bluuebunny/crossref_metadata_2025 huggingface dataset:
Oral Tacrolimus in Steroid Refractory and Dependent Pediatric Ulcerative Colitis—A Systematic Review and Meta-Analysis
Authors: Bolia Rishi , Goel Akhil , Semwal Pooja , Srivastava Anshu
Published: May 2023

Background:

There are limited treatment options for children with steroid-refractory or dependent ulcerative colitis (UC). A few observational studies suggest efficacy of oral tacrolimus. We performed a systematic review and meta-analysis to assess the efficacy of tacrolimus in pediatric UC.

Methods:

PubMed and Scopus were searched for publications related to the use of oral tacrolimus in pediatric UC. Data regarding the clinical response and colectomy-free survival were extracted from studies that met the selection criteria.

Results:

The search strategy yielded 492 articles of which 7 studies were included in the final review. They included 166 children (111 steroid-refractory, 52 steroid-dependent, 3 no steroids). Majority of cases (150/166 [90%]) were naïve to biologics. An initial response to tacrolimus therapy was seen in 84% (95% CI: 73%–93%) (n = 7 studies). No difference was observed between children with high (>10 ng/mL) or low tacrolimus levels (127/150 [85%] vs 12/16 [75%], P = 0.3). No difference in initial response between the children who were steroid refractory or dependent (92/111 [83%] vs 46/52 [88%], P = 0.36). The response in the biologic-exposed group (n = 10) was 70%. At 1-year follow-up, 15.2% (95% CI: 7%–21%) (n = 2 studies, 85 patients) had a sustained response on only tacrolimus. The pooled frequency of 1-year colectomy-free survival in children treated with initial oral tacrolimus was 64% (95% CI: 53%–75%). Twelve (7.2%) patients required cessation of therapy because of side effects.

Conclusion:

Tacrolimus has a high initial response in biologic naïve UC children. It can be effectively used as a bridge to other therapies with a 1-year colectomy-free survival of 64%.
Pancreatitis-Associated Medication Use in Hospitalized Pediatric and Young Adult Patients With Acute Pancreatitis
Authors: Collen Lauren V. , Mitchell Paul D. , Fox Victor L. , Grover Amit S.
Published: May 2023

Objective:

The objective of this study is (1) to describe the prevalence of pancreatitis-associated medication (PAM) use at admission and discharge in pediatric and young adult patients hospitalized with acute pancreatitis (AP) and (2) to describe the prevalence of PAM use at admission in patients classified as having idiopathic AP.

Study Design:

A single-center retrospective study of patients <21 years who were hospitalized with AP or acute recurrent pancreatitis from March 2015 to July 2017 was performed. Charts were reviewed for demographic data, etiology of pancreatitis, comorbidities, and use of PAMs at admission and discharge. PAMs were defined and scored based on an evidence-based classification system, with class I PAMs having strongest evidence for causation. Standard descriptive statistics were used to report prevalence data.

Results:

Our cohort was comprised of 119 patients; 50% of patients were using a PAM at admission and 67% were taking a PAM at discharge, reflecting a significant change (P = 0.0009); 44% of patients classified as having idiopathic pancreatitis were taking a PAM on admission, reflecting a possibly missed role of medication in their presentation. Comorbidities significantly associated with PAM use included seizure disorder (P = 0.005) and oncologic disease (P = 0.005). The most commonly used class I PAMs were omeprazole, trimethoprim-sulfamethazole, valproic acid, and 6-mercaptopurine. The increase in prevalence of PAM use at discharge compared to admission was partially driven by addition of omeprazole to the outpatient medication regimen during the hospital stay (P = 0.07).

Conclusion:

Medications likely play an under-recognized role in pediatric AP. The practice of using proton pump inhibitors in management of AP warrants further study.
Education Level Modulates the Presence of Poststroke Depression and Anxiety, But It Depends on Age
Authors: Samudio-Cruz María Alejandra , Toussaint-González Paola , Estrada-Cortés Berenice , Martínez-Cortéz José A. , Rodríguez-Barragán Marlene A. , Hernández-Arenas Claudia , Quinzaños-Fresnedo Jimena , Carrillo-Mora Paul
Published: May 2023

Depression and anxiety are common complications after stroke and little is known about the modulatory roles of education and age. Our study aimed to evaluate the modulatory effects of education level on anxiety and depression after stroke and their effect on each age group. Adults with first stroke took part in this cross-sectional observational clinical study. We used the following instruments: Hospital Anxiety and Depression Scale (HADS), Montreal Cognitive Scale, Pittsburgh Sleep Quality Index, Barthel index, and Functional Independence Measure. There were 89 patients. The mean (SD) age was 58.01 (13) years, mean (SD) years of education was 9.91 (5.22), 55.1% presented depression symptoms and 47.2% anxiety symptoms, 56.2% were young adults and 43.8% were older adults. We identified a negative association between education and anxiety score (r = −0. 269, p = 0.011) and depression score (r = −0.252, p = 0.017). In the linear regression analysis, we found that education is negatively associated with HADS, but this influence was more consistent in young adults. In conclusion, a higher education level reduces the risk of depression and anxiety, but their effect is less consistent in older adults.
Adverse Events During Submaximal Aerobic Exercise Testing in People With Subacute Stroke: A Scoping Review
Authors: Legasto-Mulvale Jean Michelle , Inness Elizabeth L. , Thompson Alexandra N. , Chandran Nivetha , Mathur Sunita , Salbach Nancy M.
Published: May 2023

Background and Purpose:

Concern for adverse cardiovascular events and limited guidance regarding how to conduct aerobic exercise (AEx) testing for individuals poststroke are key barriers to implementation by physical therapists in stroke rehabilitation. This study aimed to describe the nature and safety of submaximal AEx testing protocols for people with subacute stroke (PwSS) and the nature of comorbidity of PwSS who underwent submaximal AEx testing.

Methods:

We conducted a scoping review and searched MEDLINE, EMBASE, PsycINFO, CINAHL, and SPORTDiscus from inception to October 29, 2020. Studies involving submaximal AEx testing with PwSS, reporting on participant comorbidity and on adverse events during testing, were eligible. Two reviewers independently conducted title and abstract and full-text screening. One reviewer extracted data; a second reviewer verified data.

Results:

Thirteen studies involving 452 participants and 19 submaximal AEx testing protocols (10 field test, 7 incremental, and 2 constant load) were included. Hypertension (41%), diabetes (31%), and dyslipidemia (27%) were the most common comorbidities reported. No protocols resulted in a serious adverse event. The most common test termination criterion was a heart rate (HR) limit (9 protocols); a limit of 85% age-predicted maximal HR (APM-HR) most frequently reported. Average APM-HR achieved, computed using mean age and mean peak HR, ranged from 59% to 88% across 13 protocols.

Discussion and Conclusion:

Diverse submaximal AEx testing protocols with conservative test termination criteria can be safely implemented with PwSS. Results can inform clinical practice guidelines and address physical therapists' concerns with the occurrence of serious adverse events during submaximal AEx testing.

Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1 available at: http://links.lww.com/JNPT/A430).
Sclerosis in Sex Cord-Stromal Tumors Other Than the Sclerosing Stromal Tumor
Authors: Devins Kyle M. , Young Robert H.
Published: May 2023

Sclerosis is well-known in sclerosing stromal tumors (SSTs), as its name indicates, but has not been evaluated in other ovarian sex cord-stromal tumors (SCSTs). Its presence in other SCSTs has sporadically caused diagnostic problems in cases we have seen, and this prompted us to review SCSTs with appreciable sclerosis; tumors containing at least 20% sclerosis were included. Seventy cases were identified: 20 thecomas, 20 juvenile granulosa cell tumors (JGCTs), 8 adult granulosa cell tumors (AGCTs), 5 sex cord tumors with annular tubules, 6 retiform Sertoli-Leydig cell tumors (SLCTs; all of the intermediate differentiation), 4 nonretiform SLCTs (3 well-differentiated, 1 of intermediate differentiation with heterologous elements), 4 Sertoli cell tumors, and 3 microcystic stromal tumors (MSTs). Paucicellular sclerotic zones comprised 20% to 95% of the tumors and when conspicuous often obscured diagnostic features. Thirty-one tumors (10 thecomas, 19 JGCTs, 1 AGCT, and 1 MST) showed sclerotic zones focally enveloping nodules of tumor cells, imparting a pseudolobular appearance, and sclerosis often occurred within lobules as well. Ten of these (5 thecomas and 5 JGCTs) also had prominent staghorn blood vessels, generating a low-power appearance focally similar to SST. In 17 tumors, the sclerosis resulted in “compression” of the tumor cells into cords and/or solid tubules. Correct diagnosis in these cases is dependent on careful examination of the cellular zones of the neoplasms, but awareness of the extent of sclerosis that may be seen in diverse SCSTs may be crucial in suggesting the correct diagnosis particularly when the material is limited as in the intraoperative setting. Our findings highlight for the first time the occurrence and character of sclerosis in sex cord tumors other than SSTs and fibromas. Sclerosis is seen in descending proportion of the tumor types as follows: retiform SLCTs, thecomas, MSTs, JGCTs, sex cord tumors with annular tubules, Sertoli cell tumors, AGCTs, and nonretiform SLCTs. Its character can vary somewhat, having particular features in the sex cord tumor with annular tubules (hyaline material within tubules often coalescing and extending beyond the nests to form confluent aggregates) and retiform SLCTs (common in papillary cores).
Cancer Stem Cell Markers Are Differentially Expressed in Malignant Ovarian Germ Cell Tumors
Authors: Davidson Ben , Solheim Olesya
Published: May 2023

The objective of this study was to analyze the expression and potential clinical role of cancer stem cell (CSC) markers in malignant ovarian germ cell tumors (MOGCT). CD34, CD44, and SOX2 protein expression by immunohistochemistry was analyzed in 49 MOGCT from patients treated in Norway during the period 1980-2011. Expression was analyzed for association with tumor type and clinicopathologic parameters. Tumors were diagnosed as dysgerminoma (DG; n=15), immature teratoma (IT; n=15), yolk sac tumor (YST; n=12), embryonal carcinoma (n=2), and mixed MOGCT (n=5). Tumor cell CD34 expression was significantly more common in YST, whereas stromal expression was only seen in IT (both P<0.001). CD44 was infrequently expressed, most often focally, in tumor cells, particularly in YST (P=0.026). CD44 was widely expressed in leukocytes, most prominently in DG. SOX2 was most frequently expressed in IT, with predominantly focal expression in some YST and uniform absence in DG (P<0.001). Stromal CD34 (P=0.012) and tumor cell SOX2 expression (P=0.004) were negatively associated with the involvement of the ovarian surface, presumably due to the low incidence of this event in IT. No significant association was found between CSC marker expression and other clinicopathologic parameters, including age, laterality, tumor diameter, and FIGO stage. In conclusion, CSC markers are differentially expressed in various MOGCT types, suggesting differences in the regulation of cancer-related processes. Expression of CD34, CD44, and SOX2 does not appear to be associated with clinical parameters in this patient group.
Freeing the animal model: a modular, wirelessly-powered, implantable electronic platform
Authors: Greene Jacqueline J. , Gorelik Pavel , Mazor Ofer , Guarin Diego L. , Malka Ronit , Hadlock Tessa
Published: May 2023

Fully implantable electronic devices in freely-roaming animal models are useful in biomedical research, but their development is prohibitively resource intensive for many laboratories. The advent of miniaturized microcontrollers with onboard wireless data exchange capabilities has enabled cost-efficient development of myriad do-it-yourself (DIY) electronic devices that are easily customizable with open-source software (https://www.arduino.cc/). Likewise, the global proliferation of mobile devices has led to the development of low-cost miniaturized wireless power technology. We present a low-cost, rechargeable, and fully-implantable electronic device comprising a commercially available, open-source, wirelessly-powered microcontroller that is readily customizable with myriad readily available miniature sensors and actuators. We demonstrate the utility of this platform for chronic nerve stimulation in the freely-roaming rat with intermittent wireless charging over 4 weeks. Device assembly was achieved within two hours and necessitated only basic soldering equipment. Component costs totaled $115 per device. Wireless data transfer and wireless re-charging of device batteries was achieved within 30 minutes, and no harmful heat generation occurred during charging or discharging cycles as measured by external thermography and internal device temperature monitoring. Wireless communication enabled triggered cathodic pulse stimulation of the facial nerve at various user-selected programmed frequencies (1, 5, and 10 Hz) for periods of four weeks or longer. This implantable electronic platform could be further miniaturized and expanded to study a vast array of biomedical research questions in live animal models.
Walking Ability and Brain Natriuretic Peptide Are Highly Predictive of Kidney Transplant Waiting List Removal
Authors: Katz Daniel A. , Ten Eyck Patrick , Binns Grace , Manay Priyadarshini , Sanders M. Lee , Hornickel Jodell L. , Vu An , Swee Melissa , Kalil Roberto
Published: May 2023

Background:

Kidney transplant waitlist management is complex because waiting time is long, and the patients have significant comorbidities. Identification of patients at highest risk for waiting list removal for death and medical complications could allow better outcomes and allocation of resources.

Methods:

Demographics, functional and frailty assessment‚ and biochemical data were retrospectively analyzed on 313 consecutive patients listed for kidney transplant. Troponin, brain natriuretic peptide, components of the Fried frailty metrics, pedometer activity, and treadmill ability were measured at the time of transplant evaluation and at subsequent re-evaluations. Cox proportional hazards models were used to identify factors associated with death or waiting list removal for medical reasons. Multivariate models were created to identify significant predictor sets.

Results:

Among 249 patients removed while waitlisted, 19 (6.1%) died and 51 (16.3%) were removed for medical reasons. Mean follow-up duration was 2.3 y (±1.5 y). 417 sets of measurements were collected. Significant (P < 0.05) non–time-dependent variables associated with the composite outcome identified on univariate analysis included N-terminal probrain natriuretic peptide (BNP), treadmill ability, pedometer activity, diagnosis of diabetes and the Center of Epidemiological Studies Depression Scale question asking how many days per week could you not get going. Significant time-dependent factors included BNP, treadmill ability, Up and Go, pedometer activity, handgrip, 30 s chair sit-stand test, and age. The optimal time-dependent predictor set included BNP, treadmill ability, and patient age.

Conclusions:

Changes in functional and biochemical markers are predictive of kidney waitlist removal for death and medical reasons. BNP and measures of walking ability were of particular importance.
Prolonged shedding of SARS COV-2 in an asymptomatic patient– a case report
Authors: Kaur Mandeep , Singh Meenakshi , Dogra Girish , Awasthi Vandana , Dua Ajit
Published: May 2023

Background- There have been few reports of asymptomatic SARS-CoV2 patients who have shed viruses for unusually prolonged period. These cases are generally identified during contact tracing of positive SARS-CoV2 patients and remain a stumbling block for control of transmission and spread of SARS-CoV2 viral infection. We are reporting a similar case of asymptomatic SARS-CoV2 carriage in respiratory secretions of a patient for two months.
Materials and methods- The present case study discusses about an asymptomatic young male patient who was tested positive for SARS-CoV2 after a recent travel. His nasopharyngeal samples showed consistent positivity for SARS-CoV2 from June 2021 till August 2021 when tested by Real Time RT PCR and the Ct values always remained less than 25. His clinical investigations were within normal limits except for high D-dimer levels and his HIV serology was negative during initial work up. He received second dose of COVID vaccine during quarantine period. Upon six months follow up of the patient, it was learned that he died of HIV infection in March 2022.  
Discussion and conclusions- The persistence of SARS-CoV2 could be attributed to either COVID vaccination taken during quarantine period or may be due to HIV infection which might have been missed during the window period.  This report suggests that there is high risk for silent spread of SARS-CoV2 by asymptomatic persons, thus it would be imperative to include such asymptomatic patients too for dynamic surveillance.
A glimpse into the dark – The bacterial and archaeal diversity of tropical anchialine cave sediments
Authors: Meland Kenneth , Iliffe Thomas M. , Thiele Stefan
Published: May 2023

Using Ion Torrent sequencing of the V4 region of the 16S rRNA gene, we investigated the sediment from four anchialine caves on Eleuthera (Bahamas). Anchialine caves are secluded, landlocked marine ecosystems, with high degrees of endemism. In the cave sediments, the bacterial and archaeal communities differ from marine communities and between caves, while often resembling those from low oxygen or anaerobic marine sediments. The waters of all caves investigated here were mostly saline and oxygenated, with Windermere Abyss differing from the other caves. This was mirrored by the bacterial and archaeal communities, with members of the wb1-A12 clade, Nitrosopumilaceae, members of the NB1-j phylum, and Actinomarinales being dominant in Preacher’s Blue Hole, Valentine’s Cave, and Bung Hole while Desulfatiglans, Bathyarchaeia, and members of the GIF3 and Sva0485 clades were dominant in Windermere Abyss. All communities showed taxa found in oxygenated and anoxic sediments, thus indicating a variety of chemoautotrophic lifestyles, including methane-, nitrogen-, and sulfur cycling. The communities were different from other caves and included understudied or otherwise rare taxa, partially from deep sea sediments, implying that the isolation might be an evolutionary factor, and indicating that anchialine caves could be a window into the deep sea.
Brevibacterium spongiae sp. nov., isolated from marine sponge Hymeniacidon sp.
Authors: Zhang Mimi , Song Qianqian , Sang Jin , Li Zhiyong
Published: May 2023

A novel bacterial strain, designated as WHS-Z9T, was isolated from marine sponge Hymeniacidon sp. collected from Weihai (37° 25′ N, 121° 58′ E), Shandong Province, PR China. Cells of strain WHS-Z9T were Gram-stain-positive, non-spore-forming, non-motile, short-rod-shaped and light yellow-pigmented. The strain could grow at 10–40 °C (optimum, 20 °C), pH 4.5–9.5 (optimum, pH 8.5) and 2–14 % (w/v) NaCl (optimum, 4 %). The 16S rRNA gene sequence of strain WHS-Z9T showed 98.7  % similarity to that of

Brevibacterium epidermidis

NBRC 14811T, 98.5  % to

Brevibacterium sediminis

FXJ8.269T and 98.4 % to

Brevibacterium oceani

BBH7T. The phylogenetic tree based on 16S rRNA gene sequences revealed that strain WHS-Z9T was clustered with

Brevibacterium limosum

o2T. The whole genome of WHS-Z9T was approximately 4 217 721 bp in size with a G+C content of 65.2  %. The average nucleotide identity (ANI) and digital DNA–DNA hybridization (dDDH) values among WHS-Z9T and other

Brevibacterium

type strains were 83.3–85.5 % (ANI based on blast), 86.4–87.9  % (ANI based on MUMmer) and 41.9–57.5 % (dDDH). Percentage of conserved protein values between the genomes of strain WHS-Z9T and members of genera

Brevibacterium

were 76.8–82.9 %, while the average amino acid identity (AAI) values were 83.7–87.0  %. The dDDH, ANI, AAI and POCP values were below the standard cut-off criteria for the delineation of bacterial species. The sole respiratory quinone in strain WHS-Z9T was MK-8(H2), and the predominant fatty acids were anteiso-C15 : 0 and anteiso-C17 : 0. The major polar lipids of WHS-Z9T consisted of diphosphatidylglycerol and glycolipid. The diagnostic cell-wall diamino acid of strain WHS-Z9T was meso-diaminopimelic acid. Based on the data obtained in this study, strain WHS-Z9T (=MCCC 1K07845T=KCTC 49848T) should be classified as the type strain of a novel species of the genus

Brevibacterium

, for which the name Brevibacterium spongiae sp. nov. is proposed.
Identification and characterization of BmNPV Bm5 protein required for the formation of nuclear vesicle structures
Authors: Kong Xiangshuo , Chen Guanping , Li Jiale , Li Yuedong , Wu Xiaofeng
Published: May 2023

BmNPV infection induces nuclear vesicle-like structures and its Bm5 protein mediates the intranuclear lipid accumulation, which is thought to participate in the formation of nuclear vesicles. However, the relationship between viral-induced nuclear vesicles and Bm5 protein is still unclear. Here, our results indicated that BmNPV Bm5 protein participated in the baculovirus infection-induced nuclear vesicle-like structures' invagination thereby influencing the production of occlusion-derived virion (ODV) and occlusion body (OB). The process of nuclear vesicle-like structures' formation was dispensable for the transport or recruitment of ODV major envelope proteins, such as P74 and Bm14. Furthermore, baculovirus-induced nuclear F-actin might provide a direct mechanical force to mediate the scission of large vesicle-like structures from the nuclear membrane. Collectively, these findings illustrated a BmNPV Bm5 protein-induced nuclear membrane invagination pathway and revealed the function of nuclear vesicle-like structures in ODV production.
Clinical performance and safety of Cerviron®vaginal ovules in the local treatment of non-specific vaginitis: a national, multicentric clinical investigation
Authors: Toader Daniela Oana , Olaru Raluca Alexandra , Iliescu Dominic-Gabriel , Petrita Ramona , Calancea Florentina Liliana , Petre Izabella
Published: May 2023

Purpose

Non-specific vaginitis is a distinct clinical entity with particular microscopic and immunologic features. Currently, there is no standard of care for women with non-specific vaginitis. The aim of our study was to assess the change in vaginal symptoms score after a 3-months treatment with Cerviron®medical device in participants with abnormal vaginal discharge and with specific signs and symptoms. As secondary objectives, the study analyzed other clinical and microscopic features, such as vaginal discharge aspect, change in vaginal pH, change in vaginal microbiome, and vaginal inflammation.

Methods

The study population included 47 participants suffering from symptomatic vulvovaginitis, distinct from candidiasis, trichomoniasis or bacterial vaginosis. The study design included 2 research sites from Romania. The treatment protocol consisted of 1 ovule/day inserted intravaginally, during 15 consecutive days. The total study duration was 3 months.

Findings

Cerviron®had a positive impact on the vaginal symptoms score for 72.34% of the study participants. Topical administration of Cerviron®balanced vaginal pH values and significantly reduced signs of inflammation between study visits.

Implications

Cerviron®shows curative effects that supports its use as a stand-alone treatment in women with non-specific vaginitis.ClinicalTrials.govidentifier:NCT04735705.

A second clinical investigation is ongoing to evaluate its clinical efficacy in postoperative care of cervical and vaginal wounds, traumatic or secondary to surgical interventions.
Effects of Adapted Mindfulness Training on Interoception and Adherence to the Dietary Approaches to Stop Hypertension (DASH) Diet: The MB-BP Randomized Clinical Trial
Authors: Loucks Eric B. , Kronish Ian M. , Saadeh Frances B. , Scarpaci Matthew M. , Proulx Jeffrey A. , Gutman Roee , Britton Willoughby B. , Schuman-Olivier Zev
Published: May 2023

Background

Hypertension is a major cause of cardiovascular disease. The Dietary Approaches to Stop Hypertension (DASH) diet lowers blood pressure (BP). However, adherence is typically low. Mindfulness training adapted to improving health behaviors that lower BP could improve DASH adherence, in part through improved interoceptive awareness relevant to dietary consumption. The primary objective of the MB-BP trial was to evaluate effects of the Mindfulness-Based Blood Pressure Reduction (MB-BP) program on interoceptive awareness. Secondary objectives assessed whether MB-BP impacts DASH adherence, and explored whether interoceptive awareness mediates DASH dietary changes.

Methods

Parallel-group phase 2 randomized clinical trial conducted from June 2017-November 2020 with 6 months follow-up. Data analyst was blinded to group allocation. Participants had elevated unattended office BP (≥120/80 mmHg). We randomized 201 participants to MB-BP (n=101) or enhanced usual care control (n=100). Loss-to-follow-up was 11.9%. Outcomes were the Multidimensional Assessment of Interoceptive Awareness (MAIA; range 0-5) score, and the DASH adherence score (range 0-11) assessed via a 163-item Food Frequency Questionnaire.

Results

Participants were 58.7% female, 81.1% non-Hispanic white, with mean age 59.5 years. Regression analyses demonstrated that MB-BP increased the MAIA score by 0.54 (95% CI: 0.35,0.74; p<.0001) at 6 months follow-up vs. control. MB-BP increased the DASH score by 0.62 (95% CI: 0.13,1.11; p=0.01) at 6 months vs. control, in participants with poor DASH adherence at baseline.

Conclusions

A mindfulness training program adapted to improving health behaviors that lower BP improved interoceptive awareness and DASH adherence. MB-BP could support DASH dietary adherence in adults with elevated BP.

Clinical Trial Registration

Clinicaltrials.govidentifierNCT03859076(https://clinicaltrials.gov/ct2/show/NCT03859076; MAIA) andNCT03256890(https://clinicaltrials.gov/ct2/show/NCT03256890; DASH diet adherence).
Neuregulin-1 protects against respiratory viral induced mortality
Authors: Hussain Syed-Rehan A , Rohlfing Michelle , Santoro Jennifer , Resiliac Jenny , Chen Phylip , Peeples Mark E. , Grayson Mitchell H
Published: May 2023

Respiratory viral infections due to RNA viruses such as respiratory syncytial virus (RSV) and influenza lead to significant morbidity and mortality. Using a natural rodent pathogen similar to RSV, Sendai virus (SeV), we found that mice made atopic with house dust mite before viral infection all survived a normally lethal SeV infection.

Moreover, adoptive transfer of CD11c+cells from atopic mice delayed viral mortality. Neuregulin-1 (NRG1) message was highly expressed in CD11c+cells from atopic mice and atopic lungs and bronchoalveolar lavage fluid had elevated levels of NRG1 protein. Administration of NRG1 protected non-atopic mice from death and associated with reduced alveolar epithelium permeability. Utilizing anin vitrosystem of well-differentiated human bronchial epithelial cells and mouse tracheal epithelial cells NRG1 reduced RSV and SeV titers. Expression of genes that play a role in airway epithelium integrity and stability were altered by NRG1; potentially regulating viral induced dysregulation of the epithelia and suggesting NRG1 mediated maintenance of homeostasis. In conclusion, our studies demonstrate atopy induced NRG1 likely plays a novel role in survival from severe respiratory viral infections and may have therapeutic value to prevent mortality from these infections.

Significance

Severe respiratory viral infections are associated with significant mortality in infants and the elderly; however, allergic disease can protect from these outcomes. This study identified a protein called neuregulin-1 (NRG1), produced by cells of the immune system in allergic mice, that provides a survival advantage against respiratory viral infection. NRG1 pretreatment in non-atopic mice infected with a lethal dose of a rodent RNA virus (Sendai virus), similar to human respiratory syncytial virus, significantly reduced death. Further, NRG1 pretreatment reduced viral replication in human and mouse airway epithelial cell cultures. These studies signify a potential therapeutic role of NRG1 in modulating the severity of respiratory viral infections.
Characteristics and phenotypes of a COPD cohort in Uganda
Authors: Alupo Patricia , Mugenyi Levicatus , Katagira Winceslaus , Alex Kayongo , Joanitah Nalunjogi , Siddharthan Trishul , Hurst John R , Kirenga Bruce , Jones Rupert
Published: May 2023

Introduction

Chronic Obstructive Pulmonary Disease (COPD) is a heterogeneous condition with varied clinical and pathophysiologic characteristics. Although there is increasing evidence that COPD in low- and middle-income countries may have different clinical characteristics from that in high income countries, little is known about COPD phenotypes in these settings. We describe the clinical characteristics and risk factor profile of a COPD population in Uganda.

Methods

We cross sectionally analyzed the baseline clinical characteristics of 323 COPD patients aged 30 years and above who were attending two national referral outpatient facilities in Kampala, Uganda between July 2019 and March 2021. Logistic regression was used to determine factors associated with spirometric disease severity.

Results

The median age was 62 years; 51.1% females; 93.5% scored CAT >10; 63.8% mMRC >2; 71.8% had wheezing; 16.7% HIV positive; 20.4% had a history of pulmonary tuberculosis; 50% with blood eosinophilic count >3%, 51.7% had 3 or more exacerbations in the past year. Greater severity by GOLD stage was inversely related to age, (aOR=0.95, 95%CI=0.92, 0.97), and obesity compared to underweight (aOR=0.25, 95%CI=0.07, 0.82). Regarding clinical factors, more severe airflow obstruction was associated with SPO2<93% (aOR=3.79, 95%CI=2.05, 7.00), mMMRC≥2 (aOR=2.21, 95%CI=1.08, 4.53), and a history of severe exacerbations (aOR=2.64, 95%CI=1.32, 5.26).

Conclusion

COPD patients in this population had specific characteristics and risk factor profiles including HIV and TB meriting tailored preventative approaches. Further studies are needed to better understand the pathophysiological mechanisms at play and the therapeutic implications of these findings.

Key messages

What is already known on this topic.

COPD is a heterogeneous condition with the greatest burden in LMICs yet there is limited understanding of disease characteristics in this setting.

What this study adds

A cohort of patients with COPD recruited in hospital clinics in Uganda showed a high burden of disease with frequent exacerbations – 86% were GOLD category D. The cohort had a high exposure to biomass smoke and only 38% were past or present smokers.

How this study might affect research, practice, or policy

There is need for more research into effective strategies to prevent and treat COPD in LMICs - it cannot be assumed that guidelines derived in high-income countries will apply.
RNAseqCovarImpute: a multiple imputation procedure that outperforms complete case and single imputation differential expression analysis
Authors: Baker Brennan H. , Sathyanarayana Sheela , Szpiro Adam A. , MacDonald James , Paquette Alison G.
Published: May 2023

Missing covariate data is a common problem that has not been addressed in observational studies of gene expression. Here we present a multiple imputation (MI) method that accommodates high dimensional transcriptomic data by binning genes, creating separate MI datasets and differential expression models within each bin, and pooling results with Rubin’s rules. Simulation studies using real and synthetic data show that this method outperforms complete case and single imputation analyses at uncovering true positive differentially expressed genes, limiting false discovery rates, and minimizing bias. This method is easily implemented via an R package, “RNAseqCovarImpute” that integrates with the limma-voom pipeline.
The Computational Analysis ofPlasmodium falciparumHeat Shock Proteins Reveals an Interplay with Polyamines
Authors: Sesethu Godlo , Nombalentle Maxam , Yamnkela Mthembu , Anelisa Mpumza , Makumire Stanley , Mkwetshana Noxolo , Govender Krishna K , Makhoba Xolani H
Published: May 2023

The current drugs available in the market are not effective due to growing numbers of resistance to the causative agent of malaria. There are variousPlasmodiumparasites, of whichPlasmodium falciparumis the main cause of morbidity and mortality reported worldwide. Therefore, there is an urgent need to come up with an innovative and effective treatment for this disease. Polyamines play a major role in the parasite’s well-being and growth, while heat shock proteins keep the proteomics of the parasite in good shape. In this study,In Silicoanalysis of the interaction between putrescine, spermidine, spermine, and heat shock proteins was carried out to establish the binding site for drug discovery. Computational tools such as Bioedit, PROCHECK, KNIME Hub, and Schrodinger were used. The results revealed interactions between polyamines and heat shock proteins with glutamine and aspartic acid being common amino acids where interaction occurs between the chaperones and polyamines. MD shows a strong interaction between PfHsp70-1 and putrescine, but the best interaction is observed for PfHsp70-1 and spermidine. Based on these results, a follow-up study will be conducted to establish the synthesis of drugs that will be used as targets for both polyamines and heat shock proteins to eradicate malaria.

Author’s summary

The emanation and spread of Plasmodium parasites that are resistant to antimalarial therapy is one of the main problems in the treatment of malaria. This is a result of the Plasmodium parasite’s ongoing evolution and the creation of novel strategies for surviving drug toxicity. Studies of antimalarial drug development have been focused on polyamine biosynthesis by targeting precursors such as ornithine decarboxylase, adenosylmethionine decarboxylase, and spermidine synthase and protein-protein interactions betweenPlasmodium falciparumchaperones spotting out Hsp90, Hsp70, and Hsp40 as potential targets with little attention being paid to the interaction between polyamines and molecular chaperones. Therefore, to study these interactions the binding sites of all 3D structures were identified using SiteMap, and a docking was performed using the Schrödinger software with OPLS4 force field and XP.
Anin silicoCardiomyocyte Reveals the Impact of Changes in CAMKII Signalling on Cardiomyocyte Contraction Kinetics in Hypertrophic Cardiomyopathy
Authors: Adeniran Ismail , Wadee Hafsa , Degens Hans
Published: May 2023

Hypertrophic cardiomyopathy (HCM) is characterised by asymmetric left ventricular hypertrophy, ventricular arrhythmias and cardiomyocyte dysfunction that may cause sudden death. HCM is associated with mutations in sarcomeric proteins and is usually transmitted as an autosomal-dominant trait. The aim of thisin silicostudy was to assess the mechanisms that underlie the altered electrophysiological activity, contractility, regulation of energy metabolism and crossbridge cycling in HCM at the single cell level. To investigate this, we developed a human ventricular cardiomyocyte model that incorporates electrophysiology, metabolism and force generation. The model was validated by its ability to reproduce the experimentally observed kinetic properties of human HCM induced by a) remodelling of several ion channels and Ca2+-handling proteins arising from altered Ca2+/calmodulin kinase II signalling pathways; and b) increased Ca2+sensitivity of the myofilament proteins. Our simulation showed a decreased phosphocreatine to ATP ratio (−9%) suggesting a negative mismatch between energy expenditure and supply. Using a spatial myofilament half sarcomere model, we also compared the fraction of detached, weakly bound and strongly bound crossbridges in the control and HCM conditions. Our simulations showed that HCM has more crossbridges in force producing states than in the control condition. In conclusion, our model reveals that impaired crossbridge kinetics is accompanied by a negative mismatch between the ATP supply : demand ratio. This suggests that improving this ratio may reduce the incidence of sudden death in HCM.
Cell type specific polyploidization in the royal fat body of termite queens
Authors: Nozaki Tomonari , Tasaki Eisuke , Matsuura Kenji
Published: May 2023

Tissue-specific endopolyploidy is widespread among plants and animals and its role in organ development and function has long been investigated. In insects, the fat body cells of sexually mature females produce substantial amounts of egg yolk precursor proteins (vitellogenins) and exhibit high polyploid levels, which is considered crucial for boosting egg production. Termites are social insects with a reproductive division of labor, and the fat bodies of mature termite queens exhibit higher ploidy levels than those of other females. The fat bodies of mature termite queens are known to be histologically and cytologically specialized in protein synthesis. However, the relationship between such modifications and polyploidization remains unknown. In this study, we investigated the relationship among cell type, queen maturation, and ploidy levels in the fat body of the termiteReticulitermes speratus. We first confirmed that the termite fat body consists of two types of cells, that is, adipocytes, metabolically active cells, and urocytes, urate- storing cells. Our ploidy analysis using flow cytometry has shown that the fat bodies of actively reproducing queens had more polyploid cells than those of newly emerged and pre-reproductive queens, regardless of the queen phenotype (adult or neotenic type). Using image-based analysis, we found that adipocytes became polyploid during queen differentiation and subsequent sexual maturation. These results suggest that polyploidization in the termite queen fat body is associated with sexual maturation and is regulated in a cell type-specific manner. Our study findings have provided novel insights into the development of insect fat bodies and provide a basis for future studies to understand the functional importance of polyploidy in the fat bodies of termite queens.
Accelerating the Characterization of Dynamic DNA Origami Devices with Deep Neural Networks
Authors: Wang Yuchen , Jin Xin , Castro Carlos
Published: May 2023

Mechanical characterization of dynamic DNA nanodevices is essential to facilitate their use in applications like molecular diagnostics, force sensing, and nanorobotics that rely on device reconfiguration and interactions with other materials. A common approach to evaluate the mechanical properties of dynamic DNA nanodevices is by quantifying conformational distributions, where the magnitude of fluctuations correlates to the stiffness. This is generally carried out through manual measurement from experimental images, which is a tedious process and a critical bottleneck in the characterization pipeline. While many tools to support analysis of static of molecular structures, there is a need for tools to facilitate the rapid characterization of dynamic DNA devices that undergo large conformational fluctuations. Here, we develop a data processing pipeline based on Deep Neural Networks (DNNs) to address this problem. The YOLOv5 and Resnet50 network architecture were used for the two key subtasks: particle detection and pose (i.e. conformation) estimation. We demonstrate effective network performance (F1 score of 0.85 in particle detection) and good agreement with experimental distributions with limited user input and small training sets. We also demonstrate this pipeline can be applied to multiple nanodevices, providing a robust approach for the rapid characterization of dynamic DNA devices.
BOLD cerebrovascular reactivity MRI to identify tissue reperfusion failure after EVT in patients with LVO acute stroke
Authors: Bellomo Jacopo , Sebök Martina , Stumpo Vittorio , van Niftrik Christiaan HB , Meisterhans Darja , Piccirelli Marco , Michels Lars , Reolon Beno , Schubert Tilman , Kulcsar Zsolt , Luft Andreas R , Wegener Susanne , Regli Luca , Fierstra Jorn
Published: May 2023

Background and purpose

In acute ischemic stroke due to large-vessel occlusion (LVO), the clinical outcome after endovascular thrombectomy (EVT) is influenced by the extent of autoregulatory hemodynamic impairment and collateral recruitment, which can be derived from blood oxygenation-level dependent cerebrovascular reactivity (BOLD-CVR). BOLD-CVR imaging identifies brain areas influenced by hemodynamic steal. We sought to investigate the presence of steal phenomenon and its relationship to DWI lesions and clinical deficit in the acute phase of ischemic stroke following successful vessel recanalization.

Methods

From the prospective longitudinal IMPreST (Interplay of Microcirculation and Plasticity after ischemic Stroke) cohort study, patients with acute ischemic unilateral LVO stroke of the anterior circulation with successful endovascular thrombectomy (EVT; mTICI scale ≥ 2b) and subsequent BOLD-CVR examination were included for this analysis. We analyzed the spatial correlation between brain areas exhibiting BOLD-CVR associated steal phenomenon and DWI infarct lesion as well as the relationship between steal phenomenon and NIHSS score at hospital discharge.

Results

Included patients (n=21) exhibited steal phenomenon to different extents, whereas there was only a partial spatial overlap with the DWI lesion (median 18.51%; IQR, 8.44-59.09). The volume of steal phenomenon outside the DWI lesion showed a positive correlation with overall DWI lesion volume and was a significant predictor for the NIHSS score at hospital discharge.

Conclusions

Patients with acute ischemic unilateral LVO stroke exhibited hemodynamic steal identified by BOLD-CVR after successful EVT. Steal volume was associated with DWI infarct lesion size and with poor clinical outcome at hospital discharge. BOLD-CVR may further aid in better understanding persisting hemodynamic impairment following reperfusion therapy.
Traditional Herbal Medicine Use Tripled the Risk of Multi-organ Dysfunction Syndrome in a Pediatric Intensive Care Unit in Ethiopia: A Prospective Cohort Study
Authors: Teshager Nahom Worku , Amare Ashenafi Tazebew , Tamirat Koku Sisay , Zeleke Mulualem Endeshaw , Taddese Asefa Adimasu
Published: May 2023

Objective

This study aimed to investigate the incidence and predictors of MODS in a Pediatric Intensive Care Unit in Ethiopia, with a focus on the association between traditional herbal medicine (THM) use and the risk of MODS.

Methods

This was a single-center prospective cohort study conducted at a PICU in Ethiopia. The study enrolled eligible patients aged one month to 18 years admitted to the PICU during the study period. Recruitment was made at the time of admission to the PICU. Data on demographic characteristics, medical history, clinical and laboratory data, and outcome measures using standard case record forms, physical examination, and patient document reviews. The predictors of MODS were assessed using Cox proportional hazards models, with a focus on the association between traditional herbal medicine use and the risk of MODS.

Results

A total of 310 patients were included in the final analysis, with a median age of 48 months and a male-to-female ratio of 1.5:1. The proportion and incidence of MODS were 30.96% (95% CI:25.8, 36.6) and 7.71(95% CI: 6.10, 9.40) per 100-person-day observation respectively. Renal failure (17.74%), neurologic failure (15.16%), and heart failure (14.52%) were the leading organ failures identified. Nearly one-third of patients (32.9%) died in the PICU, of which 59.8% had MODS. The rate of mortality was higher in patients with MODS than in those without.

The Cox proportional hazards model identified renal disease (AHR=6.32 (95%CI: 3.17,12.61)), intake of traditional herbal medication (AHR=2.45, 95% CI:1.29,4.65), modified Pediatric Index of Mortality 2 (mPIM 2) score (AHR=1.54 (95% CI: 1.38,1.71), and critical illness diagnoses (AHR=2.68 (95% CI: 1.77,4.07)) as predictors of MODS. Patients who used THM had a threefold increased risk of MODS (AHR) of 2.45 (95% CI: 1.29, 4.65).

Conclusion

The incidence of MODS was high. Renal disease, THM use, mPIM 2 scores, and critical illness diagnoses were independent predictors of MODS. A threefold increase in the risk of MODS was seen in patients who used TMH. Healthcare providers should be aware of risks associated with THM, and educate caregivers about the potential harms of these products. Future studies with larger sample sizes and more comprehensive outcome measures are needed.
Diet-induced obesity dysregulates chromatin oxygen sensing regulating efferocytosis in macrophages
Authors: Takahashi Kentaro , Liu Jinghua , Jackson Jasmine R. , Thiruppathi Muthusamy , Benevolenskaya Elizaveta V. , Koh Timothy J. , Urao Norifumi
Published: May 2023

Macrophages are plastic cell populations that normally adapt to their environment. Cellular adaptation to hypoxia occurs through transcription factors including hypoxia-inducible factors, and hypoxia-inducible transcriptions are further regulated by chromatin response through histone modification including histone methylation. However, the role of histone methylation in the hypoxia response of macrophages is not well understood. As obesity is associated with dysregulated macrophage functions, we investigated whether hypoxia response is cell-intrinsically dysregulated in macrophages in obesity.

In mouse bone marrow-derived macrophages (BMDMs), immunoblotting revealed that 1% hypoxia rapidly increases the global levels of histone 3 methylations. We found that hypoxia-induction of histone 3-lysine 4 tri-methylation (H3K4me3) is specifically inhibited in BMDMs from mice fed a high-fat diet (HFD-BMDMs) compared to BMDMs from mice fed a normal diet (ND-BMDMs). Multi-omics approach with ChIP-seq and RNA-seq identified that glycolysis-related pathways and genes includingAldoaare upregulated after prolonged hypoxia along with upregulated H3K4me3 in ND-BMDMs. In contrast, no pathway is associated with hypoxia-upregulated H3K4me3 peaks in HFD-BMDMs and hypoxia-inducedAldoaexpression is decreased in HFD-BMDMs, suggesting both the extent and the genome location of H3K4me3 response to hypoxia is dysregulated in obesity. Consistently, lactate accumulation and induction of histone lactylation under hypoxia are reduced in HFD-BMDMs. Furthermore, HFD-BMDMs exhibited decreased dying cell clearance under hypoxia due to the reduced capacity of anaerobic glycolysis. Competitive bone marrow transplantation of hematopoietic stem cells (HSCs) shows that HFD-induced long-term memory reflects the impaired dying cell clearance in differentiated BMDMs, which is rescued by inhibiting oxidative stress in HSCs.

In summary, chromatin response to hypoxia associated with H3K4me3 enrichment governs transcriptions for anaerobic glycolysis and dying cell clearance under hypoxia. Obesity dysregulates the extent and the genome location of H3K4me3 enrichment, glycolysis, and dying cell clearance of BMDMs under hypoxia, which is initiated in HSPCs via oxidative stress.