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Xylobezoar is indeed a rare condition associated with xylophagia, characterized by varying degrees of intestinal obstruction due to the entrapment of undigested paper in the gastrointestinal tract. Xylophagia is a form of pica that primarily affects children from low socioeconomic backgrounds with mental conditions and nutritional deficiencies. It is rarely seen in adults. Medical and endoscopic interventions are often challenging in these patients, and surgical intervention is often required. We present an endoscopically challenging case of pancolonic obstruction due to toilet paper accumulation in a patient with pica secondary to iron deficiency anemia., (© 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Children and adolescents diagnosed with an eating disorder often meet the diagnosis of another mental health disorder. In addition to eating disorders, individuals with comorbid disorders have higher suicide rates and more severe and chronic eating disorder symptoms. The present research aimed to investigate the influence of comorbid conditions on the treatment outcomes of children and adolescents that attended a public community mental health service. It was hypothesised that the patients with comorbidities would have a more extended treatment duration, slower rates of weight restoration, more hospital admissions for medical compromise, and poorer functioning than those without comorbidities. Data from 78 past patients at the Eating Disorder Program in Queensland, Australia, were analysed. Patients with comorbidities demonstrated similar recovery rates to those without comorbidities. However, those with comorbid conditions had longer episodes of treatment. The study's results support using Family Based Treatment for patients with and without comorbidities. The implications of the findings for public mental health services and directions for future research are discussed.

Purpose: This work proposes a 2D/3D hybrid inflow MRA technique for fast scanning and high SNR and contrast-to-noise (CNR) efficiencies., Methods: Localized quadratic (LQ) encoding was combined with a sliding-slice spiral acquisition. Inflow MRAs around the circle of Willis and the carotid bifurcations were collected on four healthy volunteers. Spiral images were deblurred without or with water-fat separation for sliding-slice LQ (ssLQ) out-of-phase (OP) and Dixon inflow MRAs, respectively. Results were compared to multiple overlapping thin slab acquisitions (MOTSA) and 2D OP inflow MRAs. Noise data were also acquired with RF and gradients turned off to compute maps of SNR and SNR efficiency. Quantitative assessment of relative contrast, CNR, and CNR efficiency for flow were performed in regions of interest., Results: The sliding-slice spiral technique alone reduces scan time by 10% to 40% compared with a standard spiral acquisition scheme. The proposed spiral ssLQ OP achieves 50% higher scan speed than the spiral MOTSA with comparable SNR and CNR efficiencies, which are ∼100% higher than the Cartesian MOTSA for intracranial inflow MRAs. Spiral ssLQ Dixon inflow MRA provides better visibility for vessels around the fat compared to spiral ssLQ OP inflow MRA, with a trade-off of scan speed. Spiral ssLQ MRA with thinner slice thickness is two to five times faster than the 2D Cartesian inflow neck MRA around the carotid bifurcations, while also achieving higher SNR efficiency., Conclusion: The proposed spiral ssLQ is a fast and flexible MRA method with improved SNR and CNR efficiencies over traditional Cartesian inflow MRAs., (© 2023 International Society for Magnetic Resonance in Medicine.)

Acute myocardial infarction (MI) may concomitantly occur with acute ischemic stroke. The incidence and outcomes of acute non-ST-elevation MI (NSTEMI) in acute ischemic stroke are not well studied. We examined hospitalized patients with acute ischemic stroke and a concomitant NSTEMI diagnosis who were included in the National Inpatient Sample 2016 to 2019. Acute ischemic stroke and NSTEMI were defined by using the International Classification of Diseases, Tenth Revision codes. Patients with ST-elevation MI were excluded. The outcomes were expressed as percentages. A multivariable logistic regression analysis was used to examine the association of concomitant acute ischemic stroke and NSTEMI with the primary outcome of mortality and the secondary outcomes. A subgroup analysis of patients with NSTEMI with acute ischemic stroke that underwent percutaneous coronary intervention (PCI) (angiography and angioplasty) was also performed. Of the total hospitalized patients with acute ischemic stroke (n = 1,726,265), 1.60% (n = 27,630) patients (mean age 73.5 years, 52.2% women, 67% White race) had NSTEMI diagnosed during the hospitalization. Of these, 14.1% (n = 3,890) died in the NSTEMI group and 3.4% (n = 57,670) died in the non-NSTEMI group. The most common outcomes in the NSTEMI group were Acute kidney injury 31.8%, Intracranial hemorrhage 6.6%, and sepsis 6.13%. NSTEMI in acute ischemic stroke was associated with mortality (odds ratio [OR] 3.60, 95% confidence interval [CI] 3.29 to 3.93, p ≤0.001), ICH (OR 1.46, 95% CI 1.30 to 1.63, p <0.001), and having any of the secondary outcomes (OR 2.73, 95% CI 2.57 to 2.90, p <0.001). PCI was performed in 9.14% of patients with acute ischemic stroke with NSTEMI. PCI was associated with having any of the secondary outcomes (OR 0.83, 95% CI 0.7 to 1.02, p = 0.8), mortality (OR 0.35, 95% CI 0.23 to 0.54, p <0.001), and ICH (OR 0.42, 95% CI 0.25 to 0.7, p = 0.01). In conclusion, NSTEMI in acute ischemic stroke is associated with increased mortality and other adverse events. PCI in the subgroup of patients with NSTEMI was not associated with increased mortality or intracranial bleeding., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: An accurate field map is essential to separate fat and water signals in a dual-echo chemical shift encoded spiral MRI scan. A rapid low-resolution B 0 map prescan is usually performed before each exam. Occasional inaccuracy in these field map estimates can lead to misclassification of the water and fat signals as well as blurring artifacts in the reconstruction. The present work proposes a self-consistent model to evaluate residual field offsets according to the image data to improve the reconstruction quality and facilitate the scan efficiency., Theory and Methods: The proposed method compares the phase differences of the two-echo data after correcting for fat frequency offsets. A more accurate field map is approximated according to the phase discrepancies and improved image quality. Experiments were conducted with simulated off-resonance on a numerical phantom, five volunteer head scans, and four volunteer abdominal scans for validation., Results: The initial reconstruction of the demonstrated examples exhibit blurring artifacts and misregistration of fat and water because of the inaccuracy of the field map. The proposed method updates the field map to amend the fat and water estimation and improve image quality., Conclusions: This work presents a model to improve the quality of fat-water imaging of the spiral MRI by estimating a better field map from the acquired data. It allows reducing the field map pre-scans before each spiral scan under normal circumstances to increase scan efficiency., (© 2023 International Society for Magnetic Resonance in Medicine.)

Guidelines recommend managing patients aged ≥75 with non-ST-segment elevation myocardial infarction (NSTEMI) similar to younger patients. We analyze disparities in NSTEMI management and compare those ≥80 years to those <80 years. This is a matched case-control study using the 2016 National Inpatient Sample data of adults with NSTEMI receiving percutaneous coronary intervention with drug-eluting stent (PCI-DES) - one artery or no intervention. We included the statistically significant variables in univariate analysis in exploratory multivariate logistic regression models. Total sample included 156,328 patients, out of which 43,265 were ≥ 80 years, and 113,048 were < 80 years. Patients ≥80 years were more likely to not have an intervention (73.3%) when compared to those <80 (44.1%), P < 0.0005. Regardless of age, PCI-DES-one artery improved survival compared to no intervention (Age < 80: OR 0.230, 95% CI 0.189-0.279, and ≥ 80: OR 0.265, 95% CI 0.195-0.361, P < 0.0005). Women (OR 0.785, 95% CI 0.766-0.804, P < 0.0005) and non-white race (OR 0.832, 95% CI 0.809-0.855, P < 0.0005) were less likely to receive an intervention. Non-Medicare/Medicaid insurance was associated with 40% lower likelihood of dying in <80 age group (OR 0.596, 95% CI 0.491-0.724, P < 0.0005), and 16% higher chance of intervention overall (OR 1.160, 95% CI 1.125-1.197, P < 0.0005). Patients aged ≥80 with NSTEMI were 29% less likely to receive an intervention compared to patients aged <80, even though patients >80 derived similar mortality benefits from the intervention. There were gender, payor, and race-based disparities in NSTEMI management in 2016., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The clinical development of farnesyltransferase inhibitors (FTI) for HRAS -mutant tumors showed mixed responses dependent on cancer type. Co-occurring mutations may affect response. We aimed to uncover cooperative genetic events specific to HRAS -mutant tumors and study their effect on FTI sensitivity. Using targeted sequencing data from MSK-IMPACT and DFCI-GENIE databases we identified co-mutations in HRAS - vs KRAS - and NRAS -mutant cancers. HRAS -mutant cancers had a higher frequency of co-altered mutations (48.8%) in MAPK, PI3K, or RTK pathways genes compared to KRAS - and NRAS -mutant cancers (41.4% and 38.4%, respectively; p < 0.05). Class 3 BRAF, NF1, PTEN, and PIK3CA mutations were more prevalent in HRAS -mutant lineages. To study the effect of comutations on FTI sensitivity, Hras G13R was transfected into 'RASless' ( Kras lox/lox ; Hras -/- ; Nras -/- ) mouse embryonic fibroblasts (MEFs) which sensitized non-transfected MEFs to tipifarnib. Comutation in the form of Pten or Nf1 deletion or Pik3ca H1047R or Braf G466E transduction led to relative resistance to tipifarnib in Hras G13R MEFs in the presence or absence of Kras WT . Combined treatment of tipifarnib with MEK inhibition sensitized cells to tipifarnib, including in MEFs with PI3K pathway comutations. HRAS -mutant tumors demonstrate lineage demonstrate lineage-dependent MAPK/PI3K pathway alterations that confer relative resistance to tipifarnib. Combined FTI and MEK inhibition is a promising combination for HRAS -mutant tumors., Competing Interests: Competing Interest Statement: No additional competing interests to disclose

In this paper, simple imine-based organic fluorophore 4-amino-3-(anthracene-9 yl methyleneamino) phenyl (phenyl) methanone (APM) has been synthesized via a greener approach and the same was used to construct a fluorescent immunoassay for the detection of Listeria monocytogenes (LM). A monoclonal antibody of LM was tagged with APM via the conjugation of the amine group in APM and the acid group of anti-LM through EDC/NHS coupling. The designed immunoassay was optimized for the specific detection of LM in the presence of other interfering pathogens based on the aggregation-induced emission mechanism and the formation of aggregates and their morphology was confirmed with the help of scanning electron microscopy. Density functional theory studies were done to further support the sensing mechanism-based changes in the energy level distribution. All photophysical parameters were measured by using fluorescence spectroscopy techniques. Specific and competitive recognition of LM was done in the presence of other relevant pathogens. The immunoassay shows a linear appreciable range from 1.6 × 10 6 -2.7024 × 10 8 cfu/mL using the standard plate count method. The LOD has been calculated from the linear equation and the value is found as 3.2 cfu/mL, and this is the lowest LOD value reported for the detection of LM so far. The practical applications of the immunoassay were demonstrated in various food samples, and their accuracy obtained was highly comparable with the standard existing ELISA method., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

A more effective vaccine against tuberculosis than Bacille Calmette-Guérin (BCG) is urgently needed. BCG derived recombinant VPM1002 has been found to be more efficacious and safer than the parental strain in mice models. Newer candidates, such as VPM1002 Δ pdx1 (PDX) and VPM1002 Δ nuoG (NUOG), were generated to further improve the safety profile or efficacy of the vaccine. Herein, we assessed the safety and immunogenicity of VPM1002 and its derivatives, PDX and NUOG, in juvenile goats. Vaccination did not affect the goats' health in regards to clinical/hematological features. However, all three tested vaccine candidates and BCG induced granulomas at the site of injection, with some of the nodules developing ulcerations approximately one month post-vaccination. Viable vaccine strains were cultured from the injection site wounds in a few NUOG- and PDX- vaccinated animals. At necropsy (127 days post-vaccination), BCG, VPM1002, and NUOG, but not PDX, still persisted at the injection granulomas. All strains, apart from NUOG, induced granuloma formation only in the lymph nodes draining the injection site. In one animal, the administered BCG strain was recovered from the mediastinal lymph nodes. Interferon gamma (IFN-γ) release assay showed that VPM1002 and NUOG induced a strong antigen-specific response comparable to that elicited by BCG, while the response to PDX was delayed. Flow cytometry analysis of IFN-γ production by CD4 + , CD8 + , and γδ T cells showed that CD4 + T cells of VPM1002- and NUOG-vaccinated goats produced more IFN-γ compared to BCG-vaccinated and mock-treated animals. In summary, the subcutaneous application of VPM1002 and NUOG induced anti-tuberculous immunity, while exhibiting a comparable safety profile to BCG in goats.

Day programs have received significant consideration within psychological literature as part of a continuum of mental health services. With increasing attention on the prevalence of eating disorders in children and adolescents, and the need for early intervention to minimize the costs and burden of the disorder, eating disorder day programs (also referred as partial hospitalization) have begun to emerge around the world. Despite their widespread use, no reviews to date have examined the efficacy of day programs for the treatment of eating disorders in children and adolescents. The current narrative literature review aims to describe and evaluate the efficacy of day programs for children and adolescents. The literature review was conducted according to the PRISMA guidelines and aimed to explore the outcomes and common program elements of day programs to guide clinical practice and service development. The review found variations amongst the day programs related to program elements, measures utilized and outcomes. Overall, the results suggest that day programs for children and adolescents are effective at restoring body weight, reducing eating disorder symptoms and addressing comorbid mental health concerns., (© 2022 The Authors. European Eating Disorders Review published by Eating Disorders Association and John Wiley & Sons Ltd.)

Purpose: To develop a free-breathing (FB) 2D radial balanced steady-state free precession cine cardiac MRI method with 100% respiratory gating efficiency using respiratory auto-calibrated motion correction (RAMCO) based on a motion-sensing camera., Methods: The signal from a respiratory motion-sensing camera was recorded during a FB retrospectively electrocardiogram triggered 2D radial balanced steady-state free precession acquisition using pseudo-tiny-golden-angle ordering. With RAMCO, for each acquisition the respiratory signal was retrospectively auto-calibrated by applying different linear translations, using the resulting in-plane image sharpness as a criterium. The auto-calibration determines the optimal magnitude of the linear translations for each of the in-plane directions to minimize motion blurring caused by bulk respiratory motion. Additionally, motion-weighted density compensation was applied during radial gridding to minimize through-plane and non-bulk motion blurring. Left ventricular functional parameters and sharpness scores of FB radial cine were compared with and without RAMCO, and additionally with conventional breath-hold Cartesian cine on 9 volunteers., Results: FB radial cine with RAMCO had similar sharpness scores as conventional breath-hold Cartesian cine and the left ventricular functional parameters agreed. For FB radial cine, RAMCO reduced respiratory motion artifacts with a statistically significant difference in sharpness scores (P < 0.05) compared to reconstructions without motion correction., Conclusion: 2D radial cine imaging with RAMCO allows evaluation of left ventricular functional parameters in FB with 100% respiratory efficiency. It eliminates the need for breath-holds, which is especially valuable for patients with no or impaired breath-holding capacity. Validation of the proposed method on patients is warranted., (© 2022 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Diabetes is one of the most prevalent metabolic illnesses that can be fatal, and it is the ninth-largest cause of mortality worldwide. Even though there are effective hypoglycemic medications available for the treatment of diabetes, researchers continue to look for a medication that is more effective and has fewer adverse effects by focusing on various metabolic components such as enzymes, transporters, receptors. The enzyme Glucokinase (GCK), which is present mainly in the liver and beta cells of the pancreas, is involved in maintaining blood glucose homeostasis. Hence, the present in silico study is designed to determine the interaction between GCK and compounds (ligands) of Coleus amboinicus . In the current docking investigation, we discovered that important residues, including ASP-205, LYS-169, GLY-181, and ILE-225, significantly influence in ligand binding affinity. Docking tests of these compounds with target proteins revealed that this is a suitable molecule that docks well with the target of diabetes treatment. In conclusion, we believe that the compounds of caryophyllene have anti-diabetic activity based on the present study., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Anthony Ammal et al.)

Objective . To develop a respiratory motion-resolved four-dimensional (4D) magnetic resonance imaging (MRI) technique with high-isotropic-resolution (1.1 mm) using 3D radial sampling, camera-based respiratory motion sensing, and temporal compressed sensing reconstruction for lung cancer imaging. Approach . Free-breathing half- and full-spoke 3D golden-angle radial acquisitions were performed on eight healthy volunteers and eight patients with lung tumors of varying size. A back-and-forth k-space ordering between consecutive interleaves of the 3D radial acquisition was performed to minimize eddy current-related artifacts. Data were sorted into respiratory motion states using camera-based motion navigation and 4D images were reconstructed using temporal compressed sensing to reduce scan time. Normalized sharpness indices of the diaphragm, apparent signal-to-noise ratio (aSNR) and contrast-to-noise ratio (CNR) of the lung tumor (patients only), liver, and aortic arch were compared between half- and full-spoke 4D MRI images to evaluate the impact of respiratory motion and image contrast on 4D MRI image quality. Respiration-induced changes in lung volumes and center of mass shifts were compared between half- and full-spoke 4D MRI measurements. In addition, the motion measurements from 4D MRI and the same-day 4D CT were presented in one of the lung tumor patients. Main results . Half-spoke 4D MRI provides better visualization of the lung parenchyma, while full-spoke 4D MRI presents sharper diaphragm images and higher aSNR and CNR in the lung tumor, liver, and aortic arch. Lung volume changes and center of mass shifts measured by half- and full-spoke 4D MRI were not statistically different. For the patient with 4D MRI and same-day 4D CT, lung volume changes and center of mass shifts were generally comparable. Significance . This work demonstrates the feasibility of a motion-resolved 4D MRI technique with high-isotropic-resolution using 3D radial acquisition, camera-based respiratory motion sensing, and temporal compressed sensing reconstruction for treatment planning and motion monitoring in radiotherapy of lung cancer., (Creative Commons Attribution license.)

Therapy resistance is a major challenge in the treatment of cancer. Here, we performed CRISPR-Cas9 screens across a broad range of therapies used in acute myeloid leukemia to identify genomic determinants of drug response. Our screens uncover a selective dependency on RNA splicing factors whose loss preferentially enhances response to the BCL2 inhibitor venetoclax. Loss of the splicing factor RBM10 augments response to venetoclax in leukemia yet is completely dispensable for normal hematopoiesis. Combined RBM10 and BCL2 inhibition leads to mis-splicing and inactivation of the inhibitor of apoptosis XIAP and downregulation of BCL2A1, an anti-apoptotic protein implicated in venetoclax resistance. Inhibition of splicing kinase families CLKs (CDC-like kinases) and DYRKs (dual-specificity tyrosine-regulated kinases) leads to aberrant splicing of key splicing and apoptotic factors that synergize with venetoclax, and overcomes resistance to BCL2 inhibition. Our findings underscore the importance of splicing in modulating response to therapies and provide a strategy to improve venetoclax-based treatments., Competing Interests: Declaration of interests E.M., E.C., M.J., C.B., C.-C.M., and D.M.B. are employees of Biosplice Therapeutics. O.A.-W. has served as a consultant for H3B Biomedicine, Foundation Medicine Inc., Merck, Prelude Therapeutics, and Janssen and is on the Scientific Advisory Board of Envisagenics Inc., AIChemy, Harmonic Discovery Inc., and Pfizer Boulder. O.A.-W. has received prior research funding from H3B Biomedicine, Nurix Therapeutics, and LOXO Oncology unrelated to the current manuscript. The remaining authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

The gut microbiota has not only been implicated in the development of some cancers but has also been shown to modulate the efficacy of cancer therapeutics. Although the microbiota is an attractive target in cancer therapy, there is limited data available regarding the relevance of microbiota and dietary interventions in the various types of tumors. Recently, a high salt diet (HSD) has attracted attention in cancer development owing to its profound effects on modulating microbiota and immune responses. Here, we investigated the impact of HSD on microbiota, immune responses, and the development of acute myeloid leukemia using two syngeneic transplantation models. HSD significantly changes the microbiota composition, TH17 responses, and NK cells. However, we found no influence of HSD on tumor development. The kinetics and characteristics of tumor development were similar despite varying the number of injected tumor cells. Our data show that the effects of the microbiome and dietary interventions can be tumor-specific and may not apply to all types of cancers., (© 2022. The Author(s).)

There is an increasing population of youths that report mental health issues. Research has shown that youths are reluctant to seek help for various reasons. A majority of those who do seek help are using digital mental health supports. Subsequently, efforts to promote youth mental health have focused on the use of digital applications as a means of overcoming barriers related to factors including stigma and lack of available services. The worldwide move toward recovery-oriented care led to emerging research on personal recovery amongst youths with mental health concerns. This study sought to address the need for recovery-oriented digital resources for youths. It utilised a qualitative design methodology to develop a rich interpretation of how youths are using digital interventions to support their mental health recovery journey. It sought to understand how existing digital applications are useful for youth recovery and identified characteristics associated with recovery and engagement. The content analysis generated five categories that represent facilitators of youth recovery and the thematic analysis identified key elements of digital applications that support youth recovery. The results offer complimentary support and guidance for recovery-oriented care and the use of digital mental health interventions in the promotion of personal recovery amongst youths.

Background: Inactivation of the Hippo pathway promotes Yap nuclear translocation, enabling execution of a transcriptional program that induces tissue growth. Genetic lesions of Hippo intermediates only identify a minority of cancers with illegitimate YAP activation. Yap has been implicated in resistance to targeted therapies, but the mechanisms by which YAP may impact adaptive resistance to MAPK inhibitors are unknown., Methods: We screened 52 thyroid cancer cell lines for illegitimate nuclear YAP localization by immunofluorescence and fractionation of cell lysates. We engineered a doxycycline (dox)-inducible thyroid-specific mouse model expressing constitutively nuclear YAP S127A , alone or in combination with endogenous expression of either Hras G12V or Braf V600E . We also generated cell lines expressing dox-inducible sh-miR-E-YAP and/or YAP S127A . We used cell viability, invasion assays, immunofluorescence, Western blotting, qRT-PCRs, flow cytometry and cell sorting, high-throughput bulk RNA sequencing and in vivo tumorigenesis to investigate YAP dependency and response of BRAF-mutant cells to vemurafenib., Results: We found that 27/52 thyroid cancer cell lines had constitutively aberrant YAP nuclear localization when cultured at high density (NU-YAP), which rendered them dependent on YAP for viability, invasiveness and sensitivity to the YAP-TEAD complex inhibitor verteporfin, whereas cells with confluency-driven nuclear exclusion of YAP (CYT-YAP) were not. Treatment of BRAF-mutant thyroid cancer cells with RAF kinase inhibitors resulted in YAP nuclear translocation and activation of its transcriptional output. Resistance to vemurafenib in BRAF-mutant thyroid cells was driven by YAP-dependent NRG1, HER2 and HER3 activation across all isogenic human and mouse thyroid cell lines tested, which was abrogated by silencing YAP and relieved by pan-HER kinase inhibitors. YAP activation induced analogous changes in BRAF melanoma, but not colorectal cells., Conclusions: YAP activation in thyroid cancer generates a dependency on this transcription factor. YAP governs adaptive resistance to RAF kinase inhibitors and induces a gene expression program in BRAF V600E -mutant cells encompassing effectors in the NRG1 signaling pathway, which play a central role in the insensitivity to MAPK inhibitors in a lineage-dependent manner. HIPPO pathway inactivation serves as a lineage-dependent rheostat controlling the magnitude of the adaptive relief of feedback responses to MAPK inhibitors in BRAF- V600E cancers., (© 2022. The Author(s).)

Aim: To provide insight into the characteristics and treatment outcomes of children and adolescents accessing outpatient Child and Youth Mental Health Services (CYMHS), and to explore whether outcomes differ by age, sex, and ancestry background. This information can guide how to optimize the treatment delivered at these services., Methods: An observational retrospective study was performed based on data from 3098 children and adolescents between age 5 and 18 who received treatment at Brisbane, Australia, community CYMHS between 2013-2018. Patient characteristics, service use, and clinician and parent rated Routine Outcome Measures (ROM) were extracted from electronic health records., Results: Anxiety and mood disorders were the most common mental disorders (37% and 19%). In 1315 children and adolescents (42%), two or more disorders were diagnosed, and the far majority (88%) had experienced at least one psychosocial stressor. The ROM scores improved between start and end of treatment with Cohen's d effect sizes of around 0.9. However, ~50% of the children still scored in the clinical range at the end of treatment. Outcomes did not differ over gender and Indigenous status., Conclusions: Children and adolescents accessing CYMHS have severe and complex mental disorders as reflected by high rates of comorbidity, exposure to adverse circumstances and high symptom scores at the start of treatment. Despite the clinically relevant and substantial improvement, end ROM scores indicated the presence of residual symptoms. As this increases the risk for relapse, services should explore ways to improve treatment to further reduce mental health symptoms., (© 2022 The Authors. Early Intervention in Psychiatry published by John Wiley & Sons Australia, Ltd.)

Personal recovery represents a paradigm shift in how individuals are seen to benefit from mental health interventions, from a narrow view of symptom reduction to a holistic, multi-dimensional view of well-being, functional gains and rehabilitation. Although there is a large body of evidence supporting the use of recovery-oriented care in adults, research on personal recovery amongst youth with mental health concerns is an emerging area of research. Efforts to promote youth mental health have also focussed on the use of digital applications and platforms as a means of overcoming barriers related to factors including stigma and lack of available services. This systematic review aims to review the literature on existing internet-based, youth mental health interventions with regard to (a) identifying elements of the programs that align with the personal recovery and (b) outcome measures utilised in assessing personal recovery. Eleven papers were identified that met the inclusion criteria. Five of the programs reviewed from these eleven papers showed efficacy for recovery processes. The results offer preliminary support and guidance for the use of internet-based mental health interventions in the promotion of personal recovery amongst youth. Future research and practice are suggested to further develop understanding in this area., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© The Author(s) 2022.)

The NtrC family of proteins senses external stimuli and accordingly stimulates stress and virulence pathways via activation of associated σ 54 -dependent RNA polymerases. However, the structural determinants that mediate this activation are not well understood. Here, we establish using computational, structural, biochemical, and biophysical studies that MopR, an NtrC protein, harbors a dynamic bidirectional electrostatic network that connects the phenol pocket to two distal regions, namely the "G-hinge" and the "allosteric linker." While the G-hinge influences the entry of phenol into the pocket, the allosteric linker passes the signal to the downstream ATPase domain. We show that phenol binding induces a rewiring of the electrostatic connections by eliciting dynamic allostery and demonstrates that perturbation of the core relay residues results in a complete loss of ATPase stimulation. Furthermore, we found a mutation of the G-hinge, ∼20 Å from the phenol pocket, promotes altered flexibility by shifting the pattern of conformational states accessed, leading to a protein with 7-fold enhanced phenol binding ability and enhanced transcriptional activation. Finally, we conducted a global analysis that illustrates that dynamic allostery-driven conserved community networks are universal and evolutionarily conserved across species. Taken together, these results provide insights into the mechanisms of dynamic allostery-mediated conformational changes in NtrC sensor proteins., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Patients with SARS-CoV-2 infection are at an increased risk of cardiovascular and thrombotic complications conferring an extremely poor prognosis. COVID-19 infection is known to be an independent risk factor for acute ischemic stroke and myocardial infarction (MI). We developed a risk assessment model (RAM) to stratify hospitalized COVID-19 patients for arterial thromboembolism (ATE). This multicenter, retrospective study included adult COVID-19 patients admitted between 3/1/2020 and 9/5/2021. Among 3531 patients from the training cohort, 15.5% developed acute in-hospital ATE, including stroke, MI, and other ATE, compared to 13.4% in the validation cohort. The 16-item final score was named SARS-COV-ATE (Sex: male = 1, Age [40-59 = 2, > 60 = 4], Race: non-African American = 1, Smoking = 1 and Systolic blood pressure elevation = 1, Creatinine elevation = 1; Over the range: leukocytes/lactate dehydrogenase/interleukin-6, B-type natriuretic peptide = 1, Vascular disease (cardiovascular/cerebrovascular = 1), Aspartate aminotransferase = 1, Troponin-I [> 0.04 ng/mL = 1, troponin-I > 0.09 ng/mL = 3], Electrolytes derangement [magnesium/potassium = 1]). RAM had a good discrimination (training AUC 0.777, 0.756-0.797; validation AUC 0.766, 0.741-0.790). The validation cohort was stratified as low-risk (score 0-8), intermediate-risk (score 9-13), and high-risk groups (score ≥ 14), with the incidence of ATE 2.4%, 12.8%, and 33.8%, respectively. Our novel prediction model based on 16 standardized, commonly available parameters showed good performance in identifying COVID-19 patients at risk for ATE on admission., (© 2022. The Author(s).)

Tuberculous granulomas are highly dynamic structures reflecting the complex host-mycobacterium interactions. The objective of this study was to compare granuloma development at the site of vaccination with BCG and its recombinant derivatives in goats. To characterize the host response, epithelioid cells, multinucleated giant cells (MNGC), T cell subsets, B cells, plasma cells, dendritic cells and mycobacterial antigen were labelled by immunohistochemistry, and lipids and acid-fast bacteria (AFB) were labelled by specific staining. Granulomas with central caseous necrosis developed at the injection site of most goats though lesion size and extent of necrosis differed between vaccine strains. CD4 + T and B cells were more scarce and CD8 + cells were more numerous in granulomas induced by recombinant derivatives compared to their parental BCG strain. Further, the numbers of MNGCs and cells with lipid bodies were markedly lower in groups administered with recombinant BCG strains. Microscopic detection of AFB and mycobacterial antigen was rather frequent in the area of central necrosis, however, the isolation of bacteria in culture was rarely successful. In summary, BCG and its recombinant derivatives induced reproducibly subcutaneous caseous granulomas in goats that can be easily monitored and surgically removed for further studies. The granulomas reflected the genetic modifications of the recombinant BCG-derivatives and are therefore suitable models to compare reactions to different mycobacteria or TB vaccines.

Background: Coronavirus disease-2019 (COVID-19) is associated with thromboembolism. Antiphospholipid antibody (APLa) formation is one of the mechanisms. Vitamin D deficiency has been associated with thrombosis in antiphospholipid antibody syndrome., Objective: Measure APLa and vitamin D in hospitalized COVID-19 patients with and without thrombosis to evaluate if thromboembolism is associated with concomitant APLa and vitamin D deficiency., Methods: Case-control study. Hospitalized COVID-19 patients with a thromboembolic event (ischemic stroke, myocardial infarction, deep venous thrombosis/pulmonary embolism, Cases n = 20). Controls (n = 20): Age, sex-matched without thromboembolic events. Patients with autoimmune disorders, antiphospholipid antibody syndrome, thrombophilia, anticoagulation therapy, prior thromboembolism, chronic kidney disease 3b, 4, end-stage renal disease, and malignancy were excluded. Given the limited current literature on the role of concomitant antiphospholipid antibodies and vitamin D deficiency in causing venous and/or arterial thrombosis in hospitalized COVID-19 patients, we enrolled 20 patients in each arm. Anti-cardiolipin IgG/IgM, beta-2 glycoprotein-1 IgG/IgM, lupus anticoagulant and vitamin D levels were measured in both groups., Results: Cases were 5.7 times more likely to be vitamin D deficient (OR:5.7, 95% CI:1.3-25.6) and 7.4 times more likely to have any one APLa (OR:7.4, 95% CI: 1.6-49.5) while accounting for the effects of sex. Patients with both APLa and vitamin D deficiency had significantly more thrombosis compared to patients who were antibody positive without vitamin D deficiency (100% vs 47.4%; p = 0.01)., Conclusions: Thrombosis in COVID-19 was associated with concomitant APLa and vitamin D deficiency. Future studies in COVID-19 should assess the role of vitamin D in reducing thrombosis., Competing Interests: The authors have declared that no competing interests exist.

Hypercoagulability is a recognized feature in SARS-CoV-2 infection. There exists a need for a dedicated risk assessment model (RAM) that can risk-stratify hospitalized COVID-19 patients for venous thromboembolism (VTE) and guide anticoagulation. We aimed to build a simple clinical model to predict VTE in COVID-19 patients. This large-cohort, retrospective study included adult patients admitted to four hospitals with PCR-confirmed SARS-CoV-2 infection. Model training was performed on 3531 patients hospitalized between March and December 2020 and validated on 2508 patients hospitalized between January and September 2021. Diagnosis of VTE was defined as acute deep vein thrombosis (DVT) or pulmonary embolism (PE). The novel RAM was based on commonly available parameters at hospital admission. LASSO regression and logistic regression were performed, risk scores were assigned to the significant variables, and cutoffs were derived. Seven variables with assigned scores were delineated as: DVT History = 2; High D-Dimer (>500−2000 ng/mL) = 2; Very High D-Dimer (>2000 ng/mL) = 5; PE History = 2; Low Albumin (<3.5 g/dL) = 1; Systolic Blood Pressure <120 mmHg = 1, Tachycardia (heart rate >100 bpm) = 1. The model had a sensitivity of 83% and specificity of 53%. This simple, robust clinical tool can help individualize thromboprophylaxis for COVID-19 patients based on their VTE risk category.

Propolis is a natural compound collected by honeybees from different parts of plants. Honeybees produce a sticky component besides honey by mixing the tree resin and other botanical sources with saliva called propolis or bee glue. Propolis was traditionally used as a wound healing substance, cosmetic, medicine, and many other conditions. Till now, there is no definite curable treatment for most cancers and chemotherapeutic drugs and drugs used for targeted therapies have serious side effects. According to a recent research, natural products are becoming increasingly essential in cancer prevention. Natural products are a great source of potential therapeutic agents, especially in the treatment of cancer. Previous studies have reported that the presence of caffeic acid phenethyl ester (CAPE), artepillin C, and chrysin is responsible for the anticancer potential of propolis. Most of the previous studies suggested that propolis and its active compounds inhibit cancer progression by targeting multiple signaling pathways including phosphoinositide 3-kinases (PI3K)/Akt and mitogen-activated protein kinase (MAPK) signaling molecules, and induce cell cycle arrest. Induction of apoptosis by propolis is mediated through extrinsic and intrinsic apoptotic pathways. The aim of this review is to highlight and summarize the molecular targets and anticancer potential of propolis and its active compounds on cell survival, proliferation, metastasis, and apoptosis in cancer cells., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Perumal Elumalai et al.)

Atrial arrhythmias (AAs) are common in hospitalized patients with COVID-19; however, it remains uncertain if AAs are a poor prognostic factor in SARS-CoV-2 infection. In this retrospective cohort study from 2014 to 2021, we report in-hospital mortality in patients with new-onset AA and history of AA. The incidence of new-onset congestive heart failure (CHF), hospital length of stay and readmission rate, intensive care unit admission, arterial and venous thromboembolism, and imaging outcomes were also analyzed. We further compared the clinical outcomes with a propensity-matched influenza cohort. Generalized linear regression was performed to identify the association of AA with mortality and other outcomes, relative to those without an AA diagnosis. Predictors of new-onset AA were also modeled. A total of 6,927 patients with COVID-19 were included (626 with new-onset AA, 779 with history of AA). We found that history of AA (adjusted relative risk [aRR] 1.38, confidence interval [CI], 1.11 to 1.71, p = 0.003) and new-onset AA (aRR 2.02, 95% CI 1.68 to 2.43, p <0.001) were independent predictors of in-hospital mortality. The incidence of new-onset CHF was 6.3% in history of AA (odds ratio 1.91, 95% CI 1.30 to 2.79, p <0.001) and 11.3% in new-onset AA (odds ratio 4.01, 95% CI 3.00 to 5.35, p <0.001). New-onset AA was shown to be associated with worse clinical outcomes within the propensity-matched COVID-19 and influenza cohorts. The risk of new-onset AA was higher in patients with COVID-19 than influenza (aRR 2.02, 95% CI 1.76 to 2.32, p <0.0001), but mortality associated with new-onset AA was higher in influenza (aRR 12.58, 95% CI 4.27 to 37.06, p <0.0001) than COVID-19 (aRR 1.86, 95% CI 1.55 to 2.22, p <0.0001). In a subset of the patients with COVID-19 for which echocardiographic data were captured, abnormalities were common, including valvular abnormalities (40.9%), right ventricular dilation (29.6%), and elevated pulmonary artery systolic pressure (16.5%); although there was no evidence of a difference in incidence among the 3 groups. In conclusion, new-onset AAs are associated with poor clinical outcomes in patients with COVID-19., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Atrial arrhythmias (AA) are common in hospitalized COVID-19 patients with limited data on their association with COVID-19 infection, clinical and imaging outcomes. In the related research article using retrospective research data from one quaternary care and five community hospitals, patients aged 18 years and above with positive SARS-CoV-2 polymerase chain reaction test were included. 6927 patients met the inclusion criteria. The data in this article provides demographics, home medications, in-hospital events and COVID-19 treatments, multivariable generalized linear regression regression models using a log link with a Poisson distribution (multi-parameter regression [MPR]) to determine predictors of new-onset AA and mortality in COVID-19 patients, computerized tomography chest scan findings, echocardiographic findings, and International Classification of Diseases-Tenth Revision codes. The clinical outcomes were compared to a propensity-matched cohort of influenza patients. For influenza, data is reported on baseline demographics, comorbid conditions, and in-hospital events. Generalized linear regression models were built for COVID-19 patients using demographic characteristics, comorbid conditions, and presenting labs which were significantly different between the groups, and hypoxia in the emergency room. Statistical analysis was performed using R programming language (version 4, ggplot2 package). Multivariable generalized linear regression model showed that, relative to normal sinus rhythm, history of AA (adjusted relative risk [RR]: 1.38; 95% CI: 1.11-1.71; p  = 0.003) and newly-detected AA (adjusted RR: 2.02 95% CI: 1.68-2.43; p  < 0.001) were independently associated with higher in-hospital mortality. Age in increments of 10 years, male sex, White race, prior history of coronary artery disease, congestive heart failure, end-stage renal disease, presenting leukocytosis, hypermagnesemia, and hypomagnesemia were found to be independent predictors of new-onset AA in the MPR model. The dataset reported is related to the research article entitled "Incidence, Mortality, and Imaging Outcomes of Atrial Arrhythmias in COVID-19" [Jehangir et al. Incidence, Mortality, and Imaging Outcomes of Atrial Arrhythmias in COVID-19, American Journal of Cardiology] [1]., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s). Published by Elsevier Inc.)

Background: Patients with COVID-19 infection are commonly reported to have an increased risk of venous thrombosis. The choice of anti-thrombotic agents and doses are currently being studied in randomized controlled trials and retrospective studies. There exists a need for individualized risk stratification of venous thromboembolism (VTE) to assist clinicians in decision-making on anticoagulation. We sought to identify the risk factors of VTE in COVID-19 patients, which could help physicians in the prevention, early identification, and management of VTE in hospitalized COVID-19 patients and improve clinical outcomes in these patients., Method: This is a multicenter, retrospective database of four main health systems in Southeast Michigan, United States. We compiled comprehensive data for adult COVID-19 patients who were admitted between 1st March 2020 and 31st December 2020. Four models, including the random forest, multiple logistic regression, multilinear regression, and decision trees, were built on the primary outcome of in-hospital acute deep vein thrombosis (DVT) and pulmonary embolism (PE) and tested for performance. The study also reported hospital length of stay (LOS) and intensive care unit (ICU) LOS in the VTE and the non-VTE patients. Four models were assessed using the area under the receiver operating characteristic curve and confusion matrix., Results: The cohort included 3531 admissions, 3526 had discharge diagnoses, and 6.68% of patients developed acute VTE (N = 236). VTE group had a longer hospital and ICU LOS than the non-VTE group (hospital LOS 12.2 days vs. 8.8 days, p < 0.001; ICU LOS 3.8 days vs. 1.9 days, p < 0.001). 9.8% of patients in the VTE group required more advanced oxygen support, compared to 2.7% of patients in the non-VTE group (p < 0.001). Among all four models, the random forest model had the best performance. The model suggested that blood pressure, electrolytes, renal function, hepatic enzymes, and inflammatory markers were predictors for in-hospital VTE in COVID-19 patients., Conclusions: Patients with COVID-19 have a high risk for VTE, and patients who developed VTE had a prolonged hospital and ICU stay. This random forest prediction model for VTE in COVID-19 patients identifies predictors which could aid physicians in making a clinical judgment on empirical dosages of anticoagulation., (© 2022. The Author(s).)

The effect of water, confinement and confined water on the proton transfer of 3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazole (bis-HPTA) was investigated. Water alters the proton transfer process. At higher pH, an anion is formed in water and it undergoes intermolecular proton transfer and forms a keto tautomer. Confinement of molecule in β-cyclodextrin affects the intramolecular proton transfer. It also prevents the intermolecular proton transfer of the anionic form. In reverse micelle, the molecule resides in the interfacial region and interacts with bound water. The intermolecular hydrogen bond of the surfactants opens the intramolecular hydrogen bond in the weaker β-ring of bis-HPTA. It led to single tautomer emission from bis-HPTA. An increase in water amount enhances the relative amount of trans-enol, but predominantly tautomer emission is observed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

T cells express co-receptors CD4 and CD8, which are involved in the recognition of antigen presented to T cell receptors. The expression of CD4 in thymic hematopoietic cells is crucial for the thymic development and selection of T cells. In this study, we identified a novel CD4 mutant allele that emerged spontaneously in our mouse colony. The frameshift mutation led to a truncated CD4 protein which failed to reach the plasma membrane resulting in impaired development of CD4+ helper T cells. The CRISPR mediated correction of mutant allele restored the membrane CD4 expression. Further, using an adoptive transfer of T cells, we show that this model is an ideal recipient mouse for the study of CD4+ T cells., Competing Interests: The authors have declared that no competing interests exist.

The reaction coordinates of a molecular photo-switch 2-(4'-diethylamino-2'-hydroxyphenyl)-1 H -imidazo-[4,5- b ]pyridine (DHP) was tuned with a nanoparticle and surfactant. DHP undergoes excited state intramolecular proton transfer (ESIPT) and emits normal and tautomer emissions in N,N -dimethylformamide. Silver nanoparticles suppress the ESIPT and induce twisted intramolecular charge transfer (TICT). Further addition of surfactants alters the process. Interestingly, different surfactants cause different effects. Accordingly, the luminescence characteristics are altered. The anionic surfactant sodium dodecyl sulfate (SDS) restores the ESIPT process by completely detaching the molecule from the nanoparticle. The nonionic surfactant Triton X-100 (TX-100), at lower concentration, enhances the TICT emission and the ESIPT process is also observed due to the release of some fluorophore from the nanoparticle complex. But at higher concentration the fluorophores are released completely and the ESIPT process is restored. The cationic surfactant cetyltrimethyl ammonium bromide (CTAB), at lower concentration, simply restores the ESIPT process by releasing the fluorophore. But at higher CTAB concentration, DHP enters the metalparticle-CTAB aggregate and shows enhanced ESIPT.

A 24-year-old female presented with nausea, vomiting and abdominal pain. Physical examination was unremarkable. The patient's laboratory studies showed calcium of 17.2 mg/d, white cell count: 9,000/mcL with a normal peripheral blood smear. The patient had low PTH and PTHrp. She was hydrated, given calcitonin of four units/kg every 12 hours subcutaneously for 24 hours and zoledronate IV 4mg given once, with which calcium levels normalized and symptoms resolved. The patient returned one week later, with bone pain and bruises. Platelet count: 51,000/mcL, WBC count: 9,000/mcL, with lymphocytosis. A peripheral smear showed lymphoblasts. Flow cytometry confirmed precursor B-cell acute lymphoblastic leukemia (ALL) with 43% blasts. Hypercalcemic patients may have blasts at presentation, but can be "aleukemic." Unexplained hypercalcemia with bone pain should lead to the suspicion of ALL, and a bone marrow exam should be performed even without peripheral blastosis to diagnose and treat ALL immediately., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Trikannad Ashwini Kumar et al.)

Introduction: Triple-negative breast cancer (TNBC) in men is very rare. The clinical characteristics, prognostic factors, and overall survival of men with TNBC have not been characterized., Methods: The study population consisted of men and women with a diagnosis of stage I-III TNBC between 2010 and 2016 in the National Cancer Database. Baseline demographic and tumor characteristics between men and women were compared using Pearson's Chi-Square test for categorical variables and Mann-Whitney U test for continuous variables. Kaplan-Meier and multivariate Cox proportional hazards regression model was used to compare survival and identify prognostic factors., Results: A total of 311 men and 95,406 women with TNBC were included in the final analysis. The 3-year and 5-year overall survival was 74.8% and 68.8% in men, while it was 83.2% and 74.8% in women, respectively. In multivariate analysis, men were found to have a significantly worse overall survival compared to women (HR, 1.49, 95% CI, 1.19-1.86, P= .01). Older age at diagnosis, higher TNM stage, undergoing mastectomy and not undergoing chemotherapy or radiation were identified as independent negative prognostic factors in men with TNBC., Conclusion: In one of the largest studies of men with TNBC, men were noted to have a poorer overall survival compared to women, despite adjusting for usual prognostic factors. Further research into differences in tumor biology, treatment patterns and compliance with therapy between men and women are needed to understand the underlying etiologies for the survival difference in TNBC., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Chlorhexidine is the most favored and widely used antimicrobial agent for the treatment of peri-implantitis. But, not many clinicians are aware of its side effects on dental implants and its cytotoxic effects on osteoblasts. The objectives of this review are to study the effect of chlorhexidine on osteoblasts as well as on the surface topography of dental implants., Materials and Methods: MEDLINE-PubMed (The National Library of Medicine, Washington DC) was used as a search engine. Databases were searched from 2010 to 2020 were explored using the following terms: "dental implant surface," "chlorhexidine mouthwash," "osteoblast cells," "osseointegration." From the total hits obtained, each article along with its cross-reference was manually read and filtered based on the focused question. The inclusion criteria included articles published only in English language involving human studies, randomized control trials, in vitro studies, and review articles. Exclusion criteria included studies published in languages other than English, orthodontic mini-implants, and pilot studies. The final process involved scrutinizing for any duplicate content of the hand searched articles. Following this, data was extracted from the compiled hand searched articles to obtain relevant information for the review., Results: Chlorhexidine alters the surface topography of dental implants and causes cell cytotoxicity. This, in turn, can hinder the re-osseointegration potential and hence cause dental implant failure. It is, therefore, recommended to discourage the use of chlorhexidine as a surface decontaminant for peri-implantitis cases and practice implementing other antimicrobial agents.

Respiratory infections caused by multidrug-resistant Acinetobacter baumannii are difficult to treat and associated with high mortality among critically ill hospitalized patients. Bacteriophages (phages) eliminate pathogens with high host specificity and efficacy. However, the lack of appropriate preclinical experimental models hampers the progress of clinical development of phages as therapeutic agents. Therefore, we tested the efficacy of a purified lytic phage, vB&#95;AbaM&#95;Acibel004, against multidrug-resistant A. baumannii clinical isolate RUH 2037 infection in immunocompetent mice and a human lung tissue model. Sham- and A. baumannii -infected mice received a single-dose of phage or buffer via intratracheal aerosolization. Group-specific differences in bacterial burden, immune and clinical responses were compared. Phage-treated mice not only recovered faster from infection-associated hypothermia but also had lower pulmonary bacterial burden, lower lung permeability, and cytokine release. Histopathological examination revealed less inflammation with unaffected inflammatory cellular recruitment. No phage-specific adverse events were noted. Additionally, the bactericidal effect of the purified phage on A. baumannii was confirmed after single-dose treatment in an ex vivo human lung infection model. Taken together, our data suggest that the investigated phage has significant potential to treat multidrug-resistant A. baumannii infections and further support the development of appropriate methods for preclinical evaluation of antibacterial efficacy of phages.

Endometrial carcinoma is the most common gynecological malignancy in the USA with approximately 66,570 cases and 12,940 deaths in 2020. Clear cell carcinoma (CCC) of the endometrium is an estrogen-independent type II endometrial cancer which accounts for <5% of endometrial cancer. When diagnosed roughly, 45% of patients have extrauterine metastases. Current American College of Obstetrics and Gynecology guidelines recommend transvaginal ultrasound for postmenopausal bleeding and a biopsy for those with endometrial thickness >5 mm. However, we present a case of a postmenopausal woman with a history of fibroid where endometrial biopsy has failed to make diagnosis twice. Hence, further testing should be performed in patients with unexplained postmenopausal bleeding including vaginal hysterectomy with lymph node dissection., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this article., (Copyright © 2021 by The Author(s). Published by S. Karger AG, Basel.)

Tuberculosis (TB) is the leading infectious cause of death globally. The only licensed TB vaccine, Bacille Calmette-Guérin (BCG), has low efficacy against TB in adults and is not recommended in people with impaired immunity. The incorporation of the Mycobacterium tuberculosis (Mtb) secretion system ESX-1 into BCG improves immunogenicity and protection against TB in animal models, which is associated with the secretion of the ESX-1-dependent protein ESAT-6. However, the resulting strain, BCG::ESX1 Mtb , has been deemed unsafe as a human vaccine, due to prolonged persistence and increased virulence in immunocompromised mice. In this study, we describe a new recombinant BCG strain that uncouples the beneficial aspects of ESAT-6 secretion from the detrimental ESX-1effects on virulence and persistence. The strain was constructed by fusing the ESAT-6-encoding gene esxA to the general secretion signal for the mycobacterial type VII secretion pathway protein PE25. This new strain, BCG::ESAT6-PE25SS, secretes full-length ESAT-6 via the ESX-5 secretion system, which in contrast to ESX-1 is also present in BCG. In vivo testing revealed that ESX-5-targeted ESAT-6 export, induces cytosolic contact, generates ESAT-6-specific T cells and enhances the protective efficacy against TB disease, but is associated with low virulence and reduced persistence in immunocompetent and immunocompromised mice. Additionally, compared to BCG::ESX1 Mtb and parental BCG, mucosal administration of BCG::ESAT6-PE25SS is associated with more rapid clearance from the lung. These results warrant further studies to evaluate BCG::ESAT6-PE25SS as a potential live attenuated vaccine candidate for TB., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Andreas Kupz reports financial support was provided by Australian National Health and Medical Research Council. Aliabbas Husain reports financial support was provided by Indian Government. Andreas Kupz reports a relationship with Collaboration for Tuberculosis Vaccine Discovery (Bill and Melinda Gates Foundation) that includes: board membership and travel reimbursement. Andreas Kupz has patent filing # number 2021900320 pending to James Cook University., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Therapeutic doses of anticoagulation have been administered to patients with coronavirus-19 disease (Covid-19) without thromboembolism, although there is a lack of robust evidence supporting this practice., Study Question: To compare outcomes between patients admitted to the hospital for Covid-19 who received full-dose anticoagulation purely for the indication of Covid-19 and patients who received prophylactic doses of anticoagulation., Study Design: This is a multicenter retrospective cohort study, including 7 community hospitals in Michigan. Patients were >18 years of age, confirmed positive for Covid-19 by polymerase chain reaction, and admitted to the hospital between March 10 and May 3, 2020. Exposed group: Patients receiving therapeutic dose anticoagulation for Covid-19 for any duration excluding clinically evident venous thromboembolism, atrial fibrillation, and myocardial infarction; control group: Patients receiving prophylactic anticoagulation. Propensity score matching was used to adjust for the nonrandomized nature of the study., Measures and Outcomes: The primary endpoint: 30-day in-hospital mortality. Secondary endpoints: intubation, length of hospital stay, and readmissions in survivors., Results: A total of 115 exposed and 115 control patients were analyzed. Rates of 30-day in-hospital mortality were similar (exposed: 33.0% vs. control: 28.7%). Controlling for institution, there was no significant association between treatment and 30-day in-hospital mortality (hazard ratio: 0.63; 95% confidence interval: 0.37-1.06). Survivors had statistically similar length of hospital stay and readmission rates., Conclusions: We found no difference in mortality in patients with Covid-19 without clinically evident venous thromboembolism, atrial fibrillation, and myocardial infarction who received therapeutic versus prophylactic doses of anticoagulation., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Mycofactocin is a new class of peptide-derived redox cofactors present in a selected group of bacteria including Mycobacterium tuberculosis. Mycofactocin biosynthesis requires at least six genes, including mftD , encoding putative lactate dehydrogenase, which catalyzes the penultimate biosynthetic step. Cellular functions remained unknown until recent reports on the significance of mycofactocin in primary alcohol metabolism. Here, we show that mftD transcript levels were increased in hypoxia-adapted M. tuberculosis; however, mftD functionality was found likely dispensable for l-lactate metabolism. Targeted deletion of mftD reduced the survival of M. tuberculosis in in vitro and in vivo hypoxia models but increased the bacterial growth in glucose-containing broth as well as in the lungs and spleens, albeit modestly, of aerosol-infected C57BL/6J mice. The cause of this growth advantage remains unestablished; however, the mftD -deficient M. tuberculosis strain had reduced NAD(H)/NADP(H) levels and glucose-6-phosphate dehydrogenase activity with no impairment in phthiocerol dimycocerosate lipid synthesis. An ultrastructural examination of parental and mycofactocin biosynthesis gene mutants in M. tuberculosis, M. marinum, and M. smegmatis showed no altered cell morphology and size except the presence of outer membrane-bound fibril-like features only in a mutant subpopulation. A cell surface-protein analysis of M. smegmatis mycofactocin biosynthesis mutants with trypsin revealed differential abundances of a subset of proteins that are known to interact with mycofactocin and their homologs that can enhance protein aggregation or amyloid-like fibrils in riboflavin-starved eukaryotic cells. In sum, phenotypic analyses of the mutant strain implicate the significance of MftD/mycofactocin in M. tuberculosis growth and persistence in its host. IMPORTANCE Characterization of proteins with unknown functions is a critical research priority as the intracellular growth and metabolic state of Mycobacterium tuberculosis, the causative agent of tuberculosis, remain poorly understood. Mycofactocin is a peptide-derived redox cofactor present in almost all mycobacterial species; however, its functional relevance in M. tuberculosis pathogenesis and host survival has never been studied experimentally. In this study, we examine the phenotypes of an M. tuberculosis mutant strain lacking a key mycofactocin biosynthesis gene in in vitro and disease-relevant mouse models. Our results pinpoint the multifaceted role of mycofactocin in M. tuberculosis growth, hypoxia adaptation, glucose metabolism, and redox homeostasis. This evidence strongly implies that mycofactocin could fulfill specialized biochemical functions that increase the survival fitness of mycobacteria within their specific niche.

Computational fluid dynamics (CFD) simulations of respiratory airflow have the potential to change the clinical assessment of regional airway function in health and disease, in pulmonary medicine and otolaryngology. For example, in diseases where multiple sites of airway obstruction occur, such as obstructive sleep apnea (OSA), CFD simulations can identify which sites of obstruction contribute most to airway resistance and may therefore be candidate sites for airway surgery. The main barrier to clinical uptake of respiratory CFD to date has been the difficulty in validating CFD results against a clinical gold standard. Invasive instrumentation of the upper airway to measure respiratory airflow velocity or pressure can disrupt the airflow and alter the subject's natural breathing patterns. Therefore, in this study, we instead propose phase contrast (PC) velocimetry magnetic resonance imaging (MRI) of inhaled hyperpolarized 129Xe gas as a non-invasive reference to which airflow velocities calculated via CFD can be compared. To that end, we performed subject-specific CFD simulations in airway models derived from 1H MRI, and using respiratory flowrate measurements acquired synchronously with MRI. Airflow velocity vectors calculated by CFD simulations were then qualitatively and quantitatively compared to velocity maps derived from PC velocimetry MRI of inhaled hyperpolarized 129Xe gas. The results show both techniques produce similar spatial distributions of high velocity regions in the anterior-posterior and foot-head directions, indicating good qualitative agreement. Statistically significant correlations and low Bland-Altman bias between the local velocity values produced by the two techniques indicates quantitative agreement. This preliminary in vivo comparison of respiratory airway CFD and PC MRI of hyperpolarized 129Xe gas demonstrates the feasibility of PC MRI as a technique to validate respiratory CFD and forms the basis for further comprehensive validation studies. This study is therefore a first step in the pathway towards clinical adoption of respiratory CFD., Competing Interests: Drs Hui Wang and Guruprasad Krishnamoorthy are employees of Philips. Philips did not fund this study, nor did they have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript other than the roles of these authors as articulated in the ‘author contributions’ section. These conflicts do not alter our adherence to PLOS ONE policies on sharing data and materials. No other competing interests exist.

Background: The aims of the study were to identify predictors of heparin-induced thrombocytopenia (HIT) in hospitalized adults, and to find additional factors associated with higher odds of HIT in primary hypercoagulable states., Methods: A retrospective matched case-control study using discharge data from National Inpatient Sample database (2012 - 2014) was conducted. In primary outcome analysis, hospitalized patients with and without HIT were included as cases and controls, both matched for age and gender. In secondary outcome analysis, hospitalized patients with primary hypercoagulable states with and without HIT were included as cases and controls, both matched for age and gender. The statistical analyses were performed using Statistical Package for Social Sciences version 25., Results: There are several predictors of HIT in hospitalized patients, such as obesity, malignancy, diabetes, renal failure, major surgery, congestive heart failure, and autoimmune diseases. In patients with primary hypercoagulable states, the presence of renal failure (odds ratio (OR) 2.955, 95% confidence interval (CI) 1.994 - 4.380), major surgery (OR 1.735, 95% CI 1.275 - 2.361), congestive heart failure (OR 4.497, 95% CI 2.466 - 8.202), or autoimmune diseases (OR 1.712, 95% CI 1.120 - 2.618) further increases the odds of HIT., Conclusions: In hospitalized patients with primary hypercoagulable states, especially in association with renal failure, major surgery, congestive heart failure, or autoimmune diseases, unfractionated heparin should be used with caution., Competing Interests: The authors have no conflict of interest to declare., (Copyright 2021, Kaur et al.)

There is a great interest in developing antigen-specific therapeutic approaches for the treatment of autoimmune diseases without compromising normal immune function. The key challenges are to control all antigen-specific lymphocyte populations that contribute to pathogenic inflammatory processes and to provide long-term protection from disease relapses. Here, we show that myelin oligodendrocyte glycoprotein (MOG)-specific tolerance can be established by ectopic expression of MOG in the immune organs. Using transgenic mice expressing MOG-specific CD4, CD8, and B cell receptors, we show that MOG expression in the bone marrow cells results in impaired development of MOG-specific lymphocytes. Ectopic MOG expression has also resulted in long-lasting protection from MOG-induced autoimmunity. This finding raises hope that transplantation of autoantigen-expressing bone marrow cells as a therapeutic strategy for specific autoantigen-driven autoimmune diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Na and Krishnamoorthy.)

Experimental autoimmune encephalomyelitis (EAE) is classically induced with complete Freund's adjuvant (CFA). The immune response against CFA has a confounding influence on the translational capacity of EAE as a multiple sclerosis model. Here, we compare clinical, cellular and molecular properties between syngeneic spinal cord homogenate (SCH)- and SCH + CFA-immunized Dark Agouti rats. EAE signs were observed earlier and the cumulative clinical score was higher without CFA. Also, a higher number of immune cells infiltrates in the spinal cords was noticed at the peak of EAE without CFA. High spinal cord abundance of CD8 + CD11bc + MHC class II + cells was detected in SCH-immunized rats. Myelin basic protein -specific response can be elicited in the cells from the lymph nodes draining the site of SCH immunization. This CFA-free EAE is a reliable multiple sclerosis model., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Understanding the properties of the unfolded state under folding conditions is of fundamental importance for gaining mechanistic insight into folding as well as misfolding reactions. Toward achieving this objective, the folding reaction of a small protein, monellin, has been resolved structurally and temporally, with the use of the multisite time-resolved FRET methodology. The present study establishes that the initial polypeptide chain collapse is not only heterogeneous but also structurally asymmetric and nonuniform. The population-averaged size for the segments spanning parts of the β-sheet decreases much more than that for the α-helix. Multisite measurements enabled specific and nonspecific components of the initial chain collapse to be discerned. The expanded and compact intermediate subensembles have the properties of a nonspecifically collapsed (hence, random-coil-like) and specifically collapsed (hence, globular) polymer, respectively. During subsequent folding, both the subensembles underwent contraction to varying extents at the four monitored segments, which was close to gradual in nature. The expanded intermediate subensemble exhibited an additional very slow contraction, suggestive of the presence of non-native interactions that result in a higher effective viscosity slowing down intrachain motions under folding conditions.

Sodium chloride, "salt," is an essential component of daily food and vitally contributes to the body's homeostasis. However, excessive salt intake has often been held responsible for numerous health risks associated with the cardiovascular system and kidney. Recent reports linked a high-salt diet (HSD) to the exacerbation of artificially induced central nervous system (CNS) autoimmune pathology through changes in microbiota and enhanced T H 17 cell differentiation [M. Kleinewietfeld et al. , Nature 496, 518-522 (2013); C. Wu et al. , Nature 496, 513-517 (2013); N. Wilck et al. , Nature 551, 585-589 (2017)]. However, there is no evidence that dietary salt promotes or worsens a spontaneous autoimmune disease. Here we show that HSD suppresses autoimmune disease development in a mouse model of spontaneous CNS autoimmunity. We found that HSD consumption increased the circulating serum levels of the glucocorticoid hormone corticosterone. Corticosterone enhanced the expression of tight junction molecules on the brain endothelial cells and promoted the tightening of the blood-brain barrier (BBB) thereby controlling the entry of inflammatory T cells into the CNS. Our results demonstrate the multifaceted and potentially beneficial effects of moderately increased salt consumption in CNS autoimmunity., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

A molecular photoswitch, 2-(4'-diethylamino-2'-hydroxyphenyl)-1 H -imidazo-[4,5-b]pyridine (DHP), with mutually independent paths of excited-state intramolecular proton transfer (ESIPT) and twisted intramolecular charge transfer (TICT) was developed. Control over these processes was attained by switching the solvents. Depending on the solvent's hydrogen-bond capacity and polarity, either one of the photoprocesses (ESIPT or TICT) or both can be triggered. Accordingly, normal and tautomer emissions, normal and TICT emissions, or triple emission of normal, tautomer, and TICT were obtained from the molecule. The emissions were resolved by fluorescence lifetime. The conclusions were established by synthesizing and studying the methoxy derivative of the molecule.

Coronavirus disease 2019 (COVID-19) infection has been associated with various complications such as acute respiratory distress syndrome, acute kidney failure, myocardial infection, and thromboembolism. Cold agglutinin syndrome (CAS) has been associated with other viral infections such as Epstein-Barr virus (EBV), but there have been only a few reports of cold agglutination associated with COVID-19. In this report, we describe a case of transient cold agglutinin elevation in a COVID-19-infected patient. A 61-year-old man with hypertension, diabetes mellitus, and end-stage renal disease (ESRD) presented with shortness of breath, cough, and lethargy for five days. A clinical diagnosis of COVID-19 infection was made. The COVID-19 RNA qualitative real-time polymerase-chain-reaction (PCR) assay tested positive. During the hospital stay, he had progressive dyspnea requiring intubation and mechanical ventilation. During the third week of hospital stay, an acute drop in the hemoglobin (Hb) level to 4.5 g/dl (baseline Hb: 9 g/dl) was observed. The workup for acute anemia revealed a positive result for cold agglutinins, direct antibody test (C3d), and agglutination of the red blood cells were apparent on the peripheral blood smear. Further, cold agglutinin titers peaked during the third week of the onset of illness and significantly declined during the fifth week. These observational findings indicate that cold agglutinin titers might correlate with the disease activity., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Kaur et al.)

Bacterial brain abscesses are typically spread through a haematogenous route. Open head wounds and neurosurgical interventions are uncommon aetiologies. Ectopic tissue found in the cerebral cortex is usually ascribed almost entirely from carcinomas. Here, we describe a 57-year-old gentleman who, 22 years after a fireworks related traumatic injury to the left orbit, presented with headaches and altered behaviour. Imaging revealed an abscess immediately superior to the orbit, whose bacterial aetiology was identified to be Pseudomonas aeruginosa, encapsulated by ciliated respiratory epithelium. This represents a case in which tissue was displaced during the initial trauma or craniofacial reconstructive surgery from the frontal sinus., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

In the present study lipopeptide biosurfactant with high emulsification capacity produced by human skin bacterium Paenibacillus thiaminolyticus was purified and subjected to FTIR and NMR spectral analysis which gave evidence of the active characteristics of the surfactant. To augment the antivirulent potential further, the mixer of copper and copper oxide nanoparticles (CuNPs) was synthesized, and characterized by UV-Visible spectroscopy, SEM-EDAX, TEM, and Zeta analysis. Here, we attempted to enhance the antimicrobial and antibiofilm activity with the assistance of encapsulated preparation of lipopeptide and CuNPs in multilamellar liposomes. The proposed mechanism of action of lipopeptide and CuNPs liposomal preparation negatively influences the cell metabolism, secreted virulence such as staphyloxanthin, pyocyanin, and extracellular polysaccharides. The significant decline in the growth of MRSA and P. aeruginosa in both planktonic form and biofilm by lipopeptide and CuNPs treatment were visualized using scanning electron microscopy and High content screening imaging system. In vivo studies revealed that treatment with lipopeptide and CuNPs in multilamellar liposomes extended the lifespan of infected Caenorhabditis elegans by about 75%. Therefore, this study typifies lipopeptide and CuNPs could credibly be a substantial substitute over conventional antibiotics in averting the biofilm associated pathogenesis of MRSA and P. aeruginosa.