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Human parechovirus (HPeV) is an increasingly recognised cause of severe illness and central nervous system infection in infants. Medium- to long-term neurodevelopmental outcomes post-HPeV infection remain unknown. This study aims to assess neurodevelopmental outcomes for children hospitalised as infants with HPeV infection in their second and third years of life.This prospective cohort study followed children hospitalised with HPeV in Brisbane, Queensland during the 2017/2018 outbreak. Serial application of Ages and Stages Questionnaire (ASQ) was used to assess developmental progress in the second and third years of life. Data from clinical follow-up, audiology and neuroradiology were included.In the second year of life, 63% (n = 29) of children showed some or significant concerns for developmental delay. This had largely been ameliorated by the third year of life when only 30% (n = 14) reported developmental concerns. Prematurity and apnoeas were associated with developmental concerns at 27-36 months of age. Communication was the most common domain of concern.The majority of infants hospitalised with HPeV infection in 2017-2018 showed normalisation of developmental progress by 27-36 months of age. Further investigation into more subtle neurological impairments in later childhood is required. These results can help guide clinicians in counselling parents during the acute illness and in planning appropriate follow-up.

To facilitate the delivery of accurate and timely care to patients in complex environments, process improvement methodologies such as Lean can be very effective. Lean is a quality improvement methodology that seeks to add value for patients and employees by continuously improving processes and eliminating waste. At our institution, Lean principles were applied to improve efficiency and minimize waste in the diagnostic breast imaging reading room. This paper describes how we applied Lean principles, including plan-do-study-act testing, level-loading (heijunka), and visual management, to level the workload of the diagnostic radiologists in our practice. Implementation of these principles to improve the diagnostic workflow in breast imaging is described along with examples from our practice, including challenges and future opportunities.

Key Points First report of an FLT3-targeted therapy added to nonintensive chemotherapy that has improved survival in older FLT3-ITD patients with AML.Quizartinib is well tolerated, improves response and survival in older FLT3-ITD AML patients and merits consideration in future therapies. Now amended as text above., Visual Abstract, Survival for older patients with acute myeloid leukemia (AML) unsuitable for intensive chemotherapy is unsatisfactory. Standard nonintensive therapies have low response rates and only extend life by a few months. Quizartinib is an oral Fms-like tyrosine kinase 3 (FLT3) inhibitor with reported activity in wild-type patients. As part of the AML LI trial, we undertook a randomized evaluation of low-dose ara-C (LDAC) with or without quizartinib in patients not fit for intensive chemotherapy. Overall, survival was not improved (202 patients), but in the 27 FLT3-ITD patients, the addition of quizartinib to LDAC improved response (P = .05) with complete remission/complete remission with incomplete haematological recovery for quizartinib + LDAC in 5/13 (38%) vs 0/14 (0%) in patients receiving LDAC alone. Overall survival (OS) in these FLT3-ITD+ patients was also significantly improved at 2 years for quizartinib + LDAC (hazard ratio 0.36; 95% confidence intervals: 0.16, 0.85, P = .04). Median OS was 13.7 months compared with 4.2 months with LDAC alone. This is the first report of an FLT3-targeted therapy added to standard nonintensive chemotherapy that has improved survival in this population. Quizartinib merits consideration for future triplet-based treatment approaches. This trial was registered at www.clinicaltrials.gov as ISRCTN #ISRCTN40571019 and EUDRACT @2011-000749-19.

Introduction:5-Alpha reductase inhibitor (5-ARI) use leads to a 50% decline in serum prostate specific antigen (PSA) without a concomitant decrease in prostate cancer (PCa) risk. We hypothe...

International audience; We use data from the COME-HERE longitudinal survey collected by the University of Luxembourg to assess the effects of the policy responses to the COVID-19 pandemic on life satisfaction in France, Germany, Italy, Spain and Sweden over the course of 2020. Policy responses are measured by the Stringency Index and the Economic Support Index from the Blavatnik School of Government. Stringency is systematically associated with lower life satisfaction, controlling for the intensity of the pandemic itself. This stringency effect is larger for women, those with weak ties to the labor market, and in richer households. The effect of the Economic Support is never statistically different from zero.

Reduced intensity conditioning (RIC) transplantation is increasingly offered to older patients with acute myeloblastic leukemia. We have previously shown that a RIC allograft, particularly from a sibling donor, is beneficial in intermediate-risk patients aged 35-65 years. We here present analyses from the NCRI AML16 trial extending this experience to older patients aged 60-70 inclusive lacking favorable-risk cytogenetics. Nine hundred thirty-two patients were studied, with RIC transplant in first remission given to 144 (sibling n=52, matched unrelated donor n=92) with a median follow-up for survival from complete remission of 60 months. Comparisons of outcomes of patients transplanted versus those not were carried out using Mantel-Byar analysis. Among the 144 allografted patients, 93 had intermediate-risk cytogenetics, 18 had adverse risk and cytogenetic risk group was unknown for 33. In transplanted patients survival was 37% at 5 years, and while the survival for recipients of grafts from siblings (44%) was better than that for recipients of grafts from matched unrelated donors (34%), this difference was not statistically significant (P=0.2). When comparing RIC versus chemotherapy, survival of patients treated with the former was significantly improved (37% versus 20%, hazard ratio = 0.67 [0.53-0.84]; P

Background. Although research dissemination to participants and community stakeholders is a fundamental component of translational research, it rarely occurs. The objective of this study was to create a community-led, theory-based dissemination plan to engage local Black sexual minority men in an active dissemination process throughout a sexual health research study. Method. Seven focus groups ( N = 38) were conducted with Black, cisgender sexual minority men aged 18 to 45 years. Findings were analyzed through thematic content analysis guided by McGuire’s persuasive communication theory. Findings were used to draft a dissemination plan, which was then reviewed and edited by the study’s community advisory board (CAB). The plan continues to be updated in response to community needs through CAB discussions. Results. Participants preferred messages concerning syphilis and other health concerns as well as information on local resources. Preferred sources included researchers working with trusted community organizations and leaders. Preferred channels included community events and social media, implemented with consistency. CAB feedback included expanding the target audience of dissemination efforts as well as the development of ideas for channels (i.e., events) and sources (i.e., community organizations and leaders). Additional revisions occurred in response to the COVID-19 pandemic. Conclusion. Given the continued lack of research dissemination to participant and community stakeholders, the process of developing a community-led, theory-based dissemination plan may benefit and help guide researchers to adopt this practice. It is critical that participant and community stakeholder dissemination become more highly prioritized as we strive for public health improvements and the elimination of health disparities.

Despite decades of commercial harvest of bigmouth buffalo (Ictiobus cyprinellus) from Jamestown Reservoir, North Dakota, and the recent rapid growth of sport bowfishing that targets this species, there is a lack of biological information on this native catostomid. At present, no-limit recreational and commercial harvest of bigmouth buffalo occurs in North Dakota, with no harvest-reporting for recreational take. A long-lived life history was recently documented for this species, with a life-span exceeding 100 years. At Jamestown Reservoir, bigmouth buffalo were aged to 58 years of age, with onset of sexual maturity 10 years for females. Evidence for episodic recruitment over a 60-year period was in 1962–1979, 1993–2011, and 2017, with recruitment success more likely during non-drought periods. Annual commercial harvest data from this reservoir indicate bigmouth buffalo have declined significantly over the past 30 years, most precipitously since 2010 during the bowfishing era. The demographic patterns, episodic recruitment, and harvest changes observed in this population are relevant for informing management of bigmouth buffalo and other long-lived freshwater fishes.

Recent studies have focused on optimising wave energy converter (WEC) designs, maximising their power performance and techno‐economic feasibility. Reliability has yet to be fully considered in these formulations, despite its impact on cost and performance. In this study, this gap is addressed by developing a reliability‐based design optimisation framework for WEC hull geometries to explore the trade‐off between power performance and power take‐off (PTO) system damage equivalent loading (DEL). Optimised hull geometries for two sites are considered (from the centre of the North Sea and off the west coast of Norway), and two directions of motions (heave and surge). Results indicate that site characteristics affect the potential power production and DEL for an optimal WEC design. These are also affected by the direction of motion for power extraction, which also significantly changes optimal hull shape characteristics. Optimal surging WEC designs have edges facing oncoming wave directions, while heaving WECs have pointed bottoms, both to streamline movement. Larger, more convex WECs result in greater power production and DEL, while smaller, more concave WECs result in lesser power production and DEL. These findings underline the importance of considering WEC hull geometry in early design processes to optimise cost, power production, and reliability.

We describe a case of myocarditis associated with a brown recluse spider bite in a 31-year-old man. Cardiac magnetic resonance revealed late gadolinium enhancement in the lateral wall and inferior wall. There was also regional elevation of the myocardial T2 and extracellular volume indicative of myocardial edema. (Level of Difficulty: Intermediate.), Graphical abstract

The RNA lariat debranching enzyme is the sole enzyme responsible for hydrolyzing the 2′–5′ phosphodiester bond in RNA lariats produced by the spliceosome. Here we test the ability of Dbr1 to hydrolyze branched RNAs (bRNAs) which contain a 2′–5′-phosphorothioate linkage, a modification commonly used to resist degradation. We attempted to co-crystallize a phosphorothioate branched RNA (PS-bRNA) with wild-type Entamoeba histolytica Dbr1 (EhDbr1) but observed in-crystal hydrolysis of the phosphorothioate bond. The crystal structure revealed EhDbr1 in a product-bound state, with the hydrolyzed 2′–5′ fragment of the PS-bRNA mimicking the binding mode of the native bRNA substrate. These findings suggest that product inhibition may contribute to the kinetic mechanism of Dbr1. We show that Dbr1 enzymes cleave phosphorothioate linkages at rates ~10,000-fold more slowly than native phosphate linkages. This new product-bound crystal structure offers atomic details which can aid inhibitor design. Dbr1 inhibitors could be therapeutic or investigative compounds for human diseases such as HIV, ALS, cancer, and viral encephalitis.

This paper presents a new approach to combining the information in point and density forecasts from the Survey of Professional Forecasters (SPF) and assesses the incremental value of the density forecasts. Our starting point is a model, developed in companion work, that constructs quarterly term structures of expectations and uncertainty from SPF point forecasts for quarterly fixed horizons and annual fixed events. We then employ entropic tilting to bring the density forecast information contained in the SPF’s probability bins to bear on the model estimates. In a novel application of entropic tilting, we let the resulting predictive densities exactly replicate the SPF’s probability bins. Our empirical analysis of SPF forecasts of GDP growth and inflation shows that tilting to the SPF’s probability bins can visibly affect our model-based predictive distributions. Yet in historical evaluations, tilting does not offer consistent benefits to forecast accuracy relative to the model-based densities that are centered on the SPF’s point forecasts and reflect the historical behavior of SPF forecast errors. That said, there can be periods in which tilting to the bin information helps forecast accuracy. Replication files are available at https://github.com/elmarmertens/ClarkGanicsMertensSPFfancharts

Insufficient insulin secretion to meet metabolic demand results in diabetes. The intracellular flux of Ca2+into β-cells triggers insulin release. Since genetics strongly influences variation in islet secretory responses, we surveyed islet Ca2+dynamics in eight genetically diverse mouse strains. We found high strain variation in response to four conditions: 1) 8 mM glucose; 2) 8 mM glucose plus amino acids; 3) 8 mM glucose, amino acids, plus 10 nM GIP; and 4) 2 mM glucose. These stimuli interrogate β-cell function, α-cell to β-cell signaling, and incretin responses. We then correlated components of the Ca2+waveforms to islet protein abundances in the same strains used for the Ca2+measurements. To focus on proteins relevant to human islet function, we identified human orthologues of correlated mouse proteins that are proximal to glycemic-associated SNPs in human GWAS. Several orthologues have previously been shown to regulate insulin secretion (e.g. ABCC8, PCSK1, and GCK), supporting our mouse-to-human integration as a discovery platform. By integrating these data, we nominated novel regulators of islet Ca2+oscillations and insulin secretion with potential relevance for human islet function. We also provide a resource for identifying appropriate mouse strains in which to study these regulators.

Recent studies have found increasing rates of overweight and obesity in bulimia nervosa (BN). However, the relationships between body mass index (BMI) and BN symptoms and other clinically relevant constructs are unknown. Participants (

We develop a model that permits the estimation of a term structure of both expectations and forecast uncertainty for application to professional forecasts such as the Survey of Professional Forecasters (SPF). Our approach exactly replicates a given data set of predictions from the SPF (or a similar forecast source) without measurement error. Our model captures fixed horizon and fixed-event forecasts, and can accommodate changes in the maximal forecast horizon available from the SPF. The model casts a decomposition of multi-period forecast errors into a sequence of forecast updates that may be partially unobserved, resulting in a multivariate unobserved components model. In our empirical analysis, we provide quarterly term structures of expectations and uncertainty bands. Our preferred specification features stochastic volatility in forecast updates, which improves forecast performance and yields model estimates of forecast uncertainty that vary over time. We conclude by constructing SPF-based fan charts for calendar-year forecasts like those published by the Federal Reserve. Replication files are available at https://github.com/elmarmertens/ClarkGanicsMertensSPFfancharts.

A phenomenological model has been developed for the mechanism of action of phase modifiers as additives that control aggregation phenomena within water-in-oil emulsions. The "Dispersion by Competitive Intermolecular Interaction" model (DCI) explicitly considers the strength and prevalence of different

Although community or cluster identification is becoming a standard tool within the simulation community, traditional algorithms are challenging to adapt to time-dependent data. Here, we introduce temporal community identification using the Δ-screening algorithm, which has the flexibility to account for varying community compositions, merging and splitting behaviors within dynamically evolving chemical networks. When applied to a complex chemical system whose varying chemical environments cause multiple time scale behavior, Δ-screening is able to resolve the multiple time scales of temporal communities. This computationally efficient algorithm is easily adapted to a wide range of dynamic chemical systems; flexibility in implementation allows the user to increase or decrease the resolution of temporal features by controlling parameters associated with community composition and fluctuations therein.

SummaryThe pre-mRNA life cycle requires intron processing; yet, how intron processing defects influence splicing and gene expression is unclear. Here, we find TTDN1, which is frequently mutated in non-photosensitive trichothiodystrophy (NP-TTD), functionally links intron lariat processing to the spliceosome. The conserved TTDN1 C-terminal region directly binds lariat debranching enzyme DBR1, while its N-terminal intrinsically disordered region (IDR) binds the intron binding complex (IBC). The IDR forms condensatesin vitroand is needed for IBC interaction. TTDN1 loss causes significant intron lariat accumulation, as well as splicing and gene expression defects, mirroring phenotypes observed in NP-TTD patient cells.Ttdn1Δ/Δmice recapitulate intron processing defects and neurodevelopmental phenotypes seen in NP-TTD. A DBR1-IDR fusion recruits DBR1 to the IBC and circumvents the requirement for TTDN1, indicating this tethering role as its major molecular function. Collectively, our findings unveil key functional connections between lariat processing, splicing outcomes, and NP-TTD molecular pathology.

Extrathyroidal extension (ETE) in patients with papillary thyroid carcinoma (PTC) is an indication of disease progression and can influence treatment aggressiveness. This meta-analysis assesses the diagnostic accuracy of ultrasonography (US) in detecting ETE. A systematic review and meta-analysis were performed by searching PubMed, Embase, and Cochrane for studies published up to April 2022. The pooled sensitivity, specificity, and diagnostic odds ratio (DOR) were calculated. The areas under the curve (AUC) for summary receiver operating curves were compared. A total of 11 studies analyzed ETE in 3795 patients with PTC. The sensitivity of ETE detection was 76% (95%CI = 74–78%). The specificity of ETE detection was 51% (95%CI = 49–54%). The DOR of detecting ETE by US was 5.32 (95%CI = 2.54–11.14). The AUC of ETE detection was determined to be 0.6874 ± 0.0841. We report an up-to-date analysis elucidating the diagnostic accuracy of ETE detection by US. Our work suggests the diagnostic accuracy of US in detecting ETE is adequate. Considering the importance of ETE detection on preoperative assessment, ancillary studies such as adjunct imaging studies and genetic testing should be considered.

Objective Research suggests families whose infants are admitted to the Neonatal Intensive Care Unit (NICU) experience elevated distress and may have pre-existing risk factors for maladjustment. This study sought to validate the newly developed Psychosocial Assessment Tool (PAT-NICU/Cardiac Intensive Care Unit [CICU]), a comprehensive screening measure for family psychosocial risk in the NICU. Methods The sample included 171 mothers, who completed the PAT-NICU/CICU and other related measures within 2 weeks of their infant’s NICU admission at a level 4 unit within a large pediatric hospital. PAT-NICU/CICU scores were compared to a companion risk survey completed by NICU social workers. Test–retest reliability was assessed through repeated measures at 2-month follow-up. Results Analyses suggest the PAT-NICU/CICU is effective in classifying psychosocial risk. This is supported by statistically significant correlations between the PAT-NICU/CICU and validated measures, in addition to elevated scores on concurrent measures by risk classification. Internal consistency, test–retest reliability, and acceptability for the PAT-NICU/CICU were satisfactory. Conclusions This preliminary study demonstrates the validity, reliability, and acceptability of the PAT-NICU/CICU as a psychosocial screening tool to aid identification of families who may benefit from supportive services during NICU admission. This new measure is a more comprehensive tool that assesses a wide variety of risk factors and stress responses. However, future studies of this measure are needed with more diverse samples. Prompt screening of NICU parents may facilitate earlier linkage with appropriate levels of resources or intervention. This research is crucial in improving risk assessment and psychosocial care for families in the NICU.

ObjectivesThe Choice and Partnership Approach (CAPA) was developed to create an accessible, child-centred and family-centred model of child and adolescent mental health service delivery that is adaptable to different settings. We sought to describe the state of evidence regarding the extent, outcomes and contextual considerations of CAPA implementation in community mental health services.DesignScoping review.Data sourcesPublished and grey literature were searched using MEDLINE, Embase, CINAHL, PsycINFO, Scopus and Google to 13 and 20 July 2022, respectively.Eligibility criteriaWe included reports focused on the implementation, outcomes (clinical, programme or system) or a discussion of contextual factors that may impact CAPA implementation in either child and adolescent or adult mental health services.Data extraction and synthesisData were extracted using a codebook that reflected the five domains of the Consolidated Framework for Implementation Research (CFIR) and reviewed for agreement and accuracy. Data were synthesised according to the five CFIR domains.ResultsForty-eight reports describing 36 unique evaluations were included. Evaluations were observational in nature; 10 employed pre–post designs. CAPA implementation, regardless of setting, was largely motivated by long wait times. Characteristics of individuals (eg, staff buy-in or skills) were not reported. Processes of implementation included facilitative leadership, data-informed planning and monitoring and CAPA training. Fidelity to CAPA was infrequently measured (n=9/36) despite available tools. Health system outcomes were most frequently reported (n=28/36); few evaluations (n=7/36) reported clinical outcomes, with only three reporting pre/post CAPA changes.ConclusionsGaps in evidence preclude a systematic review and meta-analysis of CAPA implementation. Measurement of clinical outcomes represents an area for significant improvement in evaluation. Consistent measurement of model fidelity is essential for ensuring the accuracy of outcomes attributed to its implementation. An understanding of the change processes necessary to support implementation would be strengthened by more comprehensive consideration of contextual factors.

Hereditary angioedema (HAE) is a rare genetic disorder in which patients experience sudden onset of swelling in various locations of the body. HAE is associated with uncontrolled plasma kallikrein (PKa) enzyme activity and generation of the potent inflammatory mediator, bradykinin, resulting in episodic attacks of angioedema. Herein, we disclose the discovery and optimization of novel small molecule PKa inhibitors. Starting from molecules containing highly basic P1 groups, which typically bind to an aspartic acid residue (Asp189) in the serine protease S1 pocket, we identified novel P1 binding groups likely to have greater potential for oral-drug-like properties. The optimization of P4 and the central core together with the particularly favorable properties of 3-fluoro-4-methoxypyridine P1 led to the development of sebetralstat, a potent, selective, orally bioavailable PKa inhibitor in phase 3 for on-demand treatment of HAE attacks.

We have previously shown that skeletal muscle-derived Sca-1