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Abstract Background For patients with interstitial lung diseases (ILDs) presenting with a progressive pulmonary fibrosis (PPF) phenotype, current knowledge of disease characteristics at diagnosis, patient journey, and treatment is limited. This study aimed to describe demographics and clinical experiences of patients presenting with PPF in a European real-world setting. Methods Data were analysed from the Adelphi Real World PPF-ILD Disease Specific Programme™, a cross-sectional survey of pulmonologists and rheumatologists in five European countries (France, Germany, Italy, Spain, United Kingdom) and internal medicine specialists (France) from April to October 2022. Physicians provided data for up to 12 consecutive patients with physician-confirmed ILD with a progressive phenotype other than idiopathic pulmonary fibrosis. Analyses were descriptive. Results Overall, 265 physicians reported on 1,335 patients. Mean (standard deviation) age at survey date was 60.4 (11.6) years, 91.2% were white, 58.1% female, 44.0% non-smokers. Most patients (63.3%) first consulted a primary care physician. There was a mean delay of 7.8 (22.7) months between first ILD symptom and healthcare professional visit, and another 7.7 (12.8) months to ILD diagnosis. At survey date, 47.7% of patients had physician-reported moderate ILD, 42.3% had mild ILD and 10.0% had severe ILD. Disease progression was reported in the 12 months prior to the survey for 19.5% of patients; of these, progression was based on worsening symptom in 27.3% and lung function decline in 25.8%. For patients experiencing symptoms prior to ILD diagnosis (72.8%), the most common symptoms were dyspnoea on exertion (80.5%) and cough (57.8%). Overall, 17.4% of patients were misdiagnosed prior to ILD diagnosis, with chronic obstructive pulmonary disease suspected in 39.2% of them. The most frequent comorbidities were anxiety (16.9%) and gastroesophageal reflux (15.5%). Although 77.8% of patients were receiving treatment for ILD at survey date, 15.6% of patients had never been prescribed treatment for ILD. Conclusions This real-world study expands our understanding of patients, diagnostic delays and treatment gaps experienced by patients diagnosed with PPF in Europe. There was a mean delay of 15.5 months between first ILD symptoms and ILD diagnosis. Given the progressive nature of PPF, diagnostic delay may lead to poor outcomes, including shorter survival. Trial registration N/a.

Abstract Though conceptually attractive, the use of water-soluble prodrug technology to enhance oral bioavailability of highly insoluble small molecule therapeutics has not been widely adopted. In large part, this is due to the rapid enzymatic or chemical hydrolysis of prodrugs within the gastrointestinal tract, resulting in drug precipitation and no overall improvement in oral bioavailability relative to standard formulation strategies. We reasoned that an optimal water-soluble prodrug could be attained if the rate of prodrug hydrolysis were reduced to favor drug absorption rather than drug precipitation. In doing so, the rate of hydrolysis provides a pharmacokinetic control point for drug delivery. Herein, we report the discovery of a water-soluble promoiety (Sol-moiety) technology to optimize the oral bioavailability of highly insoluble small molecule therapeutics, possessing various functional groups, without the need for sophisticated, often toxic, lipid or organic solvent-based formulations. The power of the technology is demonstrated with marked pharmacokinetic improvement of the commercial drugs enzalutamide, vemurafenib, and paclitaxel. This led to a successful efficacy study of a water-soluble orally administered prodrug of paclitaxel in a mouse pancreatic tumor model.

The meaning of care in residential child care is under-developed. It can often be represented through its absence, seen as offering at best basic physical tending but lacking emotional connection or warmth. At worst, residential care settings said to be institutionally abusive can be characterised as being antithetical to what we might imagine care should be. Residential schools and especially those run by religious orders attract particular opprobrium in this regard. In this article, I adopt a broadly autoethnographic approach to reflect on how boys (now men in their late 40s and early 50s) brought up in the 1980s in a Scottish residential school recall being cared for. The article uses Axel Honneth’s theory of recognition and its three pillars of love, rights and solidarity to group themes from how former pupils speak about their experiences of care. These accounts challenge the received narrative of such settings failing to offer care. The discussion reflects some ideas around care and about how we understand public care historically.

Abstract In this letter to the editor, we present questionnaire-based data assessing the patient journey of adults with moderate–severe Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) in the USA and five European countries. These data highlight how long and difficult the patient journey with CRSwNP can be and how improved disease awareness among physicians could lead to more timely diagnosis and treatment, and hence improved management of patients.

Rationale & Objective: The incidence of arrhythmia varies by time of day. How this affects individuals on maintenance dialysis is uncertain. Our objective was to quantify the relationship of arrhythmia with the time of day and timing of dialysis. Study Design: Secondary analysis of the Monitoring in Dialysis study, a multicenter prospective cohort study. Settings & Participants: Loop recorders were implanted for continuous cardiac monitoring in 66 participants on maintenance dialysis with a follow up of 6 months. Exposure: Time of day based on 6-hour intervals. Outcomes: Event rates of clinically significant arrhythmia. Analytical Approach: Negative binomial mixed effects regression models for repeated measures were used to evaluate data from the Monitoring in Dialysis study for differences in diurnal patterns of clinically significant arrhythmia among those with end-stage kidney disease with heart failure and end-stage kidney disease alone. We additionally analyzed rates according to presence of heart failure, time of dialysis shift, and dialysis versus nondialysis day. Results: Rates of clinically significant arrhythmia peaked between 12:00 AM and 5:59 AM and were more than 1.5-fold as frequent during this interval than the rest of the day. In contrast, variations in atrial fibrillation peaked between 6:00 AM and 11:59 AM, but variations across the day were qualitatively small. Clinically significant arrhythmia occurred at numerically higher rate in individuals with end-stage kidney disease and heart failure (5.9 events/mo; 95% CI, 1.3-26.8) than those without heart failure (4.0 events/mo; 95% CI, 0.9-17.9). Although differences in overall rate were not significant, their periodicity was significantly different (P

BackgroundThe proliferation of digital disease-detection systems has led to an increase in earlier warning signals, which subsequently have resulted in swifter responses to emerging threats. Such highly sensitive systems can also produce weak signals needing additional information for action. The delays in the response to a genuine health threat are often due to the time it takes to verify a health event. It was the delay in outbreak verification that was the main impetus for creating EpiCore. ObjectiveThis paper describes the potential of crowdsourcing information through EpiCore, a network of voluntary human, animal, and environmental health professionals supporting the verification of early warning signals of potential outbreaks and informing risk assessments by monitoring ongoing threats. MethodsThis paper uses summary statistics to assess whether EpiCore is meeting its goal to accelerate the time to verification of identified potential health events for epidemic and pandemic intelligence purposes from around the world. Data from the EpiCore platform from January 2018 to December 2022 were analyzed to capture request for information response rates and verification rates. Illustrated use cases are provided to describe how EpiCore members provide information to facilitate the verification of early warning signals of potential outbreaks and for the monitoring and risk assessment of ongoing threats through EpiCore and its utilities. ResultsSince its launch in 2016, EpiCore network membership grew to over 3300 individuals during the first 2 years, consisting of professionals in human, animal, and environmental health, spanning 161 countries. The overall EpiCore response rate to requests for information increased by year between 2018 and 2022 from 65.4% to 68.8% with an initial response typically received within 24 hours (in 2022, 94% of responded requests received a first contribution within 24 h). Five illustrated use cases highlight the various uses of EpiCore. ConclusionsAs the global demand for data to facilitate disease prevention and control continues to grow, it will be crucial for traditional and nontraditional methods of disease surveillance to work together to ensure health threats are captured earlier. EpiCore is an innovative approach that can support health authorities in decision-making when used complementarily with official early detection and verification systems. EpiCore can shorten the time to verification by confirming early detection signals, informing risk-assessment activities, and monitoring ongoing events.

Aims and method Recently, the Health of the Nation Outcome Scales 65+ (HoNOS65+) were revised. Twenty-five experts from Australia and New Zealand completed an anonymous web-based survey about the content validity of the revised measure, the HoNOS Older Adults (HoNOS OA). Results All 12 HoNOS OA scales were rated by most (≥75%) experts as ‘important’ or ‘very important’ for determining overall clinical severity among older adults. Ratings of sensitivity to change, comprehensibility and comprehensiveness were more variable, but mostly positive. Experts’ comments provided possible explanations. For example, some experts suggested modifying or expanding the glossary examples for some scales (e.g. those measuring problems with relationships and problems with activities of daily living) to be more older adult-specific. Clinical implications Experts agreed that the HoNOS OA measures important constructs. Training may need to orient experienced raters to the rationale for some revisions. Further psychometric testing of the HoNOS OA is recommended.

Abstract Background Seasonal floods pose a commonly-recognised barrier to women’s access to maternal services, resulting in increased morbidity and mortality. Despite their importance, previous GIS models of healthcare access have not adequately accounted for floods. This study developed new methodologies for incorporating flood depths, velocities, and extents produced with a flood model into network- and raster-based health access models. The methodologies were applied to the Barotse Floodplain to assess flood impact on women’s walking access to maternal services and vehicular emergency referrals for a monthly basis between October 2017 and October 2018. Methods Information on health facilities were acquired from the Ministry of Health. Population density data on women of reproductive age were obtained from the High Resolution Settlement Layer. Roads were a fusion of OpenStreetMap and data manually delineated from satellite imagery. Monthly information on floodwater depth and velocity were obtained from a flood model for 13-months. Referral driving times between delivery sites and EmOC were calculated with network analysis. Walking times to the nearest maternal services were calculated using a cost-distance algorithm. Results The changing distribution of floodwaters impacted the ability of women to reach maternal services. At the peak of the dry season (October 2017), 55%, 19%, and 24% of women had walking access within 2-hrs to their nearest delivery site, EmOC location, and maternity waiting shelter (MWS) respectively. By the flood peak, this dropped to 29%, 14%, and 16%. Complete inaccessibility became stark with 65%, 76%, and 74% unable to access any delivery site, EmOC, and MWS respectively. The percentage of women that could be referred by vehicle to EmOC from a delivery site within an hour also declined from 65% in October 2017 to 23% in March 2018. Conclusions Flooding greatly impacted health access, with impacts varying monthly as the floodwave progressed. Additional validation and application to other regions is still needed, however our first results suggest the use of a hydrodynamic model permits a more detailed representation of floodwater impact and there is great potential for generating predictive models which will be necessary to consider climate change impacts on future health access.

Background: Pulmonary arterial hypertension (PAH) is a life-threatening, progressive disease often diagnosed late in its course. Objectives: To present patient-reported data that were captured within a large, multinational, point-in-time survey of PAH-treating physicians and their patients to better understand the diagnostic journey. Design: Cross-sectional survey conducted in five European countries (EU5), Japan and the USA. Methods: PAH-treating pulmonologists, cardiologists, rheumatologists or internists (USA only) completed a patient record form (PRF) for the next four consecutive adult PAH patients they saw; these patients filled in a patient self-completion (PSC) form on an anonymous, voluntary basis. Our report focuses on patient data; data are from PSC forms unless stated otherwise. Results: Physician-reported PRFs and self-completed PSC forms were obtained for 1152 and 572 patients, respectively. Patients’ mean (SD) age was 59.1 (14.0) years, 55.6% were female, and 57.3% had idiopathic PAH. Patient-reported data showed an average delay of 17.0 months between symptom onset and PAH diagnosis. This is longer than physicians estimated (13.8 months): this disparity may be partly due to the time taken by patients to consult a physician about their symptoms [9.6 months overall, longest in the USA (15.3 months)]. Most patients (71.6%) initially consulted primary care physicians about their symptoms and 76.4% of patients were referred to a specialist. Misdiagnoses occurred in 40.9% of patients [most frequent in the USA (51.3%), least common in Japan (27.6%)] and they saw an average of 2.9 physicians overall (3.5 in EU5 versus 2.0 in Japan/USA) before being diagnosed. Diagnosis was most often made by cardiologists (50.4%) or pulmonologists (49.3%). Conclusion: Our data suggest that diagnostic delay in PAH results from patient- and physician-related factors, which differ across regions and include lack of awareness of PAH on both sides. Development of better screening strategies may help address this barrier to timely PAH diagnosis.

BackgroundSeasonal respiratory viruses had lower incidence during their 2019-2020 and 2020-2021 seasons, which overlapped with the COVID-19 pandemic. The widespread implementation of precautionary measures to prevent transmission of SARS-CoV-2 has been seen to also mitigate transmission of seasonal influenza. The COVID-19 pandemic also led to changes in care seeking and access. Participatory surveillance systems have historically captured mild illnesses that are often missed by surveillance systems that rely on encounters with a health care provider for detection. ObjectiveThis study aimed to assess if a crowdsourced syndromic surveillance system capable of detecting mild influenza-like illness (ILI) also captured the globally observed decrease in ILI in the 2019-2020 and 2020-2021 influenza seasons, concurrent with the COVID-19 pandemic. MethodsFlu Near You (FNY) is a web-based participatory syndromic surveillance system that allows participants in the United States to report their health information using a brief weekly survey. Reminder emails are sent to registered FNY participants to report on their symptoms and the symptoms of household members. Guest participants may also report. ILI was defined as fever and sore throat or fever and cough. ILI rates were determined as the number of ILI reports over the total number of reports and assessed for the 2016-2017, 2017-2018, 2018-2019, 2019-2020, and 2020-2021 influenza seasons. Baseline season (2016-2017, 2017-2018, and 2018-2019) rates were compared to the 2019-2020 and 2020-2021 influenza seasons. Self-reported influenza diagnosis and vaccination status were captured and assessed as the total number of reported events over the total number of reports submitted. CIs for all proportions were calculated via a 1-sample test of proportions. ResultsILI was detected in 3.8% (32,239/848,878) of participants in the baseline seasons (2016-2019), 2.58% (7418/287,909) in the 2019-2020 season, and 0.27% (546/201,079) in the 2020-2021 season. Both influenza seasons that overlapped with the COVID-19 pandemic had lower ILI rates than the baseline seasons. ILI decline was observed during the months with widespread implementation of COVID-19 precautions, starting in February 2020. Self-reported influenza diagnoses decreased from early 2020 through the influenza season. Self-reported influenza positivity among ILI cases varied over the observed time period. Self-reported influenza vaccination rates in FNY were high across all observed seasons. ConclusionsA decrease in ILI was detected in the crowdsourced FNY surveillance system during the 2019-2020 and 2020-2021 influenza seasons, mirroring trends observed in other influenza surveillance systems. Specifically, the months within seasons that overlapped with widespread pandemic precautions showed decreases in ILI and confirmed influenza. Concerns persist regarding respiratory pathogens re-emerging with changes to COVID-19 guidelines. Traditional surveillance is subject to changes in health care behaviors. Systems like FNY are uniquely situated to detect disease across disease severity and care seeking, providing key insights during public health emergencies.

Benefits realisation management (BRM) aims to facilitate the process of identifying, measuring and tracking desired benefits derived from a project. Improvement methodology frameworks often describe BRM as integral to identifying and measuring value derived from transformation initiatives within the National Health Service and beyond. Despite this, reporting of benefits realisation plans and methodological approaches to identifying and measuring benefits remains surprisingly scarce.This project aimed to pilot and evaluate the application of a purpose-designed benefits mapping template with seven newly funded transformation projects across three hospitals in the UK. The scope of the template was to identify key project benefits and metrics associated with the project initiatives. Plan-do-study-act (PDSA) cycles were used to capture the approach and utilisation of the template by project teams. These methods also enabled critical review of the template as an enabler to identifying relevant benefits and project metrics.Stakeholder engagement with the templates was variable. This was attributed to clinical pressures induced by the second wave of COVID-19 in the UK. Despite this, teams were able to produce completed templates outlining a number of wide-ranging benefits. Themes of benefits drawn from the maps include patient experience, patient outcomes, staff experience, access to care and efficiency. Qualitative feedback from teams included the reported value of a structured template to help recognise all the potential benefits associated with each project initiative. The PDSA cycles highlighted the template as an early step in BRM. Further components to this process are recommended to include consensus of the key metrics to be measured, a tool that summarises the reporting details of those metrics, and an effective means to collate reported metrics overtime.

Abstract Chronic low back pain (CLBP) is a disabling condition worldwide. In CLBP, neuroimaging studies demonstrate abnormal activities in cortical areas responsible for pain modulation, emotional, and sensory components of pain experience [i.e., pregenual and dorsal anterior cingulate cortex (pgACC, dACC), and somatosensory cortex (SSC), respectively]. This pilot study, conducted in a university setting, evaluated the feasibility, safety, and acceptability of a novel electroencephalography-based infraslow-neurofeedback (EEG ISF-NF) technique for retraining activities in pgACC, dACC and SSC and explored its effects on pain and disability. Participants with CLBP (n = 60), recruited between July’20 to March’21, received 12 sessions of either: ISF-NF targeting pgACC, dACC + SSC, a ratio of pgACC*2/dACC + SSC, or Placebo-NF. Descriptive statistics demonstrated that ISF-NF training is feasible [recruitment rate (7 participants/month), dropouts (25%; 20–27%), and adherence (80%; 73–88%)], safe (no adverse events reported), and was moderate to highly acceptable [Mean ± SD: 7.8 ± 2.0 (pgACC), 7.5 ± 2.7 (dACC + SCC), 8.2 ± 1.9 (Ratio), and 7.7 ± 1.5 (Placebo)]. ISF-NF targeting pgACC demonstrated the most favourable clinical outcomes, with a higher proportion of participants exhibiting a clinically meaningful reduction in pain severity [53%; MD (95% CI): − 1.9 (− 2.7, − 1.0)], interference [80%; MD (95% CI): − 2.3 (− 3.5, − 1.2)], and disability [73%; MD (95% CI): − 4.5 (− 6.1, − 2.9)] at 1-month follow-up. ISF-NF training is a feasible, safe, and an acceptable treatment approach for CLBP.

The development of hypersonic weapons and their introduction into an increasingly competitive multipolar world order has generated much debate around their potential implications for stability. This research paper adds to the debate by examining how the introduction of hypersonic weapons may impact the future military relationship between NATO and Russia through the lens of offence-defence balance theory. It is contended that these weapons will not fundamentally alter the military balance between NATO and Russia, their offensive use being constrained by their potential to escalate conflict into the nuclear domain. Hypersonic weapons will increase the salience of nuclear weapons and missile defences within the relationship which may have more serious consequences for stability in the future. The fear of what hypersonic weapons might achieve, rather than their objective utility, is driving a cycle of action and reaction, but opportunities exist for these fears to be ameliorated without either side having their security materially undermined.

Abstract Background The core intrinsic connectivity networks (core-ICNs), encompassing the default-mode network (DMN), salience network (SN) and central executive network (CEN), have been shown to be dysfunctional in individuals with internalizing disorders (IDs, e.g. major depressive disorder, MDD; generalized anxiety disorder, GAD; social anxiety disorder, SOC). As such, source-localized, closed-loop brain training of electrophysiological signals, also known as standardized low-resolution electromagnetic tomography (sLORETA) neurofeedback (NFB), targeting key cortical nodes within these networks has the potential to reduce symptoms associated with IDs and restore normal core ICN function. We intend to conduct a randomized, double-blind (participant and assessor), sham-controlled, parallel-group (3-arm) trial of sLORETA infraslow (

Background: Chronic rhinosinusitis with nasal polyposis (CRSwNP) affects up to 4% of individuals. Common symptoms include nasal congestion/obstruction, nasal discharge, facial pain, and reduced sense of smell. This study describes patient- and physician-reported CRSwNP symptom burden and health-related quality of life (HRQOL) in a real-world clinical setting. Methods: This multinational, geographically diverse, point-in-time survey invited physicians to evaluate 5 consecutive adults with confirmed bilateral moderate to severe CRSwNP (consecutive sampling) plus the next 2 patients with recurrent nasal polyps and ≥1 surgery for polyp removal (oversampling). Patients’ and physicians’ surveys were assessed in the entire consecutive sample and by categories of physician-determined CRSwNP severity, and by categories of asthma comorbidity (total sample). Patients’ and physicians’ responses were compared in a matched sample. Results: The total sample of 1,782 patients comprised 1,296 (72.7%) from consecutive sampling and 486 (27.3%) from oversampling. Among the consecutive sample (mean age, 46.9 years), 1,122 (86.6%) had moderate and 174 (13.4%) had severe CRSwNP. Of 1,697 patients from total sampling with known asthma status, 708 (41.7%) had asthma and 989 (58.3%) did not. Patients’ self-reported symptom frequency, severity, and burden on HRQOL worsened with increasing CRSwNP severity and comorbid asthma. Physicians underreported prevalence, severity, and impact of symptoms on daily activities compared with patients (matched sample). Conclusion: Patients and physicians from real-world settings both described a considerable burden of CRSwNP, but physicians consistently reported fewer and less severe symptoms than patients. This suggests a more patient-centric view is needed when assessing CRSwNP symptom burden and HRQOL.

Effective chromosome synapsis and crossover formation during meiosis are essential for fertility, especially in grain crops such as wheat. These processes function most efficiently in wheat at temperatures between 17-23 °C, although the genetic mechanisms for such temperature dependence are unknown. In a previously identified mutant of the hexaploid wheat reference variety ‘Chinese Spring’ lacking the long arm of chromosome 5D, exposure to low temperatures during meiosis resulted in asynapsis and crossover failure. In a second mutant (ttmei1), containing a 4 Mb deletion in chromosome 5DL, exposure to 13 °C led to similarly high levels of asynapsis and univalence. Moreover, exposure to 30 °C led to a significant, but less extreme effect on crossovers. Previously, we proposed that, of 41 genes deleted in this 4 Mb region, the major meiotic gene TaDMC1-D1 was the most likely candidate for preservation of synapsis and crossovers at low (and possibly high) temperatures. In the current study, using RNA-guided Cas9, we developed a new Chinese Spring CRISPR mutant, containing a 39 bp deletion in the 5D copy of DMC1, representing the first reported CRISPR-Cas9 targeted mutagenesis in Chinese Spring, and the first CRISPR mutant for DMC1 in wheat. In controlled environment experiments, wild-type Chinese Spring, CRISPR dmc1-D1 and backcrossed ttmei1 mutants were exposed to either high or low temperatures during the temperature-sensitive period from premeiotic interphase to early meiosis I. After 6-7 days at 13 °C, crossovers decreased by over 95% in the dmc1-D1 mutants, when compared with wild-type plants grown under the same conditions. After 24 hours at 30 °C, dmc1-D1 mutants exhibited a reduced number of crossovers and increased univalence, although these differences were less marked than at 13 °C. Similar results were obtained for ttmei1 mutants, although their scores were more variable, possibly reflecting higher levels of background mutation. These experiments confirm our previous hypothesis that DMC1-D1 is responsible for preservation of normal crossover formation at low and, to a certain extent, high temperatures. Given that reductions in crossovers have significant effects on grain yield, these results have important implications for wheat breeding, particularly in the face of climate change.

Tetraploid (AABB) and hexaploid (AABBDD) wheat have multiple sets of similar chromosomes, with successful meiosis and preservation of fertility relying on synapsis and crossover (CO) formation only taking place between homologous chromosomes. In hexaploid wheat, the major meiotic gene TaZIP4-B2 (Ph1) on chromosome 5B, promotes CO formation between homologous chromosomes, whilst suppressing COs between homeologous (related) chromosomes. In other species, ZIP4 mutations eliminate approximately 85% of COs, consistent with loss of the class I CO pathway. Tetraploid wheat has three ZIP4 copies: TtZIP4-A1 on chromosome 3A, TtZIP4-B1 on 3B and TtZIP4-B2 on 5B. Here, we have developed single, double and triple zip4 TILLING mutants and a CRISPR Ttzip4-B2 mutant, to determine the effect of ZIP4 genes on synapsis and CO formation in the tetraploid wheat cultivar ‘Kronos’. We show that disruption of two ZIP4 gene copies in Ttzip4-A1B1 double mutants, results in a 76-78% reduction in COs when compared to wild-type plants. Moreover, when all three copies are disrupted in Ttzip4-A1B1B2 triple mutants, COs are reduced by over 95%, suggesting that the TtZIP4-B2 copy may also affect class II COs. If this is the case, the class I and class II CO pathways may be interlinked in wheat. When ZIP4 duplicated and diverged from chromosome 3B on wheat polyploidization, the new 5B copy, TaZIP4-B2, could have acquired an additional function to stabilize both CO pathways. In tetraploid plants deficient in all three ZIP4 copies, synapsis is delayed and does not complete, consistent with our previous studies in hexaploid wheat, when a similar delay in synapsis was observed in a 59.3 Mb deletion mutant, ph1b, encompassing the TaZIP4-B2 gene on chromosome 5B. These findings confirm the requirement of ZIP4-B2 for efficient synapsis, and suggest that TtZIP4 genes have a stronger effect on synapsis than previously described in Arabidopsis and rice. Thus, ZIP4-B2 in wheat accounts for the two major phenotypes reported for Ph1, promotion of homologous synapsis and suppression of homeologous COs.

BackgroundFood allergy to peanut and soybean, both legumes, is highly prevalent. The consumption of other legumes and legume protein isolates, some of which may be considered novel foods, is increasing. This may lead to an increase in sensitization and allergy and may pose a risk for legume-allergic (e.g. peanut and soybean) patients due to cross-reactivity.ObjectiveThis study investigated the frequency of co-sensitization and co-allergy between legumes and the role of different protein families.MethodsSix legume-allergic patient groups were included: peanut (n = 30), soybean (n = 30), lupine (n = 30), green pea (n = 30), lentil (n = 17), bean (n = 9). IgE binding to total extracts, protein fractions (7S/11S globulin, 2S albumin, albumin), and 16 individual proteins from 10 legumes (black lentil, blue lupine, chickpea, faba bean, green lentil, pea, peanut, soybean, white bean, and white lupine) was measured by line blotResultsCo-sensitization varied from 36.7% to 100%. Mono-sensitization was only found in soybean (16.7%), peanut (10%), and green pea-allergic (3.3%) patients. A high frequency of co-sensitization between the 7S/11S globulin fractions of all 10 legumes and individual 7S and 11S globulins was observed. In peanut and soybean-allergic patients, co-allergies for other legumes were uncommon (≤16,7%), while in green pea, lupine, lentil, and bean-allergic patients co-allergy for peanut (64.7%–77.8%) or soybean (50%–64.7%) was frequently seen.ConclusionCo-sensitization between legumes was high, but generally not clinically relevant. Co-allergy to other legumes was not often seen in peanut- and soybean allergic patients. The 7S and 11S globulins were likely responsible for the observed co-sensitization.

Abstract Background Laryngeal paragangliomas (LP) comprise a rare subset of head and neck neoplasms and are an important differential in the patient with a submucosal laryngeal mass. Methods We discuss an operative technique using coblation assisted excision via laryngofissure in the cases of four confirmed LPs and discuss the current literature with respect to diagnosis and management of these patients. Results Our case series of four patients demonstrate the laryngofissure approach for LP is safe, provides oncological cure and preserves laryngeal function. This technique with coblation has not been previously discussed in the surgical management of LPs. Patient‐reported postoperative voice and swallowing outcomes were excellent in all patients. Whole body imaging techniques were utilized in all patients, with octreotide scintigraphy demonstrating synchronous lesions in two of the four patients—one had a retroperitoneal lesion, whilst another patient had multiple lesions in the skull base, paravertebral region, liver, and adrenal gland. Conclusions Our cases also highlight the changing clinical paradigms in the diagnostic approach of LPs and an emerging role for octreotide scintigraphy in the workup of these patients. Coblation assisted excision via laryngofissure is efficient and effective in the surgical resection of LP. In patients with multicentric forms of LP, the size, side, and anatomic location of synchronous lesions should be considered in surgical planning to determine feasibility and safety of operative management. Level of Evidence IV

Abstract Background The COVID-19 pandemic has highlighted the importance of whole genome sequencing (WGS) of SARS-CoV-2 to inform public health policy. By enabling definition of lineages it facilitates tracking of the global spread of the virus. The evolution of new variants can be monitored and knowledge of specific mutations provides insights into the mechanisms through which the virus increases transmissibility or evades immunity. To date almost 1 million SARS-CoV-2 genomes have been sequenced by members of the COVID-19 Genomics UK (COG-UK) Consortium. To achieve similar feats in a more cost-effective and sustainable manner in future, improved high throughput virus sequencing protocols are required. We have therefore developed a miniaturized library preparation protocol with drastically reduced consumable use and costs. Results We present the ‘Mini-XT’ miniaturized tagmentation-based library preparation protocol available on protocols.io ( https://doi.org/10.17504/protocols.io.bvntn5en ). SARS-CoV-2 RNA was amplified using the ARTIC nCov-2019 multiplex RT-PCR protocol and purified using a conventional liquid handling system. Acoustic liquid transfer (Echo 525) was employed to reduce reaction volumes and the number of tips required for a Nextera XT library preparation. Sequencing was performed on an Illumina MiSeq. The final version of Mini-XT has been used to sequence 4384 SARS-CoV-2 samples from N. Ireland with a COG-UK QC pass rate of 97.4%. Sequencing quality was comparable and lineage calling consistent for replicate samples processed with full volume Nextera DNA Flex (333 samples) or using nanopore technology (20 samples). SNP calling between Mini-XT and these technologies was consistent and sequences from replicate samples paired together in maximum likelihood phylogenetic trees. Conclusions The Mini-XT protocol maintains sequence quality while reducing library preparation reagent volumes eightfold and halving overall tip usage from sample to sequence to provide concomitant cost savings relative to standard protocols. This will enable more efficient high-throughput sequencing of SARS-CoV-2 isolates and future pathogen WGS.

Aegilops sharonensis is a wild diploid relative of wheat. Here, the authors assemble the genome of Ae. sharonensis and use the assembly as an aid to clone the Ae. sharonensis-derived stem rust resistance gene Sr62 in the allohexaploid genome of wheat.

Introduction: Atrial fibrillation (AF) is common in patients with kidney failure on hemodialysis (KF-HD). We determined both AF incidence and burden in patients with KF-HD using implantable loop recorder (ILR) monitoring. Methods: Patients with KF-HD were enrolled and received an ILR. In 6 monitoring months, the incidence of AF events lasting ≥6 minutes was captured. Demographic, clinical, and dialysis characteristics were collected, and associations with incident AF were estimated using negative binomial regression models and expressed as incidence rate ratios and 95% CIs. Results: We enrolled 66 patients with KF-HD (mean age = 56 years, 70% male); 59 (90%) were without previously diagnosed AF. AF lasting ≥6 minutes was detected in 18 of 59 subjects (31%) without previously diagnosed AF and in 5 of 7 subjects (71%) with a previous AF diagnosis. Among the 23 with detected AF, episodes were present on 16% of patient days. Although 14 of 23 patients (61%) had AF on 2.5 vs. 2.5 mEq/l: incidence rate ratio = 0.62; 95% CI, 0.48–0.80) was associated with lower AF risk whereas higher dialysate bicarbonate concentrations (>35 vs. 35 mEq/l: incidence rate ratio = 3.18; 95% CI, 1.13–8.94) were associated with higher AF risk. Conclusion: New AF was detected in approximately one-third of patients with KF-HD. AF affects a substantial proportion of patient days and may be an underappreciated cause of stroke in KF-HD.

IntroductionNew Zealand health training institutions have an important role in supporting health workforce training programmes in the Pacific Region. AimTo explore the experience of Pacific Island country-based doctors from the Cook Islands, Niue, and Samoa, studying in New Zealand’s University of Otago distance-taught Rural Postgraduate programme. MethodsDocument analysis (16 documents) was undertaken. Eight semi-structured interviews were conducted with Pacific Island country-based students. Thematic analysis of the interviews was undertaken using the framework method. The two data sources were analysed separately, followed by a process to converge and corroborate findings. ResultsFor Pacific Island countries with no previous option for formal general practice training, access to a recognised academic programme represented a milestone. Immediate clinical relevance and applicability of a generalist medical curriculum with rural remote emphasis, delivered mainly at a distance, was identified as a major strength. Although technologies posed some issues, these were generally easily solved. The main challenges identified related to the provision of academic and other support. Traditional university support services and resources were campus focused and not always easily accessed by this group of students who cross educational pedagogies, health systems and national borders to study in a New Zealand programme. Study for individuals worked best when it was part of a recognised and supported Pacific in-country training pathway. DiscussionThe University of Otago’s Rural Postgraduate programme is accessible, relevant and achievable for Pacific Island country-based doctors. The programme offers a partial solution for training in general practice for the Pacific region. Student experience could be improved by tailoring and strengthening support services and ensuring their effective delivery.

Abstract In this paper we present a detailed study of the four-body decay B 0 → K + π − ℓ + ℓ − , where tensions with the Standard Model predictions have been observed. Our analysis of the decay with P- and S-wave contributions to the K + π − system develops a complete understanding of the symmetries of the distribution, in the case of massless and massive leptons. In both cases, the symmetries determine relations between the observables in the B 0 → K + π − ℓ + ℓ − decay distribution. This enables us to define the complete set of observables accessible to experiments, including several that have not previously been identified. The new observables arise when the decay rate is written differentially with respect to m K π $$ {m}_{K_{\pi }} $$ . We demonstrate that experiments will be able to fit this full decay distribution with currently available data sets and investigate the sensitivity to new physics scenarios given the experimental precision that is expected in the future. The symmetry relations provide a unique handle to explore the behaviour of S-wave observables by expressing them in terms of P-wave observables, therefore minimising the dependence on poorly-known S-wave form factors. Using this approach, we construct two theoretically optimized S-wave observables and explore their sensitivity to new physics. By further exploiting the symmetry relations, we obtain the first bounds on the S-wave observables using two different methods and highlight how these relations may be used as cross-checks of the experimental methodology and the parametrization of the B 0 → K + π − ℓ + ℓ − differential decay rate. We identify a zero-crossing point that would be at a common dilepton invariant mass for a subset of P- and S-wave observables, and explore the information on new physics and hadronic effects that this zero point can provide.

BackgroundBreast cancer- related lymphedema (BCRL) affects about 3 to 5 million patients worldwide, with about 20,000 per year in the United States. As breast cancer mortality is declining due to improved diagnostics and treatments, the long-term effects of treatment for BCRL need to be addressed.MethodsThe American Society of Breast Surgeons Lymphatic Surgery Working Group conducted a large review of the literature in order to develop guidelines on BCRL prevention and treatment. This was a comprehensive but not systematic review of the literature. This was inclusive of recent randomized controlled trials, meta-analyses, and reviews evaluating the prevention and treatment of BCRL. There were 25 randomized clinical trials, 13 systemic reviews and meta-analyses, and 87 observational studies included.ResultsThe findings of our review are detailed in the paper, with each guideline being analyzed with the most recent data that the group found evidence of to suggest these recommendations.ConclusionsPrevention and treatment of BCRL involve a multidisciplinary team. Early detection, before clinically apparent, is crucial to prevent irreversible lymphedema. Awareness of risk factors and appropriate practice adjustments to reduce the risk aids are crucial to decrease the progression of lymphedema. The treatment can be costly, time- consuming, and not always effective, and therefore, the overall goal should be prevention.

Fecal microbiota transplantation (FMT) is an attractive strategy to correct microbial dysbiosis in diarrhea-predominant irritable bowel syndrome (IBS-D). Although the mechanism of FMT is thought to be bacterial engraftment, the best approach to achieve engraftment after FMT in IBS-D (and other diseases) is not clear. We evaluated the effect of FMT (with or without pretreatment with antibiotics) on gut microbiome and symptoms in patients with IBS-D. In this randomized, placebo-controlled, single-center study, 44 patients with IBS-D with a least moderate severity (IBS severity scoring system, i.e., IBS-SSS, ≥175) were randomly assigned to one of four groups: single-dose oral FMT alone, single-dose oral FMT following a 7-day pretreatment course of Ciprofloxacin and Metronidazole (CM-FMT) or Rifaximin (R-FMT), or Placebo FMT. Primary endpoint was engraftment post-FMT and secondary endpoints were changes in IBS-SSS, and IBS-quality of life (IBS-QOL) at week 10. Median engraftment was significantly different among the three FMT groups (P = .013). Engraftment post-FMT was significantly higher in the FMT alone arm (15.5%) compared to that in R-FMT group (5%, P = .04) and CM-FMT group (2.4%, P = .002). The mean change in IBS-SSS and IBS-QOL from baseline were not significantly different among the four groups or between the three FMT groups combined vs. placebo at week 10. In summary, antibiotic pretreatment significantly reduced bacterial engraftment after FMT in patients with IBS-D.

Abstract Biological and non-biological variables unrelated to acute myeloid leukemia (AML) preclude standard therapy in many settings, with “real world” patients under-represented in clinical trials and prognostic models. Here, using a case-based format, we illustrate the impact that socioeconomic and anthropogeographical constraints can have on optimally managing AML in 4 different healthcare systems. The granular details provided, emphasize the need for the development and targeting of socioeconomic interventions that are commensurate with the changing landscape of AML therapeutics, in order to avoid worsening the disparity in outcomes between patients with biologically similar disease.

Abstract Background Fecal microbiota transplantation (FMT) is a promising new strategy in the treatment of Inflammatory Bowel Disease, but long-term delivery systems are lacking. This randomized study was designed as a safety and feasibility study of long-term FMT in subjects with mild to moderate UC using frozen, encapsulated oral FMT (cFMT). Methods Subjects were randomized 1:1 to receive FMT induction by colonoscopy, followed by 12 weeks of daily oral administration of frozen encapsulated cFMT or sham therpay. Subjects were followed for 36 weeks and longitudenal clinical assessments included multiple subjective and objective markers of disease severity. Ribosomal 16S bacterial sequencing was used to assess donor-induced changes in the gut microbiota. Changes in T regulatory (Treg) and mucosal associated invariant T (MAIT) cell populations were evaluated by flow cytometry as an exploratory endpoint. Results Twelve subjects with active UC were randomized: 6 subjects completed the full 12-week course of FMT plus cFMT, and 6 subjects received sham treatment by colonic installation and longitudinal oral placebo capules. Chronic administration of cFMT was found to be safe and well-tolerated but home storage concerns exist. Protocol adherence was high, and none of the study subjects experienced FMT-associated treatment emergent adverse events. Two subjects that received cFMT achieved clinical remission versus none in the placebo group (95% CI = 0.38-infinity, p = 0.45). cFMT was associated with sustained donor-induced shifts in fecal microbial composition. Changes in MAIT cell cytokine production were observed in cFMT recipients and correlated with treatment response. Conclusion These pilot data suggest that daily encapsulated cFMT may extend the durability of index FMT-induced changes in gut bacterial community structure and that an association between MAIT cell cytokine production and clinical response to FMT may exist in UC populations. Oral frozen encapsulated cFMT is a promising FMT delivery system and may be preferred for longterm treatment strategies in UC and other chronic diseases but further evaluations will have to address home storage concerns. Larger trials should be done to explore the benefits of cFMT and to determine its long-term impacts on the colonic microbiome. Trial registration: ClinicalTrials.gov (NCT02390726). Registered 17 March 2015, https://clinicaltrials.gov/ct2/show/NCT02390726?term=NCT02390726&draw=2&rank=1 .

BackgroundParticipatory surveillance systems augment traditional surveillance systems through bidirectional community engagement. The digital platform evolution has enabled the expansion of participatory surveillance systems, globally, for the detection of health events impacting people, animals, plants, and the environment, in other words, across the entire One Health spectrum. ObjectiveThe aim of this landscape was to identify and provide descriptive information regarding system focus, geography, users, technology, information shared, and perceived impact of ongoing participatory surveillance systems across the One Health spectrum. MethodsThis landscape began with a systematic literature review to identify potential ongoing participatory surveillance systems. A survey was sent to collect standardized data from the contacts of systems identified in the literature review and through direct outreach to stakeholders, experts, and professional organizations. Descriptive analyses of survey and literature review results were conducted across the programs. ResultsThe landscape identified 60 ongoing single-sector and multisector participatory surveillance systems spanning five continents. Of these, 29 (48%) include data on human health, 26 (43%) include data on environmental health, and 24 (40%) include data on animal health. In total, 16 (27%) systems are multisectoral; of these, 9 (56%) collect animal and environmental health data; 3 (19%) collect human, animal, and environmental health data; 2 (13%) collect human and environmental health data; and 2 (13%) collect human and animal health data. Out of 60 systems, 31 (52%) are designed to cover a national scale, compared to those with a subnational (n=19, 32%) or multinational (n=10, 17%) focus. All systems use some form of digital technology. Email communication or websites (n=40, 67%) and smartphones (n=29, 48%) are the most common technologies used, with some using both. Systems have capabilities to download geolocation data (n=31, 52%), photographs (n=29, 48%), and videos (n=6, 10%), and can incorporate lab data or sample collection (n=15, 25%). In sharing information back with users, most use visualization, such as maps (n=43, 72%); training and educational materials (n=37, 62%); newsletters, blogs, and emails (n=34, 57%); and disease prevention information (n=32, 53%). Out of the 46 systems responding to the survey regarding perceived impacts of their systems, 36 (78%) noted “improved community knowledge and understanding” and 31 (67%) noted “earlier detection.” ConclusionsThe landscape demonstrated the breadth of applicability of participatory surveillance around the world to collect data from community members and trained volunteers in order to inform the detection of events, from invasive plant pests to weekly influenza symptoms. Acknowledging the importance of bidirectionality of information, these systems simultaneously share findings back with the users. Such directly engaged community detection systems capture events early and provide opportunities to stop outbreaks quickly.

The future of radiation oncology is exceptionally strong as we are increasingly involved in nearly all oncology disease sites due to extraordinary advances in radiation oncology treatment management platforms and improvements in treatment execution. Due to our technology and consistent accuracy, compressed radiation oncology treatment strategies are becoming more commonplace secondary to our ability to successfully treat tumor targets with increased normal tissue avoidance. In many disease sites including the central nervous system, pulmonary parenchyma, liver, and other areas, our service is redefining the standards of care. Targeting of disease has improved due to advances in tumor imaging and application of integrated imaging datasets into sophisticated planning systems which can optimize volume driven plans created by talented personnel. Treatment times have significantly decreased due to volume driven arc therapy and positioning is secured by real time imaging and optical tracking. Normal tissue exclusion has permitted compressed treatment schedules making treatment more convenient for the patient. These changes require additional study to further optimize care. Because data exchange worldwide have evolved through digital platforms and prisms, images and radiation datasets worldwide can be shared/reviewed on a same day basis using established de-identification and anonymization methods. Data storage post-trial completion can co-exist with digital pathomic and radiomic information in a single database coupled with patient specific outcome information and serve to move our translational science forward with nimble query elements and artificial intelligence to ask better questions of the data we collect and collate. This will be important moving forward to validate our process improvements at an enterprise level and support our science. We have to be thorough and complete in our data acquisition processes, however if we remain disciplined in our data management plan, our field can grow further and become more successful generating new standards of care from validated datasets.

BackgroundThe globally dominant treatment with curative intent for locally advanced esophageal squamous cell carcinoma (ESCC) is neoadjuvant chemoradiotherapy (nCRT) with subsequent esophagectomy. This multimodal treatment leads to around 60% overall 5-year survival, yet with impaired post-surgical quality of life. Observational studies indicate that curatively intended chemoradiotherapy, so-called definitive chemoradiotherapy (dCRT) followed by surveillance of the primary tumor site and regional lymph node stations and surgery only when needed to ensure local tumor control, may lead to similar survival as nCRT with surgery, but with considerably less impairment of quality of life. This trial aims to demonstrate that dCRT, with selectively performed salvage esophagectomy only when needed to achieve locoregional tumor control, is non-inferior regarding overall survival, and superior regarding health-related quality of life (HRQOL), compared to nCRT followed by mandatory surgery, in patients with operable, locally advanced ESCC.MethodsThis is a pragmatic open-label, randomized controlled phase III, multicenter trial with non-inferiority design with regard to the primary endpoint overall survival and a superiority hypothesis for the experimental intervention dCRT with regard to the main secondary endpoint global HRQOL one year after randomization. The control intervention is nCRT followed by preplanned surgery and the experimental intervention is dCRT followed by surveillance and salvage esophagectomy only when needed to secure local tumor control. A target sample size of 1200 randomized patients is planned in order to reach 462 events (deaths) during follow-up.Clinical Trial Registrationwww.ClinicalTrials.gov, identifier: NCT04460352.

Abstract Background Food proteins differ in their allergenic potential. Currently, there is no predictive and validated bio-assay to evaluate the allergenicity of novel food proteins. The objective of this study was to investigate the potential of a human peripheral blood mononuclear cell (PBMC) gene expression assay to identify biomarkers to predict the allergenicity of legume proteins. Results PBMCs from healthy donors were exposed to weakly and strongly allergenic legume proteins (2S albumins, and 7S and 11S globulins from white bean, soybean, peanut, pea and lupine) in three experiments. Possible biomarkers for allergenicity were investigated by exposing PBMCs to a protein pair of weakly (white bean) and strongly allergenic (soybean) 7S globulins in a pilot experiment. Gene expression was measured by RNA-sequencing and differentially expressed genes were selected as biomarkers. 153 genes were identified as having significantly different expression levels to the 7S globulin of white bean compared to soybean. Inclusion of multiple protein pairs from 2S albumins (lupine and peanut) and 7S globulins (white bean and soybean) in a larger study, led to the selection of CCL2, CCL7, and RASD2 as biomarkers to distinguish weakly from strongly allergenic proteins. The relevance of these three biomarkers was confirmed by qPCR when PBMCs were exposed to a larger panel of weakly and strongly allergenic legume proteins (2S albumins, and 7S and 11S globulins from white bean, soybean, peanut, pea and lupine). Conclusions The PBMC gene expression assay can potentially distinguish weakly from strongly allergenic legume proteins within a protein family, though it will be challenging to develop a generic method for all protein families from plant and animal sources. Graded responses within a protein family might be of more value in allergenicity prediction instead of a yes or no classification.

Purpose: Periorbital tumor location presents a significant challenge with 3-dimensional conformal radiation therapy or intensity modulated radiation therapy due to high tumor dose needed in the setting of close proximity to orbital structures with lower tolerance. Proton beam therapy (PBT) is felt to be an effective modality in such cases due to its sharp dose gradient. Materials and Methods: We reviewed our institutional PBT registry and identified 17 patients with tumor epicenters within 2 cm of the eye and optic apparatus treated with passive scatter PBT with comparison volumetric arc therapy plans available. Maximum and mean doses to organs at risk of interest, including optic nerves, optic chiasm, lens, eye ball, pituitary, cochlea, lacrimal gland, and surrounding brain, were compared using the paired Wilcoxon signed rank test. Overall survival was determined using the Kaplan-Meier method. Results: Median age was 67. Median follow-up was 19.7 months. Fourteen patients underwent upfront resection and received postoperative radiation and 3 received definitive radiation. One patient received elective neck radiation, 2 underwent reirradiation, and 3 had concurrent chemotherapy. There was a statistically significant reduction in mean dose to the optic nerves and chiasm, brain, pituitary gland, lacrimal glands, and cochlea as well as in the maximum dose to the optic nerves and chiasm, pituitary gland, lacrimal glands, and cochlea with PBT. The 18-month cumulative incidence of local failure was 19.1% and 1-year overall survival was 80.9%. Conclusion: Proton beam therapy resulted in significant dose reductions to several periorbital and optic structures compared with volumetric arc therapy. Proton beam therapy appears to be the optimal radiation modality in such cases to minimize risk of toxicity to periorbital organs at risk.

This rapid realist review explored the key components of age-friendly ecosystems that promote community participation among older adults. The study (undertaken in 2021 and updated in 2023) synthesized evidence from 10 peer-reviewed and grey literature databases to identify the underlying mechanisms and contextual factors that shape why, under what circumstances, and for whom an age-friendly ecosystems might be effective as well as the intervention outcomes. A total of 2823 records were initially identified after deduplication. Title and abstract screening produced a potential dataset of 126 articles, reducing to 14 articles after full text screening. Data extraction focused on the contexts, mechanisms, and outcomes of ecosystems for older adults’ community participation. Analysis suggested that age-friendly ecosystems that aim to promote community participation are characterized by the provision of accessible and inclusive physical environments, the availability of supportive social networks and services, and the creation of opportunities for meaningful engagement in community life. The review also highlighted the importance of recognizing the diverse needs and preferences of older adults and involving them in the design and implementation of age-friendly ecosystems. Overall, the study has provided valuable insights into the mechanisms and contextual factors that contribute to the success of age-friendly ecosystems. Ecosystem outcomes were not well discussed in the literature. The analysis has important implications for policy and practice, emphasizing the need to develop interventions that are tailored to the specific needs and contexts of older adults, and that promote community participation as a means of enhancing health, wellbeing, and quality of life in later life.

Abstract Background The Barotse floodplains of the upper Zambezi River and its tributaries are a highly dynamic environment, with seasonal flooding and transhumance presenting a shifting mosaic of potential larval habitat and human and livestock blood meals for malaria vector mosquitoes. However, limited entomological surveillance has been undertaken to characterize the vector community in these floodplains and their environs. Such information is necessary as, despite substantial deployment of insecticide-treated nets (ITNs) and indoor residual spraying (IRS) against Anopheles vectors, malaria transmission persists across Barotseland in Zambia’s Western Province. Methods Geographically extensive larval surveys were undertaken in two health districts along 102 km of transects, at fine spatial resolution, during a dry season and following the peak of the successive wet season. Larvae were sampled within typical Anopheles flight range of human settlements and identified through genetic sequencing of cytochrome c oxidase I and internal transcribed spacer two regions of mitochondrial and nuclear DNA. This facilitated detailed comparison of taxon-specific abundance patterns between ecological zones differentiated by hydrological controls. Results An unexpected paucity of primary vectors was revealed, with An. gambiae s.l. and An. funestus representing < 2% of 995 sequenced anophelines. Potential secondary vectors predominated in the vector community, primarily An. coustani group species and An. squamosus. While the distribution of An. gambiae s.l. in the study area was highly clustered, secondary vector species were ubiquitous across the landscape in both dry and wet seasons, with some taxon-specific relationships between abundance and ecological zones by season. Conclusions The diversity of candidate vector species and their high relative abundance observed across diverse hydro-ecosystems indicate a highly adaptable transmission system, resilient to environmental variation and, potentially, interventions that target only part of the vector community. Larval survey results imply that residual transmission of malaria in Barotseland is being mediated predominantly by secondary vector species, whose known tendencies for crepuscular and outdoor biting renders them largely insensitive to prevalent vector control methods.

Predicting the allergenicity of novel proteins is challenging due to the absence of validated predictive methods and a well-defined reference set of proteins. The prevalence of sensitization could be a parameter to select reference proteins to characterize allergenic proteins. This study investigated whether the prevalence of sensitization of legume extracts and proteins can indeed be used for this purpose. A random sample of suspected food-allergic patients (n=106) was therefore selected. 10 extracts (processed and non-processed) and 18 individual proteins (2S albumins, 7S and 11S globulins) from black lentil, blue and white lupine, chickpea, faba bean, green lentil, pea, peanut, soybean, and white bean were isolated and the prevalence of sensitization and the intensity of IgE binding were evaluated. The prevalence of sensitization ranged from 5.7 % (faba bean and green lentil) to 14.2 % (peanut). The prevalence of sensitization for individual legume proteins ranged from 0.0 % for albumin 1 (pea) to 15.1 %–17.9 % for Ara h 1, 2, 3, and 6 (peanut). The prevalence of sensitization correlated strongly with the intensity of IgE binding for individual proteins (p

Acute pain is a physiological response that causes an unpleasant sensory and emotional experience in the presence of actual or potential tissue injury. Anatomically and symptomatically, chronic pathological pain can be divided into three distinct but interconnected pathways, a lateral “painfulness” pathway, a medial “suffering” pathway and a descending pain inhibitory circuit. Pain (fullness) can exist without suffering and suffering can exist without pain (fullness). The triple network model is offering a generic unifying framework that may be used to understand a variety of neuropsychiatric illnesses. It claims that brain disorders are caused by aberrant interactions within and between three cardinal brain networks: the self-representational default mode network, the behavioral relevance encoding salience network and the goal oriented central executive network. A painful stimulus usually leads to a negative cognitive, emotional, and autonomic response, phenomenologically expressed as pain related suffering, processed by the medial pathway. This anatomically overlaps with the salience network, which encodes behavioral relevance of the painful stimuli and the central sympathetic control network. When pain lasts longer than the healing time and becomes chronic, the pain- associated somatosensory cortex activity may become functionally connected to the self-representational default mode network, i.e., it becomes an intrinsic part of the self-percept. This is most likely an evolutionary adaptation to save energy, by separating pain from sympathetic energy-consuming action. By interacting with the frontoparietal central executive network, this can eventually lead to functional impairment. In conclusion, the three well-known pain pathways can be combined into the triple network model explaining the whole range of pain related co-morbidities. This paves the path for the creation of new customized and personalized treatment methods.

Abstract Introduction Narrowband imaging (NBI) is a special endoscopic optical enhancement setting allowing better visualization of mucosal microvasculature compared to white light endoscopy. This study evaluates the validity of NBI using the Ni classification in the detection and differentiation of severe dysplasia (SD) and glottic squamous cell carcinoma (SCC). Methods Patients with suspicious vocal cord lesions underwent conventional white light endoscopy followed by clinically indicated biopsy. At the same time, NBI images were obtained and graded independently. Lesions were graded from I to V according to the Ni classification and compared to histopathological findings. Results Fifty‐two patients were included in this study (40 SCC and 12 SD). The sensitivity and specificity of NBI in diagnosing laryngeal cancer was 95.0% (CI, 83.9%‐99.4%) and 83.3% (CI, 51.6%‐97.9%), respectively. The negative likelihood ratio was 0.06. Higher Ni grades correlated very strongly with more advanced disease. Conclusions NBI using the Ni classification is a sensitive diagnostic tool for the detection and differentiation of early neoplastic and preneoplastic glottic lesions. As higher Ni classification correlates strongly with advanced disease, it serves as a useful adjunct to white light endoscopy in the diagnosis of laryngeal cancer. Level of Evidence: Level IV.

Introduction: There is an unmet medical need for pruritus associated with chronic kidney disease, a distressing complication characterized by generalized and persistent itch affecting 20% to 40% of patients undergoing hemodialysis. Here we report the results of a phase 2 trial evaluating the efficacy and safety of a novel peripherally restricted kappa opioid receptor agonist, difelikefalin, in adult patients undergoing hemodialysis with pruritus. Methods: In this study, 174 hemodialysis patients with moderate-to-severe pruritus were randomly assigned to receive difelikefalin (0.5, 1.0, or 1.5 μg/kg) or placebo intravenously thrice weekly after each hemodialysis session for 8 weeks in a double-blind, controlled trial. The primary endpoint was the change from baseline at week 8 in the weekly mean of the 24-hour Worst Itching Intensity Numerical Rating Scale score. The secondary efficacy endpoint was the change in itch-related quality of life measured by the Skindex-10 questionnaire. Other endpoints included safety, sleep quality, and additional measures including the 5-D itch scale. Results: A significant reduction from baseline in itch intensity scores at week 8 favored all difelikefalin doses combined versus placebo (P = 0.002). Difelikefalin also showed improvement over placebo in Skindex-10, 5-D itch, and sleep disturbance scores (P ≤ 0.005). Overall, 78% of patients receiving difelikefalin reported treatment-emergent adverse events versus 42% of patients given placebo, with diarrhea, dizziness, nausea, somnolence, and fall being the most frequent (≥5%). Conclusion: In this trial, difelikefalin effectively reduced itching intensity and improved sleep and itch-related quality of life. Keywords: chronic kidney disease, CKD-aP, CR845, hemodialysis, kappa opioid receptor agonist, uremic pruritus

Purpose: Reirradiation in the scalp area can be challenging given the proximity to organs at risk (OARs), such as the eye and brain. Our aim is to evaluate the dosimetric differences of volumetric modulated arc therapy (VMAT) and electron beam therapy (EBT) compared with 3-dimensional proton beam therapy (PBT). Patients and Methods: We evaluated a patient with recurrent angiosarcoma of the left temporal scalp after prior surgical resections and radiation therapy to 60 Gy in 30 fractions who needed reirradiation. We generated VMAT, EBT, and PBT plans using the Pinnacle Treatment Planning System (TPS). Both VMAT and EBT plans used a skin bolus, whereas no bolus was used for the proton plan. Doses to the OARs, including cochlea, eyes, lens, lacrimal glands, optic nerves, optic chiasm, pituitary gland, and underlying brain, were compared. Results: The reirradiation treatment dose was 60 Gy(RBE). Target volume coverage was comparable in all plans. Compared with VMAT and EBT, the PBT plan showed reductions in mean and maximum doses to all OARs. Without the use of protons, several OARs would have exceeded dose tolerance utilizing VMAT or electrons. Dose reduction of up to 100% was achieved for central and contralateral OARs. Conclusion: Compared with VMAT and EBT, PBT resulted in dose reductions to all OARs, while maintaining excellent target coverage. PBT showed a significant advantage in treating superficially located skin cancers, such as angiosarcoma, without the need for a bolus. PBT can be considered in the upfront treatment and certainly in the reirradiation setting.

Abstract Background Cerebral cavernous malformations (CCMs), a major neurosurgical condition, characterized by abnormally dilated intracranial capillaries, result in increased susceptibility to stroke. KRIT1 (CCM1), MGC4607 (CCM2), and PDCD10 (CCM3) have been identified as causes of CCMs in which at least one of them is disrupted in most familial cases. Our goal is to identify potential biomarkers and genetic modifiers of CCMs, using a global comparative omics approach across several in vitro studies and multiple in vivo animal models. We hypothesize that through analysis of the CSC utilizing various omics, we can identify potential biomarkers and genetic modifiers, by systemically evaluating effectors and binding partners of the CSC as well as second layer interactors. Methods We utilize a comparative omics approach analyzing multiple CCMs deficient animal models across nine independent studies at the genomic, transcriptomic, and proteomic levels to dissect alterations in various signaling cascades. Results Our analysis revealed a large set of genes that were validated across multiple independent studies, suggesting an important role for these identified genes in CCM pathogenesis. Conclusion This is currently one of the largest comparative omics analysis of CCM deficiencies across multiple models, allowing us to investigate global alterations among multiple signaling cascades involved in both angiogenic and non-angiogenic events and to also identify potential biomarker candidates of CCMs, which can be used for new therapeutic strategies.

Background: Antimicrobial resistance (AMR) in Gram-negative bacteria-causing bloodstream infections (BSIs), such as Klebsiella pneumoniae and non-typhoidal Salmonella (NTS), is a major public health concern. Nonetheless, AMR surveillance remains scarce in sub-Saharan Africa, where BSI treatment is largely empirical. The aim of the study was to determine the distribution and AMR patterns of BSI-causing NTS, K. pneumoniae, and other Gram-negative bacteria in Ghana. Methods: A cross-sectional study was conducted between April and December 2021 at eleven sentinel health facilities across Ghana as part of a pilot study on the feasibility and implementation of the human sector AMR surveillance harmonized protocol in sub-Saharan Africa. Gram-negative bacteria recovered from blood specimens of febrile patients were identified using MALDI-TOF and evaluated for antimicrobial resistance using the BD Phoenix M50 analyzer and Kirby-Bauer disc diffusion. The Department of Medical Microbiology at the University of Ghana served as the reference laboratory. Results: Out of 334 Gram-negative blood isolates, there were 18 (5.4%) NTS, 85 (25.5%) K. pneumoniae, 88 (26.4%) Escherichia coli, 40 (12.0%) Acinetobacter baumannii, 25 (7.5%) Pseudomonas aeruginosa, and 77 (23.1%) other Gram-negative bacteria. As a composite, the isolates displayed high resistance to the antibiotics tested—amoxicillin (89.3%), tetracycline (76.1%), trimethoprim-sulfamethoxazole (71.5%), and chloramphenicol (59.7%). Resistance to third-generation cephalosporins [ceftriaxone (73.7%), cefotaxime (77.8%), and ceftazidime (56.3%)] and fluoroquinolones [ciprofloxacin (55.3%)] was also high; 88% of the isolates were multidrug resistant, and the rate of extended-spectrum beta-lactamase (ESBL) production was 44.6%. Antibiotic resistance in K. pneumoniae followed the pattern of all Gram-negative isolates. Antibiotic resistance was lower in NTS blood isolates, ranging between 16.7–38.9% resistance to the tested antibiotics. Resistance rates of 38.9%, 22.2%, and 27.8% were found for cefotaxime, ceftriaxone, and ceftazidime, respectively, and 27.8% and 23.8% for ciprofloxacin and azithromycin, respectively, which are used in the treatment of invasive NTS. The prevalence of multidrug resistance in NTS isolates was 38.9%. Conclusions: Multicenter AMR surveillance of Gram-negative blood isolates from febrile patients was well-received in Ghana, and the implementation of a harmonized protocol was feasible. High resistance and multidrug resistance to first- or second-choice antibiotics, including penicillins, third-generation cephalosporins, and fluoroquinolones, were found, implying that these antibiotics might have limited effectiveness in BSI treatment in the country. Continuation of AMR surveillance in Gram-negative blood isolates is essential for a better understanding of the extent of AMR in these pathogens and to guide clinical practice and policymaking.

BackgroundTechnology-based innovations that are created collaboratively by local technology specialists and health experts can optimize the addressing of priority needs for disease prevention and control. An EpiHack is a distinct, collaborative approach to developing solutions that combines the science of epidemiology with the format of a hackathon. Since 2013, a total of 12 EpiHacks have collectively brought together over 500 technology and health professionals from 29 countries. ObjectiveWe aimed to define the EpiHack process and summarize the impacts of the technology-based innovations that have been created through this approach. MethodsThe key components and timeline of an EpiHack were described in detail. The focus areas, outputs, and impacts of the twelve EpiHacks that were conducted between 2013 and 2021 were summarized. ResultsEpiHack solutions have served to improve surveillance for influenza, dengue, and mass gatherings, as well as laboratory sample tracking and One Health surveillance, in rural and urban communities. Several EpiHack tools were scaled during the COVID-19 pandemic to support local governments in conducting active surveillance. All tools were designed to be open source to allow for easy replication and adaptation by other governments or parties. ConclusionsEpiHacks provide an efficient, flexible, and replicable new approach to generating relevant and timely innovations that are locally developed and owned, are scalable, and are sustainable.

Cutaneous non-tuberculous mycobacterial (NTM) infections are an emerging infectious disease and require a protracted course of combination antibiotics. Antimicrobial choice is limited by resistance and toxicity. Tedizolid is a new oxazolidinone antibiotic with in vitro activity against some NTM, but its use in the management of extrapulmonary NTM has not been described. We report on the utility of prolonged tedizolid use (8 months), after linezolid intolerance, in combination therapy in a case of difficult Mycobacterium chelonae cutaneous infection. Although tedizolid contributed to clinical remission, it may have also contributed to a multifocal peripheral neuropathy. Its efficacy may also have been limited by continued immunosuppression, with evidence to suggest disease relapse or treatment failure after completion of combination therapy. Tedizolid can be considered, with caution, in combination therapy for difficult cases of cutaneous NTM infection.

Background We performed a clinical trial to evaluate safety and immunogenicity of a novel long peptide vaccine administered in combinations of incomplete Freund’s adjuvant (IFA) and agonists for TLR3 (polyICLC) and TLR7/8 (resiquimod). We hypothesized that T cell responses to minimal epitope peptides (MEPs) within the long peptides would be enhanced compared with prior vaccines with MEP themselves and that T cell responses would be enhanced with TLR agonists, compared with IFA alone.Methods Participants with resected stage IIB-IV melanoma were vaccinated with seven long melanoma peptides (LPV7) from tyrosinase, gp100, MAGE-A1, MAGE-A10, and NY-ESO-1, each containing a known MEP for CD8+ T cells, plus a tetanus helper peptide (Tet) restricted by Class II MHC. Enrollment was guided by an adaptive design to one of seven adjuvant combinations. Vaccines were administered at weeks 1, 2, 3, 6, 9, 12 at rotating injection sites. T cell and IgG antibody (Ab) responses were measured with IFN-gamma ELIspot assay ex vivo and ELISA, respectively.Results Fifty eligible participants were assigned to seven study groups, with highest enrollment on arm E (LPV7+Tet+IFA+polyICLC). There was one dose-limiting toxicity (DLT) in Group E (grade 3 injection site reaction, 6% DLT rate). All other treatment-related adverse events were grades 1–2. The CD8+ T cell immune response rate (IRR) to MEPs was 18%, less than in prior studies using MEP vaccines in IFA. The CD8+ T cell IRR trended higher for IFA-containing adjuvants (24%) than adjuvants containing only TLR agonists (6%). Overall T cell IRR to full-length LPV7 was 30%; CD4+ T cell IRR to Tet was 40%, and serum Ab IRR to LPV7 was 84%. These IRRs also trended higher for IFA-containing adjuvants (36% vs 18%, 48% vs 24%, and 97% vs 60%, respectively).Conclusions The LPV7 vaccine is safe with each of seven adjuvant strategies and induced T cell responses to CD8 MEPs ex vivo in a subset of patients but did not enhance IRRs compared with prior vaccines using short peptides. Immunogenicity was supported more by IFA than by TLR agonists alone and may be enhanced by polyICLC plus IFA.Trial registration number NCT02126579.