Human red blood cells express the RNA sensor TLR7.

Red blood cells (RBCs) express the nucleic acid-binding toll-like receptor 9 (TLR9) and bind CpG-containing DNA. However, whether human RBCs express other nucleic acid-binding TLRs is unknown. Here we show that human RBCs express the RNA sensor TLR7. TLR7 is present on the red cell membrane and is associated with the RBC membrane protein Band 3. In patients with SARS-CoV2-associated sepsis, TLR7-Band 3 interactions in the RBC membrane are increased when compared with healthy controls. In vitro, RBCs bind synthetic ssRNA and RNA from ssRNA viruses. Thus, RBCs may serve as a previously unrecognized sink for exogenous RNA, expanding the repertoire of non-gas exchanging functions performed by RBCs.

Inflammatory and tissue injury marker dynamics in pediatric acute respiratory distress syndrome.

BACKGROUNDThe molecular signature of pediatric acute respiratory distress syndrome (ARDS) is poorly described, and the degree to which hyperinflammation or specific tissue injury contributes to outcomes is unknown. Therefore, we profiled inflammation and tissue injury dynamics over the first 7 days of ARDS, and associated specific biomarkers with mortality, persistent ARDS, and persistent multiple organ dysfunction syndrome (MODS).METHODSIn a single-center prospective cohort of intubated pediatric patients with ARDS, we collected plasma on days 0, 3, and 7. Nineteen biomarkers reflecting inflammation, tissue injury, and damage-associated molecular patterns (DAMPs) were measured. We assessed the relationship between biomarkers and trajectories with mortality, persistent ARDS, or persistent MODS using multivariable mixed effect models.RESULTSIn 279 patients (64 [23%] nonsurvivors), hyperinflammatory cytokines, tissue injury markers, and DAMPs were higher in nonsurvivors. Survivors and nonsurvivors showed different biomarker trajectories. IL-1α, soluble tumor necrosis factor receptor 1, angiopoietin 2 (ANG2), and surfactant protein D increased in nonsurvivors, while DAMPs remained persistently elevated. ANG2 and procollagen type III N-terminal peptide were associated with persistent ARDS, whereas multiple cytokines, tissue injury markers, and DAMPs were associated with persistent MODS. Corticosteroid use did not impact the association of biomarker levels or trajectory with mortality.CONCLUSIONSPediatric ARDS survivors and nonsurvivors had distinct biomarker trajectories, with cytokines, endothelial and alveolar epithelial injury, and DAMPs elevated in nonsurvivors. Mortality markers overlapped with markers associated with persistent MODS, rather than persistent ARDS.FUNDINGNIH (K23HL-136688, R01-HL148054).

Controlling the optical and magnetic properties of CdTeSe and Gd-doped CdTeSe alloy semiconductor nanocrystals.

In this study, CdTexSe1-x (0 ≤ x ≤ 1) and CdTeSe:Gd y% (y = 0-8.05) alloy semiconductor nanocrystals (NCs) were prepared by wet chemical method. The presence and composition of the elements in the sample were determined by energy dispersive X-ray (EDX) spectroscopy and X-ray photoelectron spectroscopy (XPS). Structural analysis of X-ray diffraction (XRD) patterns indicated that most NCs crystallized in the zinc blende (ZB) structure however some Gd-doped NCs (y = 4.52 and 8.05%) crystallized in the wurtzite (WZ) structure. The emission peak of CdTexSe1-x (0 ≤ x ≤ 1) NCs varied over a wide range when changing x while the particle size remained almost unchanged. The effect of Gd doping on the structure and optical and magnetic properties of CdTeSe NCs was studied in detail. When the Gd concentration increases from 0-8.05%: (i) the structure of CdTeSe NCs gradually changed from ZB to WZ, (ii) the emission efficiency of the material was significantly reduced, (iii) the PL lifetime of samples increased more than 10 times, and (iv) the ferromagnetic properties of the material were enhanced. The research findings demonstrated that it is possible to control the crystal structure, optical characteristics, and magnetic properties of Gd-doped CdTeSe nanocrystals by adjusting the dopant concentration and chemical composition of the host material.

Consensus recommendations for the screening, diagnosis, and management of Helicobacter pylori infection in Hong Kong.

Helicobacter pylori infection causes chronic gastric inflammation that contributes to various gastroduodenal diseases, including peptic ulcer and gastric cancer. Despite broad regional variations, the prevalence of resistance to antibiotics used to manage H pylori infection is increasing worldwide; this trend could hinder the success of eradication therapy. To increase awareness of H pylori and improve the diagnosis and treatment of its infection in Hong Kong, our consensus panel proposed a set of guidance statements for disease management. We conducted a comprehensive review of literature published during 2011 and 2021, with a focus on articles from Hong Kong or other regions of China. We evaluated the evidence using the Oxford Centre for Evidence-Based Medicine's 2011 Levels of Evidence and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system and sought consensus through online voting and a subsequent face-to-face meeting, which enabled us to develop and refine the guidance statements. This report consists of 24 statements regarding the epidemiology and burden, screening and diagnosis, and treatment of H pylori. Key guidance statements include a recommendation to use the test-and-treat approach for high-risk individuals, as well as the confirmation that triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin remains a valid first-line option for adults and children in Hong Kong.

Clinical features and outcome of retinoblastoma at the Vietnam National Cancer Hospital.

OBJECTIVES: To characterize the clinical features, treatment, and outcome of children diagnosed with retinoblastoma (RB) at Vietnam National Cancer Hospital. METHODS: The study enrolled all RB patients newly diagnosed at Vietnam National Cancer Hospital from January 2018 to December 2022. The primary endpoint was overall survival (OS) and the eye salvage rate. RESULTS: In total, 139 patients were enrolled, 51.8% patients were male. Median age was 18.9 months. Most patients presented with leukocoria (63.3%), followed by strabismus (14.4%), and 43.9% had bilateral disease. Of 200 eyes, 129 (64.5%) were classified as group E. Extraocular extension was noted in 10 of 139 patients (7.2%). About one-third of the patients lived more than 300 kilometers (km) away from these hospitals, and 17.3% of the patients belonged to minority groups, both of which were dominated by group E and extraocular or high-risk eyes at the time of consultation. Primary enucleation was done for 57 eyes (28.5%), and 51 of 61 patients (83.6%) received eye salvage therapy in bilateral RB group. At study closure, 127 children were alive at the last follow-up, 12 cases were confirmed dead. The 5-year OS and progression-free survival (PFS) rates were 90.3% and 85.9%, respectively. In particular, ethnic minority, distance to hospital more than 150 km, and extraocular disease were significantly associated with higher mortality among children with RB treated in Vietnam National Cancer Hospital. CONCLUSIONS: There is a need to support for screening RB with early symptoms in grassroots medical facilities and raise awareness among patients' families through health education programs. Besides, caring and supporting treatment for patients from the ethnic minority and who live far from hospitals are also extremely necessary.

Comparison of surface roughness of root cementum and orthodontically induced root resorption craters from high- and low-fluoridation areas: a 3D confocal microscopy study.

BACKGROUND: Fluoride has a major role in strengthening the structure of enamel against acids. Despite differences between caries and root resorption processes, both events inherently involve acidic dissolution of dental tissues. The aim of the present study was to investigate the effects of water fluoridation levels on the surface roughness of root cementum and resorption craters. The findings provided more insight into the influence of fluoride on the surfaces of intact cementum surface and resorption craters. METHODS: Twenty-eight orthodontic patients were recruited from two cities in Turkey, with high (≥ 2 ppm) and low (≤ 0.05 ppm) water fluoridation. These patients needed bilateral maxillary first premolar extraction as part of their orthodontic treatment and were allocated into two study groups (n = 14 in each group) based on water fluoridation exposure level: the high-fluoride group (HF) and low-fluoride group (LF). 150 g of buccal tipping forces was applied to all maxillary first premolar teeth for 12 weeks with a beta-titanium spring which was reactivated every 4 weeks. All maxillary premolars were removed at the end of the experiment for surface roughness assessment using three-dimensional confocal microscopy and the associated software. The buccal root surface and the largest buccal resorption crater were investigated. RESULTS: Resorption craters were significantly rougher in LF group compared to HF group (p = 0.002). Craters were rougher than the intact root surfaces (p = 0.000). Cervical and apical regions were significantly rougher than the middle region (p = 0.000 and p = 0.024, respectively). CONCLUSIONS: Higher water fluoridation level of ≥ 2 ppm resulted in significantly smoother root resorption craters than low water fluoridation level of ≤ 0.05 ppm when the teeth were subjected to 150 g of buccal tipping force. Fluoride seems to have a protective role at the interface of root resorption, and further mineral or histological studies may shed light on the exact protective process against root resorption.

Bat Red Blood Cells Express Nucleic Acid-Sensing Receptors and Bind RNA and DNA.

RBCs demonstrate immunomodulatory capabilities through the expression of nucleic acid sensors. However, little is known about bat RBCs, and no studies have examined the immune function of bat erythrocytes. In this study, we show that bat RBCs express the nucleic acid-sensing TLRs TLR7 and TLR9 and bind the nucleic acid ligands, ssRNA, and CpG DNA. Collectively, these data suggest that, like human RBCs, bat erythrocytes possess immune function and may be reservoirs for nucleic acids. These findings provide unique insight into bat immunity and may uncover potential mechanisms by which virulent pathogens of humans are concealed in bats.

Physical properties of root cementum: Part 28. Effects of high and low water fluoridation on orthodontic root resorption: A microcomputed tomography study.

INTRODUCTION: Transient inflammatory surface resorption, referred to as orthodontic induced inflammatory root resorption (OIIRR), is an iatrogenic consequence of orthodontic tooth movement. Systemic fluoride has been associated with a reduction of OIIRR. This study aimed to investigate the effects of water fluoridation levels on OIIRR in a clinically applicable human orthodontic model. METHODS: Twenty-eight patients who required bilateral maxillary first premolar extraction as part of orthodontic treatment were selected from 2 cities with high and low water fluoridation of ≥2 ppm and ≤0.05 ppm, respectively. Patients were separated into high fluoride (HF) and low fluoride (LF) groups on the basis of water fluoridation levels. Bilateral maxillary first premolar teeth were subjected to 150 g of buccal tipping forces for 12 weeks with reactivation every 4 weeks. Teeth were extracted at the end of 12 weeks. Root resorption crater volume was determined using microcomputed tomography and 3-dimensional reconstruction. RESULTS: HF group showed significantly less mean root resorption volume on the palatal root surface when compared with the LF group (P = 0.025). This difference was specifically displayed at palatal apical regions (P = 0.041). When root resorption volumes from the zones of orthodontic pressure (buccal cervical, palatal apical) were combined, the mean difference between HF and LF groups was statistically significant (P = 0.045). CONCLUSIONS: Findings of the present study indicated a positive correlation between water fluoridation and the reduction of OIIRR, especially at the zones of orthodontic pressure, using a clinically relevant human orthodontic model.

DNA binding to TLR9 expressed by red blood cells promotes innate immune activation and anemia.

Red blood cells (RBCs) are essential for aerobic respiration through delivery of oxygen to distant tissues. However, RBCs are currently considered immunologically inert, and few, if any, secondary functions of RBCs have been identified. Here, we showed that RBCs serve as critical immune sensors through surface expression of the nucleic acid­sensing Toll-like receptor 9 (TLR9). Mammalian RBCs expressed TLR9 on their surface and bound CpG-containing DNA derived from bacteria, plasmodia, and mitochondria. RBC-bound mitochondrial DNA was increased during human and murine sepsis and pneumonia. In vivo, CpG-carrying RBCs drove accelerated erythrophagocytosis and innate immune activation characterized by increased interferon signaling. Erythroid-specific deletion of TLR9 abrogated erythrophagocytosis and decreased local and systemic cytokine production during CpG-induced inflammation and polymicrobial sepsis. Thus, detection and capture of nucleic acid by TLR9-expressing RBCs regulated red cell clearance and inflammatory cytokine production, demonstrating that RBCs function as immune sentinels during pathologic states. Consistent with these findings, RBC-bound mitochondrial DNA was elevated in individuals with viral pneumonia and sepsis secondary to coronavirus disease 2019 (COVID-19) and associated with anemia and severity of disease. These findings uncover a previously unappreciated role of RBCs as critical players in inflammation distinct from their function in gas transport.

Wilson Sims Fall Risk Assessment Tool Versus Morse Fall Scale in Psychogeriatric Inpatients: a Multicentre Study.

OBJECTIVE: To compare predictive validity of the Wilson Sims Fall Risk Assessment Tool (WSFRAT) with that of the Morse Fall Scale (MFS) in psychogeriatric inpatients. METHODS: Psychogeriatric patients from Shatin Hospital, Tai Po Hospital, Castle Peak Hospital, and United Christian Hospital who had fall incident between April 2019 and April 2020 were identified. Their fall risks were assessed by the WSFRAT and the MFS, and their falls incidents during hospitalisation were recorded. Patients were classified as having high fall risk when their MFS score was ≥45 and when their WSFRAT score was ≥7. Sensitivity, specificity, and positive and negative predictive values of the two scales were calculated. RESULTS: We identified 183 (90 male and 93 female) psychogeriatric patients aged ≥65 years who had fall incident and were assessed by both the WSFRAT and the MFS during the study period. Among the 183 patients, four sustained a fall during hospital stay, giving a prevalence of 2.19%. All four patients were classified as having high risk of fall by WSFRAT, but only two of them were classified so by MFS. The sensitivity of WSFRAT was 100%, which was higher than the 50% by MFS, but specificity of MFS was higher than that of WSFRAT (45.81% vs 54.75%). CONCLUSION: WSFRAT is a better fall risk assessment scale for psychiatric inpatients than MFS, because of higher sensitivity (100% vs 50%). It has items specific to psychiatric patients and should replace MFS in psychiatric settings.

Effects of rapid and slow maxillary expansion on root resorption: a micro-computed tomography study.

AIM: To compare root resorption (RR) after rapid maxillary expansion (RME) and slow maxillary expansion (SME) through micro-computed tomography (micro-CT). SUBJECTS AND METHODS: Twenty-six subjects who required maxillary expansion and bilateral upper first premolar extraction were randomly assigned to RME (n = 13, mean age: 13.25 ± 0.88 years) or SME (n = 13, mean age: 13.53±1.28 years) group. A hyrax-type acrylic bonded expansion appliance was used. The Hyrax screw was activated » turn twice a day for 20 days in the RME group and » turn every second day for 80 days in the SME group. One randomly selected upper first premolar was extracted in each patient after active expansion. The appliance was left in situ for a 24-week retention period then the contralateral upper first premolar was extracted. Extracted teeth were scanned with micro-CT and the volume of the resorption craters was analysed with a specialized software. Transversal skeletal and dental widths were measured on posteroanterior radiographs taken before and after expansion and retention periods. RESULTS: The resorption craters were concentrated mostly on the buccal surface and middle level in all samples. The total RR in the RME group was less post-expansion (P ≤ 0.05) and more post-retention (P > 0.05) than the SME group. During retention, there was a significant decrease in the total RR in the SME group (P > 0.05) and an increase in the RME group. Both RME and SME groups displayed a similar increase in skeletal transverse dimensions, but inter-molar width increased significantly more in the SME group during the whole experimental period. CONCLUSION: RME does not have an advantage over SME in terms of skeletal expansion and the amount of RR when a retention period of six months is followed.

Erythrocytes identify complement activation in patients with COVID-19.

COVID-19, the disease caused by the SARS-CoV-2 virus, can progress to multisystem organ failure and viral sepsis characterized by respiratory failure, arrhythmias, thromboembolic complications, and shock with high mortality. Autopsy and preclinical evidence implicate aberrant complement activation in endothelial injury and organ failure. Erythrocytes express complement receptors and are capable of binding immune complexes; therefore, we investigated complement activation in patients with COVID-19 using erythrocytes as a tool to diagnose complement activation. We discovered enhanced C3b and C4d deposition on erythrocytes in COVID-19 sepsis patients and non-COVID sepsis patients compared with healthy controls, supporting the role of complement in sepsis-associated organ injury. Our data suggest that erythrocytes may contribute to a precision medicine approach to sepsis and have diagnostic value in monitoring complement dysregulation in COVID-19-sepsis and non-COVID sepsis and identifying patients who may benefit from complement targeted therapies.

Adjuvant T-DM1 versus trastuzumab in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer: subgroup analyses from KATHERINE.

BACKGROUND: In the KATHERINE study (NCT01772472), patients with residual invasive early breast cancer (EBC) after neoadjuvant chemotherapy (NACT) plus human epidermal growth factor receptor 2 (HER2)-targeted therapy had a 50% reduction in risk of recurrence or death with adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab. Here, we present additional exploratory safety and efficacy analyses. PATIENTS AND METHODS: KATHERINE enrolled HER2-positive EBC patients with residual invasive disease in the breast/axilla at surgery after NACT containing a taxane (± anthracycline, ± platinum) and trastuzumab (± pertuzumab). Patients were randomized to adjuvant T-DM1 (n = 743) or trastuzumab (n = 743) for 14 cycles. The primary endpoint was invasive disease-free survival (IDFS). RESULTS: The incidence of peripheral neuropathy (PN) was similar regardless of neoadjuvant taxane type. Irrespective of treatment arm, baseline PN was associated with longer PN duration (median, 105-109 days longer) and lower resolution rate (∼65% versus ∼82%). Prior platinum therapy was associated with more grade 3-4 thrombocytopenia in the T-DM1 arm (13.5% versus 3.8%), but there was no grade ≥3 hemorrhage in these patients. Risk of recurrence or death was decreased with T-DM1 versus trastuzumab in patients who received anthracycline-based NACT [hazard ratio (HR) = 0.51; 95% confidence interval (CI): 0.38-0.67], non-anthracycline-based NACT (HR = 0.43; 95% CI: 0.22-0.82), presented with cT1, cN0 tumors (0 versus 6 IDFS events), or had particularly high-risk tumors (HRs ranged from 0.43 to 0.72). The central nervous system (CNS) was more often the site of first recurrence in the T-DM1 arm (5.9% versus 4.3%), but T-DM1 was not associated with a difference in overall risk of CNS recurrence. CONCLUSIONS: T-DM1 provides clinical benefit across patient subgroups, including small tumors and particularly high-risk tumors and does not increase the overall risk of CNS recurrence. NACT type had a minimal impact on safety.

Personalized prediction of transcranial magnetic stimulation clinical response in patients with treatment-refractory depression using neuroimaging biomarkers and machine learning.

BACKGROUND: Functional connectivity between the left dorsolateral prefrontal cortex (DLPFC) and subgenual cingulate (sgACC) may serve as a biomarker for transcranial magnetic stimulation (rTMS) treatment response. The first aim was to establish whether this finding is veridical or artifactually induced by the pre-processing method. Furthermore, alternative biomarkers were identified and the clinical utility for personalized medicine was examined. METHODS: Resting-state fMRI data were collected in medication-refractory depressed patients (n = 70, 16 males) before undergoing neuronavigated left DLPFC rTMS. Seed-based analyses were performed with and without global signal regression pre-processing to identify biomarkers of short-term and long-term treatment response. Receiver Operating Characteristic curve and supervised machine learning analyses were applied to assess the clinical utility of these biomarkers for the classification of categorical rTMS response. RESULTS: Regardless of the pre-processing method, DLPFC-sgACC connectivity was not associated with treatment outcome. Instead, poorer connectivity between the sgACC and three clusters (peak locations: frontal pole, superior parietal lobule, occipital cortex) and DLPFC-central opercular cortex were observed in long-term nonresponders. The identified connections could serve as acceptable to excellent markers. Combining the features using supervised machine learning reached accuracy rates of 95.35% (CI=82.94-100.00) and 88.89% (CI=63.96-100.00) in the cross-validation and test dataset, respectively. LIMITATIONS: The sample size was moderate, and features for machine learning were based on group differences. CONCLUSIONS: Long-term nonresponders showed greater disrupted connectivity in regions involving the central executive network. Our findings may aid the development of personalized medicine for medication-refractory depression.

Pre-hospital stroke screening and notification of patients with reperfusion-eligible acute ischaemic stroke using modified Face Arm Speech Time test.

OBJECTIVES: To investigate the effects of pre-hospital stroke screening and notification on reperfusion therapy for patients with acute ischaemic stroke. METHODS: Pre-hospital stroke screening criteria were established based on a modified version of the Face Arm Speech Time (FAST) test. Screening was performed during ambulance transport by emergency medical service (EMS) personnel who completed a 2-hour training session on stroke screening. Temporal trends affecting acute ischaemic stroke investigation and intervention were compared before and after implementation of the pre-hospital screening. RESULTS: From July 2018 to October 2019, 298 patients with suspected stroke were screened by EMS personnel during ambulance transport prior to hospital arrival. Of these 298 patients, 213 fulfilled the screening criteria, 166 were diagnosed with acute stroke, and 32 received reperfusion therapy. The onset-to-door time was shortened by more than 1.5 hours (100.6 min vs 197.6 min, P<0.001). The door-to-computed tomography time (25.6 min vs 32.0 min, P=0.021), door-to-needle time (49.2 min vs 70.1 min, P=0.003), and door-to-groin puncture time for intra-arterial mechanical thrombectomy (126.7 min vs 168.6 min, P=0.04) were significantly shortened after implementation of the pre-hospital screening and notification, compared with historical control data of patients admitted from January 2018 to June 2018, before implementation of the screening system. CONCLUSION: Implementation of pre-hospital stroke screening using criteria based on a modified version of the FAST test, together with pre-arrival notification, significantly shortened the door-to-reperfusion therapy time for patients with ischaemic stroke. Pre-hospital stroke screening during ambulance transport by EMS personnel who complete a 2-hour focused training session is effective for identifying reperfusion-eligible patients with stroke.