bluuebunny/crossref_metadata_2025_split huggingface dataset:
Therapeutic Drug Monitoring of Antibiotics: Defining the Therapeutic Range
Authors: Abdul–Aziz Mohd H. , Brady Kara , Cotta Menino Osbert , Roberts Jason A. 
Published: November 2021

Purpose:
In the present narrative review, the authors aimed to discuss the relationship between the pharmacokinetic/pharmacodynamic (PK/PD) of antibiotics and clinical response (including efficacy and toxicity). In addition, this review describes how this relationship can be applied to define the therapeutic range of a particular antibiotic (or antibiotic class) for therapeutic drug monitoring (TDM).

Methods:
Relevant clinical studies that examined the relationship between PK/PD of antibiotics and clinical response (efficacy and response) were reviewed. The review (performed for studies published in English up to September 2021) assessed only commonly used antibiotics (or antibiotic classes), including aminoglycosides, beta-lactam antibiotics, daptomycin, fluoroquinolones, glycopeptides (teicoplanin and vancomycin), and linezolid. The best currently available evidence was used to define the therapeutic range for these antibiotics.

Results:
The therapeutic range associated with maximal clinical efficacy and minimal toxicity is available for commonly used antibiotics, and these values can be implemented when TDM for antibiotics is performed. Additional data are needed to clarify the relationship between PK/PD indices and the development of antibiotic resistance.

Conclusions:
TDM should only be regarded as a means to achieve the main goal of providing safe and effective antibiotic therapy for all patients. The next critical step is to define exposures that can prevent the development of antibiotic resistance and include these exposures as therapeutic drug monitoring targets.
Assessment of coronary inflammation in antiretroviral treated people with HIV infection and active HIV/hepatitis C virus co-infection
Authors: Jeudy Jean , Patel Pratik , George Nivya , Burrowes Shana , Husson Jennifer , Chua Joel , Conn Lora , Weiss Robert G. , Bagchi Shashwatee 
Published: November 2021

Objective:
People with HIV (PWH) and co-infected with hepatitis C virus (PWH + HCV) have increased risk of cardiovascular disease (CVD). Peri-coronary inflammation, measured by fat attenuation index (FAI) on coronary computed tomography angiography (CCTA), independently predicts cardiovascular risk in the general population but has not been studied in the PWH + HCV population. We tested whether peri-coronary inflammation is increased in PWH or PWH + HCV, and whether inflammation changes over time.

Design:
Cross-sectional analysis to determine FAI differences among groups. Longitudinal analysis in PWH to assess changes in inflammation over time.

Methods:
Age-matched and sex-matched seropositive groups (PWH and PWH + HCV) virologically suppressed on antiretroviral therapy, HCV viremic, and without prior CVD and matched controls underwent CCTA. Peri-coronary FAI was measured around the proximal right coronary artery (RCA) and left anterior descending artery (LAD). Follow-up CCTA was performed in 22 PWH after 20.6–27.4 months.

Results:
A total of 101 participants (48 women) were studied (60 PWH, 19 PWH + HCV and 22 controls). In adjusted analyses, peri-coronary FAI did not differ between seropositive groups and controls. Low attenuation coronary plaque was significantly less common in seropositive groups compared with controls (LAD, P = 0.035; and RCA, P = 0.017, respectively). Peri-coronary FAI values significantly progressed between baseline and follow-up in PWH (RCA: P = 0.001, LAD: P = <0.001).

Conclusion:
PWH and PWH + HCV without history of CVD do not have significantly worse peri-coronary inflammation, assessed by FAI, compared with matched controls. However, peri-coronary inflammation in mono-infected PWH significantly increased over approximately 22 months. FAI measures may be an important imaging biomarker for tracking asymptomatic CVD progression in PWH.
Ethnic Variation and its Association with Malaria Awareness: A Cross-sectional Study in the East Nusa Tenggara Province (Indonesia)
Authors: Guntur Robertus Dole , Kingsley Jonathan , Islam Fakir M. Amirul 
Published: November 2021

AbstractObjectivesThis study aims to investigate ethnic variation and its association with malaria awareness in the East Nusa Tenggara Province (ENTP), Indonesia.MethodsA community-based cross-sectional study was conducted upon 1495 adults recruited by multi-stage cluster random sampling technique. A malaria awareness related questionnaire was used to collect data alongside a malaria awareness index (MAI). A logistic regression method was applied to quantify the strength of associations of factors associated with the awareness index.ResultsOf total participants, 33% were from Manggarai, 32.3% were from Atoni, 30.2% from Sumba ethnicity. The level of MAI was significantly different between these groups with the highest in Manggarai ethnicity (65.1%, 95% confidence interval (CI): 59.9 – 70.3) and the lowest in Sumba ethnicity (35%, 95% CI: 27.6 – 42.4). The most prominent factors influencing the MAI in Sumba and Manggarai ethnicity were education level, whilst it was socio-economic status (SES) in Atoni ethnicity. The level of MAI was significantly higher for adults with diploma or above education level (adjusted odds ratio (AOR): 21.4, 95% CI: 3.59 – 127.7-for Manggarai ; AOR: 6.94, 95% CI: 1.81 – 26.6 for Sumba). The level of MAI was significantly higher for adults living in high SES in Atoni (AOR 24.48, 95% CI: 8.79 – 68.21).ConclusionsPoorer education levels and low SES were more prominent factors contributing to lower levels of MAI in rural ENTP. Interventions should focus on improving malaria awareness to these groups to support the national commitment of the Indonesian government to achieve malaria elimination zone by 2030.
Cardiovascular disease biomarkers derived from circulating cell-free DNA methylation
Authors: Cuadrat Rafael R. C. , Kratzer Adelheid , Arnal Hector Giral , Wreczycka Katarzyna , Blume Alexander , Ebenal Veronika , Mauno Tiina , Osberg Brendan , Moobed Minoo , Hartung Johannes , Seppelt Claudio , Meteva Denitsa , Haghikia Arash , Leistner David , Landmesser Ulf , Akalin Altuna 
Published: November 2021

AbstractAcute coronary syndromes (ACS) remain a major cause of worldwide mortality. ACS diagnosis is done by a combination of factors, such as electrocardiogram and plasma biomarkers. These biomarkers, however, lack the power to accurately stratify patients into different risk groups. Instead, we used changes in the circulating cell-free DNA (ccfDNA) methylation profiles to estimate the extent of heart injury and the severity of ACS. Our approach relies on the fact that dying cells in acutely damaged tissue release DNA into the blood, causing an increase in the ccfDNA. In addition, each cell type has a distinct DNA methylation profile. We leverage cell type/state specificity of DNA methylation to deconvolute the cell types of origin for ccfDNA and also find DNA methylation-based biomarkers that stratify patient cohorts. The cohorts consisted of healthy subjects, and patients from three ACS conditions: ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI) and unstable angina (UA). We have used two cohorts of patients - discovery, and validation, both consisting of the same conditions. We have sequenced the ccfDNA from the discovery cohort using Whole Bisulfite Genome Sequencing (WBGS), to obtain an unbiased overview of plasma DNA methylation profiles. We have found a total of 1,614 differential methylated regions (DMRs) in the three ACS groups. Many of the regions are associated with genes involved in cardiovascular conditions and inflammation. Using linear models, we were able to narrow down to 254 DMRs significantly associated with ACS severity. The reduced list of DMRs enabled a more accurate stratification of ACS patients. The predictive power of the DMRs was validated in the confirmation cohort using targeted methylation sequencing of the validation cohort.
Three doses of COVID-19 mRNA vaccination are safe based on adverse events reported in electronic health records
Authors: Niesen Michiel J.M. , Pawlowski Colin , O’Horo John C. , Challener Doug W. , Silvert Eli , Donadio Greg , Lenehan Patrick J. , Virk Abinash , Swift Melanie D. , Speicher Leigh L. , Gordon Joel , Geyer Holly L. , Halamka John , Venkatakrishnan AJ , Soundararajan Venky , Badley Andrew 
Published: November 2021

AbstractRecent reports on waning of COVID-19 vaccine induced immunity have led to the approval and roll-out of additional dose and booster vaccinations. At risk individuals are receiving additional vaccine dose(s), in addition to the regimen that was tested in clinical trials. The risks and the adverse event profiles associated with these additional vaccine doses are currently not well understood. Here, we performed a retrospective study analyzing vaccine-associated adverse events using electronic health records (EHRs) of individuals that have received three doses of mRNA-based COVID-19 vaccines (n = 47,999). By comparing symptoms reported in 2-week time periods after each vaccine dose and in a 2-week period before the 1st vaccine dose, we assessed the risk associated with 3rd dose vaccination, for both BNT162b2 and mRNA-1273. Reporting of severe adverse events remained low after the 3rd vaccine dose, with rates of pericarditis (0.01%, 0%-0.02% 95% CI), anaphylaxis (0.00%, 0%-0.01% 95% CI), myocarditis (0.00%, 0%-0.01% 95% CI), and cerebral venous sinus thrombosis (no cases), consistent with earlier studies. Significantly more individuals (p-value < 0.05) report low-severity adverse events after their 3rd dose compared with after their 2nd dose, including fatigue (4.92% after 3rd dose vs 3.47% after 2nd dose), lymphadenopathy (2.89% vs 2.07%), nausea (2.62% vs 2.04%), headache (2.47% vs 2.07%), arthralgia (2.12% vs 1.70%), myalgia (1.99% vs 1.63%), diarrhea (1.70% vs 1.24%), fever (1.11% vs 0.81%), vomiting (1.10% vs 0.80%), and chills (0.47% vs 0.36%). Our results show that although 3rd dose vaccination against SARS-CoV-2 infection led to increased reporting of low-severity adverse events, risk of severe adverse events remained comparable to the standard 2-dose regime. This study provides support for the safety of 3rd vaccination doses of individuals that are at high-risk of severe COVID-19 and breakthrough infection.
Changing molecular epidemiology and characteristics of methicillin-resistant Staphylococcus aureus isolated from bloodstream infections: nationwide surveillance in Japan in 2019
Authors: Kaku Norihito , Sasaki Daisuke , Ota Kenji , Miyazaki Taiga , Yanagihara Katsunori 
Published: November 2021

SynopsisObjectivesSome single-centre studies have reported that MRSA carrying the staphylococcal cassette chromosome mec (SCCmec) type IV has been increasing in bloodstream infections (BSIs) in Japan. Therefore, we conducted nationwide surveillance for MRSA BSI to investigate the extent of such change across Japan.MethodsWe recruited 51 Japanese hospitals from the Japanese Association for Infectious Diseases. MRSA isolates detected in two or more sets of blood cultures were collected between January and September 2019 and subjected to antimicrobial susceptibility testing. Whole-genome sequencing was also performed to determine SCCmec typing and multilocus typing and detect drug-resistance and virulence genes.ResultsTwo hundred seventy MRSA isolates were collected from 45 hospitals. The major combination types were ST8 with SCCmec type IV (ST8-IV) (30.7%), ST1-IV (29.6%), ST2725-IV (9.5%), ST764-II (8.1%), and ST5-II (7.8%). However, there were regional differences among the most major types. The most common types in western, eastern, and northern Japan were ST1-IV, ST8-IV, and ST5-II, respectively. ST8-IV, ST1-IV, and ST2725-IV exhibited greater susceptibility to clindamycin and minocycline than ST764-II and ST5-II, but erm(A) was detected in 93.8% and 100% of ST1-IV and ST2725-IV, respectively. Based on drug-resistance and virulence genes, characteristics of ST8-IV were different from those of ST1-IV and ST2725-IV. In addition, there were two major ST8-IV types with different characteristics.ConclusionsThis study revealed that SCCmec type IV replaced SCCmec type II in MRSA BSI. In addition, SCCmec type IV was divided into several types with different characteristics.
Forecasting the COVID-19 Pandemic: Lessons learned and future directions
Authors: Sundar Saketh , Schwab Patrick , Tan Jade Z.H. , Romero-Brufau Santiago , Celi Leo Anthony , Wangmo Dechen , Penna Nicolás Della 
Published: November 2021

I.AbstractThe Coronavirus Disease 2019 (COVID-19) has demonstrated that accurate forecasts of infection and mortality rates are essential for informing healthcare resource allocation, designing countermeasures, implementing public health policies, and increasing public awareness. However, there exist a multitude of modeling methodologies, and their relative performances in accurately forecasting pandemic dynamics are not currently comprehensively understood.In this paper, we introduce the non-mechanistic MIT-LCP forecasting model, and assess and compare its performance to various mechanistic and non-mechanistic models that have been proposed for forecasting COVID-19 dynamics. We performed a comprehensive experimental evaluation which covered the time period of November 2020 to April 2021, in order to determine the relative performances of MIT-LCP and seven other forecasting models from the United States’ Centers for Disease Control and Prevention (CDC) Forecast Hub.Our results show that there exist forecasting scenarios well-suited to both mechanistic and non-mechanistic models, with mechanistic models being particularly performant for forecasts that are further in the future when recent data may not be as informative, and non-mechanistic models being more effective with shorter prediction horizons when recent representative data is available. Improving our understanding of which forecasting approaches are more reliable, and in which forecasting scenarios, can assist effective pandemic preparation and management.
Machine prescription for chronic migraine
Authors: Stubberud Anker , Gray Robert , Tronvik Erling , Matharu Manjit , Nachev Parashkev 
Published: November 2021

AbstractResponsive to treatment individually, chronic migraine remains strikingly resistant collectively, incurring the second-highest population burden of disability worldwide. A heterogeneity of responsiveness, requiring prolonged—currently heuristic— individual evaluation of available treatments, may reflect a diversity of causal mechanisms, or the failure to identify the most important, single causal factor. Distinguishing between these possibilities, now possible through the application of complex modelling to large-scale data, is critical to determining the optimal approach to identifying new interventions in migraine and making the best use of existing ones.Examining a richly phenotyped cohort of 1446 consecutive unselected patients with chronic migraine, here we use causal multitask Gaussian process models to estimate individual treatment effects across ten classes of preventatives. Such modelling enables us to quantify the accessibility of heterogeneous responsiveness to high-dimensional modelling, to infer the likely scale of the underlying causal diversity. We calculate the treatment effects in the overall population, and the conditional treatment effects among those modelled to respond and compare the true response rates between these two groups. Identifying a difference in response rates between the groups supports a diversity of causal mechanisms. Moreover, we propose a data-driven machine prescription policy, estimating the time-to-response when sequentially trialing preventatives by individualized treatment effects and compare it to expert guideline sequences. All model performances are quantified out-of-sample.We identify significantly higher true response rates among individuals modelled to respond, compared to the overall population (mean difference of 0.034; 95% CI 0.003 to 0.065; p=0.033), supporting significant heterogeneity of responsiveness and diverse causal mechanisms. The machine prescription policy yields an estimated 35% reduction in time-to-response (3.750 months; 95% CI 3.507 to 3.993; p<0.0001) compared with expert guidelines, with no substantive increase in expense per patient.We conclude that the highly distributed mode of causation in chronic migraine necessitates high-dimensional modelling for optimal management. Machine prescription should be considered an essential clinical decision-support tool in the future management of chronic migraine.
Ethnicity and outcomes in COVID-19 in the United Kingdom: a systematic review and meta-analysis
Authors: Siddiq Sania , Ahmed Saima , Akram Irfan 
Published: November 2021

SummaryThis systematic review and meta-analysis evaluated the clinical outcomes of COVID-19 disease in the ethnic minorities of the UK in comparison to the White ethnic group. Medline, Embase, Cochrane, MedRxiv, and Prospero were searched for articles published between May 2020 to April 2021. PROSPERO ID: CRD42021248117. Fourteen studies (767177 participants) were included in the review. In the adjusted analysis, the pooled Odds Ratio (OR) for the mortality outcome was higher for the Black (1.83, 95% CI: 1.21-2.76), Asian (1.16, 95% CI: 0.85-1.57), and Mixed and Other (MO) groups (1.12, 95% CI: 1.04-1.20) compared to the White group. The adjusted and unadjusted ORs of intensive care admission were more than double for all ethnicities (OR Black 2.32, 95% CI: 1.73-3.11, Asian 2.34, 95% CI: 1.89-2.90, MO group 2.26, 95% CI: 1.64-3.11). In the adjusted analysis of mechanical ventilation need the ORs were similarly significantly raised (Black group 2.03, 95% CI: 1.80-2.29, Asian group 1.84, 95% CI: 1.20-2.80, MO 2.09, 95% CI: 1.35-3.22). This review confirmed that all ethnic groups in the UK suffered from increased disease severity and mortality with regards to COVID-19. This has urgent public health and policy implications to reduce the health disparities.
Low grade systemic inflammation is a risk factor for infection death: an observational cohort study
Authors: Drozd Michael , Pujades-Rodriguez Mar , Morgan Ann W , Lillie Patrick J , Witte Klaus K , Kearney Mark T , Cubbon Richard M 
Published: November 2021

AbstractBackgroundMany diseases are associated with chronic inflammation, resulting in widening indications for anti-inflammatory therapies. Whilst effective as disease modifying agents, these increase the risk of serious infection.ObjectiveTo determine if low-grade inflammation is associated with fatal infection, irrespective of associated comorbidity or anti-inflammatory therapy.DesignObservational cohort studySettingUK Biobank studyParticipants461,052 peopleInterventionsNoneMeasurementsIncidence rate ratio (IRR) of death from infection, cardiovascular disease, or other causes, adjusted for comorbidities and use of anti-inflammatory therapies, for serum C-reactive protein (CRP) at recruitment.ResultsLow grade inflammation was common in all morbidities considered and was more prevalent as multimorbidity accrued (CRP ≥2mg/L in 23.3% of people without disease and 58.7% with 3+ comorbidities; p<0.001). After adjusting for confounding factors, CRP ≥2mg/L was associated with a higher IRR of infection death (IRR 1.70; 95% confidence interval 1.51-1.92) than cardiovascular death (IRR 1.48; 1.40-1.57) or other causes of death (IRR 1.41; 1.37-1.45); CRP thresholds of ≥5 and ≥10 mg/L yielded similar findings. Absolute rates of infection, cardiovascular and other death were 0.43, 1.59 and 5.39 per 1000 participant-years, respectively, in people with CRP ≥2mg/L. Analyses stratified by disease type, or number of comorbidities, showed consistent associations between elevated CRP and infection death.LimitationsOur observational study design precludes assessment of causality. We lacked data on the use of anti-inflammatory therapies after study recruitment.ConclusionLow grade inflammation, irrespective of associated comorbidity, identifies people at particularly increased risk of infection death. Decisions to use anti-inflammatory therapies guided by low grade inflammation require careful consideration of the associated risks and benefits.
Ad26.COV2.S breakthrough infections induce high titers of neutralizing antibodies against Omicron and other SARS-CoV-2 variants of concern
Authors: Kitchin Dale , Richardson Simone I. , van der Mescht Mieke A. , Motlou Thopisang , Mzindle Nonkululeko , Moyo-Gwete Thandeka , Makhado Zanele , Ayres Frances , Manamela Nelia P. , Spencer Holly , Lambson Bronwen , Oosthuysen Brent , Kaldine Haajira , du Pisanie Marizane , Mennen Mathilda , Skelem Sango , Williams Noleen , Ntusi Ntobeko A.B. , Burgers Wendy A. , Gray Glenda G. , Bekker Linda-Gail , Boswell Michael T. , Rossouw Theresa M. , Ueckermann Veronica , Moore Penny L. 
Published: November 2021

AbstractThe Janssen (Johnson & Johnson) Ad26.COV2.S non-replicating viral vector vaccine has been widely deployed for COVID-19 vaccination programs in resource-limited settings. Here we confirm that neutralizing and binding responses to Ad26.COV2.S vaccination are stable for 6 months post-vaccination, when tested against multiple SARS-CoV-2 variants. Secondly, using longitudinal samples from individuals who experienced clinically mild breakthrough infections 4 to 5 months after vaccination, we show dramatically boosted binding antibodies, Fc effector function and neutralization. These high titer responses are of similar magnitude to humoral immune responses measured in severely ill, hospitalized donors, and are cross-reactive against diverse SARS-CoV-2 variants, including the extremely neutralization resistant Omicron (B.1.1.529) variant that currently dominates global infections, as well as SARS-CoV-1. These data have implications for population immunity in areas where the Ad26.COV2.S vaccine has been widely deployed, but where ongoing infections continue to occur at high levels.