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In this Viewpoint, the authors explore the determinants of patients' prescription adherence behaviors as part of FIND's Advancing Access to Diagnostic Innovation essential for Universal Health Coverage and AMR Prevention (ADIP) trials (ClinicalTrials.gov identifier: NCT04081051). Research findings from Burkina Faso, Ghana, and Uganda show that basic knowledge and understanding of prescription instructions are essential for adherence and can be improved through better communication. However, there are a range of other factors that influence adherence, some of which can be influenced through tailored communication messages from healthcare workers. These messages may contribute to changes in adherence behavior but may require other reinforcing interventions to be effective. Finally, there are some drivers of nonadherence centered around costs and time pressure that require other forms of intervention.
\n \n\n \n \nBackgroundThe aim was to explore behavioral factors relating to the prescription and communication of prescription-adherence messages for patients with acute febrile illness, from which to develop a training-and-communication (T&C) intervention to be delivered as part of a clinical trial.MethodsThe study undertook a content analysis of primary, qualitative data collection using in-depth interviews and focus group discussions, informed by the Capability, Opportunity, Motivation (COM-B) theory of behavior, the Theoretical Domains Framework (TDF), and Behavior Change Wheel (BCW) approach, in health facilities (39 health workers) and communities (66 community members) in the Shai-Osudoku District of Ghana.ResultsHealth workers perceive that prescribers' and dispensers' communication with patients is influenced by the following factors: patient's educational level, existing disease conditions, health worker's workload, patient's religion, language barrier between health worker and patient, outcome of laboratory results, and medicine availability. Community members' adherence to prescription was influenced by the availability of money and affordability of medicine (outside of provision by the national health insurance scheme), the severity of the condition, work schedule, and forgetfulness.ConclusionsOur study contributes to knowledge on nesting qualitative methods in a clinical trial and reveals factors that affect the antibiotic prescription communication process. Tailored messages for patient-specific needs can shape antibiotic prescription adherence behavior and ultimately contribute to decreasing the incidence of antibiotic resistance.
\n \n\n \n \nBackgroundLong-term health outcomes in children and young people (CYP) after COVID-19 infection are not well understood and studies with control groups exposed to other infections are lacking. This study aimed to investigate the incidence of post-COVID-19 condition (PCC) and incomplete recovery in CYP after hospital discharge and compare outcomes between different SARS-CoV-2 variants and non-SARS-CoV-2 infections.MethodsA prospective exposure-stratified cohort study of individuals under 18\u00a0years old in Moscow, Russia. Exposed cohorts were paediatric patients admitted with laboratory-confirmed COVID-19 infection between April 2 and December 11, 2020 (Wuhan variant cohort) and between January 12 and February 19, 2022 (Omicron variant cohort). CYP admitted with respiratory and intestinal infections, but negative lateral flow rapid diagnostic test and PCR-test results for SARS-CoV-2, between January 12 and February 19, 2022, served as unexposed reference cohort. Comparison between the 'exposed cohorts' and 'reference cohort' was conducted using 1:1 matching by age and sex. Follow-up data were collected via telephone interviews with parents, utilising the long COVID paediatric protocol and survey developed by the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC). The WHO case definition was used to categorise PCC.ResultsOf 2595 CYP with confirmed COVID-19, 1707 (65.7%) participated in follow-up interviews, with 1183/1707 (69%) included in the final 'matched' analysis. The median follow-up time post-discharge was 6.7\u00a0months. The incidence of PCC was significantly higher in the Wuhan variant cohort (89.7 cases per 1000 person-months, 95% CI 64.3-120.3) compared to post-infection sequalae in the reference cohort (12.2 cases per 1000 person-months, 95% CI 4.9-21.9), whereas the difference with the Omicron variant cohort and reference cohort was not significant. The Wuhan cohort had higher incidence rates of dermatological, fatigue, gastrointestinal, sensory, and sleep manifestations, as well as behavioural and emotional problems than the reference cohort. The only significant difference between Omicron variant cohort and reference cohort was decreased school attendance. When comparing the Wuhan and Omicron variant cohorts, higher incidence of PCC and event rates of fatigue, decreased physical activity, and deterioration of relationships was observed. The rate of incomplete recovery was also significantly higher in the Wuhan variant cohort than in both the reference and the Omicron variant cohorts.ConclusionsWuhan variant exhibited a propensity for inducing a broad spectrum of physical symptoms and emotional behavioural changes, suggesting a pronounced impact on long-term health outcomes. Conversely, the Omicron variant resulted in fewer post-infection effects no different from common seasonal viral illnesses. This may mean that the Omicron variant and subsequent variants might not lead to the same level of long-term health consequences as earlier variants.
\n \n\n \n \nThere is a complex interplay between infectious disease outbreaks and the stigmatization of affected persons and communities. Outbreaks are prone to precipitating stigma due to the fear, uncertainty, moralisation, and abatement of freedoms associated with many infectious diseases. In turn, this stigma hampers outbreak control efforts. Understanding this relationship is crucial to improving coordinated outbreak response. This requires valid and reliable methods for assessing stigma towards and within impacted communities. We propose adopting a cross-outbreak model for developing the necessary assessment tools. A stigma-informed approach must then be integrated into outbreak preparedness and response efforts to safeguard public health and promote inclusivity and compassion in future outbreaks.
\n \n\n \n \nEpigenetic proteins containing YEATS domains (YD) are an emerging target class in drug discovery. Described herein are the discovery and characterization efforts associated with PFI-6, a new chemical probe for the YD of MLLT1 (ENL/YEATS1) and MLLT3 (AF9/YEATS3). For hit identification, fragment-like mimetics of endogenous YD ligands (crotonylated histone-containing proteins), were synthesized via parallel medicinal chemistry (PMC) and screened for MLLT1 binding. Subsequent SAR studies led to iterative MLLT1/3 binding and selectivity improvements, culminating in the discovery of PFI-6. PFI-6 demonstrates good affinity and selectivity for MLLT1/3 vs. other human YD proteins (YEATS2/4) and engages MLLT3 in cells. Small-molecule X-ray co-crystal structures of two molecules, including PFI-6, bound to the YD of MLLT1/3 are also described. PFI-6 may be a useful tool molecule to better understand the biological effects associated with modulation of MLLT1/3.
\n \n\n \n \nBackgroundApost hocanalysis of the MERGE trial was conducted, to investigate whether sex differences are evident at the mildest end of the disease spectrum, for symptoms associated with obstructive sleep apnoea (OSA) and the response to continuous positive airway pressure (CPAP) treatment.MethodsMERGE participants with mild OSA (apnoea\u2013hypopnoea index 5\u201315\u2005events\u00b7h\u22121; American Academy of Sleep Medicine 2012 criteria) were randomised to either CPAP plus standard care (sleep hygiene counselling) or standard care alone for 3\u2005months. Quality of life (QoL) was measured by questionnaires completed before and after the 3\u2005months. Thispost hocanalysis of participants of the MERGE trial compared the symptom presentation, and response to CPAP, between the sexes.Results233 patients were included; 71 (30%) were female. Females were more symptomatic at baseline in all QoL questionnaires. Specifically, females had lower 36-item Short-Form Health Survey (SF-36) Vitality scores (mean\u00b1sd39.1\u00b110.1versus44.8\u00b110.3) and higher Epworth Sleepiness Scale (ESS) scores (mean\u00b1sd11.0\u00b14.2versus9.5\u00b14.4). Both sexes experienced snoring, but more females reported fatigue and more males reported witnessed apnoeas. All symptoms improved with CPAP for both sexes; however, females had larger improvements in SF-36 Vitality scores, which was the primary outcome of the MERGE trial (mean change 9.4 (95% CI 6.8\u201312.0)versus6.0 (95% CI 4.3\u20137.7); p=0.034), and ESS (mean change \u22124.1 (95% CI \u22125.1\u2013\u2009\u22123.0)versus\u22122.5 (95% CI \u22123.1\u2013\u2009\u22121.8); p=0.015), after adjustment for baseline scores and CPAP usage.ConclusionsSex differences are apparent in patients with mild OSA. Females experience worse QoL symptoms than males at presentation to the sleep clinic; however, these improve significantly with CPAP treatment.
\n \n\n \n \nBackground Collecting and storing large number of sputum samples with a view to culturing these in the future requires an efficient initial handling method. We devised a modified sputum digestion and decontamination method that maximised storage capacity and Mycobacterium tuberculosis (M.tb) recovery from culture while minimising laboratory workload and risk of contamination. Methods We collected smear microscopy positive sputum samples from patients with pulmonary tuberculosis (TB). The sputum samples were split and processed using both the standard N-Acetyl-L-cysteine and sodium hydroxide (NALC-NaOH) method and our modified method before freezing and later culturing in BD BACTEC 960 Mycobacterium Growth Indicator Tubes (MGIT) system. We assessed the Time to Positivity (TPP) and Growth Unit (GU) data. Results We selected 22 sputum samples to compare two digestion and decontamination methods. The samples that underwent the modified method had longer TTP (p < 0.05) but similar GU in comparison to standard method. Overall, 1/22 samples failed to grow in MGIT after being processed by the modified method. We then applied the modified method to 348 sputum samples with Rifampicin resistance detected by GeneXpert MTB/RIF assay, which were frozen for between 1-25 months. The overall MGIT positive, negative, and contamination rate was 90.5%, 7.8%, and 1.7%, respectively. There was no significant difference in MGIT result when samples were grouped by duration of storage or positive smear grade. Conclusions Our modified method yielded acceptable M.tb recovery rate and low contamination risk while allowing us to collect and store thousands of sputum samples over a long period of time for future tests.
\n \n\n \n \nWe introduce the Antimicrobial Resistance Diagnostic Use Accelerator program, and the articles in this Supplement, which cover the program in 3 sub-Saharan Africa countries.
\n \n\n \n \nThis meta-analysis included 3 randomized trials conducted in sub-Saharan Africa comparing the effects of point-of-care tests and diagnostic algorithms versus routine care on antibiotic prescriptions and clinical outcomes in ambulatory patients presenting at outpatient facilities with acute uncomplicated febrile illness.
\n \n\n \n \nBackgroundIndividuals vaccinated against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), when infected, can still develop disease\u00a0that requires hospitalization. It remains unclear whether these patients differ from hospitalized unvaccinated patients with regard to presentation, coexisting comorbidities, and outcomes.MethodsHere, we use data from an international consortium to study this\u00a0question and assess whether differences between these groups are\u00a0context specific. Data from 83,163 hospitalized COVID-19 patients (34,843 vaccinated, 48,320 unvaccinated) from 38 countries were analyzed.FindingsWhile typical symptoms were more often reported in unvaccinated patients, comorbidities, including some associated with worse prognosis in previous studies, were more common in vaccinated patients. Considerable between-country variation in both in-hospital fatality risk and vaccinated-versus-unvaccinated difference in this outcome was observed.ConclusionsThese findings will inform allocation of healthcare resources in future surges as well as design of longer-term international studies to characterize changes in clinical profile of hospitalized COVID-19 patients related to vaccination history.FundingThis work was made possible by the UK Foreign, Commonwealth and Development Office and Wellcome (215091/Z/18/Z, 222410/Z/21/Z, 225288/Z/22/Z, and 220757/Z/20/Z); the Bill\u00a0& Melinda Gates\u00a0Foundation (OPP1209135); and the philanthropic support of the donors\u00a0to the University of Oxford's COVID-19 Research Response Fund (0009109). Additional funders are listed in the \"acknowledgments\" section.
\n \n\n \n \n\nOBJECTIVES:\nTo develop a clinical prediction model to risk stratify children admitted to PICUs in locations with limited resources, and compare performance of the model to nine existing pediatric severity scores.\n\n\nDESIGN:\nRetrospective, single-center, cohort study.\n\n\nSETTING:\nPICU of a pediatric hospital in Siem Reap, northern Cambodia.\n\n\nPATIENTS:\nChildren between 28 days and 16 years old admitted nonelectively to the PICU.\n\n\nINTERVENTIONS:\nNone.\n\n\nMEASUREMENTS AND MAIN RESULTS:\nClinical and laboratory data recorded at the time of PICU admission were collected. The primary outcome was death during PICU admission. One thousand five hundred fifty consecutive nonelective PICU admissions were included, of which 97 died (6.3%). Most existing severity scores achieved comparable discrimination (area under the receiver operating characteristic curves [AUCs], 0.71\u20130.76) but only three scores demonstrated moderate diagnostic utility for triaging admissions into high- and low-risk groups (positive likelihood ratios [PLRs], 2.65\u20132.97 and negative likelihood ratios [NLRs], 0.40\u20130.46). The newly derived model outperformed all existing severity scores (AUC, 0.84; 95% CI, 0.80\u20130.88; p < 0.001). Using one particular threshold, the model classified 13.0% of admissions as high risk, among which probability of mortality was almost ten-fold greater than admissions triaged as low-risk (PLR, 5.75; 95% CI, 4.57\u20137.23 and NLR, 0.47; 95% CI, 0.37\u20130.59). Decision curve analyses indicated that the model would be superior to all existing severity scores and could provide utility across the range of clinically plausible decision thresholds.\n\n\nCONCLUSIONS:\nExisting pediatric severity scores have limited potential as risk stratification tools in resource-constrained PICUs. If validated, our prediction model would be a readily implementable mechanism to support triage of critically ill children at admission to PICU and could provide value across a variety of contexts where resource prioritization is important.\n
\n \n\n \n \nBackgroundUsing a large dataset, we evaluated prevalence and severity of alterations in liver enzymes in COVID-19 and association with patient-centred outcomes.MethodsWe included hospitalized patients with confirmed or suspected SARS-CoV-2 infection from the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) database. Key exposure was baseline liver enzymes (AST, ALT, bilirubin). Patients were assigned Liver Injury Classification score based on 3 components of enzymes at admission: Normal; Stage I) Liver injury: any component between 1-3x upper limit of normal (ULN); Stage II) Severe liver injury: any component \u22653x ULN. Outcomes were hospital mortality, utilization of selected resources, complications, and durations of hospital and ICU stay. Analyses used logistic regression with associations expressed as adjusted odds ratios (OR) with 95% confidence intervals (CI).ResultsOf 17,531 included patients, 46.2% (8099) and 8.2% (1430) of patients had stage 1 and 2 liver injury respectively. Compared to normal, stages 1 and 2 were associated with higher odds of mortality (OR 1.53 [1.37-1.71]; OR 2.50 [2.10-2.96]), ICU admission (OR 1.63 [1.48-1.79]; OR 1.90 [1.62-2.23]), and invasive mechanical ventilation (OR 1.43 [1.27-1.70]; OR 1.95 (1.55-2.45). Stages 1 and 2 were also associated with higher odds of developing sepsis (OR 1.38 [1.27-1.50]; OR 1.46 [1.25-1.70]), acute kidney injury (OR 1.13 [1.00-1.27]; OR 1.59 [1.32-1.91]), and acute respiratory distress syndrome (OR 1.38 [1.22-1.55]; OR 1.80 [1.49-2.17]).ConclusionsLiver enzyme abnormalities are common among COVID-19 patients and associated with worse outcomes.
\n \n\n \n \nAbstractBackgroundCurrent clinical guidelines recommend treating chronic hepatitis B virus (HBV) infection in a minority of cases, but there are relatively scarce data on evolution or progression of liver inflammation and fibrosis in cases of chronic HBV (CHB) that do not meet treatment criteria. We aimed to assess the impact of TDF on liver disease, and the risk of renal impairment in treated CHB patients in comparison to untreated patients.MethodsWe studied a longitudinal ethnically diverse CHB cohort in the UK attending out-patient clinics between 2005 and 2018. We examined TDF treatment (vs. untreated) as the main exposure, with HBV DNA viral load (VL), ALT, elastography scores and eGFR as the main outcomes, using paired tests and mixed effects model for longitudinal measurements. Additionally, decline of eGFR during follow-up was quantified within individuals by thresholds based on clinical guidelines. Baseline was defined as treatment initiation for TDF group and the beginning of clinical follow-up for untreated group respectively.ResultsWe included 206 adults (60 on TDF, 146 untreated), with a median\u2009\u00b1\u2009IQR follow-up duration of 3.3\u2009\u00b1\u20092.8\u2009years. The TDF group was significantly older (median age 39 vs. 35\u2009years,p\u00a0=\u20090.004) and more likely to be male (63% vs. 47%,p\u00a0=\u20090.04) compared to the untreated group. Baseline difference between TDF and untreated groups reflected treatment eligibility criteria. As expected, VL and ALT declined significantly over time in TDF-treated patients. Elastography scores normalised during treatment in the TDF group reflecting regression of inflammation and/or fibrosis. However, 6/81 (7.4%) of untreated patients had a progression of fibrosis stage from F0-F1 to F2 or F3. There was no evidence of difference in rates or incidence of renal impairment during follow-up in the TDF vs. untreated group.ConclusionsRisk of liver inflammation and fibrosis may be raised in untreated patients compared to those receiving TDF, and TDF may benefit a larger percentage of the CHB population.
\n \n\n \n \nViral mimicry of host cell structures has been postulated to curtail the B cell receptor (BCR) repertoire against persisting viruses through tolerance mechanisms. This concept awaits, however, experimental testing in a setting of natural virus-host relationship. We engineered mouse models expressing a monoclonal BCR specific for the envelope glycoprotein of lymphocytic choriomeningitis virus (LCMV), a naturally persisting mouse pathogen. When the heavy chain of the LCMV-neutralizing antibody KL25 was paired with its unmutated ancestor light chain, most B cells underwent receptor editing, a behavior reminiscent of autoreactive clones. In contrast, monoclonal B cells expressing the same heavy chain in conjunction with the hypermutated KL25 light chain did not undergo receptor editing but exhibited low levels of surface IgM, suggesting that light chain hypermutation had lessened KL25 autoreactivity. Upon viral challenge, these IgMlow cells were not anergic but up-regulated IgM, participated in germinal center reactions, produced antiviral antibodies, and underwent immunoglobulin class switch as well as further affinity maturation. These studies on a persisting virus in its natural host species suggest that central tolerance mechanisms prune the protective antiviral B cell repertoire.
\n \n\n \n \nIntroductionRickettsia spp. and Orientia spp. are the causes of neglected infections that can lead to severe febrile and systemic illnesses in humans. Implementing proper biosafety practices when handling these pathogens is crucial to ensure a safe and sustainable work environment. It is essential to assess the current knowledge and identify any potential gaps to develop effective measures that minimise the risk of exposure to these pathogens. By doing so, we can establish a comprehensive framework that promotes safety, mitigates hazards, and safeguards the well-being of personnel and the surrounding community.Methods and resultsThis review aimed to synthesise and determine the evidence base for biosafety precautions for Rickettsia spp. and Orientia spp. pathogens. Enhancing our understanding of the relative infectious risk associated with different strains of Rickettsia and Orientia spp. requires identifying the infectious dose of these pathogens that can cause human disease. The application of risk groups for Rickettsia and Orientia spp. is inconsistent across jurisdictions. There is also incomplete evidence regarding decontamination methods for these pathogens. With regards to Orientia spp. most of the available information is derived from experiments conducted with Rickettsia spp.ConclusionsRickettsia and Orientia spp. are neglected diseases, as demonstrated by the lack of evidence-based and specific biosafety information about these pathogens. In the case of Orientia spp., most of the available information is derived from Rickettsia spp., which may not be appropriate and overstate the risks of working with this pathogen. The advent of effective antibiotic therapy and a better understanding of the true hazards and risks associated with pathogen manipulation should inform decisions, allowing a sustainable and safe work environment.
\n \n\n \n \nHepatitis B Virus (HBV) is a small DNA virus that replicates via an episomal covalently closed circular DNA (cccDNA) that serves as the transcriptional template for viral mRNAs. The host protein, CCCTC-binding factor (CTCF), is a key regulator of cellular transcription by maintaining epigenetic boundaries, nucleosome phasing, stabilisation of long-range chromatin loops and directing alternative exon splicing. We previously reported that CTCF binds two conserved motifs within Enhancer I of the HBV genome and represses viral transcription, however, the underlying mechanisms were not identified. We show that CTCF depletion in cells harbouring cccDNA-like HBV molecules and in de novo infected cells resulted in an increase in spliced transcripts, which was most notable in the abundant SP1 spliced transcript. In contrast, depletion of CTCF in cell lines with integrated HBV DNA had no effect on the abundance of viral transcripts and in line with this observation there was limited evidence for CTCF binding to viral integrants, suggesting that CTCF-regulation of HBV transcription is specific to episomal cccDNA. Analysis of HBV chromatin topology by Assay for Transposase Accessible Chromatin Sequencing (ATAC-Seq) revealed an accessible region spanning Enhancers I and II and the basal core promoter (BCP). Mutating the CTCF binding sites within Enhancer I resulted in a dramatic rearrangement of chromatin accessibility where the open chromatin region was no longer detected, indicating loss of the phased nucleosome up- and down-stream of the HBV enhancer/BCP. These data demonstrate that CTCF functions to regulate HBV chromatin conformation and nucleosomal positioning in episomal maintained cccDNA, which has important consequences for HBV transcription regulation.
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