worldwide, and despite the advent of improved surgical and radiation techniques, a substantial proportion of patients have disease recurrence, where systemic therapies are the mainstay of management. Recent advances in systemic therapy include the development of epidermal growth factor receptor– and programmed death 1–targeting drugs, which have produced incremental improvements in disease outcomes. However, for most patients, responses to treatment remain elusive because of primary or acquired resistance. Novel drugs and rational drug combinations need to be tested based on biomarker identification and preclinical science that will ultimately advance outcomes for our patients. This review focuses on efforts untaken for epidermal growth factor receptor targeting in head and neck squamous cell carcinoma to date.
An Algorithmic Approach to Umbilical Inset During DIEP Flap Reconstruction
Authors: Schultz Kelly P. , Mentz James A. , Reece Edward , Chu Carrie , Vorstenbosch Joshua , Winocour Sebastian J.
Published: September 2022

An aesthetically-pleasing umbilicus is a critical component to the overall cosmesis and resultant patient satisfaction after DIEP flap breast reconstruction. Patients undergoing this procedure are frequently at a higher risk of umbilical complications and poor aesthetic appearance of the neo-umbilicus, due to patient variables in body habitus, comorbidities, and technical aspects of the procedure, as compared to those undergoing cosmetic abdominoplasty. In order to minimize these potential problems and maximize the overall aesthetic appearance of the abdomen, we propose an algorithmic approach to umbilical inset after DIEP flap harvest that takes into account several critical factors: the thickness of the subcutaneous tissue of a patient’s abdominal flap, the length of the umbilical stalk, and the depth of the umbilical bowl. We believe that this simple algorithmic approach is a useful tool that will assist surgeons in minimizing umbilical complications and delivering a superior cosmetic appearance to the abdominal donor site in DIEP flap reconstruction.
Catch-22: ADM and FDA Pre-Market Approval: How Can We Construct Studies?
Authors: Boyd Carter J. , Bekisz Jonathan M. , Choi Mihye , Karp Nolan S.
Published: September 2022

As a biologic product derived from human tissue, acellular dermal matrices (ADMs) did not require pre-market approval for their initial use as a soft tissue support product. Since their first utilization in breast surgery, ADMs have allowed for numerous advances in breast reconstruction. ADMs quickly gained popularity in breast surgery and are frequently utilized in various applications. During an investigation into potential factors leading to breast implant-associated anaplastic large cell lymphoma, the United States Food and Drug Administration (FDA) made an official statement that ADMs were not approved for use in breast reconstruction and that using ADMs in breast surgery was considered off-label. This special topic article details the history of ADMs in breast surgery and describes the ongoing evolution of the relationship between the FDA and ADMs.
Effect of single housing on innate immune activation in SIV-infected pigtail macaques (Macaca nemestrina) as a model of psychosocial stress in acute HIV infection
Authors: Castell Natalie , Guerrero-Martin Selena M. , Rubin Leah H. , Shirk Erin N. , Brockhurst Jacqueline K. , Lyons Claire E. , Najarro Kevin M. , Queen Suzanne E. , Carlson Bess W. , Adams Robert J. , Morrell Craig N. , Gama Lucio , Graham David R. , Zink Christine , Mankowski Joseph L. , Clements Janice E. , Metcalf Pate Kelly A.
Published: September 2022

Objective

Simian immunodeficiency virus (SIV) infection of macaques recapitulates many aspects of HIV pathogenesis and is similarly affected by both genetic and environmental factors. Psychosocial stress is associated with immune system dysregulation and worse clinical outcomes in people with HIV (PWH). This study assessed the impact of single housing, as a model of psychosocial stress, on innate immune responses of pigtailed macaques (Macaca nemestrina) during acute SIV infection.

Methods

A retrospective analysis of acute SIV infection of two- to six-year-old male pigtailed macaques was performed to compare the innate immune responses of socially (n = 41) and singly (n = 35) housed animals. Measures included absolute monocyte count and subsets, and in a subset (n ≤ 18) platelet counts and activation data.

Results

SIV infection resulted in the expected innate immune parameter changes with a modulating effect from housing condition. Monocyte number increased post-infection for both groups, driven by classical monocytes (CD14+ CD16-), with a greater increase in socially housed animals (227%, p < 0.001, by day 14 compared to pre-inoculation timepoints). Platelet numbers recovered more quickly in the socially housed animals. Platelet activation (P-selectin) increased 65% (p = 0.004) and MHC-I surface expression 40% (p = 0.009) from pre-inoculation only in socially housed animals, while no change in these measures occurred in singly housed animals.

Conclusions

Chronic psychosocial stress produced by single housing may play an immunomodulatory role in the innate immune response to acute retroviral infection. Dysregulated innate immunity could be one of the pathways by which psychosocial stress contributes to immune suppression and increased disease severity in PWH.
MECHANISMS OF CARDIAC DYSFUNCTION IN SEPSIS
Authors: Hobai Ion A.
Published: September 2022

Studies in animal models of sepsis have elucidated an intricate network of signaling pathways that lead to the dysregulation of myocardial Ca2+ handling and subsequently to a decrease in cardiac contractile force, in a sex- and model-dependent manner. After challenge with a lethal dose of LPS, male animals show a decrease in cellular Ca2+ transients (ΔCai), with intact myofilament function, whereas female animals show myofilament dysfunction, with intact ΔCai. Male mice challenged with a low, nonlethal dose of LPS also develop myofilament desensitization, with intact ΔCai. In the cecal ligation and puncture (CLP) model, the causative mechanisms seem similar to those in the LPS model in male mice and are unknown in female subjects. ΔCai decrease in male mice is primarily due to redox-dependent inhibition of sarco/endoplasmic reticulum Ca2+ ATP-ase (SERCA). Reactive oxygen species (ROS) are overproduced by dysregulated mitochondria and the enzymes NADPH/NADH oxidase, cyclooxygenase, and xanthine oxidase. In addition to inhibiting SERCA, ROS amplify cardiomyocyte cytokine production and mitochondrial dysfunction, making the process self-propagating. In contrast, female animals may exhibit a natural redox resilience. Myofilament dysfunction is due to hyperphosphorylation of troponin I, troponin T cleavage by caspase-3, and overproduction of cGMP by NO-activated soluble guanylate cyclase. Depleted, dysfunctional, or uncoupled mitochondria likely synthesize less ATP in both sexes, but the role of energy deficit is not clear. NO produced by NO synthase (NOS)-3 and mitochondrial NOSs, protein kinases and phosphatases, the processes of autophagy and sarco/endoplasmic reticulum stress, and β-adrenergic insensitivity may also play currently uncertain roles.
Immune Cell Deformability in Depressive Disorders: Longitudinal Associations Between Depression, Glucocorticoids and Cell Deformability
Authors: Walther Andreas , Kräter Martin , Kirschbaum Clemens , Gao Wei , Wekenborg Magdalena , Penz Marlene , Rothe Nicole , Guck Jochen , Wittwer Lucas Daniel , Eder Julian
Published: September 2022

Background

Cell deformability of all major blood cell types is increased in depressive disorders (DD). Furthermore, impaired glucocorticoid secretion is causally related to DD. Nevertheless, there are no longitudinal studies examining changes in glucocorticoid output and depressive symptoms regarding cell deformability in DD.

Aim

To investigate, whether changes in depressive symptoms or hair glucocorticoids predict cell deformability in DD.

Methods

In 136 individuals, depressive symptoms (PHQ-9) and hair glucocorticoids (cortisol and cortisone) were measured at timepoint one (T1), while one year later (T2) depressive symptoms and hair glucocorticoids were remeasured and additionally cell deformability of peripheral blood cells was assessed and DD status was determined by clinical interview.

Results

Depression severity at T1 predicted higher cell deformability in monocytes and lymphocytes over the entire sample. Subjects with continuously high depressive symptoms at T1 and T2 showed elevated monocyte deformability as compared to subjects with low depressive symptoms. Depression severity at T1 of subjects with a lifetime persistent depressive disorder (PDD) was associated with elevated monocyte, neutrophil, and granulo-monocyte deformability. Depression severity at T1 of subjects with a 12-month PDD was positively associated with monocyte deformability. Furthermore, increases in glucocorticoid concentrations from T1 to T2 tended to be associated with higher immune cell deformability, while strongest associations emerged for the increase in cortisone with elevated neutrophil and granulo-monocyte deformability in the 12-month PDD group.

Conclusion

Continuously elevated depressive symptomatology as well as an increase in glucocorticoid levels over one year are associated with higher immune cell deformability, particularly in PDD. These findings suggest, that persistent depressive symptomatology associated with increased glucocorticoid secretion may lead to increased immune cell deformability thereby compromising immune cell function and likely contributing to the perpetuation of PDD.
Exploration of cortical ß-Amyloid load in Alzheimer’s disease using quantitative susceptibility mapping at 9.4T
Authors: Tuzzi Elisa , Loktyushin Alexander , Zeller Anja , Pohmann Rolf , Laske Christoph , Scheffler Klaus , Hagberg Gisela E.
Published: September 2022

Early detection of β-Amyloid (Aβ) deposits in Alzheimer’s disease (AD) patients may enable treatment in the early stages of the disease. To date, there are no validated, specific, and non-invasive routines for early Aβ detection which are suitable for clinical practice. Ultra-high resolution quantitative susceptibility mapping (QSM) at 14.1T has previously shown different contrasts in cortical areas of an AD sample that resembled distinct Aβ spatial patterns in histological sections of the same specimen. These contrasts appeared different in the QSM from a healthy control (HC) sample where, instead, no plaques were detected. In a few cases, this distinction in the cortical magnetic effects (para- and diamagnetic) between AD and HC was also observed in vivo using ultra- high resolution single-echo Acquisition Weighted (AW) gradient echo MRI at 9.4T. Based on this evidence, a method to quantify the paramagnetic and diamagnetic effects of Aβ to possibly distinguish between AD and HC was developed. In this study, we extended those results and explored the ability to use QSM to estimate β-Amyloid plaque load in the cortex of 7 elderly patients with early AD and 7 healthy age-matched HC. Besides ultra-high resolution AW images, we acquired lower resolution multi-echo (MTE) data and compared the previously used RESHARP- based method for background removal (“AW-filter”, with a high Tikhonov term and a small kernel size) with a method widely used in the literature (“mild-filter”, with a low-regularization term and a large kernel size) for the MTE processing. Paramagnetic and diamagnetic QSM changes were assessed in 16 cortical areas. All methods enabled the detection of regions with high QSM values (up to 45 ppb in AD and up to 25 ppb in HC) and known as early Aβ accumulation areas in AD progression. A distinct cortical pattern was observed at both spatial resolutions using the AW-filter. This was not the case with the mild-filter at the lower resolution. AW-QSM outperformed MTE maps with the AW-filter for the detection of areas with prominent cortical paramagnetic effects, including regions where Aβ accumulation happens in the earliest AD stages, such as the precuneus and posterior cingulate cortex. Diamagnetic changes were more prominent than the paramagnetic effects regardless of the spatial resolution used and this difference was further enhanced with the mild-filter. This explorative study points toward the development of more accessible clinical methods to non-invasively detect effects of Aβ accumulation in AD patients by exploring cortical features that can be detected by ultra-high field QSM at different spatial resolutions.
Pharmacokinetics and pharmacogenomics of clozapine in an ancestrally diverse sample: A longitudinal analysis and GWAS using clinical monitoring data from the UK
Authors: Pardiñas Antonio F. , Kappel Djenifer B. , Roberts Milly , Tipple Francesca , Shitomi-Jones Lisa M. , King Adrian , Jansen John , Helthuis Marinka , Owen Michael J. , O’Donovan Michael C. , Walters James T.R.
Published: September 2022

Background

The antipsychotic clozapine is the only drug with proven effectiveness against the treatment-resistant symptoms that affect 20-30% of those with schizophrenia. Despite this, clozapine is markedly under-prescribed, partly due to concerns about its narrow therapeutic range and adverse drug reaction profile. Both concerns are linked to drug metabolism, which varies across worldwide populations and is partially genetically determined. There is, however, a lack of clozapine pharmacogenomic data based on study participants of multiple ancestries.

Methods

We analysed data from 4,495 individuals linked to 16,068 assays from a clozapine monitoring service in the UK. Genomic information was used to identify five biogeographical ancestries (European, Sub-Saharan African, North African, Southwest Asian and East Asian) as well as admixed individuals. Pharmacokinetic modelling, GWAS, and a polygenic score association analysis were conducted on this longitudinal dataset using three outcome variables: two metabolite plasma concentrations (clozapine and norclozapine) and their ratio.

Findings

A faster average clozapine metabolism was seen in those of Sub-Saharan African ancestry compared to Europeans. In contrast, East and Southwest Asians were more likely to be slow clozapine metabolisers. Eight pharmacogenomic loci were identified in the GWAS, with consistent cross-ancestral effects. Polygenic scores generated from these loci led to significant associations with clozapine outcome variables in the whole sample and within individual ancestries, with variances explained between 0.61%-7.26%.

Interpretation

Longitudinal cross-ancestry GWAS can discover pharmacogenomic markers of clozapine metabolism that, individually or as polygenic scores, have consistent effects across ancestries. While the potential clinical role of these predictors is evaluated, we provide strong evidence that ancestral differences in clozapine metabolism should be incorporated into clozapine dosing and managing protocols to optimise their utility for diverse populations.

Funding

Medical Research Council (MRC).
A linear discriminant analysis model of imbalanced associative learning in the mushroom body compartment
Authors: Lipshutz David , Kashalikar Aneesh , Farashahi Shiva , Chklovskii Dmitri B.
Published: September 2022

To adapt to their environments, animals learn associations between sensory stimuli and unconditioned stimuli. In invertebrates, olfactory associative learning primarily occurs in the mushroom body, which is segregated into separate compartments. Within each compartment, Kenyon cells (KCs) encoding sparse odor representations project onto mushroom body output neurons (MBONs) whose outputs guide behavior. Associated with each compartment is a dopamine neuron (DAN) that modulates plasticity of the KC-MBON synapses within the compartment. Interestingly, DAN-induced plasticity of the KC-MBON synapse is imbalanced in the sense that it only weakens the synapse and is temporally sparse. We propose a normative mechanistic model of the MBON as a linear discriminant analysis (LDA) classifier that predicts the presence of an unconditioned stimulus (class identity) given a KC odor representation (feature vector). Starting from a principled LDA objective function and under the assumption of temporally sparse DAN activity, we derive an online algorithm which maps onto the mushroom body compartment. Our model accounts for the imbalanced learning at the KC-MBON synapse and makes testable predictions that provide clear contrasts with existing models.
Global observation of plankton communities from space
Authors: Kaneko Hiroto , Endo Hisashi , Henry Nicolas , Berney Cédric , Mahé Frédéric , Poulain Julie , Labadie Karine , Beluche Odette , El Hourany Roy ,   Tara Oceans Coordinators, Chaffron Samuel , Wincker Patrick , Nakamura Ryosuke , Karp-Boss Lee , Boss Emmanuel , Bowler Chris , de Vargas Colomban , Tomii Kentaro , Ogata Hiroyuki
Published: September 2022

Satellite remote sensing from space is a powerful way to monitor the global dynamics of marine plankton. Previous research has focused on developing models to predict the size or taxonomic groups of phytoplankton. Here we present an approach to identify representative communities from a global plankton network that included both zooplankton and phytoplankton and using global satellite observations to predict their biogeography. Six representative plankton communities were identified from a global co-occurrence network inferred using a novel rDNA 18S V4 planetary-scale eukaryotic metabarcoding dataset. Machine learning techniques were then applied to train a model that predicted these representative communities from satellite data. The model showed an overall 67% accuracy in the prediction of the representative communities. The prediction based on 17 satellite-derived parameters showed better performance than based only on temperature and/or the concentration of chlorophylla. The trained model allowed to predict the global spatiotemporal distribution of communities over 19-years. Our model exhibited strong seasonal changes in the community compositions in the subarctic-subtropical boundary regions, which were consistent with previous field observations. This network-oriented approach can easily be extended to more comprehensive models including prokaryotes as well as viruses.
Elevated genetic risk for multiple sclerosis originated in Steppe Pastoralist populations
Authors: Barrie William , Yang Yaoling , Irving-Pease Evan K. , Attfield Kathrine E. , Scorrano Gabriele , Jensen Lise Torp , Armen Angelos P. , Dimopoulos Evangelos Antonios , Stern Aaron , Refoyo-Martinez Alba , Ramsøe Abigail , Gaunitz Charleen , Demeter Fabrice , Jørkov Marie Louise S. , Møller Stig Bermann , Springborg Bente , Klassen Lutz , Hyldgård Inger Marie , Wickmann Niels , Vinner Lasse , Korneliussen Thorfinn Sand , Allentoft Morten E. , Sikora Martin , Kristiansen Kristian , Rodriguez Santiago , Nielsen Rasmus , Iversen Astrid K. N. , Lawson Daniel J. , Fugger Lars , Willerslev Eske
Published: September 2022

Multiple sclerosis (MS) is a modern neuro-inflammatory and -degenerative disease, which is most prevalent in Northern Europe. Whilst it is known that inherited risk to MS is located within or within close proximity to immune genes, it is unknown when, where and how this genetic risk originated1. By using the largest ancient genome dataset from the Stone Age2, along with new Medieval and post-Medieval genomes, we show that many of the genetic risk variants for MS rose to higher frequency among pastoralists located on the Pontic Steppe, and were brought into Europe by the Yamnaya-related migration approximately 5,000 years ago. We further show that these MS-associated immunogenetic variants underwent positive selection both within the Steppe population, and later in Europe, likely driven by pathogenic challenges coinciding with dietary, lifestyle, and population density changes. This study highlights the critical importance of this period as a determinant of modern immune responses and its subsequent impact on the risk of developing MS in a changing environment.
Genes and sites under adaptation at the phylogenetic scale also exhibit adaptation at the population-genetic scale
Authors: Latrille T. , Rodrigue N. , Lartillot N.
Published: September 2022

Adaptation in protein-coding sequences can be detected from multiple sequence alignments across species, or alternatively by leveraging polymorphism data inside a population. Across species, quantification of the adaptive rate relies on phylogenetic codon models, classically formulated in terms of the ratio of non-synonymous over synonymous substitution rates. Evidence of an accelerated non-synonymous substitution rate is considered a signature of pervasive adaptation. However, because of the background of purifying selection, these models are potentially limited in their sensitivity. Recent developments have led to more sophisticated mutation-selection codon models aimed at making a more detailed quantitative assessment of the interplay between mutation, purifying and positive selection. In this study, we conducted a large-scale exome-wide analysis of placental mammals with mutation-selection models, assessing their performance at detecting proteins and sites under adaptation. Importantly, mutation-selection codon models are based on a population-genetic formalism and thus are directly comparable to McDonald & Kreitman tests at the population level to quantify adaptation. Taking advantage of this relationship between phylogenetic and population genetics, we integrated divergence and polymorphism data across the entire exome for 29 populations across 7 genera, and showed that proteins and sites detected to be under adaptation at the phylogenetic scale are also under adaptation at the population-genetic scale. Altogether, our exome-wide analysis shows that phylogenetic mutation-selection codon models and population-genetic test of adaptation can be reconciled and are congruent, paving the way for integrative models and analyses across individuals and populations.

Significance Statement

Detecting genes under adaptation represents a key step in the decoding of genomes. Several methods have been proposed, focussing either on the short time scale (population genetics, e.g. human populations), or on the long time scale (phylogenetics, e.g. across mammals). However, the accuracy of these methods is still under debate, and it is still unclear whether the signatures of adaptation are congruent across evolutionary scales. In this study, using novel phylogenetic methods and gathering genome data across and within species, we show that the signatures of adaptation at the phylogenetic and population-genetic scales can be reconciled. While providing a mutual confirmation of the two approaches, our work paves the way for further methodological integration between micro- and macro-evolutionary genomics.
MegaFeed: Global database of megaherbivores’ feeding preferences
Authors: Berzaghi Fabio , Awasthi Balram
Published: September 2022

Terrestrial mammalian herbivores heavier than ~1000 kg, also known as megaherbivores, perform unique ecological functions due to their combination of heavy body mass, extended home ranges, abundant biomass consumption, and highly diverse diet. Megaherbivores can have substantial effects on ecosystem functioning, vegetation structure, and biogeochemical cycles. Elephants (family Elephantidae) and rhinoceros (family Rhinocerotidae) are two of the remaining megaherbivores that survived the late Pleistocene extinctions, but their populations have been globally declining in the last century. Feeding preferences are a key factor determining the influence of megaherbivores on ecosystems and plant communities; however, comprehensive and centralized data on megaherbivores food preferences are lacking. Here we present MegaFeed, an extensive dataset of megaherbivores’ feeding preferences across their distribution. This first version of MegaFeed here described contains more than 12,000 records of feeding preferences for the extant elephant species: Loxodonta africana (African savanna elephant), Loxodonta cyclotis (African Forest elephant), and Elephas maximus (Asian elephant). MegaFeed will contribute to a better understanding of the ecological functions of megaherbivores, evaluate the consequences of their decline, and guide rewilding and conservation initiatives such as habitat restoration and reduction of human–wildlife conflicts.