A Germinal Center Checkpoint of AIRE in B Cells Limits Antibody Diversification.

In response to antigens, B cells undergo affinity maturation and class switching mediated by activation-induced cytidine deaminase (AID) in germinal centers (GCs) of secondary lymphoid organs, but uncontrolled AID activity can precipitate autoimmunity and cancer. The regulation of GC antibody diversification is of fundamental importance but not well understood. We found that autoimmune regulator (AIRE), the molecule essential for T cell tolerance, is expressed in GC B cells in a CD40-dependent manner, interacts with AID and negatively regulates antibody affinity maturation and class switching by inhibiting AID function. AIRE deficiency in B cells caused altered antibody repertoire, increased somatic hypermutations, elevated autoantibodies to T helper 17 effector cytokines and defective control of skin Candida albicans. These results define a GC B cell checkpoint of humoral immunity and illuminate new approaches of generating high-affinity neutralizing antibodies for immunotherapy.

Harnessing artificial intelligence in radiology to augment population health.

This review article serves to highlight radiological services as a major cost driver for the healthcare sector, and the potential improvements in productivity and cost savings that can be generated by incorporating artificial intelligence (AI) into the radiology workflow, referencing Singapore healthcare as an example. More specifically, we will discuss the opportunities for AI in lowering healthcare costs and supporting transformational shifts in our care model in the following domains: predictive analytics for optimising throughput and appropriate referrals, computer vision for image enhancement (to increase scanner efficiency and decrease radiation exposure) and pattern recognition (to aid human interpretation and worklist prioritisation), natural language processing and large language models for optimising reports and text data-mining. In the context of preventive health, we will discuss how AI can support population level screening for major disease burdens through opportunistic screening and democratise expertise to increase access to radiological services in primary and community care.

Genomic epidemiology of SARS-CoV-2 in Cambodia, January 2020 to February 2021.

The first case of coronavirus disease 2019 (COVID-19) in Cambodia was confirmed on 27 January 2020 in a traveller from Wuhan. Cambodia subsequently implemented strict travel restrictions, and although intermittent cases were reported during the first year of the COVID-19 pandemic, no apparent widespread community transmission was detected. Investigating the routes of severe acute respiratory coronavirus 2 (SARS-CoV-2) introduction into the country was critical for evaluating the implementation of public health interventions and assessing the effectiveness of social control measures. Genomic sequencing technologies have enabled rapid detection and monitoring of emerging variants of SARS-CoV-2. Here, we detected 478 confirmed COVID-19 cases in Cambodia between 27 January 2020 and 14 February 2021, 81.3 per cent in imported cases. Among them, fifty-four SARS-CoV-2 genomes were sequenced and analysed along with representative global lineages. Despite the low number of confirmed cases, we found a high diversity of Cambodian viruses that belonged to at least seventeen distinct PANGO lineages. Phylogenetic inference of SARS-CoV-2 revealed that the genetic diversity of Cambodian viruses resulted from multiple independent introductions from diverse regions, predominantly, Eastern Asia, Europe, and Southeast Asia. Most cases were quickly isolated, limiting community spread, although there was an A.23.1 variant cluster in Phnom Penh in November 2020 that resulted in a small-scale local transmission. The overall low incidence of COVID-19 infections suggests that Cambodia's early containment strategies, including travel restrictions, aggressive testing and strict quarantine measures, were effective in preventing large community outbreaks of COVID-19.

Coordination of Mucosal Immunity by Innate Lymphoid Cells.

Mucosal barrier surfaces of the mammalian body are frequent sites of pathogen colonization or entry and are also densely colonized with trillions of normally beneficial microbes, termed the microbiota. Therefore, it is paramount that the host immune system recognizes these microbes and is capable of differentiating between them. To this end, a multitude of mechanisms have evolved to carefully balance the need for immune activation in the face of infections while maintaining an appropriate level of tolerance to protect both the host and the beneficial microbes from hyperactivation. These mechanisms include the deployment of an emerging class of tissue-resident innate immune cells, innate lymphoid cells (ILCs), that are enriched at mucosal barriers such as the lungs and intestines, and are critical mediators of tissue homeostasis, tolerance, repair, and innate immunity. Recent findings have provided insight into the regulation of these cells and their interactions, not only with microbes, both commensal and foreign, but also with other systems of the body to prevent disease and promote tissue health. Here, we discuss recent findings in the regulation and function of ILCs, including a focus on their interactions with bodily systems, such as the nervous system, and how these interactions affect their functionality in states of health, infection, and disease.

Genotypic confirmation of a biased phenotypic sex ratio in a dryland moss using restriction fragment length polymorphisms.

Premise: In dioicous mosses, sex is determined by a single U (female, ♀) or V (male, ♂) chromosome. Although a 1 : 1 sex ratio is expected following meiosis, phenotypic sex ratios based on the production of gametangia are often female-biased. The dryland moss Syntrichia caninervis (Pottiaceae) is notable for its low frequency of sex expression and strong phenotypic female bias. Here we present a technique to determine genotypic sex in a single shoot of S. caninervis, and report results of a case study examining genotypic and phenotypic sex ratios. Methods: We reanalyzed 271 non-expressing gametophyte shoots from a previous study on S. caninervis sex expression across microhabitats using a restriction fragment length polymorphism (RFLP) method. Results: We recovered a genotypic sex ratio in non-expressing shoots of 18.4♀ : 1♂, which exceeds the female bias of the phenotypic ratio (5.3♀ : 1♂; P = 0.013). We also found that the distribution of male and female genotypes across microsites with different levels of sun exposure was not predicted by patterns of sex expression in these microsites. Discussion: These findings contribute to our understanding of how the environment may modulate sex ratios in S. caninervis, either through its direct influence on sex expression or through selection on genotypes with particular sex expression phenotypes.

Wound repair, safety, and functional outcomes in reconstructive lower extremity foot and ankle surgery using a dehydrated amnion/chorion allograft membrane.

Amniotic membranes are known to be rich in growth factors, cytokines, and matrix proteins, which can help support wound closure and may improve patient outcomes in foot and ankle surgical interventions. In this Institutional Review Board (IRB) approved clinical study, 21 consecutive patients undergoing lower extremity soft tissue and bone reconstruction surgery received dehydrated human amnion and chorion allograft (dHACA) placed as a covering over the deep layers of the surgical wound during closure. Wound healing complications were assessed and American Orthopaedic Foot and Ankle Society (AOFAS) scores were compiled from over a 1-year follow-up period. Summary statistics were calculated for average pain, function, and alignment. The average overall AOFAS pre-treatment score was 35.8 ± 23.0 and the post-treatment score significantly improved to 87.5 ± 6.4 (P = 3.7 × 10-10 ). The pain-score improved from pre-treatment at 10.0 ± 11.0 to post-treatment at 36.7 ± 4.8 (P = 5.0 × 10-5 ). The pre-treatment function score was 18.7 ± 12.9 and at post-treatment increased to 38.5 ± 5.7 (P = 5.8 × 10-5 ). Lastly, the alignment score at pre-treatment was 7.1 ± 4.4 and at post-treatment was 12.4 ± 2.6 (P = .001). These improvements in functional scores were accompanied with clinical observations of reduced surgical complications including a lack of wound dehisance in the cohort. These clinical findings suggest that the application of aseptically processed dHACA may reduce wound complications and as such may aide in clinical improvements in foot and ankle surgical interventions however a larger comparative trial should be considered to validate these initial findings.

Diagnostic Performance of a Deep Learning Model Deployed at a National COVID-19 Screening Facility for Detection of Pneumonia on Frontal Chest Radiographs.

(1) Background: Chest radiographs are the mainstay of initial radiological investigation in this COVID-19 pandemic. A reliable and readily deployable artificial intelligence (AI) algorithm that detects pneumonia in COVID-19 suspects can be useful for screening or triage in a hospital setting. This study has a few objectives: first, to develop a model that accurately detects pneumonia in COVID-19 suspects; second, to assess its performance in a real-world clinical setting; and third, by integrating the model with the daily clinical workflow, to measure its impact on report turn-around time. (2) Methods: The model was developed from the NIH Chest-14 open-source dataset and fine-tuned using an internal dataset comprising more than 4000 CXRs acquired in our institution. Input from two senior radiologists provided the reference standard. The model was integrated into daily clinical workflow, prioritising abnormal CXRs for expedited reporting. Area under the receiver operating characteristic curve (AUC), F1 score, sensitivity, and specificity were calculated to characterise diagnostic performance. The average time taken by radiologists in reporting the CXRs was compared against the mean baseline time taken prior to implementation of the AI model. (3) Results: 9431 unique CXRs were included in the datasets, of which 1232 were ground truth-labelled positive for pneumonia. On the "live" dataset, the model achieved an AUC of 0.95 (95% confidence interval (CI): 0.92, 0.96) corresponding to a specificity of 97% (95% CI: 0.97, 0.98) and sensitivity of 79% (95% CI: 0.72, 0.84). No statistically significant degradation of diagnostic performance was encountered during clinical deployment, and report turn-around time was reduced by 22%. (4) Conclusion: In real-world clinical deployment, our model expedites reporting of pneumonia in COVID-19 suspects while preserving diagnostic performance without significant model drift.

Seroprevalence of SARS-CoV-2 antibodies among rural healthcare workers.

The objective of this longitudinal cohort study was to determine the seroprevalence of antibodies to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in healthcare workers employed at healthcare settings in three rural counties in eastern South Dakota and western Minnesota from May 13, 2020, through December 22, 2020. Three blood draws were performed at five clinical sites and tested for the presence of antibodies against the SARS-CoV-2. Serum samples were tested for the presence of antibodies using a fluorescent microsphere immunoassay (FMIA), neutralization of SARS-CoV-2 spike-pseudotyped particles (SARS-CoV-2pp) assay, and serum virus neutralization (SVN) assay. The seroprevalence was determined to be 1/336 (0.29%) for samples collected from 5/13/20 to 7/13/20, 5/260 (1.92%) for samples collected from 8/13/20 to 9/25/20, and 35/235 (14.89%) for samples collected from 10/16/20 to 12/22/20. Eight of the 35 (22.8%) seropositive individuals identified in the final draw did not report a previous diagnosis with COVID-19. There was a high correlation (>90%) between the FMIA and virus neutralization assays. Each clinical site's seroprevalence was higher than the cumulative incidence for the general public in the respective county as reported by state public health agencies. As of December 2020, there was a high percentage (85%) of seronegative individuals in the study population.

Evidence-based healthcare, knowledge translation, implementation science and radiography: What does it all mean?

Evidence-based healthcare is an approach to practice whereby decision making and service delivery considers the best available evidence, patient choice, local resources and clinical expertise. Although sound in theory, compliance with evidence-based practice is often far from optimal. To address this, related fields such as knowledge translation and implementation science have emerged, which largely focus on methods and techniques to facilitate the transfer of evidence into practice. This introductory article explains the key concepts of evidence-based healthcare by using the JBI Model as a framework to highlight the lifecycle of evidence-based information. Throughout the article we refer to exemplars from medical radiation to highlight these concepts.

The only constant in radiography is change: A discussion and primer on change in medical imaging to achieve evidence-based practice.

Medical imaging is an ever changing field with significant advancements in techniques and technologies over the years. Despite being constantly challenged by change, it can be difficult to introduce changes into healthcare settings. In this article we introduce the principles of change management to achieve an evidence-based practice in radiography.

Temporal Effects of Message Congruency on Attention to and Recall of Pictorial Health Warning Labels on Cigarette Packages.

OBJECTIVES: Recent research has shown that message congruency is beneficial to recall of pictorial health warning label (PWL) content after initial exposure. Despite less attention to the text warning, smokers exposed to congruent PWLs were more likely to recall the text and the message. This study aimed to replicate these findings and to examine whether congruency also affects recall after multiple exposures over time. METHODS: A total of 320 daily smokers (39.7% female; cigarettes/day: M = 15.31, SD = 7.15) were randomized to one congruent or incongruent PWL and attended 4 laboratory sessions over 10 days. During each session, eye movements were recorded while viewing the PWL and open-ended recall of label content was assessed after exposure. RESULTS: Smokers who were exposed to a congruent PWL were more likely to recall the text (p = .01) and the message (p = .02) and less likely to recall the image (p = .003) of the PWL after initial exposure. By day 4, incongruent PWLs were recalled equally well as congruent PWLs. Independent of condition, image recall was initially high and remained high whereas text and message recall was relatively low initially but increased over time. It was not until day 7 that about 80% of text and message recall was observed. CONCLUSIONS: Even when exposed to the same PWL over time, smokers require multiple exposures to recall the text and the message of a PWL. More research on the effects of congruency in the natural environment, where smokers are exposed to multiple PWLs, is needed. IMPLICATIONS: The findings of this study, and of previous work showing that message congruency in PWLs is beneficial to initial recall of PWL content, could potentially help to address legal challenges regarding the implementation of PWLs in the United States. Factually correct text warnings have been uncontested on US cigarettes packages since 1966. Congruent PWLs simply provide a means to visually support the same information as the existing text using a medium that better garners attention to the health information. Investigating and understanding longer-term effects of congruency are important and can empirically inform future warning label development, both in the United States via the Family Smoking Prevention and Tobacco Control Act, and via other governing bodies.

Immunology of the Uterine and Vaginal Mucosae.

Along with the maintenance of symbiotic mutualism with commensal microbes and protection against invasive infections common to all mucosal barrier tissues, female reproductive tissues have additional, unique tasks that include dynamic cyclic cellular turnover in menstruation and immunological tolerance to genetically foreign fetal antigens in pregnancy. Here we review current knowledge on distinct features of the immune cells in female reproductive tissue with regard to antimicrobial host defense and adaptations to accommodate the fetus during pregnancy. Outstanding areas for future research to obtain new functional insights on this enigmatic mucosal barrier are also highlighted.

Providing meaningful care for families experiencing stillbirth: a meta-synthesis of qualitative evidence.

OBJECTIVE: The objective of this study was to explore the meaningfulness of non-pharmacological care experienced by families throughout the experience of stillbirth from diagnosis onwards. STUDY DESIGN: A comprehensive systematic review was conducted. Multiple sources were searched for relevant studies including gray literature. Studies were included if they reported the experiences of families with the care they received throughout the experience of stillbirth, from diagnosis onwards. Studies were assessed for methodological quality prior to inclusion. Qualitative findings were extracted from included studies and pooled using a meta-aggregative approach. This paper reports the results of one meta-synthesis from the systematic review. RESULTS: Ten qualitative studies of moderate to high quality informed this meta-synthesis. The meta-aggregative synthesis included 69 findings that informed the development of 10 categories and one final, synthesized finding. Emerging themes that underpinned the meaningfulness of care provided to parents experiencing stillbirth included: information provision, the need for emotional support and appropriate maternity ward environments and systems. CONCLUSION: The results of this meta-synthesis revealed the elements of care that were experienced as meaningful from the perspective of parents who had experienced stillbirth. Exploration of these elements has provided important detail to underpin a growing understanding of how parents experience care and what may help or hinder parents' experience of distress, anxiety and grief throughout the experience of stillbirth.

Knee chondrolysis by infusion of bupivacaine with epinephrine through an intra-articular pain pump catheter after arthroscopic ACL reconstruction.

BACKGROUND: Postoperative knee chondrolysis caused by continuous intra-articular pain pumps infusing bupivacaine with epinephrine is a rare but serious complication. PURPOSE: To determine the association between postoperative intra-articular infusion of bupivacaine with epinephrine and the development of knee chondrolysis in patients who have undergone arthroscopic anterior cruciate ligament reconstruction (ACLR). The authors hypothesized that the development of knee chondrolysis after ACLR is associated with postoperative high-dose intra-articular bupivacaine with epinephrine infusion. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: In this retrospective cohort study, the charts of all patients treated with arthroscopic ACLR by a single surgeon between January 1, 2004, and December 31, 2006, were reviewed. Patients with severe articular cartilage damage at the time of the index procedure, with known knee joint infection, inflammatory arthritis, multiligament knee injury, bilateral knee injury, or any previous knee surgery, were excluded. Patients were grouped into 2 cohorts: the exposure group (those who had postoperative infusion of bupivacaine with epinephrine via an intra-articular pain pump [IAPP]) and the nonexposure group (those without postoperative infusion). RESULTS: A total of 105 patients met the inclusion and exclusion criteria. There were 57 male and 48 female patients with a mean age at surgery of 25.5 ± 8.6 years (range, 13-52 years). The exposure group consisted of 46 patients and the control group of 59 patients. Thirteen of 46 patients (28.3%) who received an IAPP developed chondrolysis. There were no cases of chondrolysis in the control group. Of those in the exposure group, 32 patients were exposed to 0.5% bupivacaine with epinephrine and 12 developed chondrolysis (37.5%), while 14 patients were exposed to 0.25% bupivacaine with epinephrine and 1 developed chondrolysis (7.1%). Patients exposed to 0.5% bupivacaine with epinephrine had a significantly higher incidence of chondrolysis compared with those exposed to 0.25% (P = .03). Patients with chondrolysis had severe pain and limitations in daily activity. CONCLUSION: The development of knee chondrolysis was associated with the intra-articular infusion of bupivacaine with epinephrine postoperatively. Furthermore, the presented evidence suggests that this occurs in a dose-dependent manner. The risk of knee chondrolysis might be reduced by avoidance of intra-articular infusion of bupivacaine with epinephrine. We recommend against continuous intra-articular infusion of local anesthetic postoperatively.

Structure-activity relationship of dihydroxy-4-methylcoumarins as powerful antioxidants: correlation between experimental & theoretical data and synergistic effect.

The chain-breaking antioxidant activities of eight coumarins [7-hydroxy-4-methylcoumarin (1), 5,7-dihydroxy-4-methylcoumarin (2), 6,7-dihydroxy-4-methylcoumarin (3), 6,7-dihydroxycoumarin (4), 7,8-dihydroxy-4-methylcoumarin (5), ethyl 2-(7,8-dihydroxy-4-methylcoumar-3-yl)-acetate (6), 7,8-diacetoxy-4-methylcoumarin (7) and ethyl 2-(7,8-diacetoxy-4-methylcoumar-3-yl)-acetate (8)] during bulk lipid autoxidation at 37 degrees C and 80 degrees C in concentrations of 0.01-1.0 mM and their radical scavenging activities at 25 degrees C using TLC-DPPH test have been studied and compared. It has been found that the o-dihydroxycoumarins 3-6 demonstrated excellent activity as antioxidants and radical scavengers, much better than the m-dihydroxy analogue 2 and the monohydroxycoumarin 1. The substitution at the C-3 position did not have any effect either on the chain-breaking antioxidant activity or on the radical scavenging activity of the 7,8-dihydroxy- and 7,8-diacetoxy-4-methylcoumarins 6 and 8. The comparison with DL-alpha-tocopherol (TOH), caffeic acid (CA) and p-coumaric acid (p-CumA) showed that antioxidant efficiency decreases in the following sequence: TOH>CA>3>4>6>5>2>1=7=8=p-CumA. Theoretical calculations and the "Lipinski's Rule of Five" were used for explaining the structure-activity relationships and pharmacokinetic behavior. A higher TGSO oxidation stability was observed in the presence of equimolar (1:1) binary mixtures of coumarins with TOH (1+TOH, 3+TOH and 5+TOH). However, the synergism (14%) was observed only for the binary mixture of 5 + TOH.

Chondrolysis of the glenohumeral joint after infusion of bupivacaine through an intra-articular pain pump catheter: a report of 18 cases.

PURPOSE: To report on our experience of patients who received infusion of bupivacaine with epinephrine after arthroscopic glenoid labral repair surgery and in whom glenohumeral joint chondrolysis subsequently developed, as well as to determine the incidence of such chondrolysis in our surgeons' patient populations. METHODS: A retrospective chart review of 18 patients diagnosed with chondrolysis was carried out. All patients were from 2 experienced orthopaedic surgeons' practices. Details of their clinical course were obtained and summarized. These data were compared with all other arthroscopies completed by the 2 surgeons to determine the incidence of chondrolysis. RESULTS: All 18 patients diagnosed with glenohumeral joint chondrolysis received postoperative infusion of bupivacaine with epinephrine through an intra-articular pain pump catheter (IAPPC). None of the patients received thermal energy as part of their procedure. None of the patients had evidence of glenohumeral joint infection, although an extensive workup was frequently undertaken. Clinically, patients presented with a stiff, painful shoulder. Examination showed decreased range of motion of the affected shoulder. Radiographs and magnetic resonance imaging showed joint space narrowing, as well as subchondral sclerosis and cyst formation. Of the 18 patients, 14 have since undergone repeat arthroscopic procedures, and 5 have received a humeral head-resurfacing operation. Within the same time period, there were 113 arthroscopies, with 45 pain pumps used. Chondrolysis developed in 16 of 32 patients with high-flow IAPPCs and 2 of 12 patients with low-flow IAPPCs (1 patient's IAPPC flow rate was not documented). CONCLUSIONS: Although we cannot establish a causal link, the development of glenohumeral chondrolysis may be related to the intra-articular infusion of bupivacaine with epinephrine postoperatively. We thus caution against the use of IAPPCs. LEVEL OF EVIDENCE: Level IV, therapeutic case series.