bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification and clinical prognosis of salinomycin binding targets in neuroblastoma (LB613)
Authors: Zhou Shuang , Wang Fengfei , Xiang Shihua , Wong Eric , Muhonen Wallace , Fonkem Ekokobe , Hsieh Tze‐chen , Li David , Zhang Ruiwen , Shabb John , Wu Joseph , Wu Min , Wu Erxi
Published: June 2021

Salinomycin, a widely used anti‐coccidial agent, was recently identified from a library of 16,000 natural and commercial chemical compounds based on its highly selective inhibitory effect on breast cancer stem cells (CSCs), with more than 100‐fold greater potency than paclitaxel. Salinomycin also exhibits cytotoxic effects on other types of cancer cells and CSCs and overcomes drug resistance. However, the exact mechanism of salinomycin, especially its direct binding target(s), and its effects on Neuroblastoma (NB) are yet not known.

NB is a common solid tumor and a leading cause of mortality in children. Currently, 35% of patients with NB remain incurable. In addition, the majority survivors of NB suffer from long‐term side effects of current therapies and are at risk for disease relapse or getting a second, different cancer. More effective therapies are pressingly needed. Since the existence of CSCs in human NB cell lines and NB tumors has been well documented, and has been closely associated with chemoresistance or tumor relapse, therapeutic targeting of NB CSCs may be a critical novel approach for NB therapy.

Aiming to improve NB therapy, we examined the efficacy and mechanism of salinomycin in human NB cells. Our study showed that salinomycin markedly inhibits NB cell proliferation and tumorsphere formation. Treatment of salinomycin induced G2 cell cycle arrest with an up‐regulation of Cyclin A and a down‐regulation of p21 protein levels. We further identified TIF1β and NCL as novel direct binding targets of salinomycin by using comprehensive methods, including chemical proteomics and functional genomics. Furthermore, by analyzing tumor samples from a cohort of 88 NB patients, we found that the elevated level of either TIF1β or NCL is associated with poor prognosis for NB patients. Thus, our results indicate salinomycin is a potential new therapeutic agent and TIF1β and NCL as new therapeutic targets/biomarkers for NB therapy.

Grant Funding Source: Supported by ND EPSCoR, NDSU, NIH P20 RR020151, NIGMS (P20 GM103505 and P30 GM103332‐01)
ACTH administration stimulates both cortisol and aldosterone secretion in fasting northern elephant seals (LB776)
Authors: Champagne Cory , Tift Mike , Houser Dorian , Crocker Daniel
Published: June 2021

During molting, northern elephant seals exhibit substantial alterations in circulating cortisol concentrations, probably to facilitate pelage synthesis while fasting. How these changes influence the hypothalamic‐pituitary‐adrenal (HPA) axis and the stress response, however, is not known. To investigate the modulation of the HPA axis during molting, we administered ACTH (25 units, intramuscularly) to sixteen juvenile elephant seals at the beginning (n=6), middle (n=5), and end (n=5) of their spring molting period in a cross‐sectional study design. Blood samples were collected immediately before, and then periodically for 2.5 hrs after, ACTH administration. We quantified circulating concentrations of ACTH, and the responses of cortisol and aldosterone. Both cortisol and aldosterone concentrations markedly increased following stimulation by ACTH and remained elevated for the duration of sampling (linear mixed model, F = 153, 25.3, respectively; p < 0.01). There were no detectable differences in the magnitude of hormone responses to ACTH administration among the study groups (p > 0.1). Nonesterified fatty acids increased following ACTH administration, suggesting upregulation of lipolysis; however, blood urea nitrogen concentrations increased only marginally, indicating that protein catabolism was less affected by ACTH administration. ACTH is not a strong aldosterone secretagogue in terrestrial mammals but several studies have measured increased aldosterone after ACTH stimulation in marine mammals, indicating its potential importance in osmoregulation during stress in these species. Cortisol and aldosterone increased in parallel following ACTH stimulation but the slope of this relationship varied among the study groups. This suggests that the release of these hormones is closely coupled in this species and possibly other marine mammals.

Grant Funding Source: Supported by the Office of Naval Research
Biochemistry and Molecular Biology Education in a Transforming Academy and a Molecular World
Authors: Brenner Charles
Published: June 2021

Every year, we welcome 3 million new undergraduates to US colleges and universities, approximately one in six of whom begin their collegiate careers with premedical intentions. Thus, approximately 500,000 students annually enroll in inorganic chemistry. However, only about 165,000 go on to take organic chemistry, and in 2008, only 42,200 applied for 18,000 slots in US medical schools, thereby producing 17,300 new US MDs in 2012. This premedical funnel has a huge effect on the organization of undergraduate colleges and the education of nearly half a million undergraduates per year who are not going to become doctors. The redesign of the 2015 MCAT was therefore an opportunity not only to think about what courses premedical students ought to take but to consider how to prepare larger populations of undergraduates with foundational molecular knowledge. Premedical students now almost universally have access to a biochemistry course either at their home campus or online. Accordingly, while medical schools are admitting students for fall 2016 enrollment who have largely taken and been examined in biochemistry and molecular biology, the basic science coursework in the first two years of medical school has simultaneously been condensed in a manner that makes it difficult to teach metabolism and genomics at the advanced levels that might have been enabled by a better prepared entering class. In this talk, I will address approaches to offer molecular education to undergraduate and health professional students that have the potential to improve our students’ appreciation of data analysis, drug and biomolecule reactivity, enzymes, metabolism and genomics.

Support or Funding Information

Educational activities supported by National Science Foundation award CHE1404147 and the Roy J. Carver Trust.
Mechanosensory function of Cav1.2 calcium channel in renal primary cilia
Authors: Kathem Sarmed H , Nauli Surya M
Published: June 2021

Primary cilia are mechanosensory organelles and play an important role in calcium signaling. However, the precise mechanistic event of cilia‐calcium axis is still debated. Here, we used kidney cells transfected with G‐CaMP3 (a green fluorescent genetically encoded calcium indicator) to assess this important event in cell function. Using modified single‐cell imaging technique, we were able to capture a single‐living cell from the side for a better viewing of the cell body and its cilium simultaneously. Recently, we also used a high‐speed imaging recording (a minimum of 200 frames per sec) to capture both cilia bending and calcium signaling with Nomarski interference contrast (NIC) with fluorescence microscopy, respective. Within 1.5 μsec after fluid‐shear induce cilia bending, we reported calcium current was detected at the cell membrane very near to cilium base. This calcium current was directionally organized with the fluid flow and cilia bending direction. When ATP was added to the cells without flow, directionally non‐organized calcium current was seen throughout the cell membrane and cytosol. Immunofluorescence staining showed that Cav1.2 calcium channel expressed at the cell membrane close to cilia base. Verapamil completely abolished flow‐induced calcium signals suggesting that Cav1.2 channel might be responsible for calcium signaling. Calcium‐depleted extracellular fluid with EGTA produced a similar result as to verapamil indicating that extracellular calcium was required to initiate this event. We conclude that the very early event in cilium‐induced calcium signaling initiated in the cell membrane close to cilium base through Cav1.2 calcium channel.

Support or Funding Information

Department of Defense (PR130153 )
Maternal Vitamin A Supplementation Expands Adipose Progenitor Population through Promoting Vascular Development
Authors: Wang Bo , Fu Xing , Zhang Shuming , Liang Xingwei , Zhu Meijun , Du Min
Published: June 2021

Retinoic acid regulates various types of progenitor differentiation and tissue development including adipose development. However, the impact of maternal vitamin A supplementation on fetal adipose development and its long‐term consequence in adulthood remain unclear. To address, we supplemented maternal mice with 0, 15 or 30 IU/mL retinyl palmitate in water during gestation and lactation. Adipose tissue and serum of weanling offspring, and E7.5, 12.5 and 18.5 fetuses were collected. We found that retinoic acid is the main retinoid in fetuses that was elevated by maternal vitamin A supplementation. The populations of platelet‐derived growth factor receptor alpha positive (PDGFRα+) adipocyte progenitors in both fetuses and weaned offspring were increased due to vitamin A supplementation, which were correlated with heightened vascular density in adipose tissue at weaning. We further found that retinoic acid upregulated vascular endothelial growth factor α (VEGFα) which might explain the enhanced vasculogenesis in adipose tissue of fetuses supplemented with vitamin A. Using florescence tracing, we found that, under cold or retinoic acid stimulation, PDGFRα+ progenitor cells were located in neovascular system. In summary, our results reveal that maternal vitamin A supplementation increases offspring adipose progenitor populations by promoting vascular system development during the fetal stage, which is mediated by retinoic acid receptor signaling.

Support or Funding Information

Supported by NIH R01HD067449 and USDA‐NIFA 2015‐67015‐23219
Unjamming and cell shape in the asthmatic airway epithelium
Authors: Fredberg Jeffrey , Mitchel Jennifer , Kim Jae Hun , Park Jin‐Ah
Published: June 2021

From coffee beans flowing in a chute to cells remodeling in a living tissue, a wide variety of close‐packed collective systems –both inert and living– have the potential to jam. The collective can sometimes flow like a fluid or jam and rigidify like a solid. The unjammed‐to‐jammed transition remains poorly understood, however, and structural properties characterizing these phases remain unknown. Using primary human bronchial epithelial cells, we show that the jamming transition in asthma is linked to cell shape, thus establishing in that system a structural criterion for cell jamming. Surprisingly, critical scaling collapse predicts a counterintuitive relationship between jamming, cell shape, and cell‐cell adhesive stresses that is borne out by direct experimental observations. Cell shape thus provides a rigorous structural signature for classification and investigation of bronchial epithelial layer jamming in asthma, and potentially in any process in disease or development in which epithelial dynamics play a prominent role.

Support or Funding Information

This research was supported by Francis Family Foundation, the Alfred P. Sloan Foundation, American Heart Association (13SDG14320004), National Research Foundation of Korea (NRF‐2013S1A2A2035518), National Science Foundation (BMMB‐1334611, DMR‐1352184), and the National Institutes of Health (K25 HL091124, P30DK065988, P30ES000002, HL007118, R01HL102373, R01HL107561, P01HL120839)
Tannase‐treated grape pomace attenuates IL‐1β‐induced inflammation in Caco‐2 cells
Authors: Martin Isabela , Macedo Gabriela , Blumberg Jeffrey , Chen C‐Y. Oliver
Published: June 2021

Grape pomace (GP) derived from wine production is rich in glycosidic phenolics which may possess a lower bioefficacy than their respective aglycones. Thus, we examined whether GP treated with Paecilomyces variotii tannin acyl hydrolase (tannase) to hydrolyze the ester and the depside bonds between conjugates and phenolics enhances anti‐inflammatory actions in vitro. GP was treated with tannase at 40 °C and pH 5.5 for 5 h. Phenolics in GP and tannase treated GP (GPT) were extracted with 70% methanol in acetate buffer, dried under N2 air, and reconstituted in PBS for tests. GPT contained 45% more quercetin and 71% less quercetin‐3‐O‐rutinoside than GP. Further, GPT had 39% more total phenols than GP and displayed 57, 215, and 12% greater total antioxidant capacity per DPPH, ORAC, and FRAP analyses, respectively. However, GP and GPT at 100 and 200 μg/mL (dry extract wt/v) displayed comparable efficacy in the reduction of ROS production in Caco‐2 cells treated with or without 50 μM AAPH. After 24‐h pretreatment, GPT at 200 μg/mL decreased 20 ng/mL IL‐1β‐induced PGE2 production by 110% and IL‐8 by 83% and down‐regulated NF‐κB activation by 68% relative to controls. GPT was more potent than GP in the amelioration of IL‐1β‐induced inflammation. Therefore, tannase treatment appears to enhance the antioxidant and anti‐inflammatory activities of grape pomace phenolics and suggests the potential application of this material in food and beverage products.

Support or Funding Information

Supported by USDA
Hepcidin attenuates zinc efflux in Caco‐2 cells
Authors: Hennigar Stephen R. , McClung James P.
Published: June 2021

Hepcidin, a peptide hormone produced by theliver in response to iron loading and inflammation, regulates body iron storesby inhibiting iron transporter function. Zinc also regulates hepcidinexpression; however, the effects of hepcidin on zinc transport and zinctransporter function have not been documented. The objective of this study wasto determine whether hepcidin affects intestinal zinc transport. Differentiatedhuman intestinal Caco‐2 cells were treated ± 1μM hepcidin for 3–24 h. Zinctransport was assessed in cells seeded on Transwell inserts. Media was collected from the apical and basolateral chambers and 67Znconcentrations were determined by ICP‐MS. Expression of metallothionein (MT1A), ZIP4 (SLC39A4), and ZnT1 (SLC30A1)was determined using RT‐qPCR and Western blot. Hepcidin attenuated zinctransport, as cells treated with hepcidin exported 20 and 26% less 67Zninto the basolateral chamber at 3 h and 24 h (P<0.05), respectively, and retained more cellular 67Zn(P<0.05) as compared to control cells. Intracellular zinc in control cells was localized to vesicles dispersed throughout the cytoplasm; however, the number of vesicles and intensity of FluoZin‐3 fluorescence decreased (P<0.05)in cells treated with hepcidin for 24 h. The mRNA abundance of metallothionein increased 1.5‐fold (P<0.05). ZIP4 protein remained unchanged (P>0.05), whereas hepcidin reduced ZnT1 protein by 75% (P<0.05) as compared to control cells. These data suggest that hepcidin is a regulatory hormone that manages zinc transport in intestinal cells by downregulating ZnT1 to reduce zinc export and increasing metallothionein to buffer the rise in intracellular zinc. Understanding the mechanism and role of hepcidin in zinc homeostasis may provide insight into the hypozincemiaassociated with inflammation and infection.

Support or Funding Information

Support provided by USAMRMC.
Skin Carotenoids as Biomarker for Vegetable and Fruit Intake: Validation of the Reflection‐Spectroscopy Based “Veggie Meter”
Authors: Ermakov Igor V , Whigham Leah D , Redelfs Alisha H , Jahns Lisa , Stookey Jodi , Bernstein Paul S , Gellermann Werner
Published: June 2021

Skin is a relatively stable storage medium for carotenoids; non‐invasive optical measurements of carotenoids in this tissue via Resonance Raman spectroscopy (RRS) serve as a non‐invasive biomarker for fruit and vegetable (F/V) intake. The RRS method has been validated with HPLC‐based measurements of carotenoid concentrations in serum and excised skin tissue samples and has been shown in feeding studies to respond to changes in F/V intake.

An attractive alternative to RRS is based on reflection spectroscopy (RS), which requires less complex instrumentation and has an advantage in also measuring skin melanin and hemoglobin absorptions. Using a suitable algorithm, the latter can be taken into account in the RS‐based derivation of skin carotenoid levels. Furthermore, these levels can be quantified in optical density units, which directly correlate with the carotenoid concentrations encountered in the measured tissue volume. The objective of this study was to validate the RS method via comparison with the RRS method.

We compared RS and RRS measurements in 5 diverse human subject cohorts of different age groups and ethnicities in community and clinical settings. These measurements included inter‐subject comparisons of carotenoid levels in 146 adults and children, tracking of carotenoid changes in response to dietary interventions in 29 adults, and an ongoing exploration of a potential correlation between skin and retinal carotenoid levels in adult patients with vision disorders. Depending on the particular study, correlation coefficients varied between R ~ 0.80 and 0.96, showing that the RS method provides a valid substitute for RRS in skin carotenoid measurements of all age groups. A compact, portable instrument configuration will be presented, which permits rapid non‐invasive measurement and tracking of F/V derived carotenoid levels. In its capacity as “Veggie Meter” it should be attractive for screening of large populations and the assessment of the effectiveness of F/V intake interventions.

Support or Funding Information

Support for this research was provided in part by the Paso del Norte Health Foundation and the USDA‐ARS.
Menstrual cycle hormones, food intake, and cravings
Authors: Krishnan Sridevi , Tryon Rebecca , Welch Lucas C , Horn William F , Keim Nancy L
Published: June 2021

Objective

Food craving and intake are affected by steroid hormones during the menstrual cycle, especially in the luteal phase, when craving for certain foods has been reported to increase. However, satiety hormones such as leptin have also been shown to affect taste sensitivity, and therefore food choices. While in vitro studies have reported that estradiol can stimulate leptin release, some human studies have shown that leptin is inversely associated with estradiol. On the contrary, progesterone has been positively associated with leptin, and therefore may play a significant role in food intake regulation. Our objective was to characterize the associations between sex steroid hormones, leptin and food intake behavior.

Methods

Seventeen healthy, women with regular menstrual cycles, 23.2 ± 4.8 y, and BMI 22.4 ±1.9 kg/m2 were studied during their late follicular and luteal phases. Estradiol, progesterone, DHEAS, SHBG, leptin and insulin were measured in fasting samples. In addition, volunteers were asked to answer validated “Food Craving inventory” (FCI) and “Carbohydrate Rich Food intake” (CRFI) questionnaires at the start of the study. The FCI captured information regarding the types of foods volunteers were craving – rich in fat, carbohydrate or sweet taste, followed by beverages and fast foods over a three month period prior to starting the study. The CFRI captured information with regard to consumption of these same foods. We used Pearson's correlation coefficients to identify positive or inverse associations between hormones and subjective food intake and craving scores.

Results

Estradiol, progesterone and leptin were not associated with each other. However, women with higher estradiol during the luteal phase reported consuming more carbohydrate‐rich foods in the past three months (r = 0.5174; p = 0.034), while also reporting increased craving for sweet foods (r = 0.4922; p = 0.045). Higher progesterone in the luteal phase was weakly associated with higher craving for sweetened beverages (r = 0.4723, p = 0.056). As expected, leptin was inversely associated with reported consumption of sweet tasting foods (r = −0.5071; p = 0.038), while also being inversely associated with craving fat rich foods (r = −0.4851; p = 0.048).

Conclusions

Estradiol is associated with increased carbohydrate rich food intake, while progesterone with craving sweetened beverage intake. Leptin, while being associated with reduced craving for fat‐rich food, and reduced sweet food intake, however, appears to not be associated with estradiol and progesterone, thereby suggesting that the female sex steroid hormones may be independent influences on food intake behaviors. Understanding the changes of estradiol, progesterone and leptin in women could clinically aid in advocating food choices during the pre‐menstrual phase.

Support or Funding Information

USDA projects #2032‐51530‐022 and #5306‐51530‐019
Insulin and Cinnamon Polyphenol Extract Regulated Diacylglycerol Acyltransferase and Tristetraprolin Gene Expression in Cultured Mouse Adipocytes and Macrophages
Authors: Cao Heping , Anderson Richard A
Published: June 2021

Diacylglycerol acyltransferases (DGATs) are integral membrane proteins that catalyze the last step of triacylglycerols (TAGs) biosynthesis in eukaryotic organisms. Plants and animals deficient in DGATs accumulate less TAGs and over‐expression of DGATs increases TAGs. DGAT knockout mice are resistant to diet‐induced obesity and lack milk secretion. Previous studies showed that cinnamon is beneficial to people with insulin resistance due in part to the insulin‐like activity of the cinnamon polyphenol extract (CPE), which also induces anti‐inflammatory zinc‐finger protein 36 (Zfp36)/tristetraprolin (Ttp) gene expression in both cultured adipocytes and macrophages. This study tested if Dgat gene expression is regulated by insulin and CPE using cultured mouse 3T3‐L1 adipocytes and RAW264.7 macrophages. The pre‐adipocytes were induced to oil‐droplet‐filled adipocytes and subsequently treated with insulin (0, 10 and 100 nM) and CPE (0, 10 and 100 μg/ml) for 0, 30, 60, 90 and 120 min. RAW macrophages were treated with CPE (100 μg/ml), insulin (100 nM) and lipopolysaccharides (LPS, 0.1 μg/ml) for 0, 30, 60, 120 and 240 min. Total RNAs were extracted from the cells and converted into cDNAs. TaqMan quantitative real‐time PCR was used to evaluate mRNA levels of mouse Dgat1, Dgat2 and Zfp36/Ttp genes using Rpl32 and Ubqln3 as internal references. Results showed that Dgat mRNA levels were generally decreased and Zfp36/Ttp mRNA levels were modestly increased by insulin and CPE in adipoctyes. Insulin and CPE effects on Dgat2 and Zfp36/Ttp gene expression were modestly increased but LPS increased Zfp36/Ttp mRNA levels up to 50‐fold in macrophages. Our results support the idea that CPE has insulin‐like effects and suggest a potential positive effect of CPE in reducing fat biosynthesis in adipocytes and increasing anti‐inflammatory activities in macrophages. The significance of this study is that CPE could be potentially useful for obesity prevention.

Support or Funding Information

USDA‐ARS Quality and Utilization of Agricultural Products Research Program 306 through CRIS 6054‐41000‐103‐00D
A Global Survey of Patient and Caregiver Experiences Throughout Care for Developmental Dysplasia of the Hip
Authors: Gibbard Marissa , Zivkovic Irena , Jivraj Bejaan , Schaeffer Emily , Robillard Julie M. , Mulpuri Kishore
Published: June 2021

Background:

Diagnosis and treatment for developmental dysplasia of the hip (DDH) varies greatly depending on condition severity, age at diagnosis, and professional opinion. Little is known about patient experiences across the globe. We aimed to characterize global patient and caregiver experiences during DDH care and to highlight patient-identified priorities.

Methods:

We developed a cross-sectional survey in collaboration with 7 DDH outreach organizations. DDH patients and/or their caregivers (above 18 y old) were invited to complete an international online survey about their experiences. Participants were recruited through web media of all collaborating organizations. Data collection took place over 3 months. Descriptive statistics were used to analyze quantitative results. Qualitative content analysis was used to categorize open-ended responses.

Results:

A total of 739 participants completed the survey, representing 638 (86.3%) parents/guardians of DDH patients, and 101 (13.7%) patients. Three hundred eighty-six (52.2%) participants received diagnosis by 3 months of age; mean age of diagnosis was 15.96 months (90% confidence interval=12.04, 19.91). Of 211 participants with family history of DDH, 68 (32.3%) did not receive DDH screening. Of 187 patients born breech, 82 (43.9%) did not receive DDH screening. In total, 36/94 (38.3%) participants with both family history and breech birth did not receive DDH screening. Most participants reported treatment (696/730, 95.3%), including bracing (n=461) surgery (n=364), and/or closed reduction (n=141). A total of 144 patients reported >1 surgery; 82 reported >3 surgeries. Participants reported a range of 1 to 400 visits to health care professionals for DDH care across 1 to 66 years. Lack of information and resources on treatment practicalities and timelines, along with emotional burden of diagnosis, were greatest challenges reported.

Conclusion:

Results demonstrate that DDH diagnosis and treatment can pose significant burden on patients and caregivers. Reliable public information is needed to support those affected. Global educational efforts are needed to raise awareness of DDH risk factors, signs, and symptoms among care providers, to increase awareness and improve identification, screening, and monitoring of at-risk children.
Epidemiologic and Clinical Characteristics of Clostridioides difficile Infections in Hospitalized and Outpatient Pediatric Oncology and Hematopoietic Stem Cell Transplant Patients
Authors: Barbar Ruba , Hayden Randall , Sun Yilun , Tang Li , Hakim Hana
Published: June 2021

Background:

The epidemiology and clinical course of Clostridioides difficile infection (CDI) in children, especially with cancer, are poorly defined. We aim to describe the epidemiology, clinical features and outcomes of CDI and to identify risk factors for recurrence in a pediatric oncology center.

Methods:

This is a retrospective cohort study of CDI in pediatric oncology and hematopoietic stem cell transplant (HSCT) patients in 2016 and 2017. CDI cases were identified by positive C. difficile test in symptomatic patients. CDI episodes were classified as incident, duplicate or recurrent and community-onset, hospital-onset or community-onset healthcare facility-associated. Data about clinical course and outcomes were abstracted. Risk factors for CDI recurrence were assessed by logistic regression.

Results:

One hundred seventy-eight patients 1 year of age and older developed 291 CDI episodes; 78% were incident and 22% recurrent. Underlying diagnoses were leukemia/lymphoma (57%) and solid/brain tumors (41%); 30% were HSCT recipients. Antibiotics, chemotherapy, antacids, steroids and laxatives were received by 96%, 82%, 70%, 47% and 15%, respectively. Half of the patients were neutropenic. Twenty-two percent of outpatients with CDI required hospitalization. Chemotherapy was delayed in 25%. There were no intensive care unit admissions nor deaths due to CDI. Exposure to H2-antagonists was identified as an independent risk factor for CDI recurrence.

Conclusions:

Although CDI in pediatric oncology and HSCT patients was associated with chemotherapy delay and hospitalization in approximately a quarter of patients, it was not associated with morbidity or mortality because patients had no attributable intensive care unit admission nor death. H2-antagonists are independent risk factors for CDI recurrence.
Trajectories of pain during pregnancy predict symptoms of postpartum depression
Authors: Mathur Vani A. , Nyman Tristin , Nanavaty Namrata , George Nevita , Brooker Rebecca J.
Published: June 2021

Introduction:

Postpartum depression imparts a significant and long-lasting burden on maternal and child health. Successful prevention or early detection of postpartum depression will rely on the identification of early risk factors. Pain during pregnancy (before childbirth) is a key potential predictor of postpartum depression risk. However, longitudinal studies characterizing pregnancy pain, its normal trajectory over time, and its prospective relations with symptoms of postpartum depression are lacking.

Methods:

We used data from a longitudinal study of maternal emotion that included assessments of pain and depressive symptoms at 3 time points—during the second and third trimester of pregnancy and at 4 months postpartum. Structural equation modelling was used to estimate longitudinal patterns of change in maternal pain over time. Latent growth curve parameters were tested as predictors of symptoms of postpartum depression.

Results:

Ninety-three healthy pregnant women enrolled in this study. Although the sample comprised women with relatively low-risk pregnancies, more than 90% of participants experienced pregnancy pain. Greater linear increases and less negative quadratic change in maternal pain over time were associated with greater levels of postpartum depression, even when controlling for prenatal depressive symptoms. Interpreting both parameters together, pain that increased in late pregnancy, when normative patterns had either levelled off or begun to decline, was associated with greater levels of postpartum depression.

Conclusion:

A developmental trajectory of pain experience that did not subside after childbirth was associated with greater postpartum depressive symptoms, suggesting that atypical trajectories of pain may be a risk factor for postpartum depression.
Highly sensitive scent-detection of COVID-19 patients in vivo by trained dogs
Authors: Vesga Omar , Agudelo Maria , Valencia-Jaramillo Andrés F. , Mira-Montoya Alejandro , Ossa-Ospina Felipe , Ocampo Esteban , Čiuoderis Karl , Pérez Laura , Cardona Andrés , Aguilar Yudy , Agudelo Yuli , Hernández-Ortiz Juan P. , Osorio Jorge E.
Published: June 2021

Timely and accurate diagnostics are essential to fight the COVID-19 pandemic, but no test satisfies both conditions. Dogs can scent-identify the unique odors of the volatile organic compounds generated during infection by interrogating specimens or, ideally, the body of a patient. After training 6 dogs to detect SARS-CoV-2 in human respiratory secretions (in vitro scent-detection), we retrained 5 of them to diagnose the infection by scenting the patient directly (in vivo scent-detection). Then, efficacy trials were designed to compare the diagnostic performance of the dogs against that of the rRT-PCR in 848 human subjects: 269 hospitalized patients (COVID-19 prevalence 30.1%), 259 hospital staff (prevalence 2.7%), and 320 government employees (prevalence 1.25%). The limit of detection in vitro was lower than 10-12 copies ssRNA/mL. In vivo, all dogs detected 92 COVID-19 patients present among the 848 study subjects. Detection was immediate, and independent of prevalence, time post-exposure, or presence of symptoms, with 95.2% accuracy and high sensitivity (95.9%; 95% C.I. 93.6-97.4), specificity (95.1%; 94.4-95.8), positive predictive value (69.7%; 65.9-73.2), and negative predictive value (99.5%; 99.2-99.7). To determine real-life performance, we waited 75 days to carry out an effectiveness assay among the riders of the Metro System of Medellin, deploying the human-canine teams without previous training or announcement. Three dogs (one of each breed) scent-interrogated 550 citizens who volunteered for simultaneous canine and rRT-PCR testing. Negative predictive value remained at 99.0% (95% C.I. 98.3-99.4), but positive predictive value dropped to 28.2% (95% C.I. 21.1-36.7). Canine scent-detection in vivo is a highly accurate screening test for COVID-19, and it detects more than 99% of infected individuals independently of the key variables. However, real-life conditions increased substantially the number of false positives, indicating the necessity of training a threshold for the limit of detection to discriminate environmental odoriferous contamination from infection.
Biallelic and de novo variants in ATP6V0A1 cause progressive myoclonus epilepsy and developmental and epileptic encephalopathy
Authors: Bott Laura C , Forouhan Mitra , Lieto Maria , Sala Ambre J , Ellerington Ruth , Johnson Janel O , Speciale Alfina A , Criscuolo Chiara , Filla Alessandro , Chitayat David , Nemeth Andrea H ,   Italian Undiagnosed Diseases Network, Angelucci Francesco , Lim Wooi Fang , Striano Pasquale , Zara Federico , Helbig Ingo , Muona Mikko , Courage Carolina , Lehesjoki Anna-Elina , Berkovic Samuel F ,   V-ATPase Consortium, Fischbeck Kenneth H , Brancati Francesco , Morimoto Richard I , Wood Matthew JA , Rinaldi Carlo
Published: June 2021

The vacuolar H+-ATPase is a large multi-subunit proton pump, composed of an integral membrane V0 domain, involved in proton translocation, and a peripheral V1 domain, catalysing ATP hydrolysis. This complex is widely distributed on the membrane of various subcellular organelles, such as endosomes and lysosomes, and plays a critical role in cellular processes ranging from autophagy to protein trafficking and endocytosis. Variants in ATP6V0A1, the brain-enriched isoform in the V0 domain, have been recently associated with developmental delay and epilepsy in four individuals. Here we identified 17 individuals from 14 unrelated families with both with new and previously characterised variants in this gene, representing the largest cohort to date. Five affected subjects with biallelic variants in this gene presented with a phenotype of early-onset progressive myoclonus epilepsy with ataxia, while 12 individuals carried de novo missense variants and showed severe developmental and epileptic encephalopathy. The R740Q mutation, which alone accounts for almost 50% of the mutations identified among our cases, leads to failure of lysosomal hydrolysis by directly impairing acidification of the endolysosomal compartment, causing autophagic dysfunction and severe developmental defect in C. elegans. Altogether, our findings further expand the neurological phenotype associated with variants in this gene and provide a direct link with endolysosomal acidification in the pathophysiology of ATP6V0A1-related conditions.
Type 2 Diabetes and Risk of Early-Onset Colorectal Cancer
Authors: Li Zitong , Chen Hanyu , Fritz Cassandra D.L , Zheng Xiaobin , Zong Xiaoyu , Nickel Katelin B. , Tipping Andrew , Nguyen Long H. , Chan Andrew T. , Giovannucci Edward L. , Colditz Graham A. , Olsen Margaret A. , Campbell Peter T. , Davidson Nicholas O. , Fields Ryan C. , Cao Yin
Published: June 2021

Objective

Early-onset colorectal cancer (CRC) is increasing in many developed countries. Type 2 diabetes mellitus has increased substantially in younger adults; however, its role in early-onset CRC remains unidentified.

Design

We conducted a claims-based nested case-control study using IBM® MarketScan® Commercial Database (2006-2015). Incident early-onset CRC diagnosed at ages 18-49 were identified by ICD-9-CM diagnosis code, and the first coded diagnostic pathology date was assigned as the index date. Controls were frequency matched with cases. Type 2 diabetes, stratified by severity, was identified through ICD-9-CM using the Klabunde algorithm. Multivariate logistic regressions were used to estimate odds ratios (ORs) and 95% confidence intervals (Cls).

Results

A total of 6001 early-onset CRC and 52104 controls were included. Type 2 diabetes was associated with an increased risk of early-onset CRC (5.0% in cases vs. 3.7% in controls; OR 1.24; 95% CI 1.09 to 1.41). The positive association was more pronounced for uncontrolled (OR 1.37; 95% CI 1.12 to 1.67) or complicated (OR 1.59; 95% CI 1.08-2.35) type 2 diabetes compared to controlled diabetes (OR 1.13; 95% CI 0.94 to 1.36). The positive association was driven by proximal (OR 1.35; 95% CI 1.03 to 1.77) and distal (OR 1.67; 95% CI 1.30 to 2.15) colon cancer but not rectal cancer.

Conclusions

Individuals with type 2 diabetes have a higher risk of early-onset CRC, with stronger associations for uncontrolled/complicated diabetes. The rising prevalence of type 2 diabetes among younger adults in the US may partially contribute to the increasing incidence of early-onset CRC.
Tracking deaths from hitherto undetected infections can be an indicator of latent sars-cov-2 cases
Authors: Rangayyan Yashaswini Mandayam , Kidambi Sriram , Raghavan Mohan
Published: June 2021

Background

With countries across the world facing repeated epidemic waves, it becomes critical to monitor, mitigate and prevent subsequent waves. Common indicators like active case numbers can flatter to deceive in the presence of systemic inefficiencies like insufficient testing or contact tracing. Test positivity rates are sensitive to testing strategies and cannot estimate the extent of undetected cases. Reproductive numbers estimated from logarithms of new incidences are inaccurate in dynamic scenarios and not sensitive enough to capture changes in efficiencies. Systemic fatigue results in lower testing, inefficient tracing and quarantining thereby precipitating the onset of the epidemic wave.

Methods

We propose a novel indicator for detecting the slippage of test-trace efficiency based on the numbers of deaths/hospitalizations resulting from known and hitherto unknown infections. This can also be used to forecast an epidemic wave that is advanced or exacerbated due to drop in efficiency.

Results

Using a modified SEIRD epidemic simulator we show that (i) Ratio of deaths/hospitalizations from an undetected infection to total deaths converges to a measure of systemic test-trace inefficiency. (ii) This index forecasts the slippage in efficiency earlier than other known metrics. (iii) Mitigation triggered by this index helps reduce peak active caseload and eventual deaths.

Conclusions

Deaths/hospitalizations accurately track the systemic inefficiencies and detect latent cases. Based on these results we make a strong case that administrations use this metric in the ensemble of indicators. Further hospitals may need to be mandated to distinctly register deaths/hospitalizations due to previously undetected infections.

Key Messages

Deaths or Hospitalizations are unmissable events in an epidemic and this paper proposes a metric Dratio based on these numbers to monitor the inefficiencies in test-track-trace performance.

The ratio of deaths(or hospitalizations) resulting from undetected infections to total deaths (or hospitalizations) detect the onset of laxity in regulations earlier than other conventional metrics like daily increase in active cases, daily deaths or even reproductive number estimates.

Mitigation by tracking the Dratio reduces or truncates the epidemic wave intensity or delays it sufficiently.
Classifying Texas counties using ARIMA Models on COVID-19 daily confirmed cases: the impact of political affiliation and face covering orders
Authors: Jiang Hao , Pulins Brigitta , Thiele Aurélie C.
Published: June 2021

The aim of this paper is to investigate whether the 254 Texas counties in the United States can be grouped in a meaningful way according to the characteristics of the ARIMA or seasonal ARIMA models fitting the logarithm of daily confirmed cases of the Coronavirus Disease 2019 (COVID-19) for 254 counties in Texas of the United States. We analyze clusters of the model’s non-seasonal parameters (p, d, q), distinguishing between county-level political affiliations and face covering orders, and also consider county-level population and poverty rate. Using data from March 4, 2020 to March 15, 2021, we find that 223 of the total 254 counties are clustered into 23 model parameters (p, d, q), while the number of cases in the remaining 31 counties could not be successfully fitted to ARIMA models. We also find the impact of the county-level infection rate and the county-level poverty rate on clusters of counties with different political affiliations and face covering orders. Further, we find that the infection rate and the poverty rate had a significant high positive correlation, and Democrat-leaning counties, which tend to have large populations, had a higher correlation coefficient between infection rate and poverty rate. We also observe a significant high positive correlation between the infection rate and the number of cumulative cases in Republican counties that had not imposed a face covering order.
Vaccine nationalism and the dynamics and control of SARS-CoV-2
Authors: Wagner Caroline E. , Saad-Roy Chadi M. , Morris Sinead E. , Baker Rachel E. , Mina Michael J. , Farrar Jeremy , Holmes Edward C. , Pybus Oliver G. , Graham Andrea L. , Emanuel Ezekiel J. , Levin Simon A. , Metcalf C. Jessica E. , Grenfell Bryan T.
Published: June 2021

Vaccines provide powerful tools to mitigate the enormous public health and economic costs that the ongoing SARS-CoV-2 pandemic continues to exert globally, yet vaccine distribution remains unequal between countries. To examine the potential epidemiological and evolutionary impacts of ‘vaccine nationalism’, we extend previous models to include simple scenarios of stockpiling. In general, we find that stockpiling vaccines by countries with high availability leads to large increases in infections in countries with low vaccine availability, the magnitude of which depends on the strength and duration of natural and vaccinal immunity. Additionally, a number of subtleties arise when the populations and transmission rates in each country differ depending on evolutionary assumptions and vaccine availability. Furthermore, the movement of infected individuals between countries combined with the possibility of increases in viral transmissibility may greatly magnify local and combined infection numbers, suggesting that countries with high vaccine availability must invest in surveillance strategies to prevent case importation. Dose-sharing is likely a high-return strategy because equitable allocation brings non-linear benefits and also alleviates costs of surveillance (e.g. border testing, genomic surveillance) in settings where doses are sufficient to maintain cases at low numbers. Across a range of immunological scenarios, we find that vaccine sharing is also a powerful tool to decrease the potential for antigenic evolution, especially if infections after the waning of natural immunity contribute most to evolutionary potential. Overall, our results stress the importance of equitable global vaccine distribution.
Language systems from lesion-symptom mapping in aphasia: A meta-analysis of voxel-based lesion mapping studies
Authors: Na Yoonhye , Jung JeYoung , Tench Christopher , Auer Dorothee P. , Pyun Sung-Bom
Published: June 2021

Background

Aphasia is one of the most common causes of post-stroke disabilities. As the symptoms and impact of post-stroke aphasia are heterogeneous, it is important to understand how topographical lesion heterogeneity in patients with aphasia is associated with different domains of language impairments. Here, we aim to provide a comprehensive overview of neuroanatomical basis in post-stroke aphasia through coordinate based meta-analysis of voxel-based lesion-symptom mapping studies.

Methods

We performed a meta-analysis of lesion-symptom mapping studies in post-stroke aphasia. We obtained coordinate-based functional neuroimaging data for 2,007 individuals with aphasia from 25 studies that met predefined inclusion criteria.

Results

Overall, our results revealed that the distinctive patterns of lesions in aphasia are associated with different language functions and tasks. Damage to the insular-motor areas impaired speech with preserved comprehension and a similar pattern was observed when the lesion covered the insular-motor and inferior parietal lobule. Lesions in the frontal area severely impaired speaking with relatively good comprehension. The repetition-selective deficits only arise from lesions involving the posterior superior temporal gyrus. Damage in the anterior-to-posterior temporal cortex was associated with semantic deficits.

Conclusion

The association patterns of lesion topography and specific language deficits provide key insights into the specific underlying language pathways. Our meta-analysis results strongly support the dual pathway model of language processing, capturing the link between the different symptom complexes of aphasias and the different underlying location of damage.
Group Testing Large Populations for SARS-CoV-2
Authors: Zabeti Hooman , Dexter Nick , Lau Ivan , Unruh Leonhardt , Adcock Ben , Chindelevitch Leonid
Published: June 2021

Group testing, the testing paradigm which combines multiple samples within a single test, was introduced in 1943 by Robert Dorfman. Since its original proposal for syphilis screening, group testing has been applied in domains such as fault identification in electrical and computer networks, machine learning, data mining, and cryptography. The SARS-CoV-2 pandemic has led to proposals for using group testing in its original context of identifying infected individuals in a population with few tests. Studies suggest that non-adaptive group testing - in which all the tests are determined in advance - for SARS-CoV-2 could help save 20% to 90% of tests depending on the prevalence. However, no systematic approach for comparing different non-adaptive group testing strategies currently exists.

In this paper we develop a software platform for evaluating non-adaptive group testing strategies in both a noiseless setting and in the presence of realistic noise sources, modelled on published experimental observations, which makes them applicable to polymerase chain reaction (PCR) tests, the dominant type of tests for SARS-CoV-2. This modular platform can be used with a variety of group testing designs and decoding algorithms. We use it to evaluate the performance of near-doubly-regular designs and a decoding algorithm based on an integer linear programming formulation, both of which are known to be optimal in some regimes. We find savings between 40% and 91% of tests for prevalences up to 10% when a small error (below 5%) is allowed. We also find that the performance degrades gracefully with noise. We expect our modular, user-friendly, publicly available platform to facilitate empirical research into non-adaptive group testing for SARS-CoV-2.