bluuebunny/crossref_metadata_2025_split huggingface dataset:
COMBINATION USTEKINUMAB AND VEDOLIZUMAB THERAPY FOR REFRACTORY INFLAMMATORY BOWEL DISEASE: A SINGLE INSTITUTION CASE SERIES
Authors: Dawoud Nabila , Roy Lucas , Elmoursi Ahmed , Elkammar Mahmoud , Eltaher Mohamed , Barrett Terrence , Perry Courtney 
Published: January 2022

Abstract

INTRODUCTION
Over the past 20 years, there have been great strides in the medical management of Inflammatory Bowel Disease (IBD). The advent of anti-TNF mAb therapy was transformative in the management of IBD and the positive effects are well documented1,2,3. While anti-TNF mAb biologics induce and maintain remission in IBD, a substantial portion of patients are refractory4. Newer biologic agents such as ustekinumab (UST) and vedolizumab (VDZ) have expanded therapeutic options for patients; however, obtaining deep remission in a subset of IBD patients remains challenging. We previously reported a successful case of deep remission in a patient with refractory stricturing Crohn’s Disease (CD) treated with maximum dosage UST + VDZ therapy5. Since this report, we have expanded our use of this combination in refractory IBD with encouraging results.

METHODS
Fifteen refractory IBD patients (12 CD, 3 UC) at the University of Kentucky were selected to initiate dual biologic therapy (DBT) with UST and VDZ. All patients previously failed other therapies, but demonstrated partial response to escalated dosing (Q4 week) of either VDZ or UST monotherapy. To determine DBT response, we analyzed fecal calprotectin (FC), C-reactive protein (CRP), albumin, BMI, hemoglobin, Harvey Bradshaw Index (HBI)/Mayo scores, endoscopic and histologic appearance. Steroid-free remission was defined by one or more of the following: 1) endoscopic and histologic remission, 2) normalization of biomarkers (FC and CRP) or 3) clinical remission defined by normalization of clinical scores AND normalization of albumin, hemoglobin, and BMI. Clinical remission was only used when endoscopic or biomarker data was not available.

RESULTS
Among the 12 CD patients receiving dual biologic therapy, 11 met criteria for remission (91.6%). Six of these CD patients had complete endoscopic and histologic remission. Three CD patients did not have follow-up endoscopic or FC data, but did have normalization of albumin, CRP, hemoglobin, and HBI scores. Two CD patients were initiated on DBT for spikes in biomarkers (FC and CRP) despite clinical remission. These biomarkers normalized after initiation of DBT. One of the CD patients did not achieve response, and no one with UC (3 patients) responded. Among the successful cases, the average time to remission was 14.9 weeks. There were no adverse events or safety concerns.

CONCLUSION
Dual biologic therapy with combination ustekinumab and vedolizumab is a promising and safe option for patients with refractory CD, particularly in those who demonstrate a partial response to monotherapy of either agent. This combination was not successful in our UC patients. This case series adds further support for the effectiveness of VDZ+ UST combination therapy in CD. Continued investigation is merited to support routine clinical use and improve access to this combination therapy.
VEDOLIZUMAB AS TREATMENT FOR COMMON VARIABLE IMMUNE DEFICIENCY (CVID): A CASE SERIES AND BRIEF REVIEW OF THE LITERATURE
Authors: Patel Sagar , Wilhoit Cameron , Williams Kelli , Forster Erin 
Published: January 2022

Abstract

INTRODUCTION
Common variable immunodeficiency (CVID) is the most common symptomatic immunodeficiency, frequently presenting as recurrent upper respiratory infections. A portion of these patients develop non-specific gastrointestinal symptoms with a smaller subset developing CVID enteropathy, characterized by chronic diarrhea with absence of plasma cells and aggregates of T cells on intestinal pathology. We describe two cases of steroid refractory CVID enteropathy who were started on Vedolizumab (VDZ) with clinical remission.

CASE 1
A 26 year-old female with primarily sinopulmonary CVID on immunoglobulin (IVIG) who developed profuse diarrhea. Infectious work-up and celiac biopsies were negative. Shortly after, colonoscopy with biopsies showing decreased plasma cells consistent with CVID enteropathy. She was started on budesonide with resolution of symptoms. After two months was weaned to 6 mg and began to have daily diarrhea. She was weaned to 3 mg budesonide daily and began to have more frequent diarrhea, bloating, weight loss. Later, budesonide was increased to 6 mg with no response then maximized to 9 mg daily. She was treated with standard induction and maintenance dosing of VDZ 300 with symptomatic remission. Budesonide was tapered off after completing third dose of vedolizumab. The patient has not had any more weight loss and stools are more formed. Her symptoms are abated until days prior to her next infusion; thus, VDZ interval was changed to every 7 weeks. She has not yet had colonoscopy to assess for mucosal healing but has had discontinuation of glucocorticoids. There were no adverse infectious events.

CASE 2
A 28-year-old female with a known history of CVID enteropathy presented to GI clinic for refractory daily diarrhea despite chronic glucocorticoid therapy. She was diagnosed with CVID in 1998 and takes subcutaneous IVIG regularly. Colonoscopy showed mild chronic focally active ileitis, chronic active colitis. She started budesonide 9 mg; however, developed striae and weaned off budesonide. Subsequently, she was trialed on tacrolimus 0.1 mg/kg BID but suffered body aches and contracted COVID-19. She successively had worsening of stool frequency. Colonoscopy revealed ileum had loss of villous architecture and histologic evidence of CVID. She was treated with standard induction and maintenance dose of VDZ 300 mg with symptomatic remission. Symptoms dramatically improved and repeat endoscopy demonstrated no colitis. There were no adverse infectious events.

DISCUSSION
VDZ is an attractive therapy as the gut selective mechanism of action lowers risk of opportunistic infections and has emerged as an appealing therapeutic choice for this specific population. Some case reports have been mixed efficacy of inducing remission with VDZ; however, we report 2 cases of steroid resistant CVID enteropathy with clinical remission after induction with VDZ.
Daptomycin-Resistant Enterococcus Bacteremia Is Associated With Prior Daptomycin Use and Increased Mortality After Liver Transplantation
Authors: Lee Rachael A , Goldman Jason , Haidar Ghady , Lewis Jessica , Arif Sana , Hand Jonathan , La Hoz Ricardo M , Pouch Stephanie , Holaday Eric , Clauss Heather , Kaye Keith S , Nellore Anoma 
Published: January 2022

Abstract

Background
Risk factors for acquisition of vancomycin-resistant Enterococcus (VRE) include immunosuppression, antibiotic exposure, indwelling catheters, and manipulation of the gastrointestinal tract, all of which occur in liver transplant recipients. VRE infections are documented in liver transplantation (LT); however, only one single center study has assessed the impact of daptomycin-resistant Enterococcus (DRE) in this patient population.

Methods
We conducted a retrospective multicenter cohort study comparing liver transplant recipients with either VRE or DRE bacteremia. The primary outcome was death within 1 year of transplantation. Multivariable logistic regression analyses were performed to calculate adjusted odds ratios for outcomes of interest.

Results
We identified 139 cases of Enterococcus bacteremia following LT, of which 78% were VRE and 22% were DRE. When adjusted for total intensive care unit days in the first transplant year, liver-kidney transplantation, and calcineurin inhibitor use, patients with DRE bacteremia were 2.65 times more likely to die within 1 year of transplantation (adjusted odds ratio [aOR], 2.648; 95% CI, 1.025–6.840; P = .044). Prior daptomycin exposure was found to be an independent predictor of DRE bacteremia (aOR, 30.62; 95% CI, 10.087–92.955; P &lt; .001).

Conclusions
In this multicenter study of LT recipients with Enterococcus bacteremia, DRE bacteremia was associated with higher 1-year mortality rates when compared with VRE bacteremia. Our data provide strong support for dedicated infection prevention and antimicrobial stewardship efforts for transplant patients. Further research is needed to support the development of better antibiotics for DRE and practical guidance focusing on identification and prevention of colonization and subsequent infection in liver transplant recipients at high risk for DRE bacteremia.
Comprehensive Evaluation of ACE2-Fc Combination with Neutralization Antibody on Broad Protection against SARS-CoV-2 and Its Variants
Authors: Tang Haoneng , Ke Yong , Ma Hang , Han Lei , Wang Lei , Zong Huifang , Yuan Yunsheng , Wang Zhenyu , He Yang , Chang Yunsong , Wang Shusheng , Liu Junjun , Yue Yali , Xu Wenbo , Zhang Xiaoju , Wang Ziqi , Yang Li , Chen Hua , Bian Yanlin , Zhang Baohong , Liao Yunji , Yin Haiyang , Chen Yi , Zhang En , Zhang Xiaoxiao , Jiang Hua , Xie Yueqing , Gilly John , Wu Mingyuan , Sun Tao , Zhu Jianwei 
Published: January 2022

AbstractEmerging SARS-CoV-2 variants are threatening the efficacy of antibody therapies. Combination treatments including ACE2-Fc have been developed to overcome the evasion of neutralizing antibodies (NAbs) in individual cases. Here we conducted a comprehensive evaluation of this strategy by combining ACE2-Fc with NAbs of diverse epitopes on the RBD. NAb+ACE2-Fc combinations efficiently neutralized HIV-based pseudovirus carrying the spike protein of the Delta or Omicron variants, achieving a balance between efficacy and breadth. In an antibody escape assay using replication-competent VSV-SARS-CoV-2-S, all the combinations had no escape after fifteen passages. By comparison, all the NAbs without combo with ACE2-Fc had escaped within six passages. Further, the VSV-S variants escaped from NAbs were neutralized by ACE2-Fc, revealing the mechanism of NAb+ACE2-Fc combinations survived after fifteen passages. We finally examined ACE2-Fc neutralization against pseudovirus variants that were resistant to the therapeutic antibodies currently in clinic. Our results suggest ACE2-Fc is a universal combination partner to combat SARS-CoV-2 variants including Delta and Omicron.
Capturing intrahost recombination of SARS-CoV-2 during superinfection with Alpha and Epsilon variants in New York City
Authors: Wertheim Joel O. , Wang Jade C. , Leelawong Mindy , Martin Darren P. , Havens Jennifer L. , Chowdhury Moinuddin A. , Pekar Jonathan , Amin Helly , Arroyo Anthony , Awandare Gordon A. , Chow Hoi Yan , Gonzalez Edimarlyn , Luoma Elizabeth , Morang’a Collins M. , Nekrutenko Anton , Shank Stephen D. , Quashie Peter K. , Rakeman Jennifer L. , Ruiz Victoria , Torian Lucia V. , Vasylyeva Tetyana I. , Kosakovsky Pond Sergei L. , Hughes Scott 
Published: January 2022

ABSTRACTRecombination is an evolutionary process by which many pathogens generate diversity and acquire novel functions. Although a common occurrence during coronavirus replication, recombination can only be detected when two genetically distinct viruses contemporaneously infect the same host. Here, we identify an instance of SARS-CoV-2 superinfection, whereby an individual was simultaneously infected with two distinct viral variants: Alpha (B.1.1.7) and Epsilon (B.1.429). This superinfection was first noted when an Alpha genome sequence failed to exhibit the classic S gene target failure behavior used to track this variant. Full genome sequencing from four independent extracts revealed that Alpha variant alleles comprised between 70-80% of the genomes, whereas the Epsilon variant alleles comprised between 20-30% of the sample. Further investigation revealed the presence of numerous recombinant haplotypes spanning the genome, specifically in the spike, nucleocapsid, and ORF 8 coding regions. These findings support the potential for recombination to reshape SARS-CoV-2 genetic diversity.
A mixed method study on supportive supervision of Community Health Workers from Central India
Authors: Revadi G , Joshi Ankur , Pakhare Abhijit P 
Published: January 2022

AbstractIntroductionSupportive supervision of the Community health workers (CHWs) are critical for their efficient functioning in various health programs. CHWs in India are supervised by facilitators known as ASHA Sahyogini. Our study aimed at investigating the linkage between knowledge and skills of CHW facilitators and their CHWs. To understand the problems encountered by the CHW facilitators while assisting their CHWs. Also, to determine the perceptions of CHWs on nature of supportive supervision of their facilitators.MethodsA mixed method explanatory study using purposive sampling was conducted in a rural block of Madhya Pradesh (Central India). The CHWs were categorised into relatively high performing (RHP) and relatively low performing (RLP) groups based on their performance-based incentives received during (2017-2018). Quantitative component comprised of self-administered questionnaire and skill assessment while the qualitative component comprised of three focussed group discussion with RHP, RLP CHWs and their facilitators.ResultsThe mean (SD) supportive supervision score given by CHW facilitators were found to be significantly associated with CHWs performance. Problems faced by CHW facilitators while assisting their CHWs resulted from inadequate education of CHWs, insufficient incentives, transport problems and repetitive surveys. While some CHWs perceived to have received good assistance from their facilitators, there were a few who were not dependant on their facilitators and executed duties by self.ConclusionCHWs performance cannot be ascribed completely to the CHW facilitators performance. The challenges perceived by CHW facilitators were unmodifiable and requires them to strongly motivate and support their CHWs in order to improve their functionality.
Effectiveness of BNT162b2 and mRNA-1273 COVID-19 boosters against SARS-CoV-2 Omicron (B.1.1.529) infection in Qatar
Authors: Abu-Raddad Laith J. , Chemaitelly Hiam , Ayoub Houssein H. , AlMukdad Sawsan , Tang Patrick , Hasan Mohammad R. , Coyle Peter , Yassine Hadi M. , Al-Khatib Hebah A. , Smatti Maria K. , Al-Kanaani Zaina , Al-Kuwari Einas , Jeremijenko Andrew , Kaleeckal Anvar Hassan , Latif Ali Nizar , Shaik Riyazuddin Mohammad , Abdul-Rahim Hanan F. , Nasrallah Gheyath K. , Al-Kuwari Mohamed Ghaith , Butt Adeel A. , Al-Romaihi Hamad Eid , Al-Thani Mohamed H. , Al-Khal Abdullatif , Bertollini Roberto 
Published: January 2022

AbstractBACKGROUNDWaning of COVID-19 vaccine protection and emergence of SARS-CoV-2 Omicron (B.1.1.529) variant have expedited efforts to scale up booster vaccination. This study compared protection afforded by booster doses of the BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) vaccines, compared to the primary series of only two doses in Qatar, during a large, rapidly growing Omicron wave.METHODSIn a population of 2,232,224 vaccinated persons with at least two doses, two matched, retrospective cohort studies were implemented to investigate effectiveness of booster vaccination against symptomatic SARS-CoV-2 infection and against COVID-19 hospitalization and death, up to January 9, 2022. Association of booster status with infection was estimated using Cox proportional-hazards regression models.RESULTSFor BNT162b2, cumulative symptomatic infection incidence was 2.9% (95% CI: 2.8-3.1%) in the booster-dose cohort and 5.5% (95% CI: 5.3-5.7%) in the primary-series cohort, after 49 days of follow-up. Adjusted hazard ratio for symptomatic infection was 0.50 (95% CI: 0.47-0.53). Booster effectiveness relative to primary series was 50.1% (95% CI: 47.3-52.8%). For mRNA-1273, cumulative symptomatic infection incidence was 1.9% (95% CI: 1.7-2.2%) in the booster-dose cohort and 3.5% (95% CI: 3.2-3.9%) in the primary-series cohort, after 35 days of follow-up. The adjusted hazard ratio for symptomatic infection was 0.49 (95% CI: 0.43-0.57). Booster effectiveness relative to primary series was 50.8% (95% CI: 43.4-57.3%). There were fewer cases of severe COVID-19 in booster-dose cohorts than in primary-series cohorts, but cases of severe COVID-19 were rare in all cohorts.CONCLUSIONSmRNA booster vaccination is associated with modest effectiveness against symptomatic infection with Omicron. The development of a new generation of vaccines targeting a broad range of variants may be warranted.
Mapping cherry blossoms from geotagged street-level photos
Authors: Funada Shuya , Tsutsumida Narumasa 
Published: January 2022

ABSTRACTFloral phenology is useful information as an indicator on climate change and ecosystem services, however its observation is not straightforward over space and time. Satellite remote sensing and official and volunteer-based in-situ observations have been conducting, but the long-term and accurate data collection is challenging due to the insufficient quality and quantity of observations and the lack of financial and human resources to sustain. Here, we demonstrate a flower detection model from street-level photos, which can be the core function of a semi-automatic observation system to tackle those issues above. We detected cherry blossoms by this model from geotagged images with the observation date, obtained from Mapillary, which is one of social sensing data sources, and mapped dates of flowering in a study site, Aizuwakamatsu, Japan in April 2018. This approach enables us to collect floral phenology information semi-automatically as a data-driven approach. It is expected to collect a large number of observations with a certain level of quality by avoiding human-induced biases for the observations.
Stabilization of E-cadherin adhesions by COX-2/GSK3β signaling is a targetable pathway in metastatic breast cancer
Authors: Balamurugan Kuppusamy , Sehareen Saadiya , Sharan Shikha , Krishnamurthy Savitri , Tang Wei , McKennett Lois , Padmanaban Veena , Czarra Kelli , Ewald Andrew J. , Ueno Naoto T. , Ambs Stefan , Poria Dipak K. , Sterneck Esta 
Published: January 2022

ABSTRACTMetastatic progression and treatment-resistance of breast cancer has been associated with epithelial-mesenchymal-transition including downregulation of E-cadherin (CDH1) expression, which can be initiated by inflammatory mediators such as COX-2. Recently, E-cadherin-mediated, cluster-based metastasis and treatment resistance has become more appreciated, though the mechanisms that maintain E-cadherin expression in this context are unknown. Through studies of inflammatory breast cancer and anin vitrotumor cell emboli culture paradigm, we identified a role for COX-2, a target gene of C/EBPδ, or its metabolite PGE2 in promoting protein stability of E-cadherin, β-catenin and p120 catenin through inhibition of GSK3β, without affectingCDH1mRNA. The COX-2 inhibitor celecoxib downregulated E-cadherin complex proteins and caused cell death. Co-expression of E-cadherin and COX-2 was seen in breast cancer patients with poor outcome and, along with inhibitory GSK3β phosphorylation, in patient-derived xenografts of triple negative breast cancer. Celecoxib alone decreased E-cadherin protein expression within xenograft tumors, reduced circulating tumor cells and clusters, and in combination with paclitaxel attenuated or regressed lung metastases. This study uncovered a mechanism by which metastatic breast cancer cells can maintain E-cadherin-mediated cell-cell adhesions and cell survival, suggesting that patients with COX-2+/E-cadherin+ breast cancer may benefit from targeting of the PGE2 signaling pathway.
Bergmann’s rule inMicrolophuslizards: testing for latitudinal and climatic gradients of body size
Authors: Toyama Ken S. , Boccia Christopher K. 
Published: January 2022

ABSTRACTBroadscale environmental gradients exert selection pressures that can result in macroevolutionary patterns of phenotypic diversity. Bergmann’s rule, one of the most studied ecogeographical patterns, states that among related species or populations, larger body sizes should occur at higher latitudes or colder climates given the efficacy of larger sizes to conserve heat. However, there is still much debate regarding the mechanisms that underlie the rule and whether they should be different between endotherms and ectotherms. Here we test for Bergmann’s rule inMicrolophuslizards, a genus distributed in western South America and the Galápagos Islands, and test for associations between body size and climatic variables. Our results indicate that mainlandMicrolophusspecies follow Bergmann’s rule, meaning that larger species are found towards the southernmost latitudes encompassed by the genus’ distribution. This relationship was similar for males and females, suggesting that patterns of sexual size dimorphism are not driven by differing latitudinal gradients of body size between the sexes. We identified negative associations between body size and temperature, precipitation, and isothermality, meaning that larger species are found in colder, drier, and more thermally variable environments. We discuss the possible mechanisms behind this pattern, the implications of insularity and ecology for the evolution of body size in this genus, and emphasize the need for additional natural history information to allow for the elucidation of the mechanisms behind the patterns presented in this work.
Phylogenetic analyses of AGO/DCL/RDR proteins in green plants refine the evolution of small RNA pathways
Authors: Bélanger Sébastien , Zhan Junpeng , Meyers Blake C. 
Published: January 2022

ABSTRACTSeveral protein families play a role in the biogenesis and function of small RNAs (sRNAs) in plants. Those with primary roles include Dicer-like (DCL), RNA-directed RNA polymerase (RDR), and Argonaute (AGO) proteins. Protein families such as double-stranded RNA-binding (DRB), SERRATE (SE), and SUPPRESSION OF SILENCING 3 (SGS3) act as partners of DCL or RDR proteins. Here, we present curated annotations and phylogenetic analyses of seven sRNA pathway protein families performed on 196 species in the Viridiplantae (aka green plants) lineage. Our results suggest that the RDR3 proteins emerged earlier than RDR1/2/6. RDR6 is found in filamentous green algae and all land plants, suggesting that the evolution of RDR6 proteins coincides with the evolution of phased small interfering RNAs (siRNAs). We traced the origin of the 24-nt reproductive phased siRNA-associated DCL5 protein back toAcorus americanus, the earliest diverged, extant monocot species. Our analyses of AGOs identified multiple duplication events ofAGOgenes that were lost, retained or further duplicated in sub-groups, indicating that the evolution ofAGOsis complex in monocots. The results also refine the evolution of several clades of AGO proteins, such as AGO4, AGO6, AGO17 and AGO18. Analyses of nuclear localization signal sequences and catalytic triads of AGO proteins provide insights into the regulatory roles of diverse AGOs. Collectively, this work generates a curated and evolutionarily coherent annotation for gene families involved in plant sRNA biogenesis/function and provides insights into the evolution of major sRNA pathways.