Risk factors for Helicobacter pylori infection in children with gastrointestinal symptoms in Vietnam.

Objectives: To investigate the prevalence and risk factors associated with Helicobacter pylori infection in Vietnamese children. Methods: Children under 16 years old with gastrointestinal symptoms underwent esophagogastroduodenoscopy and H. pylori infection was diagnosed using rapid urease test. Results: A total of 246 children with gastrointestinal symptoms were included. The mean age was 8.4 ± 2.6 years. A total 81.3% tested positive for H. pylori. Children infected with H. pylori had a lower rate of nausea but a higher rate of lesions in the duodenal bulb and nodular lesions than children without H. pylori infection (26.5% vs 45.6%, P <0.01; 40.0% vs 23.9%; P = 0.04; and 68.5% vs 30.3%, P <0.0001, respectively). Compared with children aged under 5 years, children aged 11 years and older were four times more likely to be infected with H. pylori, with odds ratio (OR) 3.50, 95% confidence interval (CI) 1.07-11.39, P = 0.04. Washing hands with soap was associated with a reduced risk of H. pylori infection by three times (OR 0.35, 95% CI 0.17-0.69, P = 0.002). Children living in a family where members had a history of H. pylori infection were nine times more likely to be infected with H. pylori (OR 8.87, 95% CI 1.15-68.45, P = 0.04). Conclusions: The prevalence of H. pylori infection in Vietnamese children with gastroenteritis is high. Our results identified several risk factors and emphasize the role of handwashing with soap before eating and after using the toilet in reducing the risk of H. pylori infection in children.

Improper disposal of cigarette butts in a southeast Asian megacity (Hanoi, Vietnam): Pollution indexes, distribution profiles, and preliminary physicochemical characterization.

Although Southeast Asia is among the largest producers and consumers of cigarettes in the world, information about environmental contamination with littered cigarette butts (CBs) in this region is very limited, especially in urban areas. In this study, we collected CBs in 58 locations of 6 categories (i.e., parks, apartments, streets, shopping malls, universities, and relic sites) in Hanoi, a megacity of Vietnam, to elucidate the occurrence, pollution levels, and physicochemical properties of this specific waste type. A total of 25,943 CBs with 86 brands from 16 origin countries was obtained, showing a density range of 0.0056 to 1.16 (mean 0.125) CB/m2 and cigarette butt pollution index (CBPI) range of 0.23 to 86.9 (mean 6.14). CB contamination levels were higher in parks, apartments, streets, and shopping malls than in universities and relic sites, but CB density and CBPI values varied greatly between locations of the same category. Generally, CB contamination levels measured in Hanoi were within a moderate range compared to other countries worldwide. Several physicochemical properties of CBs were preliminarily determined, which partly confirmed the formation of smoking-derived chemicals captured in CBs and their release potentials into surrounding environments. Further investigations are required to evaluate detailed chemical profiles, leaching behavior, and toxic effects of hazardous substances in CBs.

Different Biocompatibility and Radioprotective Activity of Squid Melanin Nanoparticles on Human Stromal Cells.

Squid ink melanin nanoparticles (NPs) have recently been demonstrated to have a number of bioactivities; however, their biocompatibility has been poorly investigated. In this study, we aimed to evaluate the effects of this NP on stromal cells, including human fibroblasts (hFBs), human umbilical vein endothelial cells (hUVECs), and human umbilical cord-derived mesenchymal stem cells (UCMSCs), and on the development of zebrafish embryos under normal X-ray irradiation conditions. The NPs showed high biocompatibility with low cytotoxicity, no cell senescence induction, and no effect on cell migration in hFBs or cell differentiation in UCMSCs. Nonetheless, this compound prevented cell movement in UCMSCs and significantly suppressed tube formation in hUVECs at a dose of 25 µg/mL. The NPs successfully penetrated the hUVECs but not the other two stromal cell types. The expression levels of functional genes involved in angiogenesis, apoptosis, antioxidant activity, and radiation sensitivity were altered in NPs subjected to hUVECs but were not affected in hFBs and UCMSCs. Melanin NPs significantly rescued cell viability and gene expression in irradiated hFBs and UCMSCs but not in hUVECs. In vivo treatments of zebrafish embryos showed that melanin NPs were nontoxic whether alone or under X-ray irradiation. These findings suggested that nanosized squid ink melanin had biocompatibility with selective stromal cells and was safe for early development.

Rifampicin tolerance and growth fitness among isoniazid-resistant clinical Mycobacterium tuberculosis isolates from a longitudinal study.

Antibiotic tolerance in Mycobacterium tuberculosis reduces bacterial killing, worsens treatment outcomes, and contributes to resistance. We studied rifampicin tolerance in isolates with or without isoniazid resistance (IR). Using a minimum duration of killing assay, we measured rifampicin survival in isoniazid-susceptible (IS, n=119) and resistant (IR, n=84) isolates, correlating tolerance with bacterial growth, rifampicin minimum inhibitory concentrations (MICs), and isoniazid-resistant mutations. Longitudinal IR isolates were analyzed for changes in rifampicin tolerance and genetic variant emergence. The median time for rifampicin to reduce the bacterial population by 90% (MDK90) increased from 1.23 days (IS) and 1.31 days (IR) to 2.55 days (IS) and 1.98 days (IR) over 15-60 days of incubation, indicating fast and slow-growing tolerant sub-populations. A 6 log10-fold survival fraction classified tolerance as low, medium, or high, showing that IR is linked to increased tolerance and faster growth (OR = 2.68 for low vs. medium, OR = 4.42 for low vs. high, p-trend = 0.0003). High tolerance in IR isolates was associated with rifampicin treatment in patients and genetic microvariants. These findings suggest that IR tuberculosis should be assessed for high rifampicin tolerance to optimize treatment and prevent the development of multi-drug-resistant tuberculosis.

Higher alpha diversity and Lactobacillus blooms are associated with better engraftment after fecal microbiota transplant in inflammatory bowel disease.

Fecal Microbiota Transplant (FMT) has shown some success in treating inflammatory bowel diseases (IBD). There is emerging evidence that host engraftment of donor taxa is a tenet of successful FMT. We undertook a double-blind, randomized, placebo-controlled pilot study to characterize the response to FMT in children and young adults with mild to moderate active Crohn's disease (CD) and ulcerative colitis (UC). Subjects with CD or UC were randomized to receive antibiotics and weekly FMT or placebo in addition to baseline medications. We enrolled 15 subjects aged 14-29 years. Four subjects had CD, and 11 had UC. Subjects exhibited a wide range of microbial diversity and donor engraftment. Specifically, engraftment ranged from 26 to 90% at week 2 and 3-92% at 2 months. Consistent with the current literature, increases over time of both alpha diversity (p < 0.05) and donor engraftment (p < 0.05) correlated with improved clinical response. We discovered that the post-antibiotic but pre-FMT time point was rich in microbial correlates of eventual engraftment. Greater residual alpha diversity after antibiotic treatment was positively correlated with engraftment and subsequent clinical response. Interestingly, a transient rise in the relative abundance of Lactobacillus was also positively correlated with engraftment, a finding that we recapitulated with our analysis of another FMT trial.

Impact of a community-based participatory research project with underserved communities at risk for hepatitis C virus in Ho Chi Minh City, Vietnam: an evaluation study.

BACKGROUND: Participatory approaches have become a widely applied research approach. Despite their popularity, there are many challenges associated with the evaluation of participatory projects. Here we describe an evaluation of a community-based participatory research study of underserved communities in Ho Chi Minh City (HCMC), Vietnam at risk for hepatitis C virus. The goals of our evaluation were to explore the main benefits and challenges of implementing and participating in a participatory study and to describe study impacts. METHODS: We conducted two meetings with leaders and members of the participating groups followed by in-depth interviews with 10 participants. We then held a dissemination meeting with over 70 participants, including the representatives of each group, researchers from non-governmental organizations (community-based, national and international), and govenrment officials from the Vietnam Ministry of Health and the Department of Health of HCMC. RESULTS: Results include four categories where we describe first the participatory impacts, followed by the collaborative impacts. Then we describe the benefits and challenges of creating and belonging to one of the groups, from members' and leaders' points of view. Finally, we describe the key suggestions that participants provided for future research. CONCLUSION: In conclusion, the evaluation approach led to both a research reflection on the 'success' of the project and enabled participants themselves to reflect on the outcomes and benefits of the study from their point of view.

Participatory approaches in research aim to include participants in an array of aspects of the study, including developing research questions, collecting data, conducting analysis, etc. It has become a more popular method, however there are still challenges surrounding the evaluation of these projects. Here we describe an evaluation of a community-based participatory research study of underserved communities in Ho Chi Minh City (HCMC), Vietnam at risk for hepatitis C virus. The goals of the evaluation were to discuss and explore the main benefits and challenges with those who participated, as well as assess study impacts. To conduct the evaluation, we conducted two meetings with leaders and members of the participating groups followed by interviews with 10 people who were involved. The evaluation results included four categories including impacts for members as well as wider impacts in the community. Then we describe the benefits and challenges of creating and belonging to one of the groups, from members' and leaders' points of view. Finally, we describe the key suggestions that participants provided for future research. In conclusion, the evaluation approach led to both a research reflection on the 'success' of the project and enabled participants themselves to reflect on the outcomes and benefits of the study from their point of view.

Correlations of LncRNA HNF4A-AS1 Alternative Transcripts with Liver Diseases and Drug Metabolism.

Hepatocyte nuclear factor 4 alpha antisense 1 (HNF4A-AS1) is a long non-coding RNA (lncRNA) gene physically located next to the transcription factor HNF4A gene in the human genome. Its transcription products have been reported to inhibit the progression of hepatocellular carcinoma (HCC) and negatively regulate the expression of cytochrome P450s (CYPs), including CYP1A2, 2B6, 2C9, 2C19, 2E1, and 3A4. By altering CYP expression, lncRNA HNF4A-AS1 also contributes to the susceptibility of drug-induced liver injury. Thus, HNF4A-AS1 lncRNA is a promising target for controlling HCC and modulating drug metabolism. However, HNF4A-AS1 has 4 annotated alternative transcripts in the human genome browsers, and it is unclear which transcripts the siRNAs or shRNAs used in the previous studies are silenced and which transcripts should be used as the target. In this study, 4 annotated and 2 newly identified transcripts were confirmed. These 6 transcripts showed different expression levels in different liver disease conditions, including metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, and obesity. The expression patterns of all HNF4A-AS1 transcripts were further investigated in liver cell growth from human embryonic stem cells to matured hepatocyte-like cells, HepaRG differentiation, and exposure to rifampicin treatment. Several HNF4A-AS1 transcripts highly displayed correlations with these situations. In addition, some of the HNF4A-AS1 transcripts also showed a strong correlation with CYP3A4 during HepaRG maturation and rifampicin exposure. Our findings provide valuable insights into the specific roles of HNF4A-AS1 transcripts, paving the way for more targeted therapeutic strategies for liver diseases and drug metabolism. Significance Statement This study explores the alternative transcripts of HNF4A-AS1, showing how their expression changes in different biological conditions, from various liver diseases to the growth and differentiation of hepatocytes, and drug metabolism. The generated knowledge is essential for understanding the independent roles of different transcripts from the same lncRNA in different liver diseases and drug metabolism situations.

Design considerations of a new freezer construction in the tubular ice machine by experimental study.

The need to improve the structure of components to create a new system compacter and cheaper, but still ensuring the system's consistent operation is always necessary and urgent. This study found the consistent of a new integrated freezer construction in the tubular ice machine by experimental study. The measuring instruments were been set for this air-cooled experimental model to validate the system stability when integrating the freezer, accumulator and heat exchanger into an integrated freezer. At a typical experiment 50 Hz inverter control, the R404a refrigerant used to evaporate at -15 °C, achieved the duration of total ice production cycle is around 29.5 min whereas the duration of ice production process takes around 24.5 min (rated 2.88 min/°C) and the defrost takes 5 min. The experimental coefficient of performance decreases from 1.77 to 1.51 and gets averagely 1.55 in the ice production process. From three others experimental results, coefficient of performance, the duration of ice production process, and saturation temperature of refrigerant in freezer change corresponding to the supplied power by inverter control for compressor.

Urinary incontinence after COVID-19 vaccination: a case study in an 8-year-old boy.

There have been many studies on the adverse effects of coronavirus disease 2019 (COVID-19) vaccines but the urinary incontinence after COVID-19 vaccination is rare. Here, we report an 8-year-old boy presented to outpatient department, Thai Binh University of Medicine Hospital, Thai Binh, Vietnam with complaints of urinary incontinence for the past 2 weeks, following the first dose of the messenger RNA vaccine. He had no other abnormalities in clinical and laboratory exams. This clinical situation suggested vaccine side effects. No specific treatment was administered upon diagnosis without toilet and bladder training. Subsequent monitoring revealed a gradual reduction in symptoms over 2 months, with complete recovery achieved at the 14th week from the onset of symptoms, without necessitating any medical intervention. This case highlights the need for thorough evaluation and assessment of potential adverse effects following vaccination, including uncommon presentations.

Homoharringtonine synergizes with venetoclax in early T cell progenitor acute lymphoblastic leukemia: Bench and bed.

BACKGROUND: Early T cell precursor acute lymphoblastic leukemia (ETP-ALL) is a distinct subtype of T-ALL with a poor prognosis. To find a cure, we examined the synergistic effect of homoharringtonine (HHT) in combination with the BCL-2 inhibitor venetoclax (VEN) in ETP-ALL. METHODS: Using in vitro cellular assays and ETP-ALL xenograft models, we first investigated the synergistic activity of HHT and VEN in ETP-ALL. Next, to explore the underlying mechanism, we employed single-cell RNA sequencing of primary ETP-ALL cells treated with HHT or VEN alone or in combination and validated the results with western blot assays. Based on the promising preclinical results and given that both drugs have been approved for clinical use, we then assessed this combination in clinical practice. FINDINGS: Our results showed that HHT synergizes strongly with VEN both in vitro and in vivo in ETP-ALL. Mechanistic studies demonstrated that the HHT/VEN combination concurrently downregulated key anti-apoptotic proteins, i.e., MCL1, leading to enhanced apoptosis. Importantly, the clinical results were very promising. Six patients with ETP-ALL with either refractory/relapsed (R/R) or newly diagnosed disease were treated with an HHT/VEN-based regimen. All patients achieved complete remission (CR) after only one cycle of treatment. CONCLUSIONS: Our findings demonstrate that a combination of HHT/VEN is effective on ETP-ALL and represents the "backbone" of a promising and safe regimen for newly diagnosed and R/R patients with ETP-ALL. FUNDING: This work was funded by the National Cancer Institute, Gehr Family Foundation, George Hoag Family Foundation, National Natural Science Foundation of China, and Key Research and Development Program of Zhejiang Province of China.

IL1RAP-specific T cell engager depletes acute myeloid leukemia stem cells.

BACKGROUND: The interleukin-1 receptor accessory protein (IL1RAP) is highly expressed on acute myeloid leukemia (AML) bulk blasts and leukemic stem cells (LSCs), but not on normal hematopoietic stem cells (HSCs), providing an opportunity to target and eliminate the disease, while sparing normal hematopoiesis. Herein, we report the activity of BIF002, a novel anti-IL1RAP/CD3 T cell engager (TCE) in AML. METHODS: Antibodies to IL1RAP were isolated from CD138+ B cells collected from the immunized mice by optoelectric positioning and single cell sequencing. Individual mouse monoclonal antibodies (mAbs) were produced and characterized, from which we generated BIF002, an anti-human IL1RAP/CD3 TCE using Fab arm exchange. Mutations in human IgG1 Fc were introduced to reduce FcγR binding. The antileukemic activity of BIF002 was characterized in vitro and in vivo using multiple cell lines and patient derived AML samples. RESULTS: IL1RAP was found to be highly expressed on most human AML cell lines and primary blasts, including CD34+ LSC-enriched subpopulation from patients with both de novo and relapsed/refractory (R/R) leukemia, but not on normal HSCs. In co-culture of T cells from healthy donors and IL1RAPhigh AML cell lines and primary blasts, BIF002 induced dose- and effector-to-target (E:T) ratio-dependent T cell activation and leukemic cell lysis at subnanomolar concentrations. BIF002 administered intravenously along with human T cells led to depletion of leukemic cells, and significantly prolonged survival of IL1RAPhigh MOLM13 or AML patient-derived xenografts with no off-target side effects, compared to controls. Of note, BiF002 effectively redirects T cells to eliminate LSCs, as evidenced by the absence of disease initiation in secondary recipients of bone marrow (BM) from BIF002+T cells-treated donors (median survival not reached; all survived > 200 days) compared with recipients of BM from vehicle- (median survival: 26 days; p = 0.0004) or isotype control antibody+T cells-treated donors (26 days; p = 0.0002). CONCLUSIONS: The novel anti-IL1RAP/CD3 TCE, BIF002, eradicates LSCs and significantly prolongs survival of AML xenografts, representing a promising, novel treatment for AML.

Mycology laboratory diagnostic capacity for invasive fungal diseases in public hospitals in Vietnam.

This was a cross-sectional study on the availability of laboratory infrastructure and capacity for the diagnosis of invasive fungal diseases in 24 public hospitals in Vietnam in 2023. Among the hospitals surveyed, 66.7% (14/21) had specialized personnel assigned for mycology testing, and 95.8% (23/24) had a separate microbiology laboratory space. Microscopy and culture methods are available in nearly all laboratories for isolate identification. Antifungal susceptibility testing is only performed for yeasts in 16/24 (66.7%) laboratories. Non-culture methods are hardly used in laboratories. Strengthening local laboratory capacities is essential to meeting health needs in these endemic regions.

There was a need for investment in fungal diagnostics to improve health services in the settings with a burden of endemic fungal infections.

Linear Gold(I) Halide Complexes with a Diamidocarbene Ligand: Synthesis, Reactivity, and Phosphorescence.

A series of halide and pseudohalide gold complexes (DAC)Au(I)X (DAC = N,N'-diamidocarbene; X = Cl, Br, I, and SCN) were prepared in high yields. All complexes possess linear geometry around the gold atom with no aurophilic interactions between neighboring molecules. Reactivity studies for (DAC)Au(I)Cl revealed that the diamido backbone of the carbene ligand is vulnerable to nucleophilic attack by a strong base, potassium tert-butoxide, resulting in cleavage of the carbene backbone and formation of a neutral trigold cluster. Halide and pseudohalide complexes are bright phosphorescent emitters in the solid state, exhibiting photoluminescence quantum yields up to unity. Phosphorescence occurs in the range 480-520 nm with lifetimes as short as 1 µs, resulting in fast radiative rates up to 9.4 × 105 s-1 which is on par with the most efficient heavy metal emitters. Photophysical properties are explained by the intrinsic π-accepting nature of the DAC carbene and are supported by TDDFT calculations.

Homoharringtonine inhibits the NOTCH/MYC pathway and exhibits antitumor effects in T-cell acute lymphoblastic leukemia.

ABSTRACT: We report on the antileukemic activity of homoharringtonine (HHT) in T-cell acute lymphoblastic leukemia (T-ALL). We showed that HHT inhibited the NOTCH/MYC pathway and induced significantly longer survival in mouse and patient-derived T-ALL xenograft models, supporting HHT as a promising agent for T-ALL.

Evaluation of video-based rPPG in challenging environments: Artifact mitigation and network resilience.

Video-based remote photoplethysmography (rPPG) has emerged as a promising technology for non-contact vital sign monitoring, especially under controlled conditions. However, the accurate measurement of vital signs in real-world scenarios faces several challenges, including artifacts induced by videocodecs, low-light noise, degradation, low dynamic range, occlusions, and hardware and network constraints. In this article, a systematic and comprehensive investigation of these issues is conducted, measuring their detrimental effects on the quality of rPPG measurements. Additionally, practical strategies are proposed for mitigating these challenges to improve the dependability and resilience of video-based rPPG systems. Methods for effective biosignal recovery in the presence of network limitations are detailed, along with denoising and inpainting techniques aimed at preserving video frame integrity. Compared to previous studies, this paper addresses a broader range of variables and demonstrates improved accuracy across various rPPG methods, emphasizing generalizability for practical applications in diverse scenarios with varying data quality. Extensive evaluations and direct comparisons demonstrate the effectiveness of these approaches in enhancing rPPG measurements under challenging environments, contributing to the development of more reliable and effective remote vital sign monitoring technologies.

Sulfur-Promoted Access to 3-Arylquinoxalin-2-ones by Oxidative Coupling of o-Phenylenediamines with Arylacetates.

We disclose the synthesis of 3-arylquinoxalin-2-ones from o-phenylenediamines and readily available arylacetates. The method harnesses the selective oxidative property of elemental sulfur in the presence of amine base catalyst and DMSO. The reactions are operationally simple and tolerate a wide range of functional groups.

DA-TransUNet: integrating spatial and channel dual attention with transformer U-net for medical image segmentation.

Accurate medical image segmentation is critical for disease quantification and treatment evaluation. While traditional U-Net architectures and their transformer-integrated variants excel in automated segmentation tasks. Existing models also struggle with parameter efficiency and computational complexity, often due to the extensive use of Transformers. However, they lack the ability to harness the image's intrinsic position and channel features. Research employing Dual Attention mechanisms of position and channel have not been specifically optimized for the high-detail demands of medical images. To address these issues, this study proposes a novel deep medical image segmentation framework, called DA-TransUNet, aiming to integrate the Transformer and dual attention block (DA-Block) into the traditional U-shaped architecture. Also, DA-TransUNet tailored for the high-detail requirements of medical images, optimizes the intermittent channels of Dual Attention (DA) and employs DA in each skip-connection to effectively filter out irrelevant information. This integration significantly enhances the model's capability to extract features, thereby improving the performance of medical image segmentation. DA-TransUNet is validated in medical image segmentation tasks, consistently outperforming state-of-the-art techniques across 5 datasets. In summary, DA-TransUNet has made significant strides in medical image segmentation, offering new insights into existing techniques. It strengthens model performance from the perspective of image features, thereby advancing the development of high-precision automated medical image diagnosis. The codes and parameters of our model will be publicly available at https://github.com/SUN-1024/DA-TransUnet.

Z-number based fuzzy MCDM models for analyzing non-traditional security threats to finance supply chains: A case study from Vietnam.

Non-traditional security (NTS) threats have a vast and profound impact on many aspects of economic, political, social, and many other areas, especially supply chain finance (SCF), particularly in countries like Vietnam, which potentially affects the economic efficiency of businesses' supply chain financial, thereby affecting the general economy of the country and the world. In order to prevent and minimize the negative impacts caused by NTS threats to SCF, this study was conducted to identify NTS threats affecting SCF in Vietnam, at the same time calculate the weight of the impact level and find out the cause and effect relationship between them. Solution strategies are also proposed and ranked, thereby serving as a reference basis for relevant parties to choose appropriate response solutions. Due to the multi-criteria nature of NTS threats, the multiple criteria decision-making (MCDM) method is used in combination with the Z-number concept and Fuzzy set theory to approach the problem of certainty and increase the accuracy of study. The NTS threats are first identified through a literature review and then validated for suitability using the DELPHI technique (DELPHI). Suitable threats will be determined by relationship, weighted by Decision Making Trial And Evaluation Laboratory (DEMATEL) method. Proposed strategies are ranked using the Technique for Order of Preference by Similarity to Ideal Solution (TOPSIS) method. The results indicate that there are 19 NTS factors affecting SCF in Vietnam, and the global economic downturn, pandemic and health crisis, financial crisis and cybersecurity risk are the four root cause factors with the most decisive influence. Businesses and concerns need to prioritize addressing these four threats because they not only have a strong impact but also entail many other threats. The two strategies considered to be the most effective are a sustainable practice and a risk-hedging strategy. Businesses, governments, and stakeholders also should pay attention to the macroeconomic environment, technology, and environment and build sustainable businesses, regularly monitoring economic fluctuations and creating plans to prevent risks.

Risk factors associated with the severity of pericoronitis of mandibular third molar.

PURPOSE: The factors related to pericoronitis severity are unclear, and this study aimed to address this knowledge gap. MATERIALS AND METHODS: In total, 113 patients with pericoronitis were included, and their demographic, clinical, and radiographic characteristics were recorded. The Patient-Clinician Pericoronitis Classification was used to score and categorize the severity of pericoronitis. Statistical analysis was conducted to examine the participants' characteristics, validity of the Patient-Clinician Pericoronitis Classification, and risk factors associated with the severity of pericoronitis. RESULTS: The demographic, clinical, and radiographic characteristics of males and females were similar, except for Winter's classification, pain, and intraoral swelling. The constructive validity of the Patient-Clinician Pericoronitis Classification was confirmed with three latent factors, including infection level, patient discomfort, and social interference. Ordinal logistic multivariate regression analysis revealed that upper respiratory tract infection was the sole risk factor associated with pericoronitis severity in males (odds ratio = 4.838). In females, pericoronitis on the right side (odds ratio = 2.486), distal radiolucency (odds ratio = 5.203), and menstruation (odds ratio = 3.416) were significant risk factors. CONCLUSION: This study demonstrated the constructive validity of the Patient-Clinician Pericoronitis Classification. Among females, pericoronitis in mandibular third molars on the right side with radiolucency in menstruating individuals was more severe. In males, upper respiratory tract infection was the sole risk factor associated with pericoronitis severity. CLINICAL RELEVANCE: Individuals with risk factors should be aware of severe pericoronitis in the coming future.

Identification of bacterial determinants of tuberculosis infection and treatment outcomes: a phenogenomic analysis of clinical strains.

BACKGROUND: Bacterial diversity could contribute to the diversity of tuberculosis infection and treatment outcomes observed clinically, but the biological basis of this association is poorly understood. The aim of this study was to identify associations between phenogenomic variation in Mycobacterium tuberculosis and tuberculosis clinical features. METHODS: We developed a high-throughput platform to define phenotype-genotype relationships in M tuberculosis clinical isolates, which we tested on a set of 158 drug-sensitive M tuberculosis strains sampled from a large tuberculosis clinical study in Ho Chi Minh City, Viet Nam. We tagged the strains with unique genetic barcodes in multiplicate, allowing us to pool the strains for in-vitro competitive fitness assays across 16 host-relevant antibiotic and metabolic conditions. Relative fitness was quantified by deep sequencing, enumerating output barcode read counts relative to input normalised values. We performed a genome-wide association study to identify phylogenetically linked and monogenic mutations associated with the in-vitro fitness phenotypes. These genetic determinants were further associated with relevant clinical outcomes (cavitary disease and treatment failure) by calculating odds ratios (ORs) with binomial logistic regressions. We also assessed the population-level transmission of strains associated with cavitary disease and treatment failure using terminal branch length analysis of the phylogenetic data. FINDINGS: M tuberculosis clinical strains had diverse growth characteristics in host-like metabolic and drug conditions. These fitness phenotypes were highly heritable, and we identified monogenic and phylogenetically linked variants associated with the fitness phenotypes. These data enabled us to define two genetic features that were associated with clinical outcomes. First, mutations in Rv1339, a phosphodiesterase, which were associated with slow growth in glycerol, were further associated with treatment failure (OR 5·34, 95% CI 1·21-23·58, p=0·027). Second, we identified a phenotypically distinct slow-growing subclade of lineage 1 strains (L1.1.1.1) that was associated with cavitary disease (OR 2·49, 1·11-5·59, p=0·027) and treatment failure (OR 4·76, 1·53-14·78, p=0·0069), and which had shorter terminal branch lengths on the phylogenetic tree, suggesting increased transmission. INTERPRETATION: Slow growth under various antibiotic and metabolic conditions served as in-vitro intermediate phenotypes underlying the association between M tuberculosis monogenic and phylogenetically linked mutations and outcomes such as cavitary disease, treatment failure, and transmission potential. These data suggest that M tuberculosis growth regulation is an adaptive advantage for bacterial success in human populations, at least in some circumstances. These data further suggest markers for the underlying bacterial processes that contribute to these clinical outcomes. FUNDING: National Health and Medical Research Council/A∗STAR, National Institutes of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, and the Wellcome Trust Fellowship in Public Health and Tropical Medicine.