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Abstract Background Legumes utilize a long-distance signaling feedback pathway, termed Autoregulation of Nodulation (AON), to regulate the establishment and maintenance of their symbiosis with rhizobia. Several proteins key to this pathway have been discovered, but the AON pathway is not completely understood. Results We report a new hypernodulating mutant, defective in autoregulation, with disruption of a gene, DAR (Medtr2g450550/MtrunA17_Chr2g0304631), previously unknown to play a role in AON. The dar-1 mutant produces ten-fold more nodules than wild type, similar to AON mutants with disrupted SUNN gene function. As in sunn mutants, suppression of nodulation by CLE peptides MtCLE12 and MtCLE13 is abolished in dar. Furthermore, dar-1 also shows increased root length colonization by an arbuscular mycorrhizal fungus, suggesting a role for DAR in autoregulation of mycorrhizal symbiosis (AOM). However, unlike SUNN which functions in the shoot to control nodulation, DAR functions in the root. Conclusions DAR encodes a membrane protein that is a member of a small protein family in M. truncatula. Our results suggest that DAR could be involved in the subcellular transport of signals involved in symbiosis regulation, but it is not upregulated during symbiosis. DAR gene family members are also present in Arabidopsis, lycophytes, mosses, and microalgae, suggesting the AON and AOM may use pathway components common to other plants, even those that do not undergo either symbiosis.

Chelating gels may initially assist in root canal preparations to help establish a glide path. While irrigation surveys have investigated liquid chelators and gels to a minor extent, no endodontic survey has focused on EDTA gels and why clinicians use them. All 395 members of the Australian Society of Endodontology (ASE) were emailed an 11-question survey concerning chelation gel usage via Qualtrics. Paper copies were also distributed at ASE events. Descriptive statistics were performed for practitioner and chelating gel data. Cross-tabulations of the practitioner type with the case percentage usage of gels were analyzed with the chi square test (adjusted p value < 0.0083). The overall response rate was 181/395 (46%). For 174 eligible responses, those who never/rarely used a gel were as follows: endodontic residents 12/14 (86%), endodontists 53/71 (75%), general dentists 39/86 (45%), and other members 0% (0/3). Most gel users said that gels helped establish a glide path. Those who never/rarely used chelating gels commented that they held no benefits over liquid EDTA. Endodontists were less likely to use a chelation gel than general dentists (p < 0.0083). Older clinicians had higher gel usage than younger ASE members (p < 0.0083), indicating a possible trend to diminished gel usage over time amongst ASE members. In conclusion, most ASE members find no need for a chelating gel, raising questions about their clinical effectiveness. Studies would therefore be warranted to investigate gel efficacy and improved clinical outcomes.

Abstract Background Dementia with Lewy Bodies (DLB) is responsible for cognitive-behavioural disorders but also for gait disorders. The latter are thought to be related to parkinsonism, but the neural bases of these disorders are not well known, especially in the early stages. The aim of this study was to investigate by volumetric Magnetic Resonance Imaging the neuronal basis of gait disorders in DLB patients, compared to Healthy Elderly Controls and Alzheimer’s Disease patients. Methods Clinical examination with motor assessment including 10-meter walking speed, one-leg balance and Timed Up and Go test, a comprehensive neuropsychological evaluation and 3D brain Magnetic Resonance Imaging were performed on 84 DLB patients, 39 Alzheimer’s Disease patients and 22 Healthy Elderly Controls. We used Statistical Parametric Mapping 12 to perform a one-sample t-test to investigate the correlation between each gait score and gray matter volume (P ≤ 0.05 corrected for family-wise error). Results We found a correlation for DLB patients between walking speed and gray matter decrease (P

Group B Streptococcus (GBS) asymptomatically colonises the vagina of up to 40% of pregnant women and can transmit to neonates during birth, causing neonatal pneumonia, sepsis, meningitis, and significant mortality. Vaginal GBS colonisation can be attributed to a range of host and bacterial factors, which may include the composition of the vaginal microbial community. There are few studies that have examined the vaginal community composition in relation to GBS colonisation throughout pregnancy. Here, we performed 16S rRNA sequencing (V3-V4) on vaginal swabs from women at 24- and 36-weeks’ gestation, who were GBS culture-negative or GBS culture-positive at either 24 weeks or 36 weeks’ gestation or at both timepoints. Vaginal swabs from 93 women were analysed; 46 women were culture-negative, 11 women GBS culture-positive at 24 weeks only, 21 women GBS culture-positive at 36 weeks only and 15 women GBS culture-positive at both timepoints on Brilliance GBS agar. V3-V4 16S rRNA gene amplicon sequencing demonstrated that in women that were GBS culture-positive at 36 weeks gestation only, G. vaginalis was significantly more abundant at 24-weeks’ gestation despite a lack of significant changes in community richness between the 24- and 36-week samples. The vaginal microbial communities of women persistently colonised with GBS, had a significantly higher abundance of Lactobacillus iners, compared to other groups where L. crispatus, L. gasseri or L. jensenii were dominant. We have characterised the vaginal microbial community composition during pregnancy in relation to GBS colonisation status, in a longitudinal study for the first time. The most interesting finding was that in women that were persistently colonised with GBS throughout pregnancy, there was a significant increase in L. iners and significant reduction in L. crispatus abundance. Given the lack of detail of the role that the vaginal microbial community plays in GBS colonisation in the literature, it is imperative that the relationship between L. iners and GBS in this unique environmental niche is further investigated.

Introduction Heavy menstrual bleeding affects up to two thirds of women on oral anticoagulation. The rates of heavy menstrual bleeding, its impact on quality of life and associated risk factors in women attending anticoagulation clinics in South Africa are largely unknown. Materials and Methods A prospective cohort study was performed over an eight-month period in women on Warfarin (n = 30) and Rivaroxaban (n = 27) for a median [interquartile range] duration of 15.5 [78.0] months attending an anticoagulation clinic in Johannesburg, South Africa. Heavy menstrual bleeding was assessed over one menstrual cycle using the validated pictorial blood loss assessment charts (PBAC) and the menstrual bleeding questionnaire (MBQ). Results In this population of predominantly African ethnicity, with a median age of 39 [8] years, 39 (68.4%) women experienced heavy menstrual bleeding, defined as a PBAC score of >100. Median cycle length on anticoagulation and MBQ scores were significantly higher among women with a PBAC score of >100 (p > 0.05). Univariate analysis identified Rivaroxaban as a risk factor for heavy menstrual bleeding (OR 5.03, 95% CI 1.40–18.12). Heavy menstrual bleeding required treatment in 29 (74.4%) women which included management of iron deficiency, anti-fibrinolytics, modification of anticoagulation and hormonal contraception. Conclusion Heavy menstrual bleeding was associated with a considerable negative impact on quality of life. This was most significant for women on Rivaroxaban as compared to Warfarin. It is essential to monitor and appropriately treat heavy menstrual bleeding in at risk women on anticoagulant treatment.

BackgroundAs the therapeutic landscape for inflammatory bowel disease (IBD) continues to expand, a need exists to understand how patients perceive and value different attributes associated with their disease as well as with current and emerging treatments. These insights can inform the development and regulation of effective interventions for IBD, benefiting various stakeholders including healthcare professionals, drug developers, regulators, Health Technology Assessment bodies, payers, and ultimately patients suffering from IBD. In response to this, the present patient preference study was developed with the aim to (1) determine the relative preference weights for IBD treatment and disease related attributes, and (2) explain how preferences may differ across patients with different characteristics (preference heterogeneity).MethodsThe patient preference study (PPS) was developed through an 8-step process, with each step being informed by an advisory board. This process included: (1) stated preference method selection, (2) attribute and level development (including a scoping literature review, focus group discussions, and advisory board meetings), (3) choice task construction, (4) sample size estimation, (5) survey implementation, (6) piloting, (7) translation, and (8) pre-testing. The resulting discrete choice experiment (DCE) survey comprises 14 attributes with between two and five varying levels. Participants will answer 15 DCE questions with a partial profile design, where each of the choice questions encompasses two hypothetical treatment profiles showing four attributes. Additionally, questions about patients' socio-demographic and clinical characteristics, as well as contextual factors are implemented. The survey is available in 15 different languages and aims to minimally recruit 700 patients globally.DiscussionThis protocol gives valuable insights toward preference researchers and decision-makers on how PPS design can be transparently reported, demonstrating solutions to remaining gaps in preference research. Results of the PPS will provide evidence regarding the disease and treatment related characteristics that are most important for IBD patients, and how these may differ across patients with different characteristics. These findings will yield valuable insights applicable to preference research, drug development, regulatory approval, and reimbursement processes, enabling decision making across the medicinal product life cycle that is aligned with the true needs of IBD patients.

Abstract Zinc nitride (Zn3N2) is a promising semiconductor for a range of optoelectronic and energy conversion applications, offering a direct bandgap of 1.0 eV, large carrier mobilities, and abundant constituent elements. However, the material is prone to bulk oxidation in ambient environments, which has thus far impeded its practical deployment. While previous approaches have focused on stabilizing the material via integration of ZnO surface layers, these strategies introduce additional challenges regarding elevated processing temperatures and limited control of interface properties. In this study, it is shown that amorphous GaN thin films can serve as highly stable protection layers on Zn3N2 surfaces and can be deposited at the same growth temperature and in the same deposition system as the underlying semiconductor. The GaN‐capped Zn3N2 structures exhibit long‐term stability, surviving over 3 years of exposure to ambient conditions with no discernible alterations in composition, structure, or electrical properties. Notably, the amorphous GaN coatings can even impede Zn3N2 oxidation under prolonged aqueous exposure. Thus, this study offers a solution to stabilize Zn3N2 in ambient conditions, providing a viable pathway to its utilization in robust and high‐performance electronic devices, such as thin film transistors and solar energy conversion systems.

Introduction A prototype lateral flow device detecting cytokine biomarkers interleukin (IL)-1α and IL-1β has been developed as a point-of-care test—called the Genital InFlammation Test (GIFT)—for detecting genital inflammation associated with sexually transmitted infections (STIs) and/or bacterial vaginosis (BV) in women. In this paper, we describe the rationale and design for studies that will be conducted in South Africa, Zimbabwe and Madagascar to evaluate the performance of GIFT and how it could be integrated into routine care.Methods and analysis We will conduct a prospective, multidisciplinary, multicentre, cross-sectional and observational clinical study comprising two distinct components: a biomedical (‘diagnostic study’) and a qualitative, modelling and economic (‘an integration into care study’) part. The diagnostic study aims to evaluate GIFT’s performance in identifying asymptomatic women with discharge-causing STIs (Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), Trichomonas vaginalis (TV) and Mycoplasma genitalium (MG)) and BV. Study participants will be recruited from women attending research sites and family planning services. Several vaginal swabs will be collected for the evaluation of cytokine concentrations (ELISA), STIs (nucleic acid amplification tests), BV (Nugent score) and vaginal microbiome characteristics (16S rRNA gene sequencing). The first collected vaginal swab will be used for the GIFT assay which will be performed in parallel by a healthcare worker in the clinic near the participant, and by a technician in the laboratory. The integration into care study aims to explore how GIFT could be integrated into routine care. Four activities will be conducted: user experiences and/or perceptions of the GIFT device involving qualitative focus group discussions and in-depth interviews with key stakeholders; discrete choice experiments; development of a decision tree classification algorithm; and economic evaluation of defined management algorithms.Ethics and dissemination Findings will be reported to participants, collaborators and local government for the three sites, presented at national and international conferences, and disseminated in peer-reviewed publications.The protocol and all study documents such as informed consent forms were reviewed and approved by the University of Cape Town Human Research Ethics Committee (HREC reference 366/2022), Medical Research Council of Zimbabwe (MRCZ/A/2966), Comité d’Ethique pour la Recherche Biomédicale de Madagascar (N° 143 MNSAP/SG/AMM/CERBM) and the London School of Hygiene and Tropical Medicine ethics committee (LSHTM reference 28046).Before the start, this study was submitted to the Clinicaltrials.gov public registry (NCT05723484).Trial registration number NCT05723484.

Abstract Background Using delirium clinical guidelines may align interprofessional clinical practice and improve the care of delirious patients and their families. The aim of this project was to adapt, implement and evaluate an interprofessional modular delirium clinical practice guideline for an inpatient palliative care unit. Methods The setting was a 31-bed adult inpatient palliative care unit within a university-affiliated teaching hospital. Participants for the evaluation were interprofessional team members. Using integration of guideline adaptation and an education initiative, an interprofessional guideline adaptation group developed a face-to-face ‘starter kit’ module and four online self-learning modules. The mixed methods evaluation comprised pre-and post-implementation review of electronic patient records, an online survey, and analysis of focus groups/ interviews using an iterative, inductive thematic analysis approach. Results Guideline implementation took 12 months. All palliative care unit staff attended a ‘starter kit’ session. Overall completion rate of the four e-Learning modules was 80.4%. After guideline implementation, nursing documentation of non-pharmacological interventions occurring before medication administration was observed. There was 60% less scheduled antipsychotic use and an increase in ‘as needed’ midazolam use. The online survey response rate was 32% (25/77). Most participants viewed the guideline’s implementation favourably. Six key themes emerged from the qualitative analysis of interviews and focus groups with ten participants: prior delirium knowledge or experiences, challenges of facilitating change, impacts on practice, collaborative effort of change, importance of standardized guidelines, and utility of guideline elements. Conclusions Guideline implementation warrants concerted effort, time, and management support. Interprofessional team support facilitates the modular approach of guideline adaptation and implementation, leading to a change in clinical practice.

Objective To assess the rates of vascular thrombotic adverse events in the first 35 days after one dose of the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) in healthcare workers in South Africa and to compare these rates with those observed in the general population.Design Open label, single arm, phase 3B study.Setting Sisonke study, South Africa, 17 February to 15 June 2021.Participants The Sisonke cohort of 477 234 healthcare workers, aged ≥18 years, who received one dose of the Ad26.COV2.S vaccine.Main outcome measures Observed rates of venous arterial thromboembolism and vaccine induced immune thrombocytopenia and thrombosis in individuals who were vaccinated, compared with expected rates, based on age and sex specific background rates from the Clinical Practice Research Datalink GOLD database (database of longitudinal routinely collected electronic health records from UK primary care practices using Vision general practice patient management software).Results Most of the study participants were women (74.9%) and median age was 42 years (interquartile range 33-51). Twenty nine (30.6 per 100 000 person years, 95% confidence interval 20.5 to 44.0) vascular thrombotic events occurred at a median of 14 days (7-29) after vaccination. Of these 29 participants, 93.1% were women, median age 46 (37-55) years, and 51.7% had comorbidities. The observed to expected ratios for cerebral venous sinus thrombosis with thrombocytopenia and pulmonary embolism with thrombocytopenia were 10.6 (95% confidence interval 0.3 to 58.8) and 1.2 (0.1 to 6.5), respectively. Because of the small number of adverse events and wide confidence intervals, no conclusions were drawn between these estimates and the expected incidence rates in the population.Conclusions Vaccine induced immune thrombocytopenia and thrombosis after one dose of the Ad26.COV2.S vaccine was found in only a few patients in this South African population of healthcare workers. These findings are reassuring if considered in terms of the beneficial effects of vaccination against covid-19 disease. These data support the continued use of this vaccine, but surveillance is recommended to identify other incidences of venous and arterial thromboembolism and to improve confidence in the data estimates.Trial registration ClinicalTrials.gov NCT04838795.

Abstract: Allogeneic stem cell transplantation (SCT) is a curative therapy for patients with hematological malignancies related largely to an immunological graft-versus-leukemia (GVL) effect mediated by donor T cells and natural killer cells. Relapse of disease after SCT represents failure of GVL and is now the major cause of treatment failure. We sought to augment GVL effects in patients (n = 29) relapsing after SCT in a prospective phase I/II clinical trial of dose-escalated pegylated interferon-2α (peg-IFNα). The administration of peg-IFNα after reinduction chemotherapy, with or without subsequent donor lymphocyte infusion (DLI), resulted in a 2-year overall survival (OS) of 31% (95% confidence interval, 17.3%-49.2%), which rejects the null hypothesis of 7% generated by observations in an institutional historical cohort. As expected, peg-IFNα was associated with graft-versus-host disease (GVHD) and hematological toxicity, which was manageable with scheduled dose modifications. Progression-free survival (PFS) was greatest in patients who experienced GVHD, although the majority of those patients still eventually progressed. Higher PFS and OS were associated with pretreatment proportions of immune cell populations with regulatory function, including mucosal invariant T cells, regulatory T cells, and plasmacytoid dendritic cells, independent of any association with GVHD. Peg-IFNα administration after relapse thus constitutes a logical strategy to invoke GVL effects and should be studied in a larger, multicenter cohort. This trial was registered at www.anzctr.org.au as #ACTRN12612000728831.

Skin ulcers are a common complication of systemic sclerosis (SSc) that can significantly impact the quality of life. There have been recent reports on the use of hyperbaric oxygen therapy (HBO2T) in the management of nonhealing systemic sclerosis skin ulcers. The effect of HBO2T on pulmonary arterial hypertension (PAH), another common and potentially life-threatening complication of SSc, is unclear with literature on the subject lacking. We present the case of a 65-year-old female with limited SSc complicated by severe PAH and a nonhealing left lower extremity venous ulcer. HBO2T was successfully used as an adjunct in her management resulting in complete resolution of the venous ulcer and improved quality of life without any adverse effects on her pulmonary arterial hypertension.

BackgroundVenous thrombo-embolism (VTE) is associated with considerable morbidity, mortality in the absence of thromboprophylaxis.MethodThe Southern African Society of Thrombosis and Haemostasis reviewed the available literature and comprehensive evidence-based guidelines on the prevention of VTE in obstetrics and gynaecology. A draft document was produced and revised by consensus agreement. The recommendations were adjudicated by an independent international expert to avoid local bias.Results and conclusionWe present concise, practical thromboprophylaxis guidelines for the clinical management of patients in obstetrics and gynaecology. Recommendations reflect current best practice, which it is hoped will lead to improved anticoagulation practice in this group of patients.

Individuals with Down syndrome (DS) can develop Alzheimer’s disease as early as 30 to 40 years old, but parkinsonism is rarely described. We report on a 20-year-old woman with Down syndrome and parkinsonism who responded dramatically to carbidopa-levodopa. We propose that the occurrence of parkinsonism in individuals with DS may be underreported. Recognizing and treating this condition may improve quality of life.

The paper discusses the outcomes of the conference organized by the InDeal project. The conference took place on 12 December 2018 in Montpellier as part of the EnerGaia energy forum 2018. A holistic interdisciplinary approach for district heating and cooling (DHC) networks is presented that integrates heterogeneous innovative technologies from various scientific sectors. The solution is based on a multi-layer control and modelling framework that has been designed to minimize the total plant production costs and optimize heating/cooling distribution. Artificial intelligence tools are employed to model uncertainties associated with weather and energy demand forecasts, as well as quantify the energy storage capacity. Smart metering devices are utilized to collect information about all the crucial heat substations’ parameters, whereas a web-based platform offers a unique user environment for network operators. Three new technologies have been further developed to improve the efficiency of pipe design of DHC systems: (i) A new sustainable insulation material for reducing heat losses, (ii) a new quick-fit joint for an easy installation, and (iii) a new coating for reducing pressure head losses. The results of a study on the development and optimization of two energy harvesting systems are also provided. The assessment of the environmental, economic and social impact of the proposed holistic approach is performed through a life cycle analysis. The validation methodology of the integrated solution is also described, whereas conclusions and future work are finally given.

Objective. To report the rate of progression of keratectasia after primary crosslinking (CXL) and evaluate the safety and efficiency of CXL redo. Materials and Methods. We conducted a retrospective analysis of the patients who underwent CXL between 2010 and 2013 at the Beirut Eye Specialist Hospital, Lebanon. Progression of keratectasia was based on the presence of an increase in maximum keratometry of 1.00 D, a change in the map difference between two consecutive topographies of 1.00 D, a deterioration of visual acuity, or any change in the refraction. Primary and redo CXL were done using the same protocol. Results. Among the 221 eyes of 130 patients who underwent CXL, 7 eyes (3.17%) of five patients met the criteria of progression. All patients reported a history of allergic conjunctivitis and eye rubbing and progressed within 9 to 48 months. No complications were noted and all patients were stable 1 year after CXL redo. Conclusion. Allergic conjunctivitis and eye rubbing were the only risk factors associated with keratoconus progression after CXL. A close followup is thus mandatory, even years after the procedure. CXL redo seems to be a safe and efficient technique to halt the progression after a primary CXL.

Microglia and astrocytes contribute to Alzheimer’s disease (AD) etiology and may mediate early neuroinflammatory responses. Despite their possible role in disease progression and despite the fact that they can respond to amyloid deposition in model systems, little is known about whether astro- or microglia can undergo proliferation in AD and whether this is related to the clinical symptoms or to local neuropathological changes. Previously, proliferation was found to be increased in glia-rich regions of the presenile hippocampus. Since their phenotype was unknown, we here used two novel triple-immunohistochemical protocols to study proliferation in astro- or microglia in relation to amyloid pathology. We selected different age-matched cohorts to study whether proliferative changes relate to clinical severity or to neuropathological changes. Proliferating cells were found across the hippocampus but never in mature neurons or astrocytes. Almost all proliferating cells were colabeled with Iba1+, indicating that particularly microglia contribute to proliferation in AD. Proliferating Iba1+ cells was specifically seen within the borders of amyloid plaques, indicative of an active involvement in, or response to, plaque accumulation. Thus, consistent with animal studies, proliferation in the AD hippocampus is due to microglia, occurs in close proximity of plaque pathology, and may contribute to the neuroinflammation common in AD.

OBJETIVO: Avaliar os resultados tardios do uso de marcapasso (MP) em pacientes portadores de miocardiopatia hipertrófica obstrutiva (MHO), sintomáticos e refratários ao tratamento medicamentoso. MÉTODO: Foram avaliados 10 pacientes portadores de MHO, refratários ao tratamento com betabloqueador e/ou verapamil, submetidos a implante de MP de dupla-câmara (DDD). Os pacientes foram acompanhados por um período médio de 4,5 anos após o implante. Foram comparados os dados clínicos (classe funcional, presença de síncope ou tontura e dor precordial) e os gradientes de pressao máximos na via de saída do VE pelo ecocardiograma, no pré-implante, na consulta entre três e seis meses e na consulta atual. Os dados clínicos foram confirmados por teste ergométrico realizado na última avaliaçao clínica. RESULTADOS: Nao houve mortalidade e sim melhora significativa (p=0,0233) da classe funcional após o implante, que persistiu até a última avaliaçao, bem como desaparecimento de dor precordial e tontura, estatisticamente significativo para tontura (p=0,0412). O gradiente máximo na via de saída do VE foi 90,6 mmHg no pré-implante, 19 com três e seis meses e 13 no exame atual (p=0,00001). Houve correlaçao entre a classe funcional avaliada clinicamente e pelo teste ergométrico. CONCLUSAO: Ocorreu melhora significativa da classe funcional e desaparecimento dos sintomas de dor precordial e tontura, bem como reduçao significativa do gradiente na via de saída do VE, que persistiu no seguimento tardio, mostrando que o uso de MP DDD foi uma opçao terapêutica segura e resolutiva em longo prazo na amostra estudada.

Between 2007 and 2009, School Drug Education and Road Aware (SDERA) and the Child Health Promotion Research Centre at Edith Cowan University (CHPRC, ECU) worked together to develop best practice principles for road safety education. One of the benefits and critical success factors of developing a best practice model for road safety education has been the ongoing involvement of key stakeholders at both a state and national level. This national and state collaboration and increased commitment is unparalleled in the area of road safety education. SDERA in conjunction with Edith Cowan University has widely disseminated the results of this project. It has been a unique initiative involving Western Australian, Australian and New Zealand stakeholders. In 2010, SDERA and ECU were jointly awarded an Injury Control Council of Western Australia Excellence in Community Safety Award in the research category for the research and development work on the Principles for school road safety education (SDERA, 2009). The principles that were developed ensure that content and delivery methods of road safety education are consistent with what is currently understood to be best practice in the field.

Amiodarone-induced thryrotoxicosis (AIT) is a rare but serious complication of amiodarone use, especially in patients with severe cardiac disease. We present a patient who developed AIT, following administration of amiodarone for life-threatening ventricular arrhythmias. We discuss the medical management of AIT and anesthetic considerations for management of patients with thyrotoxicosis and severe cardiac disease who require surgery including thyroidectomy.