HH Domain of Alzheimer’s Disease Aβ Provides Structural Basis for Neuronal Binding in PC12 and Mouse Cortical/Hippocampal Neurons

A key question in understanding AD is whether extracellular Aβ deposition of parenchymal amyloid plaques or intraneuronal Aβ accumulation initiates the AD process. Amyloid precursor protein (APP) is endocytosed from the cell surface into endosomes where it is cleaved to produce soluble Aβ which is then released into the brain interstitial fluid. Intraneuronal Aβ accumulation is hypothesized to predominate from the neuronal uptake of this soluble extracellular Aβ rather than from ER/Golgi processing of APP. We demonstrate that substitution of the two adjacent histidine residues of Aβ40 results in a significant decrease in its binding with PC12 cells and mouse cortical/hippocampal neurons. These substitutions also result in a dramatic enhancement of both thioflavin-T positive fibril formation and binding to preformed Aβ fibrils while maintaining its plaque-binding ability in AD transgenic mice. Hence, alteration of the histidine domain of Aβ prevented neuronal binding and drove Aβ to enhanced fibril formation and subsequent amyloid plaque deposition - a potential mechanism for removing toxic species of Aβ. Substitution or even masking of these Aβ histidine residues might provide a new therapeutic direction for minimizing neuronal uptake and subsequent neuronal degeneration and maximizing targeting to amyloid plaques

Effect of enhanced medical rehabilitation on functional recovery in older adults receiving skilled nursing care after acute rehabilitation: A randomized clinical trial

Importance: Enhanced medical rehabilitation (EMR) is a systematic and standardized approach for physical and occupational therapists to engage patients. Higher patient engagement in therapy might lead to improved functional recovery in rehabilitation settings, such as skilled nursing facilities (SNFs). Objective: To determine whether EMR improves older adults\u27 functional recovery. Design, Setting, and Participants: A double-blind, parallel-group, randomized clinical trial was conducted from July 29, 2014, to July 13, 2018, in 229 adults aged 65 years or older admitted to 2 US SNFs. Participants were randomized to receive EMR (n = 114) vs standard-of-care rehabilitation (n = 115). Intention-to-treat analysis was used. Interventions: The intervention group received their physical and occupational therapy from therapists trained in EMR. Based on models of motivation and behavior change, EMR is a toolkit of techniques to increase patient engagement and therapy intensity. The control group received standard-of-care rehabilitation from physical and occupational therapists not trained in EMR. Main Outcomes and Measures: The primary outcome was change in function in activities of daily living and mobility, as assessed with the Barthel Index, which measures 10 basic activities of daily living or mobility items (scale range, 0-100), from SNF admission to discharge; secondary outcomes were gait speed for 10 m, 6-minute walk test, discharge disposition, rehospitalizations, and self-reported functional status at days 30, 60, and 90. To examine the rehabilitation process, therapists\u27 engagement with patients and patient active time during therapy were measured for a sample of the sessions. Results: Of the 229 participants, 149 (65.1%) were women; 177 (77.3%) were white, and 51 (22.3%) were black; mean (SD) age was 79.3 (8.0) years. Participants assigned to EMR showed greater recovery of function than those assigned to standard of care (mean increase in Barthel Index score, 35 points; 95% CI, 31.6-38.3 vs 28 points; 95% CI, 25.2-31.7 points; P = .007). There was no evidence of a difference in the length of stay (mean [SD], 23.5 [13.1] days). However, there were no group by time differences in secondary outcome measures, including self-reported function after SNF discharge out to 90 days as measured on the Barthel Index (mean [SE] score: EMR, 83.65 [2.20]; standard of care, 84.67 [2.16]; P = .96). The EMR therapists used a median (interquartile range) of 24.4 (21.0-37.3) motivational messages per therapy session vs 2.3 (1.1-2.9) for nontrained therapists (P \u3c .001), and EMR patients were active during a mean (SD) of 52.5 (6.6%) of the therapy session time vs 41.2 (6.8%) for nontrained therapists (P = .001). Conclusions and Relevance: Enhanced medical rehabilitation modestly improved short-term functional recovery for selected older adults rehabilitating in SNFs. However, there was no evidence that the benefits persisted over the longer term. This study demonstrates the value of engaging and motivating older adults in rehabilitation therapy, but more work is needed to extend these benefits to longer-term outcomes after discharge home. Trial Registration: ClinicalTrials.gov identifier: NCT02114879

Sex‐Related Differences in the Effects of Sports‐Related Concussion: A Review

Sports‐related concussion is a serious health challenge, and females are at higher risk of sustaining a sports‐related concussion compared to males. Although there are many studies that investigate outcomes following concussion, females remain an understudied population, despite representing a large proportion of the organized sports community. In this review, we provide a summary of studies that investigate sex‐related differences in outcome following sports‐related concussion. Moreover, we provide an introduction to the methods used to study sex‐related differences after sports‐related concussion, including common clinical and cognitive measures, neuroimaging techniques, as well as biomarkers. A literature search inclusive of articles published to March 2020 was performed using PubMed. The studies were reviewed and discussed with regard to the methods used. Findings from these studies remain mixed with regard to the effect of sex on clinical symptoms, concussion‐related alterations in brain structure and function, and recovery trajectories. Nonetheless, there is initial evidence to suggest that sex‐related differences following concussion are important to consider in efforts to develop objective biomarkers for the diagnosis and prognosis of concussion. Additional studies on this topic are, however, clearly needed to improve our understanding of sex‐related differences following concussion, as well as to understand their neurobiological underpinnings. Such studies will help pave the way toward more personalized clinical management and treatment of sports‐related concussion

Preference elicitation techniques used in valuing children’s health-related quality-of-life: a systematic review

BACKGROUND AND OBJECTIVES: Valuing children’s health states for use in economic evaluations is globally relevant and is of particular relevance in jurisdictions where a cost-utility analysis is the preferred form of analysis for decision making. Despite this, the challenges with valuing child health mean that there are many remaining questions for debate about the approach to elicitation of values. The aim of this paper was to identify and describe the methods used to value children’s health states and the specific issues that arise in the use of these methods. METHODS: We conducted a systematic search of electronic databases to identify studies published in English since 1990 that used preference elicitation methods to value child and adolescent (under 18 years of age) health states. Eligibility criteria comprised valuation studies concerning both child-specific patient-reported outcome measures and child health states defined in other ways, and methodological studies of valuation approaches that may or may not have yielded a value set algorithm. RESULTS: A total of 77 eligible studies were identified from which data on country setting, aims, condition (general population or clinically specific), sample size, age of respondents, the perspective that participants were asked to adopt, source of values (respondents who completed the preference elicitation tasks) and methods questions asked were extracted. Extracted data were classified and evaluated using narrative synthesis methods. The studies were classified into three groups: (1) studies comparing elicitation methods (n = 30); (2) studies comparing perspectives (n = 23); and (3) studies where no comparisons were presented (n = 26); selected studies could fall into more than one group. Overall, the studies varied considerably both in methods used and in reporting. The preference elicitation tasks included time trade-off, standard gamble, visual analogue scaling, rating/ranking, discrete choice experiments, best-worst scaling and willingness to pay elicited through a contingent valuation. Perspectives included adults’ considering the health states from their own perspective, adults taking the perspective of a child (own, other, hypothetical) and a child/adolescent taking their own or the perspective of another child. There was some evidence that children gave lower values for comparable health states than did adults that adopted their own perspective or adult/parents that adopted the perspective of children. CONCLUSIONS: Differences in reporting limited the conclusions that can be formed about which methods are most suitable for eliciting preferences for children’s health and the influence of differing perspectives and values. Difficulties encountered in drawing conclusions from the data (such as lack of consensus and poor reporting making it difficult for users to choose and interpret available values) suggest that reporting guidelines are required to improve the consistency and quality of reporting of studies that value children’s health using preference-based techniques. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40273-022-01149-3

Guided Internet-delivered cognitive behaviour therapy for perfectionism in a non-clinical sample of adolescents: A study protocol for a randomised controlled trial

Background: Perfectionism is elevated across a range of psychopathologies and has been shown to impede treatment outcomes. There is also evidence suggesting elevated perfectionism may contribute to the onset and maintenance of non-suicidal self-injury. There is a growing body of evidence suggesting that Internet-delivered cognitive-behavioural therapy for perfectionism reduces perfectionism and symptoms of psychological disorders and that reductions are maintained at 3-month and 6-month follow-up. There may also be reductions in non-suicidal self-injury, although no study has investigated this potential benefit. Given that associations between perfectionism and psychopathology are observed across both adults and adolescents, the need for the development of interventions targeting adolescents is essential for early intervention and prevention. Methods: The present study will employ a randomised controlled trial to examine the efficacy of 8-week guided Internet-delivered cognitive-behavioural therapy for perfectionism in adolescents compared to a waitlist control group. The primary outcome is perfectionism, and secondary outcomes include symptoms of psychological disorders, well-being, and non-suicidal self-injury. Outcomes will be assessed at pre-intervention, post-intervention, 1-month follow-up, 3-month follow-up, and 6-month follow-up. A minimum of 240 participants will be recruited online through social media, Australian universities, and schools across Australia. Generalised linear mixed models will be used to test for changes in outcomes between the intervention group and the waitlist control. Discussion: The outcomes of this trial will contribute to the literature on perfectionism and psychopathology in adolescents, as well as the efficacy of guided Internet-delivered interventions for adolescents. Trial registration: The trial was registered on the 20th of June 2019 at the Australia New Zealand Clinical Trials Registry (ACTRN12619000881134). Trial status: This is protocol version 1.0. Participant recruitment began on 31 July 2019 and is still actively running with an anticipated completion date in the fourth quarter of 2020

Biomarker panel predicts survival after resection in pancreatic ductal adenocarcinoma: a multi-institutional cohort study.

Background: Up to 60% of patients who undergo curative-intent pancreatic ductal adenocarcinoma (PDAC) resection experience disease recurrence within six months. We recently published a systematic review of prognostic immunohistochemical biomarkers in PDAC and shortlisted a panel of those reported with the highest level of evidence, including p53, p16, Ca-125, S100A4, FOXC1, EGFR, mesothelin, CD24 and UPAR. This study aims to discover and validate the prognostic significance of a combinatorial panel of tumor biomarkers in patients with resected PDAC. Methods: Patients who underwent PDAC resection were included from a single institution discovery cohort and a multi-institutional validation cohort. Tumors in the discovery cohort were stained immunohistochemically for all nine shortlisted biomarkers. Biomarkers significantly associated with overall survival (OS) were reevaluated as a combinatorial panel in both discovery and validation cohorts for its prognostic significance. Results: 224 and 191 patients were included in the discovery and validation cohorts, respectively. In both cohorts, S100A4, Ca-125 and mesothelin expression were associated with shorter OS. In both cohorts, the number of these biomarkers expressed was significantly associated with OS (discovery cohort 36.8 vs. 26.4 vs 16.3 vs 12.8 months, P < 0.001; validation cohort 25.2 vs 18.3 vs 13.6 vs 11.9 months, P = 0.008 for expression of zero, one, two and three biomarkers, respectively). On multivariable analysis, expression of at least one of three biomarkers was independently associated with shorter OS. Conclusion: Combinations of S100A4, Ca-125 and mesothelin expression stratify survival after resection of localized PDAC. Co-expression of all three biomarkers is associated with the poorest prognostic outcome

The Small RNA Teg41 Regulates Expression of the Alpha Phenol-Soluble Modulins and Is Required for Virulence in \u3ci\u3eStaphylococcus aureus\u3c/i\u3e

Small RNAs (sRNAs) remain an understudied class of regulatory molecules in bacteria in general and in Gram-positive bacteria in particular. In the major human pathogen Staphylococcus aureus, hundreds of sRNAs have been identified; however, only a few have been characterized in detail. In this study, we investigate the role of the sRNA Teg41 in S. aureus virulence. We demonstrate that Teg41, an sRNA divergently transcribed from the locus that encodes the cytolytic alpha phenolsoluble modulin (αPSM) peptides, plays a critical role in αPSM production. Overproduction of Teg41 leads to an increase in αPSM levels and a corresponding increase in hemolytic activity from S. aureus cells and cell-free culture supernatants. To identify regions of Teg41 important for its function, we performed an in silico RNA-RNA interaction analysis which predicted an interaction between the 3= end of Teg41 and the αPSM transcript. Deleting a 24-nucleotide region from the S. aureus genome, corresponding to the 3= end of Teg41, led to a 10-fold reduction in αPSM-dependent hemolytic activity and attenuation of virulence in a murine abscess model of infection. Restoration of hemolytic activity in the Teg41Δ3= strain was possible by expressing full-length Teg41 in trans. Restoration of hemolytic activity was also possible by expressing the 3= end of Teg41, suggesting that this region of Teg41 is necessary and sufficient for αPSMdependent hemolysis. Our results show that Teg41 is positively influencing αPSM production, demonstrating for the first time regulation of the αPSM peptides by an sRNA in S. aureus

Systematic review of the relative social value of child and adult health

Objectives: We aimed to synthesise knowledge on the relative social value of child and adult health. Methods: Quantitative and qualitative studies that evaluated the willingness of the public to prioritise treatments for children over adults were included. A search to September 2023 was undertaken. Completeness of reporting was assessed using a checklist derived from Johnston et al. Findings were tabulated by study type (matching/person trade-off, discrete choice experiment, willingness to pay, opinion survey or qualitative). Evidence in favour of children was considered in total, by length or quality of life, methodology and respondent characteristics. Results: Eighty-eight studies were included; willingness to pay (n = 9), matching/person trade-off (n = 12), discrete choice experiments (n = 29), opinion surveys (n = 22) and qualitative (n = 16), with one study simultaneously included as an opinion survey. From 88 studies, 81 results could be ascertained. Across all studies irrespective of method or other characteristics, 42 findings supported prioritising children, while 12 provided evidence favouring adults in preference to children. The remainder supported equal prioritisation or found diverse or unclear views. Of those studies considering prioritisation within the under 18 years of age group, nine findings favoured older children over younger children (including for life saving interventions), six favoured younger children and five found diverse views. Conclusions: The balance of evidence suggests the general public favours prioritising children over adults, but this view was not found across all studies. There are research gaps in understanding the public’s views on the value of health gains to very young children and the motivation behind the public’s views on the value of child relative to adult health gains. Clinical Trial Registration: The review is registered at PROSPERO number: CRD42021244593. There were two amendments to the protocol: (1) some additional search terms were added to the search strategy prior to screening to ensure coverage and (2) a more formal quality assessment was added to the process at the data extraction stage. This assessment had not been identified at the protocol writing stage.</p

Identifying the SN 2022acko progenitor with JWST

We report on analysis using the James Webb Space Telescope (JWST) to identify a candidate progenitor star of the Type II-plateau supernova SN 2022acko in the nearby, barred spiral galaxy NGC 1300. To our knowledge, our discovery represents the first time JWST has been used to localize a progenitor system in pre-explosion archival Hubble Space Telescope (HST) images. We astrometrically registered a JWST NIRCam image from 2023 January, in which the SN was serendipitously captured, to pre-SN HST F160W and F814W images from 2017 and 2004, respectively. An object corresponding precisely to the SN position has been isolated with reasonable confidence. That object has a spectral energy distribution (SED) and overall luminosity consistent with a single-star model having an initial mass possibly somewhat less than the canonical 8 Msun theoretical threshold for core collapse (although masses as high as 9 Msun for the star are also possible); however, the star's SED and luminosity are inconsistent with that of a super-asymptotic giant branch star which might be a forerunner of an electron-capture SN. The properties of the progenitor alone imply that SN 2022acko is a relatively normal SN II-P, albeit most likely a low-luminosity one. The progenitor candidate should be confirmed with follow-up HST imaging at late times, when the SN has sufficiently faded. This potential use of JWST opens a new era of identifying SN progenitor candidates at high spatial resolution.Comment: 8 pages, substantial changes from v1, to appear in MNRA

SN 2022jox: An extraordinarily ordinary Type II SN with Flash Spectroscopy

We present high cadence optical and ultraviolet observations of the Type II supernova (SN), SN 2022jox which exhibits early spectroscopic high ionization flash features of \ion{H}{1}, \ion{He}{2}, \ion{C}{4}, and \ion{N}{4} that disappear within the first few days after explosion. SN 2022jox was discovered by the Distance Less than 40 Mpc (DLT40) survey $\sim$0.75 days after explosion with followup spectra and UV photometry obtained within minutes of discovery. The SN reached a peak brightness of M$_V \sim$ $-$17.3 mag, and has an estimated $^{56}$Ni mass of 0.04 M$_{\odot}$, typical values for normal Type II SNe. The modeling of the early lightcurve and the strong flash signatures present in the optical spectra indicate interaction with circumstellar material (CSM) created from a progenitor with a mass loss rate of $\dot{M} \sim 10^{-3}-10^{-2}\ M_\odot\ \mathrm{yr}^{-1}$. There may also be some indication of late-time CSM interaction in the form of an emission line blueward of H$\alpha$ seen in spectra around 200 days. The mass-loss rate is much higher than the values typically associated with quiescent mass loss from red supergiants, the known progenitors of Type II SNe, but is comparable to inferred values from similar core collapse SNe with flash features, suggesting an eruptive event or a superwind in the progenitor in the months or years before explosion.Comment: Submitted to Ap