The prevalence of the failure of fixed orthodontic bonded retainers: a systematic review and meta-analysis.

OBJECTIVES: To systematically assess the scientific literature for the prevalence of failure rate of fixed orthodontic bonded retainer (FOBR). METHOD: Randomized clinical trials (RCTs) and prospective non-RCTs involving participants who had FOBR fitted were included. The Cochrane Central Register of Controlled Trials, Web of science, MEDLINE, and EMBASE via OVID were searched from inception to January 2023. Risk of bias was assessed using the Cochrane RoB 2 and Newcastle-Ottawa tools. The main outcome was the failure rate of FOBRs. The secondary outcome was to identify factors that can influence the failure of FOBR. Meta-analyses and sensitivity analyses were undertaken using Revman, version5.4. A random-effects model was used. Quality assessment using Grading of Recommendations Assessment, Development, and Evaluation. RESULTS: Thirty-four studies (25 RCTs and 9 prospective clinical studies) (3484 participants) were included in this review. The overall failure rate of bonded retainers, after excluding high-risk studies, was 35.22% (95% confidence interval [CI] 27.46-42.98). The failure rate is increased with the duration of follow up; with short-term follow-up rate 24.18% (95% CI 20.16-28.21), medium-term follow up 40.09% (95% CI 30.92-49.26), and long-term follow up 53.85% (95% CI 40.31-67.39). There is a low level of evidence to suggest there is no statistically significant difference in the failure rate of fixed retainers using direct versus indirect bonding methods, using liquid resin versus without liquid resin, and fibre-reinforced composite retainers compared to multi-stranded stainless steel retainers. DISCUSSION: There is low-quality evidence to suggest that the failure rate of FOBR is relatively high. There is a need for high-quality, well-reported clinical studies to assess factors that can influence the failure rate of FOBR. REGISTRATION: CRD42021190910.

Purification and Characterization of Human DNA Ligase IIIα Complexes After Expression in Insect Cells.

With improvements in biophysical approaches, there is growing interest in characterizing large, flexible multi-protein complexes. The use of recombinant baculoviruses to express heterologous genes in cultured insect cells has advantages for the expression of human protein complexes because of the ease of co-expressing multiple proteins in insect cells and the presence of a conserved post-translational machinery that introduces many of the same modifications found in human cells. Here we describe the preparation of recombinant baculoviruses expressing DNA ligase IIIα, XRCC1, and TDP1, their subsequent co-expression in cultured insect cells, the purification of complexes containing DNA ligase IIIα from insect cell lysates, and their characterization by multi-angle light scattering linked to size exclusion chromatography and negative stain electron microscopy.

Residual malaria among migrant workers in Myanmar: why still persistent and how to eliminate it?

BACKGROUND: Residual malaria is probably an important source for the re-emergence of malaria infection in the elimination era. Assessment to identify the factors influencing residual malaria in high-risk groups is needed to develop evidence-based decisions by stakeholders and policymakers. METHODS: This study was conducted to explore the factors influencing the residual malaria infection among migrant workers in two sentinel sites (endemic vs. pre-elimination areas) in Myanmar using the mixed-model method. RESULTS: A total of 102 migrant respondents (65 in Bamauk and 37 in Shwegyin) were included for the quantitative assessment using pretested questionnaires during household visits. Although 87.3% of them had insecticidal bed nets (ITNs/LLINs), only 68.3% of the migrants in Bamauk and 57.9% in Shwegyin used it regularly. The use of any bed net was high (79.9% in Bamauk vs. 91.0% in Shwegyin). The mean LLINs in their families were 1.64 (95%CI: 1.48-1.81) in Bamauk and 2.89 (95%CI: 2.67-3.11) in Shwegyin. Most of them received no health information for malaria prevention within the last year and their knowledge about malaria was low. Their working nature was a challenge for control measures against malaria in migrants. CONCLUSION: The strategy for distributing LLINs and health promotion activities for mobile/migrant populations should be reviewed, and an appropriate action plan should be developed for the specific migrant group. Moreover, health promotion activities for behavior change communication should be strengthened in the migrant population in Myanmar.

Measurement properties of all versions of the Stroke Specific Quality of Life Scale (SS-QOL) 2.0: a systematic review protocol.

OBJECTIVE: The aim of this review is to critically appraise and summarize the quality of the measurement properties of all versions of the Stroke Specific Quality of Life Scale (SS-QOL) version 2.0. INTRODUCTION: The Stroke Specific Quality of Life Scale version 2.0 was developed as a comprehensive measure in assessing the quality of life of stroke survivors. The shortened version and cross-culturally translated versions are further developed in different countries. A systematic review will clarify the levels of reliability and validity of all versions. INCLUSION CRITERIA: The population of interest for this review will include adult stroke survivors of either sex diagnosed with a stroke (ischemic or hemorrhagic) who have no other comorbidities affecting their quality of life. The SS-QOL version 2.0 will be the specific instrument of interest, and the quality of life of stroke survivors will be the construct of interest in this review. The measures of reliability, validity, and responsiveness will be assessed as outcomes. Only the studies evaluating the reliability, validity, and responsiveness of all versions of the SS-QOL 2.0 will be included in the review. METHODS: A literature search will be conducted for published studies in MEDLINE and Embase, and unpublished data in Google Scholar and ProQuest Dissertations and Theses. After a three-step search strategy, study selection will be done by two reviewers independently. Then, the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) methodology will be applied for assessment of methodological quality, data extraction, and synthesis. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42020211727.

Pyrazinamide resistance and pncA mutations in drug resistant Mycobacterium tuberculosis clinical isolates from Myanmar.

Pyrazinamide (PZA) is an important anti-tuberculosis drug, which is active against semi-dormant bacilli and used as a component of first-line drugs and drug-resistant tuberculosis regimens. Mutations in pncA and its promoter region are main cause of PZA resistance. There are limited PZA susceptibility data as there is no routine drug susceptibility testing (DST) for PZA. This study was aimed to determine the proportion of PZA resistance among rifampicin-resistant tuberculosis patients and to identify mutations which are responsible for PZA resistance in pncA and its promoter region. Liquid-based DST was performed to detect PZA susceptibility on 192 culture positive rifampicin-resistant isolates collected from National Tuberculosis Reference Laboratory. Sequencing on pncA including its promoter region was performed and analysis was done on 157 isolates. Phenotypic PZA resistance was detected in 58.9% of isolates. Sixty-five different mutations were distributed in pncA or promoter region of 82 isolates. Sensitivity and specificity of pncA sequencing in detection of PZA resistance showed 89.8% and 95.6% respectively. High proportion of PZA resistance among rifampicin-resistant cases highlighted the need for effective treatment regimen development for PZA-resistant MDR-TB. It is also suggested that routine PZA susceptibility test should be incorporated to treatment monitoring regimen and National Drug Resistance surveys.

Treatment of infections caused by Gram-negative pathogens: current status on the pharmacokinetics/pharmacodynamics of parenteral and inhaled polymyxins in patients.

Polymyxins are increasingly used as a last resort for the treatment of infections caused by multidrug-resistant Gram-negative bacteria in patients. Over the last decade, significant progress has been made in understanding the pharmacokinetics/pharmacodynamics/toxicodynamics (PK/PD/TD) of parenteral and inhaled polymyxins. This mini-review provides an overview of polymyxin chemistry, different dose definitions, and the latest research on their clinical use, toxicities, and PK/PD after intravenous and inhalation administration. Optimising the PK/PD/TD of polymyxins in patients is critical to maximise their efficacy while minimising toxicities and the emergence of resistance.

Lipid A profiling and metabolomics analysis of paired polymyxin-susceptible and -resistant MDR Klebsiella pneumoniae clinical isolates from the same patients before and after colistin treatment.

BACKGROUND: The increased incidence of polymyxin-resistant MDR Klebsiella pneumoniae has become a major global health concern. OBJECTIVES: To characterize the lipid A profiles and metabolome differences between paired polymyxin-susceptible and -resistant MDR K. pneumoniae clinical isolates. METHODS: Three pairs of K. pneumoniae clinical isolates from the same patients were examined [ATH 7 (polymyxin B MIC 0.25 mg/L) versus ATH 8 (64 mg/L); ATH 15 (0.5 mg/L) versus ATH 16 (32 mg/L); and ATH 17 (0.5 mg/L) versus ATH 18 (64 mg/L)]. Lipid A and metabolomes were analysed using LC-MS and bioinformatic analysis was conducted. RESULTS: The predominant species of lipid A in all three paired isolates were hexa-acylated and 4-amino-4-deoxy-l-arabinose-modified lipid A species were detected in the three polymyxin-resistant isolates. Significant metabolic differences were evident between the paired isolates. Compared with their corresponding polymyxin-susceptible isolates, the levels of metabolites in amino sugar metabolism (UDP-N-acetyl-α-d-glucosamine and UDP-N-α-acetyl-d-mannosaminuronate) and central carbon metabolism (e.g. pentose phosphate pathway and tricarboxylic acid cycle) were significantly reduced in all polymyxin-resistant isolates [fold change (FC) > 1.5, P < 0.05]. Similarly, nucleotides, amino acids and key metabolites in glycerophospholipid metabolism, namely sn-glycerol-3-phosphate and sn-glycero-3-phosphoethanolamine, were significantly reduced across all polymyxin-resistant isolates (FC > 1.5, P < 0.05) compared with polymyxin-susceptible isolates. However, higher glycerophospholipid levels were evident in polymyxin-resistant ATH 8 and ATH 16 (FC > 1.5, P < 0.05) compared with their corresponding susceptible isolates. CONCLUSIONS: To our knowledge, this study is the first to reveal significant metabolic perturbations associated with polymyxin resistance in K. pneumoniae.

Pan-transcriptomic analysis identified common differentially expressed genes of Acinetobacter baumannii in response to polymyxin treatments.

Multidrug-resistant Acinetobacter baumannii is a top-priority Gram-negative pathogen and polymyxins are a last-line therapeutic option. Previous systems pharmacological studies examining polymyxin killing and resistance usually focused on individual strains, and the derived knowledge could be limited by strain-specific genomic context. In this study, we examined the gene expression of five A. baumannii strains (34654, 1207552, 1428368, 1457504 and ATCC 19606) to determine the common differentially expressed genes in response to polymyxin treatments. A pan-genome containing 6061 genes was identified for 89 A. baumannii genomes from RefSeq database which included the five strains examined in this study; 2822 of the 6061 genes constituted the core genome. After 2 mg L-1 or 0.75 × MIC polymyxin treatments for 15 min, 41 genes were commonly up-regulated, including those involved in membrane biogenesis and homeostasis, lipoprotein and phospholipid trafficking, efflux pump and poly-N-acetylglucosamine biosynthesis; six genes were commonly down-regulated, three of which were related to fatty acid biosynthesis. Additionally, comparison of the gene expression at 15 and 60 min in ATCC 19606 revealed that polymyxin treatment resulted in a rapid change in amino acid metabolism at 15 min and perturbations on envelope biogenesis at both time points. This is the first pan-transcriptomic study for polymyxin-treated A. baumannii and our results identified that the remodelled outer membrane, up-regulated efflux pumps and down-regulated fatty acid biosynthesis might be essential for early responses to polymyxins in A. baumannii. Our findings provide important mechanistic insights into bacterial responses to polymyxin killing and may facilitate the optimisation of polymyxin therapy against this problematic 'superbug'.

Polymyxin Triple Combinations against Polymyxin-Resistant, Multidrug-Resistant, KPC-Producing Klebsiella pneumoniae.

Resistance to polymyxin antibiotics is increasing. Without new antibiotic classes, combination therapy is often required. We systematically investigated bacterial killing with polymyxin-based combinations against multidrug-resistant (including polymyxin-resistant), carbapenemase-producing Klebsiella pneumoniae Monotherapies and double- and triple-combination therapies were compared to identify the most efficacious treatment using static time-kill studies (24 h, six isolates), an in vitro pharmacokinetic/pharmacodynamic model (IVM; 48 h, two isolates), and the mouse thigh infection model (24 h, six isolates). In static time-kill studies, all monotherapies (polymyxin B, rifampin, amikacin, meropenem, or minocycline) were ineffective. Initial bacterial killing was enhanced with various polymyxin B-containing double combinations; however, substantial regrowth occurred in most cases by 24 h. Most polymyxin B-containing triple combinations provided greater and more sustained killing than double combinations. Standard dosage regimens of polymyxin B (2.5 mg/kg of body weight/day), rifampin (600 mg every 12 h), and amikacin (7.5 mg/kg every 12 h) were simulated in the IVM. Against isolate ATH 16, no viable bacteria were detected across 5 to 25 h with triple therapy, with regrowth to ∼2-log10 CFU/ml occurring at 48 h. Against isolate BD 32, rapid initial killing of ∼3.5-log10 CFU/ml at 5 h was followed by a slow decline to ∼2-log10 CFU/ml at 48 h. In infected mice, polymyxin B monotherapy (60 mg/kg/day) generally was ineffective. With triple therapy (polymyxin B at 60 mg/kg/day, rifampin at 120 mg/kg/day, and amikacin at 300 mg/kg/day), at 24 h there was an ∼1.7-log10 CFU/thigh reduction compared to the starting inoculum for all six isolates. Our results demonstrate that the polymyxin B-rifampin-amikacin combination significantly enhanced in vitro and in vivo bacterial killing, providing important information for the optimization of polymyxin-based combinations in patients.

Experiences of family caregivers caring for critically ill children hospitalized in a pediatric intensive care unit: a qualitative systematic review protocol.

REVIEW OBJECTIVE: This review aims to synthesize the best available evidence on the experiences of family caregivers in caring for their critically ill children who have been hospitalized in a pediatric intensive care unit. INTRODUCTION: The participation of family caregivers in providing health care for critically ill children is increasingly important. Family caregivers are defined as adult family members, including parents and siblings, and are often described as hidden patients, as their health can be neglected when caring for others. Understanding how family caregivers of critically ill children describe their experience will be beneficial in providing family-centered care to these children. INCLUSION CRITERIA: This review will consider studies that include adult family caregivers caring for children hospitalized with critical illness in pediatric intensive care units. Any family with a child experiencing a life-threatening illness that may result in significant morbidity or mortality will be considered. Studies that disclose the physical, psychosocial, financial and spiritual experiences of family caregivers will be considered with no geographical limitation. Only English-language studies will be included, with no date limitation. METHOD: MEDLINE, CINAHL, PsycINFO, Embase, ProQuest Dissertations and Theses, Scopus, ASSIA, SciELO, and Google Scholar will be searched for relevant papers following the completion of the three-step search process. Retrieval of full-text studies, assessment of methodological quality and data extraction will be performed independently by two reviewers. Meta-aggregation will be performed, and a ConQual presented.

Multifaceted mechanisms of colistin resistance revealed by genomic analysis of multidrug-resistant Klebsiella pneumoniae isolates from individual patients before and after colistin treatment.

OBJECTIVES: Polymyxins (i.e., polymyxin B and colistin) are used as a last-line therapy to combat multidrug-resistant (MDR) Klebsiella pneumoniae. Worryingly, polymyxin resistance in K. pneumoniae is increasingly reported worldwide. This study identified the genetic variations responsible for high-level colistin resistance in MDR K. pneumoniae clinical isolates. METHODS: Sixteen MDR K. pneumoniae isolates were obtained from stool samples of 8 patients before and after colistin treatment. Their genomes were sequenced on Illumina MiSeq to determine genetic variations. RESULTS: Fifteen of 16 isolates harboured ISKpn26-like element insertion at nucleotide position 75 of mgrB, abolishing its negative regulation on phoPQ; while colistin-susceptible ATH7 contained intact mgrB and phoQ. Interestingly, each of the 7 mgrB-disrupted, colistin-susceptible isolates contained a nonsynonymous substitution in PhoQ (G39S, L239P, N253T or V446G), potentially impairing its function and intergenically suppressing the effect caused by mgrB inactivation. Additionally, three of the 7 corresponding mgrB-disrupted, colistin-resistant isolates harboured a secondary nonsynonymous substitution in PhoQ (N253P, D438H or T439P). CONCLUSIONS: This is the first report of phoQ mutations in mgrB-disrupted, colistin-susceptible K. pneumoniae clinical isolates. We also discovered multiple phoQ mutations in mgrB-disrupted, colistin-resistant strains. Our findings highlight the multifaceted molecular mechanisms of colistin resistance in K. pneumoniae.

A Study of Burkholderia pseudomallei in the Environment of Farms in Thanlyin and Hmawbi Townships, Myanmar.

Melioidosis is a tropical infection, first described in Myanmar but now rarely diagnosed there, which is widespread in Southeast Asia. The infection is predominantly acquired by people and animals through contact with soil or water. This study aimed to detect the causative organism, Burkholderia pseudomallei, in environmental samples from farms in Thanlyin and Hmawbi townships near Yangon, Myanmar. One hundred and twenty soil samples and 12 water samples were collected and processed using standard microbiological methods. Burkholderia species were isolated from 50 of the 120 (42%) soil samples but none of the water samples. Arabinose assimilation was tested to differentiate between B. pseudomallei and the nonpathogenic Burkholderia thailandensis, and seven of 50 isolates (14%) were negative. These were all confirmed as B. pseudomallei by a species-specific multiplex polymerase chain reaction (PCR). This is the first study to detect environmental B. pseudomallei in Myanmar and confirms that melioidosis is still endemic in the Yangon area.

Development of an 'Enteral tube feeding decision support tool' for hip fracture patients: A modified Delphi approach.

OBJECTIVES: Malnutrition after hip fracture is recognised as the co-morbidity most likely to impact hospital length of stay and cost. Despite this, the role of enteral tube feeding in hip fracture patients remains unclear. METHODS: A modified Delphi process was used to establish consensus for an enteral tube feeding decision support tool. Three rounds of the Delphi survey were administered to a purposeful sample of twenty multidisciplinary clinicians from the Australian and New Zealand Hip Fracture Registry. RESULTS: Consensus markedly improved across the three rounds (33, 44 and 87%, respectively). More than 80% of participants positively supported implementing the tool in clinical practice. CONCLUSIONS: This study describes experienced, multidisciplinary clinician consensus and support for an 'Enteral tube feeding decision support tool' to be applied in acute hip fracture settings. Further studies are being undertaken to identify the impact of the checklist tool on informed consent decision processes in this population.

Regulation of FANCD2 and FANCI monoubiquitination by their interaction and by DNA.

FANCD2 and FANCI function together in the Fanconi anemia network of deoxyribonucleic acid (DNA) crosslink repair. These proteins form the dimeric ID2 complex that binds DNA and becomes monoubiquitinated upon exposure of cells to DNA crosslinking agents. The monoubiquitinated ID2 complex is thought to facilitate DNA repair via recruitment of specific nucleases, translesion DNA polymerases and the homologous recombination machinery. Using the ubiquitin conjugating enzyme (E2) UBE2T and ubiquitin ligase (E3) FANCL, monoubiquitination of human FANCD2 and FANCI was examined. The ID2 complex is a poor substrate for monoubiquitination, consistent with the published crystal structure showing the solvent inaccessibility of the target lysines. Importantly, FANCD2 monoubiquitination within the ID2 complex is strongly stimulated by duplex or branched DNA, but unstructured single-stranded DNA or chromatinized DNA is ineffective. Interaction of FANCL with the ID2 complex is indispensable for its E3 ligase efficacy. Interestingly, mutations in FANCI that impair its DNA binding activity compromise DNA-stimulated FANCD2 monoubiquitination. Moreover, we demonstrate that in the absence of FANCD2, DNA also stimulates FANCI monoubiquitination, but in a FANCL-independent manner. These results implicate the role of a proper DNA ligand in FANCD2 and FANCI monoubiquitination, and reveal regulatory mechanisms that are dependent on protein-protein and protein-DNA interactions.

Xeroderma pigmentosum complementation group C protein (XPC) serves as a general sensor of damaged DNA.

The Xeroderma pigmentosum complementation group C protein (XPC) serves as the primary initiating factor in the global genome nucleotide excision repair pathway (GG-NER). Recent reports suggest XPC also stimulates repair of oxidative lesions by base excision repair. However, whether XPC distinguishes among various types of DNA lesions remains unclear. Although the DNA binding properties of XPC have been studied by several groups, there is a lack of consensus over whether XPC discriminates between DNA damaged by lesions associated with NER activity versus those that are not. In this study we report a high-throughput fluorescence anisotropy assay used to measure the DNA binding affinity of XPC for a panel of DNA substrates containing a range of chemical lesions in a common sequence. Our results demonstrate that while XPC displays a preference for binding damaged DNA, the identity of the lesion has little effect on the binding affinity of XPC. Moreover, XPC was equally capable of binding to DNA substrates containing lesions not repaired by GG-NER. Our results suggest XPC may act as a general sensor of damaged DNA that is capable of recognizing DNA containing lesions not repaired by NER.