bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Genomic Basis of Rapid Adaptation to Antibiotic Combination Therapy in Pseudomonas aeruginosa
Authors: Barbosa Camilo , Mahrt Niels , Bunk Julia , Graßer Matthias , Rosenstiel Philip , Jansen Gunther , Schulenburg Hinrich 
Published: September 2020

Abstract
Combination therapy is a common antibiotic treatment strategy that aims at minimizing the risk of resistance evolution in several infectious diseases. Nonetheless, evidence supporting its efficacy against the nosocomial opportunistic pathogen Pseudomonas aeruginosa remains elusive. Identification of the possible evolutionary paths to resistance in multidrug environments can help to explain treatment outcome. For this purpose, we here performed whole-genome sequencing of 127 previously evolved populations of P. aeruginosa adapted to sublethal doses of distinct antibiotic combinations and corresponding single-drug treatments, and experimentally characterized several of the identified variants. We found that alterations in the regulation of efflux pumps are the most favored mechanism of resistance, regardless of the environment. Unexpectedly, we repeatedly identified intergenic variants in the adapted populations, often with no additional mutations and usually associated with genes involved in efflux pump expression, possibly indicating a regulatory function of the intergenic regions. The experimental analysis of these variants demonstrated that the intergenic changes caused similar increases in resistance against single and multidrug treatments as those seen for efflux regulatory gene mutants. Surprisingly, we could find no substantial fitness costs for a majority of these variants, most likely enhancing their competitiveness toward sensitive cells, even in antibiotic-free environments. We conclude that the regulation of efflux is a central target of antibiotic-mediated selection in P. aeruginosa and that, importantly, changes in intergenic regions may represent a usually neglected alternative process underlying bacterial resistance evolution, which clearly deserves further attention in the future.
Rewiring of growth-dependent transcription regulation by a point mutation in region 1.1 of the housekeeping σ factor
Authors: Pletnev Philipp , Pupov Danil , Pshanichnaya Lizaveta , Esyunina Daria , Petushkov Ivan , Nesterchuk Mikhail , Osterman Ilya , Rubtsova Maria , Mardanov Andrey , Ravin Nikolai , Sergiev Petr , Kulbachinskiy Andrey , Dontsova Olga 
Published: September 2020

AbstractIn bacteria, rapid adaptation to changing environmental conditions depends on the interplay between housekeeping and alternative σ factors, responsible for transcription of specific regulons by RNA polymerase (RNAP). In comparison with alternative σ factors, primary σs contain poorly conserved region 1.1, whose functions in transcription are only partially understood. We found that a single mutation in region 1.1 in Escherichia coli σ70 rewires transcription regulation during cell growth resulting in profound phenotypic changes. Despite its destabilizing effect on promoter complexes, this mutation increases the activity of rRNA promoters and also decreases RNAP sensitivity to the major regulator of stringent response DksA. Using total RNA sequencing combined with single-cell analysis of gene expression we showed that changes in region 1.1 disrupt the balance between the "greed" and "fear" strategies thus making the cells more susceptible to environmental threats and antibiotics. Our results reveal an unexpected role of σ region 1.1 in growth-dependent transcription regulation and suggest that changes in this region may facilitate rapid switching of RNAP properties in evolving bacterial populations.
Functional Impairment of Skin Appendages Due to Peripheral Nerve Involvement by Mycobacterium leprae
Authors: Granger Donald L , Rosado-Santos Harry , Lo Tze Shien , Florell Scott R , Shimwella Rehema A T 
Published: September 2020

AbstractIn the earliest stage of Mycobacterium leprae infection, bacteria parasitize fine fiber twigs of autonomic peripheral nerves supplying efferent impulses to appendages of the skin. This obligate intracellular pathogen invades Schwann cells, the glial cells of peripheral nerves. Intracellular events inhibit Schwann cell physiology in complex ways, which include demyelination and dedifferentiation. Ultimately, axons embraced by their surrounding dysfunctional glia are damaged by poorly understood mechanisms. Loss of nerve conduction impairs the functions of skin appendages including hair growth, sebaceous gland secretion, sweating, and skin pigmentation. At the clinical level, these changes may be subtle and may precede the more obvious anesthetic skin lesions associated with Hansen’s disease. Recognizing the early signs of skin appendage malfunction may aid in diagnosis leading to initiation of antimycobacterial treatment. Effective therapy administered early during infection may prevent irreversible peripheral nerve destruction, the presage for morbid complications of leprosy.
Characterization of Prolonged COVID-19 Symptoms in an Outpatient Telemedicine Clinic
Authors: Cellai Michele , O’Keefe James B 
Published: September 2020

AbstractWe identified patients with coronavirus disease 2019 in a telemedicine clinic who requested ongoing follow-up calls 6 weeks after symptom onset. In this group, respiratory symptoms are the most common complaints, asthma and lung disease are frequent comorbidities, and patients often have not returned to work or usual activity.
Prolonged Low-Dose Methylprednisolone in Patients With Severe COVID-19 Pneumonia
Authors: Salton Francesco , Confalonieri Paola , Meduri G Umberto , Santus Pierachille , Harari Sergio , Scala Raffaele , Lanini Simone , Vertui Valentina , Oggionni Tiberio , Caminati Antonella , Patruno Vincenzo , Tamburrini Mario , Scartabellati Alessandro , Parati Mara , Villani Massimiliano , Radovanovic Dejan , Tomassetti Sara , Ravaglia Claudia , Poletti Venerino , Vianello Andrea , Gaccione Anna Talia , Guidelli Luca , Raccanelli Rita , Lucernoni Paolo , Lacedonia Donato , Foschino Barbaro Maria Pia , Centanni Stefano , Mondoni Michele , Davì Matteo , Fantin Alberto , Cao Xueyuan , Torelli Lucio , Zucchetto Antonella , Montico Marcella , Casarin Annalisa , Romagnoli Micaela , Gasparini Stefano , Bonifazi Martina , D’Agaro Pierlanfranco , Marcello Alessandro , Licastro Danilo , Ruaro Barbara , Volpe Maria Concetta , Umberger Reba , Confalonieri Marco 
Published: September 2020

Abstract

Background
In hospitalized patients with coronavirus disease 2019 (COVID-19) pneumonia, progression to acute respiratory failure requiring invasive mechanical ventilation (MV) is associated with significant morbidity and mortality. Severe dysregulated systemic inflammation is the putative mechanism. We hypothesize that early prolonged methylprednisolone (MP) treatment could accelerate disease resolution, decreasing the need for intensive care unit (ICU) admission and mortality.

Methods
We conducted a multicenter observational study to explore the association between exposure to prolonged, low-dose MP treatment and need for ICU referral, intubation, or death within 28 days (composite primary end point) in patients with severe COVID-19 pneumonia admitted to Italian respiratory high-dependency units. Secondary outcomes were invasive MV-free days and changes in C-reactive protein (CRP) levels.

Results
Findings are reported as MP (n = 83) vs control (n = 90). The composite primary end point was met by 19 vs 40 (adjusted hazard ratio [aHR], 0.41; 95% CI, 0.24–0.72). Transfer to ICU and invasive MV were necessary in 15 vs 27 (P = .07) and 14 vs 26 (P = .10), respectively. By day 28, the MP group had fewer deaths (6 vs 21; aHR, 0.29; 95% CI, 0.12–0.73) and more days off invasive MV (24.0 ± 9.0 vs 17.5 ± 12.8; P = .001). Study treatment was associated with rapid improvement in PaO2:FiO2 and CRP levels. The complication rate was similar for the 2 groups (P = .84).

Conclusion
In patients with severe COVID-19 pneumonia, early administration of prolonged, low dose MP treatment was associated with a significantly lower hazard of death (71%) and decreased ventilator dependence. Treatment was safe and did not impact viral clearance. A large randomized controlled trial (RECOVERY trial) has been performed that validates these findings.
Clinical trial registration. ClinicalTrials.gov NCT04323592.
Occult Colonic Perforation in a Patient With Coronavirus Disease 2019 After Interleukin-6 Receptor Antagonist Therapy
Authors: Schwab Kristin , Hamidi Sepehr , Chung Augustine , Lim Raymond J , Khanlou Negar , Hoesterey Daniel , Dumitras Camelia , Adeyiga Oladunni B , Phan-Tang Michelle , Wang Tisha S , Saggar Rajan , Goldstein Jeffrey , Belperio John A , Dubinett Steven M , Kim Jocelyn T , Salehi-Rad Ramin 
Published: September 2020

Abstract

Background
Interleukin-6 blockade (IL-6) has become a focus of therapeutic investigation for the coronavirus disease 2019 (COVID-19).

Methods
We report a case of a 34-year-old with COVID-19 pneumonia receiving an IL-6 receptor antagonist (IL-6Ra) who developed spontaneous colonic perforation. This perforation occurred despite a benign abdominal exam and in the absence of other known risk factors associated with colonic perforation.

Results
Examination of the colon by electron microscopy revealed numerous intact severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virions abutting the microvilli of the colonic mucosa. Multiplex immunofluorescent staining revealed the presence of the SARS-CoV-2 spike protein on the brush borders of colonic enterocytes that expressed angiotensin-converting enzyme 2. However, no viral particles were observed within the enterocytes to suggest direct viral injury as the cause of colonic perforation.

Conclusions
These data and absence of known risk factors for spontaneous colonic perforation implicate IL-6Ra therapy as the potential mediator of colonic injury in this case. Furthermore, this report provides the first in situ visual evidence of the virus in the colon of a patient presenting with colonic perforation adding to growing evidence that intact infectious virus can be present in the stool.
Endothelial Dysfunction Is Related to Monocyte Activation in Antiretroviral-Treated People With HIV and HIV-Negative Adults in Kenya
Authors: Temu Tecla M , Polyak Stephen J , Zifodya Jerry S , Wanjalla Celestine N , Koethe John R , Masyuko Sarah , Nyabiage Jerusha , Kinuthia John , Gervassi Ana L , Oyugi Julius , Page Stephanie , Farquhar Carey 
Published: September 2020

Abstract

Background
Residual monocyte activation may contribute to increased risk for endothelial dysfunction and subsequent atherosclerotic cardiovascular diseases (CVDs) among people with HIV (PWH) on antiretroviral therapy (ART). We examined the relationship between monocyte activation and endothelial activation in PWH in Kenya.

Methods
Serum levels of markers of endothelial activation (soluble/circulating intercellular [sICAM-1] and vascular [sVCAM-1] cell adhesion molecule–1), intestinal barrier dysfunction (intestinal fatty acid binding protein [I-FABP]), and monocyte activation (soluble CD14 [sCD14]) were measured in 275 PWH on ART and 266 HIV-negative persons. Linear regression was used to evaluate associations, adjusting for demographic and traditional CVD risk factors.

Results
Among 541 participants, the median age was 43 years, 50% were female, and most PWH were virally suppressed (97%). sICAM-1 and sVCAM-1 levels were significantly higher in PWH than in HIV-negative participants (P &lt; .001 for both). After further adjustment for traditional CVD risk factors, HIV infection remained associated with 49% (95% CI, 33% to 67%) greater sICAM-1 and 30% (95% CI, 14% to 48%) greater sVCAM-1 relative to uninfected controls. Adjustment for sCD14 substantially attenuated the difference between PWH and HIV-negative individuals. In a stratified analysis of PWH, both sICAM-1 and sVCAM-1 were positively associated with sCD14 (P &lt; .001).

Conclusions
Despite viral suppression, African PWH have evidence of enhanced endothelial activation associated with sCD14, suggesting that monocyte activation plays a role in atherosclerotic plaque development. Future studies are needed to determine mechanistic pathways leading to monocyte activation in this population.
Solar Ultraviolet Radiation and Vitamin D Deficiency on Epstein-Barr Virus Reactivation: Observational and Genetic Evidence From a Nasopharyngeal Carcinoma-Endemic Population
Authors: Mai Zhi-Ming , Lin Jia-Huang , Ngan Roger Kai-Cheong , Kwong Dora Lai-Wan , Ng Wai-Tong , Ng Alice Wan-Ying , Ip Kai-Ming , Chan Yap-Hang , Lee Anne Wing-Mui , Ho Sai-Yin , Lung Maria Li , Lam Tai-Hing 
Published: September 2020

Abstract

Background
We investigated the relationship of Epstein-Barr virus viral capsid antigen (EBV VCA-IgA) serostatus with ambient and personal ultraviolet radiation (UVR) and vitamin D exposure.

Methods
Using data from a multicenter case-control study, we included 1026 controls subjects in 2014–2017 in Hong Kong, China. Odds ratios (ORs) and 95% confidence intervals (CIs) of the association between UVR exposure and EBV VCA-IgA (seropositivity vs seronegativity) were calculated using unconditional logistic regression models adjusted for potential confounders.

Results
We observed a large increase in seropositivity of EBV VCA-IgA in association with duration of sunlight exposures at both 10 years before recruitment and age 19–30 years (adjusted OR = 3.59, 95% CI = 1.46–8.77; and adjusted OR = 2.44, 95% CI = 1.04–5.73 for ≥8 vs &lt;2 hours/day; P for trend = .005 and .048, respectively). However, no association of EBV VCA-IgA serostatus with other indicators of UVR exposure was found. In addition, both circulating 25-hydroxyvitamin D (25OHD) and genetic predicted 25OHD were not associated with EBV VCA-IgA serostatus.

Conclusions
Our results suggest that personal UVR exposure may be associated with higher risk of EBV reactivation, but we did not find clear evidence of vitamin D exposure (observational or genetic), a molecular mediator of UVR exposure. Further prospective studies in other populations are needed to confirm this finding and to explore the underlying biological mechanisms. Information on photosensitizing agents, and serological markers of EBV, and biomarkers related to systemic immunity and inflammation should be collected and are also highly relevant in future studies.
Management of Gram-Negative Bloodstream Infections in the Era of Rapid Diagnostic Testing: Impact With and Without Antibiotic Stewardship
Authors: Claeys Kimberly C , Heil Emily L , Hitchcock Stephanie , Johnson J Kristie , Leekha Surbhi 
Published: September 2020

Abstract

Background
Verigene Blood-Culture Gram-Negative is a rapid diagnostic test (RDT) that detects gram-negatives (GNs) and resistance within hours from gram stain. The majority of the data support the use of RDTs with antimicrobial stewardship (AMS) intervention in gram-positive bloodstream infection (BSI). Less is known about GN BSI.

Methods
This was a retrospective quasi-experimental (nonrandomized) study of adult patients with RDT-target GN BSI comparing patients pre-RDT/AMS vs post-RDT/pre-AMS vs post-RDT/AMS. Optimal therapy was defined as appropriate coverage with the narrowest spectrum, accounting for source and co-infecting organisms. Time to optimal therapy was analyzed using Kaplan-Meier and multivariable Cox proportional hazards regression.

Results
Eight-hundred thirty-two patients were included; 237 pre-RDT/AMS vs 308 post-RDT/pre-AMS vs 237 post-RDT/AMS, respectively. The proportion of patients on optimal antibiotic therapy increased with each intervention (66.5% vs 78.9% vs 83.2%; P &lt; .0001). Time to optimal therapy (interquartile range) decreased with introduction of RDT: 47 (7.9–67.7) hours vs 24.9 (12.4–55.2) hours vs 26.5 (10.3–66.5) hours (P = .09). Using multivariable modeling, infectious diseases (ID) consult was an effect modifier. Within the ID consult stratum, controlling for source and ICU stay, compared with the pre-RDT/AMS group, both post-RDT/pre-AMS (adjusted hazard ratio [aHR], 1.34; 95% CI, 1.04–1.72) and post-RDT/AMS (aHR, 1.28; 95% CI, 1.01–1.64), improved time to optimal therapy. This effect was not seen in the stratum without ID consult.

Conclusions
With the introduction of RDT and AMS, both proportion and time to optimal antibiotic therapy improved, especially among those with an existing ID consult. This study highlights the beneficial role of RDTs in GN BSI.
Surprisingly Low Levels of Measles Immunity in Persons With HIV: A Seroprevalence Survey in a United States HIV Clinic
Authors: Rearigh Lindsey , O’Neill Jennifer , Kubat Maureen , Sayles Harlan , Swindells Susan , Bares Sara H 
Published: September 2020

Abstract

Background
Measles outbreaks have become increasingly common due to deteriorating vaccination rates, fluctuating herd immunity, and varying antibody decline. Limited knowledge exists regarding prevalence and risk factors associated with measles seronegativity among persons with HIV (PWH).

Methods
This was a cross-sectional study conducted at an academic HIV clinic in Omaha, Nebraska. Participants were screened for the presence of measles IgG antibody. Demographic and clinical information was obtained through electronic medical record review. Simple and multivariable logistic regressions were performed to identify risk factors for measles seronegativity.

Results
Three hundred fifty-one participants were enrolled, with a measles seroprevalence rate of 70.3%. The mean age (range) was 48 (20–74) years, 77% were male, and 53% were Caucasian. The mean CD4 nadir (range) was 334 (1–1675) cells/mm3. At the time of testing, 86% and 87% of the seronegative and seropositive participants had an HIV RNA &lt;50 copies/mL, respectively. Younger age was significantly associated with measles seronegativity (P = .003), as was birth year after 1957 (P = .021). Prior history of measles infection was associated with seropositivity (P = .011). All other risk factors evaluated, including written documentation of adequate vaccination, were not associated with seronegativity.

Conclusions
Our study demonstrates a measles seroprevalence rate that is remarkably lower than previously reported in PWH (92%), and, more importantly, is considerably lower than the rate needed to maintain herd immunity (95%). With higher than expected seronegativity and absence of notable risk factors aside from age, our findings support expanded measles immunity screening for PWH who are at risk of measles exposure.
Dynamics of Human Immunodeficiency Virus-1 Genetic Diversification During Acute Infection
Authors: Song Hongshuo , Bose Meera , Pinyakorn Suteeraporn , Sanders-Buell Eric , O’Sullivan Anne Marie , Silas Daniel , Trichavaroj Rapee , Nuntapinit Bessara , Pham Phuc T , Akapirat Siriwat , Kroon Eugène , de Souza Mark , Gramzinski Robert , Michael Nelson L , Robb Merlin L , Vasan Sandhya , Tovanabutra Sodsai , Ananworanich Jintanat 
Published: September 2020

Abstract
We analyzed human immunodeficiency virus envelope diversity in 98 acute infections. The within-host genetic diversity, divergence from transmitted/founder (T/F) strain, and the observed frequency of multiple T/F infections increased with Fiebig stage. These data identify rapid viral dynamics during acute infection with implications for clinical trials conducted in this setting.
Transmission of SARS-CoV-2 in Public Transportation Vehicles: A Case Study in Hunan Province, China
Authors: Luo Kaiwei , Lei Zhao , Hai Zheng , Xiao Shanliang , Rui Jia , Yang Hao , Jing Xinping , Wang Hui , Xie Zhengshen , Luo Ping , Li Wanying , Li Qiao , Tan Huilu , Xu Zicheng , Yang Yang , Hu Shixiong , Chen Tianmu 
Published: September 2020

AbstractHere we report a case study of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak event during bus trips of an index patient in Hunan Province, China. This retrospective investigation suggests potential airborne transmission of SARS-CoV-2 and the possibility of superspreading events in certain close contact and closed space settings, which should be taken into account when control strategies are planned.
Measuring the Impact of Continuous Disinfection Strategies on Environmental Burden in Outpatient Settings: A Prospective Randomized Controlled Trial
Authors: Warren Bobby G , Turner Nicholas , Smith Becky , Addison Rachel , Marden Samantha , Weber David J , Rutala William A , Anderson Deverick J 
Published: September 2020

Abstract

Background
Our primary objective was to determine the effectiveness of 2 enhanced disinfection strategies compared with standard disinfection: “near-UV” light (Arm 1) and a persistent organosilane quaternary ammonium disinfectant (Arm 2) using a triple-blind study design. Our secondary objective was to characterize environmental contamination of outpatient clinics.

Methods
This trial was conducted at 2 clinics: the wound and pulmonary outpatient clinics at Duke University Health System in Durham, North Carolina. In Arm 1, room overhead lights were replaced with 405-nm near-UV visible light bulbs. In Arm 2, the organosilane quaternary ammonium disinfectant was applied to all room surfaces. The control arm received no intervention. All arms received routine disinfection. Room contamination was measured twice daily (before and after clinic) over 25 clinic days.

Results
The primary outcome was the change in total contamination, measured in colony forming units (CFUs), on environmental surfaces at the end of the clinic day compared with the beginning of the clinic day. Results from each intervention arm were compared against results from the control arm. The median delta total CFU for Arm 1 was 2092 CFUs (interquartile range [IQR], −1815 to 8566); the median delta for Arm 2 was 2016 CFUs (IQR, −1443 to 7430). Compared with the control arm (median delta = 1987 [IQR, −1611 to 15 857]), neither intervention led to a significant decrease in daily room contamination change (P for Arm 1 = 0.78 and P for Arm 2 = 0.71).

Conclusions
Neither near-UV lights or a persistent organosilane quaternary ammonium disinfectant reduced environmental contamination in 2 outpatient clinics compared with control rooms but did reduce the number of clinically important pathogens recovered.