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Transgenerational continuity: Persistence as a dimension of inheritance and evolution.

Transgenerational continuity (TC) describes the persistence of inherited molecular architectures across generations. Progress in identity-by-descent (IBD) detection, recombination dynamics, and epigenetic research highlights the growing need for a more comprehensive model of inheritance. This theoretical framework synthesizes evidence from genomics, population studies, and epigenetics to outline how inherited molecular architectures, which are transmitted through IBD, together with heritable epigenetic modifications, can preserve ancestral information across generations. IBD captures genomic continuity across three nested scales, where recent familial segments link close relatives, population-level haplotypes are shared across cohorts, and archaic fragments from Neanderthal and Denisovan admixture persist as molecular fossils of ancient lineages. Although recombination and selection reshape these regions, their persistence across time scales highlights the evolutionary durability of genomic continuity. Epigenetic memory reflects regulatory persistence, whereby molecular modifications can preserve functional states across cell divisions and sometimes across generations. Together with familial and population-level IBD persistence and the long-term retention of introgressed haplotypes, these findings demonstrate that inherited molecular architectures can persist across multiple timescales. Evolutionary processes shape this persistence. Purifying selection preferentially removes deleterious inherited variants, whereas positive selection can favor the persistence of functionally relevant genomic architectures. From this perspective, evolutionary dynamics arise not only from the generation of variation, but also from the differential persistence of inherited molecular architectures through selection. Transgenerational continuity therefore provides a conceptual framework in which persistence serves as an explanatory dimension of inheritance and evolution that complements variation and explains the persistence of biological identity across generations and evolutionary time.

Biological identity↗

Phage vB_KpnM_NB cocktail synergizing with amikacin in inhibiting persister cells of Klebsiella pneumoniae.

UNLABELLED: The emergence of multidrug-resistant Klebsiella pneumoniae (KPN) and antibiotic-tolerant persister cells poses a significant challenge to existing anti-infection therapies. Given the urgent need for sustainable alternatives to antibiotics, phage cocktails are emerging as a promising alternative to control K. pneumoniae infections. We isolated three lytic phages vB_KpnM_NB (1-3) from Ningbo environmental samples, classified them into the Drexlerviridae family, and determined the biological characteristics of two representative phages. Genomic analysis confirmed that these phages are closely related and lack resistance and virulence genes, ensuring biosafety. Subsequently, a stable KPN persister model was established using amikacin, with a biphasic killing pattern observed during treatment. At a multiplicity of infection of 10, the phage cocktail eliminated 99.00% of persister cells, while individual phages were less effective. The phage cocktail also inhibited persister-derived biofilm formation, showing improved results when combined with amikacin. This combination significantly reduced capsule polysaccharide production in persisters, weakening the outer membrane barrier. These findings demonstrate that the phage cocktail-amikacin combination effectively targets planktonic cells, persister cells, and biofilms, providing a promising strategy against persisters and recurrent K. pneumoniae infections. IMPORTANCE: This study fills the critical gap in understanding how phage cocktails synergize with amikacin against K. pneumoniae persister cells. By constructing a highly specific phage vB_KpnM_NB cocktail, establishing a stable persister model, and performing in vitro bactericidal and biofilm assays, we demonstrate that the cocktail effectively eliminates planktonic cells, persisters, and biofilms. We clarify the core synergistic mechanism: inhibiting capsular polysaccharide synthesis, improving phage adsorption, and disrupting the bacterial outer membrane barrier. These findings provide experimental evidence for the prevention and control of multidrug-resistant and carbapenem-resistant K. pneumoniae persister infections, establishing a safe and effective phage-antibiotic combination therapy. The results are crucial for addressing antibiotic tolerance and controlling chronic, recurrent infections. They hold significant theoretical and translational value for the treatment of refractory infections in clinical settings and offer new insights into the development of novel antimicrobial strategies.

Klebsiella pneumoniae↗

Persistent pain and well-being: a World Health Organization Study in Primary Care.

CONTEXT: There is little information on the extent of persistent pain across cultures. Even though pain is a common reason for seeking health care, information on the frequency and impacts of persistent pain among primary care patients is inadequate. OBJECTIVE: To assess the prevalence and impact of persistent pain among primary care patients. DESIGN AND SETTING: Survey data were collected from representative samples of primary care patients as part of the World Health Organization Collaborative Study of Psychological Problems in General Health Care, conducted in 15 centers in Asia, Africa, Europe, and the Americas. PARTICIPANTS: Consecutive primary care attendees between the age of majority (typically 18 years) and 65 years were screened (n = 25 916) and stratified random samples interviewed (n = 5438). MAIN OUTCOME MEASURES: Persistent pain, defined as pain present most of the time for a period of 6 months or more during the prior year, and psychological illness were assessed by the Composite International Diagnostic Interview. Disability was assessed by the Groningen Social Disability Schedule and by activity-limitation days in the prior month. RESULTS: Across all 15 centers, 22% of primary care patients reported persistent pain, but there was wide variation in prevalence rates across centers (range, 5.5%-33.0%). Relative to patients without persistent pain, pain sufferers were more likely to have an anxiety or depressive disorder (adjusted odds ratio [OR], 4.14; 95% confidence interval [CI], 3.52-4.86), to experience significant activity limitations (adjusted OR, 1.63; 95% CI, 1.41 -1.89), and to have unfavorable health perceptions (adjusted OR, 1.26; 95% CI, 1.07-1.49). The relationship between psychological disorder and persistent pain was observed in every center, while the relationship between disability and persistent pain was inconsistent across centers. CONCLUSIONS: Persistent pain was a commonly reported health problem among primary care patients and was consistently associated with psychological illness across centers. Large variation in frequency and the inconsistent relationship between persistent pain and disability across centers suggests caution in drawing conclusions about the role of culture in shaping responses to persistent pain when comparisons are based on patient samples drawn from a limited number of health care settings in each culture.

Adult↗

Molecular mechanisms of poliovirus persistence: key role of capsid determinants during the establishment phase.

As viral persistence is of major medical importance, well-characterized, simple models are needed to improve our understanding of persistent infections. We have chosen to study the molecular mechanisms of viral persistence with the poliovirus (PV), because this picornavirus is one of the best characterized animal viruses, it infects the central nervous system which is a target organ for viral persistence, and it belongs to the Picornaviridae family of viruses, which includes several naturally persisting viruses. We have developed models of PV persistence in neuronal and epidermoid cells, and the present review will focus on the latter one because both lytic and persistent PV strains can be used to study the PV-HEp-2 cell interactions. The viral determinants of persistence have been investigated with this model, and PV determinants have proven to be of crucial importance for the establishment of persistence in HEp-2 cells. Precise determinants of PV persistence have been identified for PV serotypes 1 and 3, in capsid proteins VP1 and VP2. These determinants modify the early steps of the PV cycle, and in particular, the conformational modifications of the capsid following virus adsorption onto its receptor. These results permit us to propose several hypotheses concerning PV persistence and the early steps of the PV cycle.

Animals↗

Persister cells and the riddle of biofilm survival.

This review addresses a long-standing puzzle in the life and death of bacterial populations--the existence of a small fraction of essentially invulnerable cells. Bacterial populations produce persisters, cells that neither grow nor die in the presence of bactericidal agents, and thus exhibit multidrug tolerance (MDT). The mechanism of MDT and the nature of persisters, which were discovered in 1944, have remained elusive. Our research has shown that persisters are largely responsible for the recalcitrance of infections caused by bacterial biofilms. The majority of infections in the developed world are caused by biofilms, which sparked a renewed interest in persisters. We developed a method to isolate persister cells, and obtained a gene expression profile of Escherichia coli persisters. The profile indicated an elevated expression of toxin-antitoxin modules and other genes that can block important cellular functions such as translation. Bactericidal antibiotics kill cells by corrupting the target function, such as translation. For example, aminoglycosides interrupt translation, producing toxic peptides. Inhibition of translation leads to a shutdown of other cellular functions as well, preventing antibiotics from corrupting their targets, which will give rise to tolerant persister cells. Overproduction of chromosomally-encoded "toxins" such as RelE, an inhibitor of translation, or HipA, causes a sharp increase in persisters. Deletion of the hipBA module produces a sharp decrease in persisters in both stationary and biofilm cells. HipA is thus the first validated persister/MDT gene. We conclude that the function of "toxins" is the exact opposite of the term, namely, to protect the cell from lethal damage. It appears that stochastic fluctuations in the levels of MDT proteins lead to formation of rare persister cells. Persisters are essentially altruistic cells that forfeit propagation in order to ensure survival of kin cells in the presence of lethal factors.

Anti-Bacterial Agents↗

Comparison of measures of medication persistency using a prescription drug database.

PURPOSE: Studies of medication persistency using drug databases use different definitions of persistency, making it difficult to compare the results from separate studies. We undertook a study of persistency to statins using various definitions to compare the results obtained with the different definitions. METHODS: All patients with an acute myocardial infarction in the province of Quebec between April 1999 and March 2004 who filled a prescription for a statin within 30 days of discharge were identified. The main outcomes were the 1-year rates of persistency defined as (1) the proportion of individuals with a medication possession ratio > or = 80%, (2) the proportion of individuals having filled a prescription in the last 60 days of the year, and (3) the proportion of individuals with continuous exposure after the initial prescription, using a grace period of 7 days or 25% of the duration of the previous prescription between successive prescriptions. Kaplan-Meier analysis was also performed to assess continuous persistency over time using a 7-day grace period. RESULTS: Of the 20,239 patients identified, 1 year persistency to statins ranged from 41% to 90%, depending on the definition used: 85% had a medication possession ratio for statins > or = 80%, 90% filled a prescription in the last 60 days of the year, 41% to 44% had continuous persistency, and, in survival analysis, the probability of continuous persistency was 41%. CONCLUSIONS: Measures of medication persistency yield different results, depending on the definition used to define persistency. Results of studies of persistency should thus be interpreted with caution.

Aged↗

Role of computed tomographic angiography in the detection and comprehensive evaluation of persistent sciatic artery.

PURPOSE: To define the role of computed tomographic (CT) angiography in the evaluation of persistent sciatic artery and to identify its potential advantages as a diagnostic modality. METHODS: Between July 2002 and August 2004, 307 consecutive patients underwent CT angiography for suspected lower-extremity arterial insufficiency. All CT angiograms were retrospectively reviewed to determine the presence and laterality of persistent sciatic artery and its associated vascular abnormalities, such as aneurysm, thrombus, distal thromboembolism, and atherosclerotic change. The relationship of persistent sciatic artery with adjacent structures, such as sciatic nerve, muscle, accompanying vein, and femoral artery, as well as the presence of other anomalies, was analyzed. Clinical data regarding the presenting symptoms and hospital course were obtained from patient charts. RESULTS: Six persistent sciatic arteries, with or without occlusion, were identified in five female patients (age range, 54 to 80 years). CT angiography revealed unilateral persistent sciatic artery in four patients (left, 3; right, 1) and bilateral persistent sciatic artery in one patient. Aneurysm was present in two (mean size, 26 mm x 20 mm), thrombosis in three, and distal thromboembolism in all six persistent sciatic arteries. All persistent sciatic arteries coursed along the sciatic nerve and continued as popliteal artery. Characteristically, in all these instances, the superficial femoral arteries were hypoplastic and tapered smoothly. Anomalous popliteal venous drainage was noted in all ipsilateral limbs with persistent sciatic artery and even in contralateral limbs with normal superficial femoral artery in all but one. CONCLUSION: CT angiography enables the detection of persistent sciatic artery even in the presence of complete occlusion and is useful in the comprehensive evaluation of various complications and associated venous anomalies. It can potentially be used as the sole imaging modality for persistent sciatic artery.

Aged↗

SARS-CoV-2 genomic diversity and within-host evolution in individuals with persistent infection in the UK: an observational, longitudinal, population-based surveillance study.

BACKGROUND: Persistent SARS-CoV-2 infections in hospitalised immunocompromised individuals are known to facilitate accelerated within-host viral evolution, potentially contributing to the emergence of highly divergent variants. However, little is known about the evolutionary dynamics and transmission risks of persistent infections in the general population. We aimed to characterise the within-host evolution of SARS-CoV-2 during persistent infections identified through a large community surveillance study. METHODS: We used data from the Office for National Statistics COVID-19 Infection Survey (ONS-CIS), a large-scale, longitudinal, population-based surveillance study conducted in the UK from April, 2020, to March, 2023. For this analysis, we focused on infections with high viral load (cycle threshold &#x2264;30) and available genome sequences, from seven major SARS-CoV-2 lineages (alpha, delta, BA.1, BA.2, BA.4, BA.5, and XBB). ONS-CIS participants were randomly selected from the general population and tested regularly by RT-PCR, regardless of symptoms. We defined persistent infections as those with sustained or rebounding high viral RNA titres for 26 days or longer. We examined associated host characteristics and used raw sequence data to identify de novo mutations and estimate within-host synonymous and non-synonymous evolutionary rates across the SARS-CoV-2 genome. FINDINGS: Between Nov 2, 2020, and March 21, 2023, we identified 576 persistent infections with at least two sequences, including 11 alpha, 106 delta, 102 BA.1, 204 BA.2, 16 BA.4, 133 BA.5, and 4 XBB. Persistent infections were more common in males than females (p<0&#xb7;0001) and individuals older than 60 years (p=0&#xb7;0027). The median within-host genome-wide evolutionary rate was 7&#xb7;9&#x2009;&#xd7;&#x2009;10-4 substitutions per site per year (IQR 7&#xb7;0-9&#xb7;0&#x2009;&#xd7;&#x2009;10-4), with high inter-individual variability driven largely by non-synonymous mutations, particularly in the N-terminal and receptor-binding domains of the spike protein. Longer infection duration was associated with higher evolutionary rates, while no associations were found with age, sex, vaccination status, previous infection, or virus lineage. We found no clear evidence of transmission beyond the first month of infection in any of the 84 persistent infections lasting 56 days or longer. In total, we identified 379 recurrent mutations, including many with known or predicted negative fitness effects and low prevalence at the population level, as well as de novo reversions to the Wuhan-Hu-1 reference sequence, which were likely under positive selection within those individuals. INTERPRETATION: This study highlights the heterogeneous nature of within-host SARS-CoV-2 evolution in individuals with persistent infection in the community. Notably, a small subset of persistent infections with high viral loads underwent accelerated viral evolution or recurrently acquired hallmark mutations found in novel variants. In addition, onward transmission from a persistent infection during the later stages of infection is likely to be rare. These insights have important implications for prioritising genomic surveillance and managing patients with persistent infections. FUNDING: Department of Health and Social Care.

Humans↗

Determinants of persistence in canine distemper viruses.

Viral persistence in the central nervous system is the driving force behind the chronic progressive disease caused by natural canine distemper virus (CDV) infection in dogs. Persistence of CDV is associated with non-cytolytic spread and impaired viral budding. Since budding is to a large extend dependent on the nucleocapsid-(N) and matrixproteins (M) of the virus, we analyzed the nucleotide- and deduced amino acid sequences of the corresponding genes of a spectrum of CDV strains, that differ with respect to virulence and persistence in vivo and in vitro. The wild type CDV (A75/17), which is capable of causing a persistent infection in vivo was compared to two tissue culture adapted CDV strains (passaged A75/17-CDV and Rockborn-CDV), which CDV strains, that differ with respect to virulence and persistence in vivo and in vitro. The wild type CDV (A75/17), which is capable of causing a persistent infection in vivo was compared to two tissue culture adapted CDV strains (passaged A75/17-CDV and Rockborn-CDV), which retain a residual virulence and the capacity to spontaneously persist in vitro. A modified distemper virus (Snyder Hill-CDV), which is neurovirulent but not capable of causing a persistent infection in vivo, and an avianized virus (Onderstepoort-CDV) which is completely apathogenic and spreads by budding in cell cultures were also examined. Differences were found in the C-terminal of the nucleocapsid protein, which--comparing the two extremes of the spectrum (wild A75/17-CDV and OP-CDV)--lead to changes of the predicted protein structure. Such changes could affect the budding process and thus play a role in persistence. Marked changes in the M-gene were found in its non-coding region: the nucleotide sequences of the SH-CDV and OP-CDV differed considerably from the other three strains. Moreover, an additional second open reading frame was detected in the 'non-coding' region of the M gene in the wild A75-CDV, the two tissue culture adapted CDV strains and SH-CDV, but not in OP-CDV. The presence of this additional open reading frame correlated with the ability to cause a spontaneous persistent infection in vitro. Our findings support the notion that both N- and M-genes of CDV harbor determinants of viral persistence.

Amino Acid Sequence↗

Interleukin-10 production genotype protects against acute persistent rejection after lung transplantation.

BACKGROUND: Our previous studies demonstrated that cytokine gene polymorphisms are related to acute rejection in pediatric heart transplantation; a decreased tumor necrosis factor (TNF)-alpha production genotype combined with an increased or intermediate interleukin (IL)-10 production genotype was associated with the smallest incidence of acute rejection. The objective of this study was to determine whether cytokine genotypes TNF-alpha, IL-10, IL-6, interferon-gamma, and transforming growth factor beta were associated with acute persistent rejection after lung transplantation. METHODS: Cytokine genotyping was performed in 119 adult lung transplantation recipients who underwent surveillance transbronchial biopsies during their first year after transplantation. We categorized recipients with acute persistent rejection if they had 2 consecutive biopsy specimens at >/=Grade A2 despite anti-rejection treatment. We performed cytokine genotyping using the polymerase chain reaction-sequence specific primers technique, with a commercially available kit. RESULTS: We analyzed the IL-10 genotype in 116 patients. For the increased IL-10 production genotype, 7 of 20 patients (35%) were persistent rejecters. In comparison, 57 of 96 patients (59%) with intermediate or decreased IL-10 production genotype had acute persistent rejection (p = 0.046). For IL-10 haplotypes associated with intermediate IL-10 production, 30 of 45 patients with GCC/ACC haplotype (67%) had acute persistent rejection compared with 10 of 22 patients with GCC/ATA (45%). In the patients with intermediate IL-10 production, 17 of 22 (77%) with IL-10 GCC/ACC and IL-6 G/C had acute persistent rejection, whereas only 2 of 7 patients (29%) with IL-10 GCC/ATA and IL-6 G/G had acute persistent rejection (p = 0.018). CONCLUSIONS: In lung transplant recipients, the increased IL-10 production genotype protects against acute persistent rejection when compared with the intermediate or decreased IL-10 production genotypes. The intermediate IL-10 production genotype in lung transplant recipients can be differentiated into 2 haplotype responses, with the GCC/ACC haplotype associated more with acute persistent rejection. In lung transplant recipients, the immunomodulatory effects of IL-6 are differentiated in the G/C and G/G alleles in conjunction with IL-10 haplotypes, with G/C being associated with more acute persistent rejection in conjunction with the IL-10 GCC/ACC haplotype. Future pharmacogenomic models may incorporate these associations with acute persistent rejection in lung transplant recipients to formulate individualized therapeutic regimens.

Acute Disease↗

Persistence of cigarette smoking: familial liability and the role of nicotine dependence.

AIMS: It has been suggested that high genetic vulnerability may explain why smoking persists in spite of general acceptance of the health risks of cigarette smoking. Indeed, heritability estimates for smoking persistence range from 27% to 70%. It has also been suggested that genetic influences on smoking persistence may operate through nicotine dependence, which epidemiological studies have found to be an important risk factor for smoking persistence. We examined alternative ways that familial liability to persistence, nicotine dependence and smoking persistence may be related. DESIGN: Cohort study. SETTING: South-east Michigan, United States. PARTICIPANTS: A subset of 389 daily smokers informative for familial smoking characteristics from an epidemiological sample of young adults 26-35 years old (n = 979). MEASUREMENTS: Nicotine dependence criteria were assessed using the NIMH-DIS revised interview and diagnosed according to the DSM-III-R. Familial smoking characteristics were assessed by subject report. FINDINGS: Absent nicotine dependence, daily smokers with medium and high familial density of persistence were at increased risk of smoking persistence (OR = 4.2 and 7.0, respectively). However, familial density of persistence was not associated with smoking persistence among nicotine dependent daily smokers. Level of education also appeared to limit the influence of familial liability, although nicotine dependence also modified this effect. CONCLUSIONS: Nicotine dependence does not appear to be in the causal pathway from familial liability to smoking persistence, but rather modifies the association between them.

Adult↗

Characterisation of persistent and sporadic Listeria monocytogenes strains by pulsed-field gel electrophoresis (PFGE) and amplified fragment length polymorphism (AFLP).

This study was set up to evaluate the genetic similarity or dissimilarity of persistent and sporadic Listeria monocytogenes strains existing in eleven food processing facilities, including fish, dairy, meat and poultry processing plants. In each plant persistent and sporadic strains were selected on the basis of PFGE typing results. A total of 17 strains representing persistent strains and 38 sporadic strains originating from eleven food processing plants were included in the study. PFGE macrorestriction patterns of persistent and sporadic strains from different processing plants were compared and the strains were further studied by amplified fragment length polymorphism (AFLP), being a characterisation method giving more whole genome based information. The 17 persistent and 38 sporadic strains showed 14 and 35 pulsotypes, 14 and 28 AFLP types, respectively. The combination of PFGE and AFLP typing results yielded a total of 48 genotypes. Thirteen of 15 genotypes presented by persistent strains were only associated with persistent strains and similarly 94% (33/35) of genotypes showed by sporadic strains were recovered among sporadic strains only. Our results showed that L. monocytogenes strains causing persistent contamination differ from sporadic strains. In AFLP analysis persistent strains did not, however, form any specific clusters and neither was there any difference between the known two genomic groups. These results indicate that even though persistent strains differ from sporadic strains there seems not to be any specific evolutional lineage of persistent strains.

Bacterial Typing Techniques↗

Predicting persistent neck pain: a 1-year follow-up of a population cohort.

STUDY DESIGN: A population cohort study to determine the 1-year persistence of neck pain. OBJECTIVES: The aim of this study was to determine the persistence of neck pain over a 12-month period among the general adult population and to explore socio-demographic, health-related, occupational, physical, and lifestyle factors that might be linked to such persistence. SUMMARY OF BACKGROUND DATA: Musculoskeletal clinicians report that neck patients frequently return to consult for recurring episodes of pain. However, the persistent nature of neck pain has been less researched than other common chronic pain syndromes. METHODS: First, to identify a cohort of current neck pain sufferers, a baseline cross-sectional survey was conducted in a general population of 7,669 adults, 18 to 75 years of age, registered with two primary care practices in South Manchester, UK. The second phase was a follow-up survey, 12 months later, to determine the 1-year persistence of neck pain among those who had reported neck pain at baseline. Persistence of neck pain was compared across groups of responders stratified by potential prognostic factors measured at baseline. "Persistent" neck pain was defined according to shading within the region of the neck on a blank body mannequin. The term "persistent" neck pain could therefore reflect chronic, recurrent, or continuous pain. RESULTS: There were 1,359 neck pain responders in the baseline survey, and these subjects formed the study population for the prospective study. At follow-up, 786 (58%) subjects responded, of whom 48% reported having neck pain lasting for more than 1 day, during the previous month. Significant baseline characteristics, which independently predicted persistent neck pain, were age (odds ratio [OR] = 3.4), being off work at the time of the baseline survey (OR = 1.6), comorbid low back pain (OR = 1.6), and cycling as a regular activity (OR = 2.4). CONCLUSION: Among the general population, neck pain persists at 12 months in around half of those who report neck pain at the start of the period. An increased risk of persistent neck pain was associated with age 45 to 59 years and low back pain, and also with cycling. The link with psychological distress and the absence of a link with occupational factors compares with other previous findings for common musculoskeletal syndromes in the community.

Adolescent↗

Specialized persister cells and the mechanism of multidrug tolerance in Escherichia coli.

Bacterial populations produce persisters, cells that neither grow nor die in the presence of bactericidal agents, and thus exhibit multidrug tolerance (MDT). The mechanisms of MDT and the nature of persisters have remained elusive. Our previous research has shown that persisters are largely responsible for the recalcitrance of biofilm infections. A general method for isolating persisters was developed, based on lysis of regular cells by ampicillin. A gene expression profile of persisters contained toxin-antitoxin (TA) modules and other genes that can block important cellular functions such as translation. Bactericidal antibiotics kill cells by corrupting the target function (for example, aminoglycosides interrupt translation, producing toxic peptides). We reasoned that inhibition of translation will lead to a shutdown of cellular functions, preventing antibiotics from corrupting their targets, giving rise to MDT persister cells. Overproduction of the RelE toxin, an inhibitor of translation, caused a sharp increase in persisters. Functional expression of a putative HipA toxin also increased persisters, while deletion of the hipBA module caused a sharp decrease in persisters in both stationary and biofilm populations. HipA is thus the first validated persister-MDT gene. We suggest that random fluctuation in the levels of MDT proteins leads to the formation of rare persister cells. The function of these specialized dormant cells is to ensure the survival of the population in the presence of lethal factors.

Anti-Bacterial Agents↗

Persistent bisphosphonate use and the risk of osteoporotic fractures in clinical practice: a database analysis study.

INTRODUCTION: International guidelines on the treatment and prevention of osteoporosis recommend the use of bisphosphonates to prevent fractures in this population. However, low persistent use of bisphosphonates could considerably limit the prevention of fractures in clinical practice. OBJECTIVE: This study aimed to investigate the association between persistent use of bisphosphonates and the risk of osteoporotic fractures in clinical practice. METHODS: Data were obtained from the PHARMO Record Linkage System, which includes, among other databases, drug-dispensing records from community pharmacies linked to hospital discharge records of more than two million subjects in defined areas in the Netherlands. Persistence with bisphosphonate therapy was assessed during a period of 3 years. A nested matched case control study (cases:controls = 1:10) was performed to study the association between persistent bisphosphonate use and hospitalisation for osteoporotic fractures and analysed by conditional logistic regression analysis. The analyses were adjusted for patient characteristics such as previous hospitalisations for fractures, co-morbidity and co-medication. RESULTS: 14,760 new female users of bisphosphonates were identified of which 541 women had a hospitalisation for osteoporotic fracture after start of bisphosphonate treatment (1-3 years follow-up). One-year persistence rates increased from 33% with alendronate daily to 48% with alendronate weekly, an increase of 15%. Similar results were obtained with risedronate daily and weekly. One year persistent use of bisphosphonates resulted in a statistical significant 26% lower fracture rate (OR 0.74; 95%CI 0.57-0.95) whereas 2 year persistent use resulted in a 32% lower rate (OR 0.68; 95%CI 0.47-0.96). CONCLUSIONS: Persistent use of bisphosphonates decreases the risk of osteoporotic fractures in clinical practice. Approximately 6% of fractures among users of bisphosphonates could be prevented if persistence was improved by 20%. However, current persistence with bisphosphonate therapy is suboptimal and strategies that further increase persistence are likely to further prevent the number of fractures.

Aged↗

Medication persistence with weekly versus daily doses of orally administered bisphosphonates.

OBJECTIVE: To compare medication persistence among patients receiving daily orally administered bisphosphonates with persistence among patients receiving weekly orally administered bisphosphonates to ascertain whether less frequent dosing is associated with better long-term treatment persistence. METHODS: A large, longitudinal cohort of female patients (N = 211,319) receiving prescriptions for alendronate or risedronate from approximately 14,000 US retail pharmacies was assessed. Medication persistence was defined as the percentage of patients who continued to take bisphosphonate therapy during each month (that is, having at least 1 day of medication supply in that month) for a 1-year observation period. RESULTS: The inconvenience and complexity of required dosing procedures with oral bisphosphonate therapy for the prevention and treatment of osteoporosis are thought to be major factors that hinder medication persistence, and poor persistence is associated with suboptimal health-care outcomes. In this study, the percentage of patients continuing to take bisphosphonate therapy steadily declined with both daily and weekly oral treatment regimens during the course of the 12-month observation period. Consistently, however, medication persistence was higher among patients receiving the weekly rather than the daily regimen. Only 56.7% of patients receiving the weekly regimen and only 39.0% of patients receiving the daily regimen continued to take bisphosphonate therapy at month 12 of the study period (P<0.0001). CONCLUSION: This study demonstrates that weekly dosing of orally administered bisphosphonates is associated with higher medication persistence than is daily dosing. Nevertheless, more than 40% of patients did not persist with weekly bisphosphonate therapy for at least 12 months. Thus, medication persistence was inadequate even with use of the weekly regimen. Additional research is needed to determine whether persistence can be further improved by extending the dosing interval beyond once weekly.

Administration, Oral↗

Persistence with hypertension treatment among community-dwelling BC seniors.

BACKGROUND: Previous research has documented low levels of persistence with prescribed hypertension treatment in Canada. With growing recognition of the value of appropriate drug therapy, rates of persistence may be improving over time. The purpose of this study was to examine persistence with prescribed hypertension treatment among newly treated community-dwelling seniors in British Columbia. METHODS: BC PharmaCare data was used to determine the cohort of seniors who were newly-treated hypertensives over the period 1993 to 2000. Medical and hospital claims from the BCLHD were searched for diagnoses indicating the presence of essential hypertension and potentially confounding conditions. Rates of persistence with drug therapy were analysed, accounting for patient, age, sex, clinical complexity, the existence of potentially confounding conditions, and type of drug first prescribed. RESULTS: For the period 1993 to 2000, 82,824 seniors were identified as new users of hypertension drugs with diagnosed essential hypertension. Fifty-one percent of these newly-treated hypertensives filled a contiguous series of hypertension prescriptions for at least one full year. There was a slight improvement in the rate of persistence over time (p<0.001). Evidence of specific co-morbidities that potentially complicate essential hypertension increased the likelihood of persistence among first-time users (p<0.001), whereas greater overall clinical complexity decreased the likelihood of persistence (p<0.001). Persistence was highest amongst patients initiated on newer anti-hypertensive drug therapies. CONCLUSIONS: Despite modest improvement, persistence with hypertension treatment among the elderly is very low. Further research into the reasons for non-persistence would be advanced through primary data collection, including survey-based research. New policies and practices are needed to encourage persistence with evidence-based therapies.

Aged↗

Duration of virus persistence and its relationship to inflammation in the chronic phase of coxsackievirus B1-induced murine polymyositis.

Mice infected with the Tucson strain of coxsackievirus B1 (CVB1T) develop chronic T cell-mediated polymyositis that is manifest as the acute infection resolves and is characterized by hindquarter weakness and muscle inflammation. This model system was used to study persistence of CVB1T RNA by using reverse transcriptase-polymerase chain reaction (RT-PCR). For the most part, RNA persistence reflected the myotropic and neurotropic nature of the virus. At 1 month after infection, infectious virus was not detected in muscle, but persistent viral RNA was found in both skeletal and cardiac muscle, brain, and spinal cord. The kidney was weakly positive for viral RNA, whereas the liver and spleen were negative. Hindquarter muscle was assayed for persistent viral RNA at 1, 3, 6, 9, and 12 months after infection. In a few cases, persistent viral RNA was detected as late as 12 months after infection. The incidence of persistent viral RNA was high at 1 month after infection and gradually declined until, at 6 months and beyond, it was maintained in 3% to 12% of the muscles tested. Long-term viral RNA persistence was not more common in severely weak animals. However, the degree of hindquarter weakness that developed by 1 month was static thereafter and did not change over the 12-month study period. In contrast, separate experiments revealed that typical mononuclear cell (MNC) infiltration of muscle followed a time course similar to that of viral RNA persistence, peaking at 1 month and gradually resolving by 6 months. Infiltrating polymorphonuclear leukocytes (PMNs) and mast cells were present at 3 to 12 months after infection, signifying that some inflammatory activity remained. Other signs of myopathy that persisted for 12 months included a lack of muscle regeneration, variations in fiber size, and myofiber atrophy with increased perimysial and endomysial connective tissue. These results demonstrate that coxsackievirus RNA can persist in muscle for extended periods of time and are compatible with the idea that persistent virus is involved in maintaining the chronic MNC inflammation observed in murine polymyositis.

Animals↗