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More than two decades ago, in the central-eastern region of the Mediterranean island of Sardinia, a mountain area was identified where the population displays exceptional longevity, especially among men (the Longevity Blue Zone, LBZ). This community was thoroughly investigated to understand the underlying causes of the phenomenon. The present study analyzed 11 genetic markers previously associated with increased survival in several long-lived populations. APOE (rs429358 and rs7412), APOE promoter (rs449647, rs769446, and rs405509), ACE1 (rs1799752), IL6 ‒174G/C (rs1800795), TNFα ‒308G/A (rs1800629), FOXO3A (rs2802292), KLOTHO (rs9536314) and G6PD (rs5030868) polymorphisms were investigated. PCR-based genotyping was performed following genomic DNA extraction from 150 nonagenarians living in the LBZ and 150 controls from a nearby area. No significant deviation in the frequency of the analyzed markers was detected between the two subgroups except for a weak association with the − 174G > C gene variant in the IL-6 gene (p = 0.040), which codes for a major modulator of the inflammatory response. Overall, the findings of this study do not support a significant association of known genetic variants on survival in the population of the Sardinian LBZ, suggesting that other genetic or epigenetic traits not yet identified might play a role. [ABSTRACT FROM AUTHOR]

Objectives: To describe member adherence to a mail-based, health insurer-sponsored gap closure program for colorectal cancer (CRC) screening using multi-target stool DNA (mt-sDNA; Cologuard®) tests. Methods: Combined patient data from Exact Sciences Laboratories LLC and data from mass-mailed mt-sDNA orders placed by a large Medicare Advantage Insurance Plan were analyzed (03/01/2023-06/30/2023). Adherence and time to test return were the primary and secondary outcomes, respectively. Their association with patient characteristics was evaluated using multivariable regression. Results: Among the 3201 member-patients included (86.6% aged 65-75 years; 58.7% female), adherence rate was 49.4%, and mean time to test return was 25.5 days. After multivariable adjustment, the odds of test return were significantly higher among 65- to 75-year-olds (odds ratio [OR] = 1.59 relative to 45- to 64-year-olds), those living in small towns (OR = 1.43 relative to metropolitan-located individuals), and with digital outreach via both SMS and email (OR = 4.31 relative to no digital outreach). Time to test return was shorter in 65- to 75-year-olds than in 45- to 64-year-olds and was not associated with other patient characteristics. Conclusions: Mass-mailed mt-sDNA tests for CRC screening were associated with an overall adherence rate of about 50% in this Medicare Advantage population, with higher likelihood of test return among patients receiving digital outreach. [ABSTRACT FROM AUTHOR]

At the heart of this article lies the unique question of whether feelings of (in)authenticity can act as a resource for ethical social work practice. In adopting an affirmative position, I posit that emotional labour is traceable to feeling inauthentic and that for social workers possessing a virtuous sensibility such feelings represent sites of ethical struggle. For workers who are reflectively alert to their sense of self I argue that these feelings become ethical markers for practice, offering guidance for that which is ethically just. Within this debate, the idea of virtue as being morally good is framed around an interpretation that sees it as supportive of social justice. The article thus concludes that the deliberation of feelings – of being (in)authentic – can act as a disruptive prompt for practice that could prove unjust or oppressive. Within this original discussion, conceptions of authenticity, emotional work and virtue are critically explored in relation to the self. [ABSTRACT FROM AUTHOR]

Background Approximately 10% of people with HIV in Australia had active hepatitis C virus (HCV) infection prior to availability of government-subsidized direct-acting antiviral (DAA) therapy in 2016. This analysis evaluated progress toward HCV elimination among people with HIV in Australia between 2014 and 2023. Methods The CEASE cohort study enrolled adults with HIV with past or current HCV infection (anti-HCV antibody positive) from 14 primary and tertiary clinics. Biobehavioral, clinical, and virologic data were collected at enrollment (2014–2016), follow-up 1 (2017–2018), and follow-up 2 (2021–2023). HCV treatment uptake, outcome, and HCV RNA prevalence (current infection) were evaluated. Death and HCV reinfection incidence and risk were assessed. Results Of 402 participants, 341 (85%) had current HCV infection (RNA positive) at enrollment. Among the sample, 83% were gay and bisexual men, 13% had cirrhosis, and 80% had a history of injecting drug use (42%, past 6 months). DAA treatment was scaled up rapidly, with cumulative treatment uptake increasing from 12% in 2014 to 2015 to 92% in 2022 to 2023. HCV RNA prevalence declined from 85% (95% CI, 81%–88%) at enrollment (2014–2016) to 8% (95% CI, 6%–12%) at follow-up 1 (2017–2018) and 0.5% (95% CI, 0%–3%) at follow-up 2 (2020–2023). Sixteen reinfections occurred (incidence, 1.41 per 100 person-years; 95% CI,.81–2.29) as well as 30 deaths (incidence, 1.64 per 100 person-years; 95% CI, 1.11–2.34). HCV reinfection incidence declined over time while mortality remained stable. Conclusions Universal access and rapid DAA uptake were associated with a dramatic reduction in HCV prevalence and reinfection incidence among people with HIV to levels consistent with microelimination. Registration: NCT02102451 (ClinicalTrials.gov). [ABSTRACT FROM AUTHOR]

The aim of this study was to develop a cervical screening decision aid for countries which could choose between self- or clinician-collected sample for primary Human Papillomavirus (HPV) based cervical screening. A structured development process based on the International Patient Decision Aid Standards was used, including a systematic literature search for existing decision aids, a medical literature review, structured development of the decision aid which includes many iterative revisions, focus group discussions with screen eligible women, internal and external peer review by Gynaecology and non-Gynaecology experts, and finally field tested among 360 women. Most women considered the decision aid clear, helpful in decision making and would recommend it to others. This systematically developed decision aid appears to be suitable for wider use. [ABSTRACT FROM AUTHOR]

Background: Diagnosis is essential for engagement in care for chronic hepatitis B (CHB) and chronic hepatitis C (CHC), however, many Australians remain undiagnosed, especially for CHB. Primary care represents an important setting for testing, and this study sought to examine coverage in a large representative cohort of patients. Methods: We analysed retrospective data from the electronic medical records of active patients visiting 566 primary care clinics in Victoria, Australia. Pathology records were assessed to identify the proportion of patients with a record of CHB/CHC serology testing based on risk factors identified in national guidelines (ethnicity, Indigenous status, history of injecting drug use, diagnosed HIV, and/or indications of liver disease). Results: Of 1,593,774 patients, 393,948 (24.7%) had an indication for testing for CHB and/or CHC, of which 150,821 (38.3%) had evidence of testing. This proportion was highest in patients with HIV (65.6%) or injecting drug use history (60.0%), and lowest for those whose Indigenous status/ethnicity indicated testing (38.2%) or with elevated liver enzymes (39.1%). The proportion with evidence of testing was only moderate among those with a cirrhosis diagnosis (48.6%) or probable cirrhosis based on laboratory testing (50.6%). Conclusions: This analysis demonstrated considerable gaps in testing for CHB and CHC in a large population of patients, including many with evidence of cirrhosis, suggesting higher risk of adverse outcomes. Primary care practices should be supported to comprehensively offer testing for viral hepatitis, particularly where there is evidence of liver disease, and these findings should be used to guide future interventions. Gaps in diagnosis of chronic hepatitis B (CHB) and chronic hepatitis C (CHC) contribute to ongoing adverse outcomes, however, data regarding testing coverage are limited. In a large representative primary care population, a key setting for testing, a substantial proportion of people with established indications for testing had no evidence of it, including many with evidence of liver disease. Primary care practices should be supported to comprehensively offer testing for viral hepatitis for those at risk. [ABSTRACT FROM AUTHOR]

As part of their evolving social and digital mission, museums are tasked with fostering sustainability and inclusion throughout the physical-digital continuum and increasingly focus on accessible, participatory and representative culture. While openness is key in the service of society, museums face an open culture dilemma as copyright complicates their decision-making. Despite the topic's relevance, research is limited: little has been done to integrate the management and copyright domains, and the legal viewpoint predominates. This theoretical study adopts an interdisciplinary perspective to shed light on the open culture dilemma affecting museum strategies and practices. These aspects are closely intertwined with ethical issues and reveal contrasting perspectives within managerial and copyright frameworks. Building on convergence-divergence discourses on openness/closure of culture in these disciplines, the authors designed an exploratory matrix of approaches to open culture management in relation to copyright in museums to be operationalised and tested through empirical analysis. [ABSTRACT FROM AUTHOR]

Tidal wetland restoration is integral to achieving the Delta coequal goals. Deeply subsided islands limit the potential for tidal wetland restoration. Floating peats may offer an opportunity to create tidal habitat in the subsided western and central Delta. We conducted a mesocosm experiment to assess the feasibility of floating peat blocks, and the potential food-web benefits, biomass production, carbon sequestration, methane emissions, and water-quality effects. We evaluated the effect of varying water residence time and initial peat-block density. The peat blocks floated during the entire experiment, and accreted biomass at rates consistent with those reported for Delta nontidal managed wetlands. Peat blocks placed in mesocosms with 45% open water expanded horizontally about 21% per year. We estimated average vertical accretion rates of 5.5 to 8.6 cm yr-1 for all the mesocosms. Vertical and horizontal expansion increase floating peat-block stability. We measured a 3-fold zooplankton population increase during the first year after deployment, relative to the Mokelumne River, which was the mesocosm's water source. Measured and modeled methane emissions were lower than those reported in Delta non-tidal managed wetlands. Aqueous methane concentrations and methane fluxes were significantly lower for the shorter water-residence-time of about 5 days compared to longer residence times of about 11 days. Elevated dissolved oxygen (DO) concentrations generally corresponded with low methane concentrations. Our estimated net ecosystem carbon balance of - 820+/-137 g Cm-2 yr-1 indicates that the floating wetlands are potentially greater carbon sinks than Delta non-tidal wetlands. Nitrogen data indicated consumption by wetland plants, and denitrification and dissimilatory nitrate reduction in the mesocosms. Our preliminary results point to potential ecosystem benefits of floating peats on a larger scale. [ABSTRACT FROM AUTHOR]

The illegal wildlife trade (IWT) is one of the largest global crime economies, directly threatening species and their habitats, and biodiversity, and indirectly the global climate, and countries' economies. Syndicates operating within the IWT are often involved in trafficking of humans, weapons, and drugs. IWT takes place in large scale through international ports, with wildlife being smuggled inside shipping containers. Current methods to combat IWT and screen these shipping containers, such as X-ray scans, are expensive and time-consuming. Scent-detection animals present an innovative approach to combatting IWT, as animals may be better suited to distinguish between organic materials and less susceptible to visual concealment methods. Previous scent-detection work has largely focused on conservation dogs (Canis lupus familiaris). Here, we present a series of proof-of-principle studies training African giant pouched rats (Cricetomys ansorgei) to detect illegally trafficked wildlife. As initial proof-of-principle within a controlled laboratory environment, we trained rats (n=11) to detect the scent of pangolin scales (Manis spp.) and a threatened African hardwood (Dalbergia melanoxylon). In subsequent experiments, we trained these rats (n=10) to detect rhinoceros horn (family Rhinocerotidae), and elephant tusks (Loxodonta spp.). At the conclusion of these studies, rats (n=7) accurately identified all four target species (although ivory samples may have been cross-contaminated, and results should be interpreted with caution) while correctly rejecting non-target items commonly used by traffickers to conceal the presence of illicit material. Rats detected the presence of wildlife targets even when these were concealed in mixtures among non-target items. These results provide the foundation to train rats for scent-detection of illegally trafficked wildlife to combat IWT. The unique attributes of rats could allow them to complement existing screening technologies in the fight against IWT. Rats have low training and maintenance costs, flexibly work with multiple handlers, have a long lifespan, and a sophisticated sense of smell. Their small size also offers unique capabilities for the screening of shipping containers, such as being able to navigate densely packed areas or be lifted to assess contents of sealed containers by screening ventilation systems. Future directions include assessing operational feasibility of deploying rats at ports. [ABSTRACT FROM AUTHOR]

Background: Older adults often experience adverse health outcomes including malnutrition following discharge from emergency departments (ED). Discharge to community care is a transitionary time where nutritional vulnerability could be mitigated with the instigation of targeted nutrition care pathways in ED settings. Aims and objectives: This scoping review aimed to establish and describe the level of nutrition care provided to older adults admitted and subsequently discharged from EDs. Research design: Systematic searches of nine academic and grey literature databases (Medline (Ovid), Pubmed, CINAHL Complete (EBSCOhost), EMBASE, Cochrane Library and Scopus), grey literature sources (DART-Europe E-theses portal, Open Grey, and Trip Medical database) and four websites (Google, Google Scholar, NICE and LENUS) for relevant professional and organisational publications of research, policy, practice, and guidelines between January 2011 to 2023 were completed. Eligible studies included a population of older adults (≥ 65 years) with an ED attendance and subsequent community discharge, and where nutrition screening had identified malnutrition. Data were extracted on the level of nutrition and dietetic care initiated for older adults in the ED according to the Nutrition Care Process Model and summarised descriptively. Results: Overall, 22 studies were included in the review. Nutrition status was screened on admission to the ED using validated tools: Mini Nutritional Assessment-Short Form (n = 13), Malnutrition Universal Screening Tool (n = 2), Short Nutritional Assessment Questionnaire (n = 2), NRS-2002 (n = 1) and the Mini Nutritional Assessment – Full Form (n = 1). A full nutrition assessment was reported by 5 studies. Only one study referred to documentation of malnutrition in healthcare records. Subsequent nutrition intervention after discharge from the ED for older adults was not described in any study. Conclusion: While there is evidence to support malnutrition screening is taking place in EDs, there is a lack of information about subsequent nutrition care including assessment and therapy interventions. This points to the need for comprehensive exploration of nutrition care pathways, practice, policy, and research to inform models of integrated care for older persons. [ABSTRACT FROM AUTHOR]

Background: Zaire Ebolavirus disease (EVD) outbreaks can be controlled using rVSV-ZEBOV vaccination and other public health measures. People in high-risk areas may have pre-existing antibodies from asymptomatic Ebolavirus exposure that might affect response to rVSV-ZEBOV. Therefore, we assessed the impact pre-existing immunity had on post-vaccination IgG titre, virus neutralisation, and reactogenicity following vaccination. Methods: In this prospective cohort study, 2115 consenting close contacts ("proches") of EVD survivors were recruited. Proches were vaccinated with rVSV-ZEBOV and followed up for 28 days for safety and immunogenicity. Anti-GP IgG titre at baseline and day 28 was assessed by ELISA. Samples from a representative subset were evaluated using live virus neutralisation. Results: Ten percent were seropositive at baseline. At day 28, IgG in baseline seronegative (GMT 0.106 IU/ml, 95% CI: 0.100 to 0.113) and seropositive (GMT 0.237 IU/ml, 0.210 to 0.267) participants significantly increased from baseline (both p < 0.0001). There was strong correlation between antibody titres and virus neutralisation in day 28 samples (Spearman's rho 0.75). Vaccinees with baseline IgG antibodies against Zaire Ebolavirus had similar safety profiles to those without detectable antibodies (63.6% vs 66.1% adults experienced any adverse event; 49.1% vs 60.9% in children), with almost all adverse events graded as mild. No serious adverse events were attributed to vaccination. No EVD survivors tested positive for Ebolavirus by RT-PCR. Conclusions: These data add further evidence of rVSV-ZEBOV safety and immunogenicity, including in people with pre-existing antibodies from suspected natural ZEBOV infection whose state does not blunt rVSV-ZEBOV immune response. Pre-vaccination serological screening is not required. [ABSTRACT FROM AUTHOR]

International and European Union (EU) law jointly promote cultural development as a global and cross-border value, mandating national efforts for the preservation, enjoyment, and enhancement of cultural heritage. Cultural development is also the specific objective underlying Art. 14 of the EU Copyright in Digital Single Market Directive (CDSMD), designed to ensure that works of visual arts in the public domain remain a vital source of cultural enrichment across the Union. Against this backdrop, the Italian legal system is currently showing some resistance against such legal obligations. Its transposition of Art. 14 CDSMD explicitly refers to the applicability of the Italian Cultural Heritage Code, which typically requires permission and, in many cases, a fee payment to use reproductions of works of cultural significance, notwithstanding their public domain status. Concurrently, Italian courts have engineered new forms of exclusivity over cultural heritage belonging to the public domain, ignoring copyright law and other applicable norms. The study examines the Italian legal framework on public domain cultural heritage, unveiling a significant degree of incompatibility with international and EU legal obligations. Through a literal, systematic, and teleological legal analysis, the authors unearth how the Italian legal system fails to balance norms regarding cultural heritage, copyright, and data, thus calling for coordinated EU and national interventions towards a sound application of legal rules safeguarding the public domain. [ABSTRACT FROM AUTHOR]

Blood biomarkers are an emerging diagnostic and prognostic tool that reflect a range of neuropathological processes following traumatic brain injury (TBI). Their effectiveness in identifying long-term neuropathological processes after TBI is unclear. Studying biomarkers in the chronic phase is vital because elevated levels in TBI might result from distinct neuropathological mechanisms during acute and chronic phases. Here, we examine plasma biomarkers in the chronic period following TBI and their association with amyloid and tau PET, white matter microarchitecture, brain age and cognition. We recruited participants ≥40 years of age who had suffered a single moderate–severe TBI ≥10 years previously between January 2018 and March 2021. We measured plasma biomarkers using single molecule array technology [ubiquitin C-terminal hydrolase L1 (UCH-L1), neurofilament light (NfL), tau, glial fibrillary acidic protein (GFAP) and phosphorylated tau (P-tau181)]; PET tracers to measure amyloid-β (18F-NAV4694) and tau neurofibrillary tangles (18F-MK6240); MRI to assess white matter microstructure and brain age; and the Rey Auditory Verbal Learning Test to measure verbal-episodic memory. A total of 90 post-TBI participants (73% male; mean = 58.2 years) were recruited on average 22 years (range = 10–33 years) post-injury, and 32 non-TBI control participants (66% male; mean = 57.9 years) were recruited. Plasma UCH-L1 levels were 67% higher {exp(b) = 1.67, P = 0.018, adjusted P = 0.044, 95% confidence interval (CI) [10% to 155%], area under the curve = 0.616} and P-tau181 were 27% higher {exp(b) = 1.24, P = 0.011, adjusted P = 0.044, 95% CI [5% to 46%], area under the curve = 0.632} in TBI participants compared with controls. Amyloid and tau PET were not elevated in TBI participants. Higher concentrations of plasma P-tau181, UCH-L1, GFAP and NfL were significantly associated with worse white matter microstructure but not brain age in TBI participants. For TBI participants, poorer verbal-episodic memory was associated with higher concentration of P-tau181 {short delay: b = −2.17, SE = 1.06, P = 0.043, 95% CI [−4.28, −0.07]; long delay: b P-tau = −2.56, SE = 1.08, P = 0.020, 95% CI [−4.71, −0.41]}, tau {immediate memory: b Tau = −6.22, SE = 2.47, P = 0.014, 95% CI [−11.14, −1.30]} and UCH-L1 {immediate memory: b UCH-L1 = −2.14, SE = 1.07, P = 0.048, 95% CI [−4.26, −0.01]}, but was not associated with functional outcome. Elevated plasma markers related to neuronal damage and accumulation of phosphorylated tau suggest the presence of ongoing neuropathology in the chronic phase following a single moderate–severe TBI. Plasma biomarkers were associated with measures of microstructural brain disruption on MRI and disordered cognition, further highlighting their utility as potential objective tools to monitor evolving neuropathology post-TBI. [ABSTRACT FROM AUTHOR]

Background and Aims: Hepatitis C virus (HCV) burden is higher among people in prison given high prevalence of injecting drug use. This study evaluated direct‐acting antiviral (DAA) treatment outcome in prisons. Methods: The Surveillance and Treatment of Prisoners with hepatitis C (SToP‐C) study enrolled individuals incarcerated in four Australian prisons (2017–2019). Participants with detectable HCV RNA were offered sofosbuvir‐velpatasvir for 12 weeks. Sustained virological response (SVR) was assessed in intention‐to‐treat (ITT; participants commencing treatment and due for SVR assessment before study close) and per‐protocol (PP; participants with documented treatment completion and SVR assessment) populations. Results: Among 799 participants with HCV, 324 (41%) commenced treatment (94% male; median age, 32 years; median duration of incarceration, 9 months). In ITT population (n = 310), 201 had documented treatment completion (65% [95% CI: 59–70]), and 137 achieved SVR (ITT‐SVR: 44% [95% CI: 39–50]). In PP population (n = 143), 137 achieved SVR (PP‐SVR: 96% [95% CI: 91–98]). Six participants had quantifiable HCV RNA at SVR assessment from treatment failure (n = 2) or reinfection (n = 4). Release or inter‐prison transfer was common reasons for no documented treatment completion (n = 106/109 [97%]) and no SVR assessment (n = 57/58 [98%]). In ITT analysis, longer incarceration was associated with increased SVR (adjusted OR per month 1.03 [95% CI: 1.01–1.04]). Conclusion: Among participants who completed DAA treatment and were assessed for SVR, treatment outcome was consistent with non‐prison clinical studies. However, most individuals did not complete treatment or lacked study‐documented treatment outcome due to release or transfer. Strategies to accommodate dynamic prisoner populations are required to ensure continuity of HCV care, including treatment completion and post‐treatment care. [ABSTRACT FROM AUTHOR]

Due to its high sensitivity to numerous variability sources, it is hard to define the typicity of a monovarietal virgin olive oil (VOO) according to its phenolic profile. In this study, we aimed to identify the features of phenolic composition that are persistent and minimally affected by variability sources, making them potential varietal markers. We separately analyzed three databases of monovarietal VOO phenolic compositions, determined by liquid chromatography, from three different cultivars. The first database was produced from the original data of the Bosana cultivar. The other two were obtained through a systematic analysis of scientific literature on Coratina and Frantoio cultivars. Several statistical tools, including coefficient of variability, correlations, and linear regression models, were used to find recurring proportions or ratios unaffected by variability sources suitable to define typical varietal traits. Some proportions between molecules, mostly within the same phenolic class, remain constant. Strong correlations between (i) flavonoids were observed in Bosana and Frantoio VOOs (R2 = 0.87 and 0.77, respectively), (ii) oleacein-oleocanthal (Bosana, R2 = 0.81) (iii) oleuropein aglycon-ligstroside aglycon (Frantoio, R2 = 0.88), and (iv) lignans (Coratina, R2 = 0.84). These traits could be useful tools for defining the typicity of monovarietal VOOs. [ABSTRACT FROM AUTHOR]

The primary aim of this study was to establish the feasibility of implementing a larger RCT designed to evaluate the effect of financial incentives on HCV treatment initiation among persons receiving opioid agonist therapy and/or who have injected drugs in the prior six months. ETHOS Engage is an observational cohort of participants recruited from drug treatment and needle and syringe programs in Australia. Among 11 drug and alcohol clinics, participants who were HCV RNA-positive were randomized (1:1) to receive standard of care or a AUD $60 gift card at treatment initiation. Regarding feasibility, 100% (57/57) of eligible participants enrolled to take part. Twenty-eight participants were randomised to the financial incentive arm (AUD $60 gift card) plus standard of care and 29 participants to the standard of care arm. In this pilot RCT (n = 57), median age was 42 years (IQR 37–49), 63% were male (n = 36), 35% Indigenous (n = 20) and 36% (n = 21) reported injecting drugs daily in the past month. Twelve weeks post-study enrolment, 11 (39%) participants in the financial incentive arm and 17 (59%) participants in the standard of care arm initiated HCV treatment. Findings indicate high feasibility among people who inject drugs to be randomised to receive financial incentives to initiate HCV treatment. [ABSTRACT FROM AUTHOR]

Palmitoylation, a lipid-based posttranslational protein modification, plays a crucial role in regulating various aspects of neuronal function through altering protein membrane-targeting, stabilities, and protein–protein interaction profiles. Disruption of palmitoylation has recently garnered attention as disease mechanism in neurodegeneration. Many proteins implicated in neurodegenerative diseases and associated neuronal dysfunction, including but not limited to amyloid precursor protein, β-secretase (BACE1), postsynaptic density protein 95, Fyn, synaptotagmin-11, mutant huntingtin, and mutant superoxide dismutase 1, undergo palmitoylation, and recent evidence suggests that altered palmitoylation contributes to the pathological characteristics of these proteins and associated disruption of cellular processes. In addition, dysfunction of enzymes that catalyze palmitoylation and depalmitoylation has been connected to the development of neurological disorders. This review highlights some of the latest advances in our understanding of palmitoylation regulation in neurodegenerative diseases and explores potential therapeutic implications. [ABSTRACT FROM AUTHOR]

Creativity in pivot AVT is a burning issue, since the pivot text can be seen as imposing pre-existing patterns, which may limit the translator's decision-making process and influence their creative output. To verify this, we examined the Italian subtitled and dubbed versions of the film Parasite (Bong Joon-ho, 2019), a well-known example of Korean audiovisual content transferred interlinguistically using English as a pivot language. The preliminary textual analysis of the data showed that both the Italian versions were also created using the pivot translation by Darcy Paquet. Being unable to retrieve the name of the Italian subtitler, we examined the Italian subtitles and found they are very close to the English pivot, often replicating some creative and controversial choices. For the Italian dubbing, we managed to interview the Italian dialogue writer (and dubbing director) and the translator. Their feedback on the translation process and the comparative analysis of the Korean source text, English subtitles and Italian dubbing demonstrated that the Italian dubbing team relied not only on the English subtitles but also on subtitles in other languages and the Korean script to create a text that often departs from the English pivot, and it is closer to the original. [ABSTRACT FROM AUTHOR]

Background: It has long been known that thyroid disease can lead to changes in energy metabolism, thermoregulation, and anxiety behavior. While these actions have been partially attributed to thyroid hormone (TH) receptor α1 (TRα1) action in the brain, the precise neuroanatomical substrates have remain elusive. Methods: We used PET-CT scans to identify brain regions affected by TH. We then inhibited TRα1 signaling specifically in the most affected region, the zona incerta (ZI), a still mysterious region previously implicated in thermogenesis and anxiety. To this end, we used an adeno-associated virus (AAV) expressing a dominant-negative TRα1R384C in wild-type mice and phenotyped the animals. Finally, we used tyrosine hydroxylase-Cre mice to test specifically the contribution of ZI dopaminergic neurons. Results: Our data showed that AAV-mediated inhibition of TRα1 signaling in the ZI lead to increased energy expenditure at thermoneutrality, while body temperature regulation remained unaffected. Moreover, circulating glucocorticoid levels were increased, and a mild habituation problem was observed in the open field test. No effects were observed when TRα1 signaling was selectively inhibited in dopaminergic neurons. Conclusions: Our findings suggest that altered TH signaling in the ZI is not involved in body temperature regulation but can affect basal metabolism and modulates stress responses. [ABSTRACT FROM AUTHOR]

Supramolecular materials have been assembled using a wide range of interactions, including the hydrophobic effect, DNA base‐pairing, and hydrogen bonding. Specifically, DNA amphiphiles with a hydrophobic building block self‐assemble into diverse morphologies depending on the length and composition of both blocks. Herein, we take advantage of the orthogonality of different supramolecular interactions – the hydrophobic effect, Watson‐Crick‐Franklin base pairing and RNA kissing loops – to create hierarchical self‐assemblies with controlled morphologies on both the nanometer and the micrometer scales. Assembly through base‐pairing leads to the formation of hybrid, multi‐phasic hydrogels with high stiffness and self‐healing properties. Assembly via hydrophobic core interactions gives anisotropic, discrete assemblies, where DNA fibers with one sequence are terminated with DNA spheres bearing different sequences. This work opens new avenues for the bottom‐up construction of DNA‐based materials, with promising applications in drug delivery, tissue engineering, and the creation of complex DNA structures from a minimum array of components. [ABSTRACT FROM AUTHOR]

Background: Intrahepatic cholangiocarcinoma (iCCA) is a lethal primary liver tumor characterized by clinical aggressiveness, poor prognosis, and scarce therapeutic possibilities. Therefore, new treatments are urgently needed to render this disease curable. Since cumulating evidence supports the oncogenic properties of the Heat Shock Factor 1 (HSF1) transcription factor in various cancer types, we investigated its pathogenetic and therapeutic relevance in iCCA. Methods: Levels of HSF1 were evaluated in a vast collection of iCCA specimens. The effects of HSF1 inactivation on iCCA development in vivo were investigated using three established oncogene-driven iCCA mouse models. In addition, the impact of HSF1 suppression on tumor cells and tumor stroma was assessed in iCCA cell lines, human iCCA cancer-associated fibroblasts (hCAFs), and patient-derived organoids. Results: Human preinvasive, invasive, and metastatic iCCAs displayed widespread HSF1 upregulation, which was associated with a dismal prognosis of the patients. In addition, hydrodynamic injection of a dominant-negative form of HSF1 (HSF1dn), which suppresses HSF1 activity, significantly delayed cholangiocarcinogenesis in AKT/NICD, AKT/YAP, and AKT/TAZ mice. In iCCA cell lines, iCCA hCAFs, and patient-derived organoids, administration of the HSF1 inhibitor KRIBB-11 significantly reduced proliferation and induced apoptosis. Cell death was profoundly augmented by concomitant administration of the Bcl-xL/Bcl2/Bcl-w inhibitor ABT-263. Furthermore, KRIBB-11 reduced mitochondrial bioenergetics and glycolysis of iCCA cells. Conclusions: The present data underscore the critical pathogenetic, prognostic, and therapeutic role of HSF1 in cholangiocarcinogenesis. [ABSTRACT FROM AUTHOR]

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Purpose: We describe a case of intraocular inflammation and palpable purpura in a patient with Pasteurella multocida pneumonia. Methods: A 75-year-old pseudophakic woman with type-2 diabetes and chronic obstructive pulmonary disease complained of lower limb palpable purpura and right vision loss of five-day duration. On admission, right visual acuity was hand motion. Slit-lamp examination disclosed severe conjunctival and ciliary injection, corneal oedema, 3-mm hypopyon with heavy fibrin accumulation and blood clots, and synechiae to the IOL. Results: Chest computed tomography revealed interstitial pneumonia. Sputum culture yielded P. multocida. Amoxicillin/clavulanic tablets (1 g × 3/daily) and topical and systemic steroids were given. Later on, fluorescein angiography showed multiple choroidal lesions bilaterally. With the above-mentioned therapy, there was full recovery of the skin, lung, and eye lesions. Conclusion: This report emphasizes that P. multocida infection should be considered in patients with intraocular inflammation, palpable purpura, and interstitial pneumonia. A multidisciplinary approach is necessary for a correct diagnosis and management. [ABSTRACT FROM AUTHOR]

ORF virus (ORFV) causes contagious ecthyma ("ORF"), a disease of sheep and goats characterized by lesions ranging from vesicles and pustules to atypical papilloma-like and angiomatous lesions in the skin and mucosae. The authors investigated the molecular factors leading to the ORF-associated atypical tumor-like changes. Fifteen lambs, 15 kids, and an adult ram clinically affected by natural ORFV infection were enrolled in the study and examined by several methods. ORFV was detected by viral culture or real-time polymerase chain reaction (RT-PCR) in the lesioned tissues and in the blood of the clinically affected sheep and goats. Surprisingly, ORFV was also detected in the blood of healthy goats from an affected herd. Microscopically, they found a pseudo-papillomatous proliferation of the epithelium, while the dermis and lamina propria were expanded by a proliferating neovascular component that highly expressed the viral vascular endothelial growth factor (vVEGF) and its host receptor vascular endothelial growth factor receptor 2 (VEGFR2). Immunohistochemistry, immunofluorescence, and in situ hybridization for mRNA showed that epidermal growth factor receptor (EGFR) was expressed in the fibrovascular component, in the infiltrating CD163+ macrophages, and in the basal stratum of the epidermis. Confocal immunofluorescence microscopy demonstrated that CD163+ macrophages were associated with VEGF and VEGFR2. Finally, they found by quantitative RT-PCR the overexpression of the interleukin-6 and VEGFR2 genes in the lesioned tissues. These findings suggest that ORFV activates an inflammatory reaction characterized by CD163+ macrophages expressing EGFR and VEGFR2, which might play an oncogenic role through synergistic action with vVEGF signaling. [ABSTRACT FROM AUTHOR]

Background/Objectives: Overweight and obesity are generally considered risk factors for premature mortality. However, scientific evidence suggests that among older populations, mild conditions of overweight might be associated with reduced comorbidity and longer survival. This study investigates the potential association between anthropometric parameters and survival among a cohort of nonagenarians in Sardinia, Italy. Methods: This study included 200 subjects (50% females) aged 89 and older, enrolled in 2018 in the Sardinian Blue Zone—a population known for longevity—and followed for up to six years. Anthropometric variables such as body height, weight, age, sex, comorbidity, disability, and food group intake were collected using validated questionnaires and analyzed through multivariable analysis. Results: Out of 200 participants at baseline, 28 (14%) were still alive after six years of follow-up (females 10%, males 18%). Mean survival was 3.36 years (range 0.1–6.9 years) for males and 3.03 years (range 0.2–6.6 years) for females. Participants with a Body Mass Index (BMI) in the range of 25.0–27.0 kg/m2 among males and 25.0–27.2 kg/m2 among females had longer survival compared to those who were underweight (p = 0.002) or obese (p < 0.0001). The Cox proportional hazards regression model, adjusted for age, sex, and comorbidity, revealed a statistically significant association between the BMI and survival, demonstrating an inverted–U relationship. This indicates that mild overweight was associated with a survival advantage compared to both normal weight and obesity. Conclusions: Our study indicates that mild, but not severe, overweight in nonagenarians is associated with extended lifespan. Therefore, primary care physicians and geriatricians should exercise caution before recommending calorie-restricted diets for mildly overweight elderly patients. [ABSTRACT FROM AUTHOR]

NMDA-type glutamate receptors (NMDARs) are widely recognized as master regulators of synaptic plasticity, most notably for driving long-term changes in synapse size and strength that support learning. NMDARs are unique among neurotransmitter receptors in that they require binding of both neurotransmitter (glutamate) and co-agonist (e.g., D-serine) to open the receptor channel, which leads to the influx of calcium ions that drive synaptic plasticity. Over the past decade, evidence has accumulated that NMDARs also support synaptic plasticity via ion flux-independent (non-ionotropic) signaling upon the binding of glutamate in the absence of co-agonist, although conflicting results have led to significant controversy. Here, we hypothesized that a major source of contradictory results might be attributed to variable occupancy of the co-agonist binding site under different experimental conditions. To test this hypothesis, we manipulated co-agonist availability in acute hippocampal slices from mice of both sexes. We found that enzymatic scavenging of endogenous co-agonists enhanced the magnitude of long-term depression (LTD) induced by non-ionotropic NMDAR signaling in the presence of the NMDAR pore blocker MK801. Conversely, a saturating concentration of D-serine completely inhibited LTD and spine shrinkage induced by glutamate binding in the presence of MK801 or Mg2+. Using a Förster resonance energy transfer (FRET)-based assay in cultured neurons, we further found that D-serine completely blocked NMDA-induced conformational movements of the GluN1 cytoplasmic domains in the presence of MK801. Our results support a model in which D-serine availability serves to modulate NMDAR signaling and synaptic plasticity even when the NMDAR is blocked by magnesium. [ABSTRACT FROM AUTHOR]

Background: Escherichia coli is the predominant urinary pathogen in children. Irish and international studies have demonstrated increasing antimicrobial resistance (AMR) to antibiotics such as co-amoxiclav. Aims: We aimed to (1) examine the AMR patterns of paediatric urinary E. coli isolates, from both hospital and community sources, over a 10-year period; (2) assess the effectiveness of Children's Health Ireland (CHI) antimicrobial guidance given local susceptibility data; and (3) review the clinical management of an admitted patient sub-set over a 6-year period. Methods: Pure growth of urinary E. coli from patients aged ≤ 14 from 2012 to 2021 were analysed for AMR. Differences in susceptibility rates were assessed. A retrospective chart review conducted on inpatients aged ≥ 2 months to ≤ 14 years, 2016–2021. Results: E. coli accounted for 70.8% of likely significant positive pure growth cultures (9314 isolates). Susceptibility to co-amoxiclav significantly increased over time, from 66.7% to 80.4% (2016–2021, p < 0.001). Nitrofurantoin and cefalexin had significantly higher susceptibility rates than trimethoprim (< 70% annually). 85.1% of isolates were susceptible to the combination of co-amoxiclav and gentamicin, recommended for those > 2months and systemically unwell. The additional gain in empiric susceptibility provided by gentamicin above that provided by co-amoxiclav alone has fallen from 16.4% to 6.7% (2016–2021). The 222 clinical cases reviewed showed improved antimicrobial guideline compliance over time. Conclusions: This study provides important regional AMR data. Co-amoxiclav susceptibility increased significantly over time, contrasting with previous studies. This was temporally associated with stewardship measures reducing co-amoxiclav prescribing. Decreasing utility of gentamicin supports recent CHI guideline updates reducing gentamicin use. [ABSTRACT FROM AUTHOR]

The global trade in nonhuman primates represents a substantial threat to ecosystem health, human health, and primate conservation worldwide. Most of the primate trade involves trade for pet-keeping, consumption, or biomedical experimentation. We present an overview of international primate trade through five case studies; each describes a different facet of this trade. We draw on published scientific literature, media outlets, and open access datasets, including the CITES Trade Database to build these case studies. Case study 1 describes the role of introduced island populations of Macaca and Chlorocebus in trade for biomedical experimentation; case study 2 covers the global health threats posed by the primate trade, including zoonotic disease transmission once animals enter the trade pipeline; case study 3 addresses the ways that changing patterns of primate trade, from local markets to online, have increased the demand for primates as pets; case study 4 recognizes the role that local environmental activism can play in mitigating trade; and case study 5 shows variation between global regions in their contribution to the primate trade. We recommend greater oversight of primate trade, especially domestic trade within primate range countries, and real-time reporting to CITES to accurately track primate trade. Effective conservation-focused regulations that can minimise the negative effects of primate trade must be tailored to specific regions and species and require transparency, careful regulation, field research, and an understanding of the magnitude of this trade. [ABSTRACT FROM AUTHOR]

Introduction: The aims of this work were to evaluate the real-world efficacy and safety of a loading dose of intravitreal faricimab in eyes with active neovascular age-related macular degeneration (n-AMD) or diabetic macular edema (DME) and to analyze the treatment outcome in relation to specific biomarkers. Methods: Patients with active n-AMD or DME, treated with four monthly intravitreal injections of faricimab, were enrolled in this retrospective, uncontrolled study. Best-corrected visual acuity (BCVA), central subfield thickness (CST), presence of retinal fluid (RF) on optical coherence tomography (OCT), and adverse events were assessed at baseline and at weeks 4, 8, 12, and 16. Predefined biomarkers were evaluated at baseline (BL) and at last visit. Results: Sixteen eyes of 15 patients with n-AMD (n-AMD group) and 15 eyes of 12 patients with DME (DME group) were included. Mean (± standard deviation) logarithm of minimum angle of resolution (logMAR) BL BCVA changed from 0.68 (± 0.43) to 0.53 (± 0.36; P = 0.13) and from 0.51 (± 0.34) to 0.32 (± 0.24; P: 0.048) at week 16 in n-AMD and DME group, respectively. A statistically significant mean CST reduction was reported in both groups at last visit (n-AMD: − 166.5 μm; P = 0.0009/DME: − 110.8 μm; P = 0.0086). Seventy-five and 33% of eyes with n-AMD and DME respectively achieved complete RF resolution at last visit. Subfoveal inner and outer retinal damage correlated with a lower final BCVA in n-AMD group. The presence of large (> 100 μm) juxtafoveal microaneurysms (MAs) was significantly correlated with a higher chance of residual fluid in eyes with DME. Conclusions: Both n-AMD and DME groups achieved satisfactory anatomical results after a loading-dose of intravitreal faricimab. BCVA improvement might be hampered by pre-existing retinal damage in eyes with n-AMD. Large, juxtafoveal MAs might represent a hallmark of a slower anatomical response to the treatment in eyes with DME. [ABSTRACT FROM AUTHOR]

Primary ciliary dyskinesia (PCD) is a rare, chronic genetic condition with variable features arising from motile cilia dysfunction, including recurrent respiratory infections, sinonasal disease, reduced hearing, infertility and situs inversus. The aim of the study was to understand the experiences of young people with PCD as they transition into adulthood and adult healthcare services. An interpretative phenomenological analytical method was applied. Semi-structured interviews were conducted with three participants aged 18–24 years. Four interconnected group experiential themes were identified: (1) reconceptualising a stigmatised identity, (2) sharing the journey to independence, (3) entering adulthood with newfound autonomy, (4) anticipating an uncertain future. Overall, we found that transition for young people with PCD presents as a complex period marked by identity-formation, creating systems of support and becoming an autonomous adult. Facilitation of personalised and integrated approaches to care should be prioritised. Our findings are important to help health professionals provide appropriate, anticipatory support. [ABSTRACT FROM AUTHOR]

An LC–Orbitrap–HRMS method was developed and validated for the simultaneous determination of four tetracyclines—oxytetracycline (OTC), tetracycline (TC), doxycycline (DC), and chlortetracycline (CTC)—in milk. This method involves sample extraction with McIlvaine–EDTA buffer solution (pH 4) and solid-phase extraction (SPE) with Oasis HLB cartridges, followed by the evaporation of the extract and its reconstitution with a 14% methanol aqueous solution before injection into the instrumental system. This method has been validated in terms of linearity, sensitivity, selectivity, precision, and accuracy, in accordance with Commission Decision 2002/657/EC requirements. Compared to existing methods, this approach optimally combines a quantitative procedure for extracting analytes from the milk of different species, including sheep, bovines, and goats, with a very short LC–Orbitrap–HRMS instrumental analysis time (only 8 min), simultaneously ensuring high precision, sensitivity, and applicability as a rapid confirmation method in official food control laboratories. The proposed method was applied to determine the concentration levels of OTC in milk samples derived from healthy Sardinian sheep and those naturally infected with Streptococcus uberis, after the intramuscular administration of an antibiotic, in order to evaluate how much of the drug was "subtracted" during penetration from blood into milk, with a potential effect of reducing its therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Heavy oxygen isotopic species of HCO+ are important optically thin astrophysical tracers. The ground-state rotational spectrum of HC18O+, DC18O+, HC17O+, and DC17O+ has been recorded in the laboratory in the frequency range from 85 GHz to 1.3 THz. The ions have been produced in the negative column of a glow-discharge plasma, and their spectrum has been recorded in absorption using a frequency-modulation submillimeter-wave spectrometer. Various sources of systematic error have been carefully accounted for in order to obtain highly accurate line-position measurements. Theoretical estimates of the molecular parameters and of the collision effects on the line shape have been obtained by high-level ab initio calculations. The analysis yielded much improved rotational and centrifugal distortion constants, thus bringing the spectroscopic characterization of these rare isotopic variants to the same level of the parent species. Also, the first experimental rotational data for DC17O+ have been provided. These results allow for the calculation of an updated set of rest frequencies to support current and future astrophysical studies. The derived data set for the widely used HC18O+ tracer reaches an accuracy of a few parts in 109 up to 1.5 THz. Such accuracy is important for the analysis of astrophysical objects targeted by Atacama Large Millimeter/submillimeter Array observations at the submillimeter regime. [ABSTRACT FROM AUTHOR]

Introduction: Females of childbearing age with hepatitis C virus (HCV) face increased marginalisation with intersecting, sex‐specific barriers to direct acting antiviral (DAA) therapy. We assessed the factors associated with uptake of DAA therapy among females of childbearing age, including those with evidence of recent drug dependence. Methods: HCV notifications in New South Wales, Australia (1995–2017) were linked to opioid agonist therapy (OAT), hospitalisations, incarcerations, perinatal, HIV notifications, deaths and prescription databases. Recent drug dependence was defined as hospitalisation due to injectable drugs or receipt of OAT occurring in the DAA era (2016–2018). Logistic regression was used to analyse factors associated with DAA uptake among females of childbearing age (18–44), including those with recent drug dependence. Results: Among 57,467 people with evidence of chronic HCV in the DAA era (2016–2018), 20,161 (35%) were female, including 33% (n = 6563/20,161) of childbearing age (18–44). Among all females of childbearing age (n = 6563) and those with evidence of recent drug dependence (n = 2278/6563, 35%), DAA uptake was lower among those who had given birth in the DAA era (vs. no birth record, all females of childbearing age; aOR: 0.74, 95% CI 0.61, 0.89; those with recent drug dependence; aOR 0.69, 95% CI 0.51, 0.93) and Aboriginal and Torres Strait Islander peoples (all females of childbearing age; aOR 0.81, 95% CI 0.71, 0.93; those with recent drug dependence aOR 0.75, 95% CI 0.62, 0.90). Conclusion: Females of childbearing age should be considered a key population for DAA therapy. Enhancing antenatal and postnatal HCV care may be critical in the pursuit towards elimination. [ABSTRACT FROM AUTHOR]

Background: People with Parkinson's disease (PD) have an increased risk of dementia, yet patients and clinicians frequently avoid talking about it due to associated stigma, and the perception that "nothing can be done about it". However, open conversations about PD dementia may allow people with the condition to access treatment and support, and may increase participation in research aimed at understanding PD dementia. Objectives: To co‐produce information resources for patients and healthcare professionals to improve conversations about PD dementia. Methods: We worked with people with PD, engagement experts, artists, and a PD charity to open up these conversations. 34 participants (16 PD; 6 PD dementia; 1 Parkinsonism, 11 caregivers) attended creative workshops to examine fears about PD dementia and develop information resources. 25 PD experts contributed to the resources. Results: While most people with PD (70%) and caregivers (81%) shared worries about cognitive changes prior to the workshops, only 38% and 30%, respectively, had raised these concerns with a healthcare professional. 91% of people with PD and 73% of caregivers agreed that PD clinicians should ask about cognitive changes routinely through direct questions and perform cognitive tests at clinic appointments. We used insights from the creative workshops, and input from a network of PD experts to co‐develop two open‐access resources: one for people with PD and their families, and one for healthcare professionals. Conclusion: Using artistic and creative workshops, co‐learning and striving for diverse voices, we co‐produced relevant resources for a wider audience to improve conversations about PD dementia. [ABSTRACT FROM AUTHOR]

Background and Objectives: Aberrant upregulation of fatty acid synthase (FASN), catalyzing de novo synthesis of fatty acids, occurs in various tumor types, including human hepatocellular carcinoma (HCC). Although FASN oncogenic activity seems to reside in its pro-lipogenic function, cumulating evidence suggests that FASN's tumor-supporting role might also be metabolic-independent. Materials and Methods: In the present study, we show that FASN inactivation by specific small interfering RNA (siRNA) promoted the downregulation of the S-phase kinase associated-protein kinase 2 (SKP2) and the consequent induction of p27KIP1 in HCC cell lines. Results: Expression levels of FASN and SKP2 directly correlated in human HCC specimens and predicted a dismal outcome. In addition, forced overexpression of SKP2 rendered HCC cells resistant to the treatment with the FASN inhibitor C75. Furthermore, FASN deletion was paralleled by SKP2 downregulation and p27KIP1 induction in the AKT-driven HCC preclinical mouse model. Moreover, forced overexpression of an SKP2 dominant negative form or a p27KIP1 non-phosphorylatable (p27KIP1-T187A) construct completely abolished AKT-dependent hepatocarcinogenesis in vitro and in vivo. Conclusions: In conclusion, the present data indicate that SKP2 is a critical downstream effector of FASN and AKT-dependent hepatocarcinogenesis in liver cancer, envisaging the possibility of effectively targeting FASN-positive liver tumors with SKP2 inhibitors or p27KIP1 activators. [ABSTRACT FROM AUTHOR]

New long-acting HIV treatment products have the potential to change the HIV epidemic in the United States and globally. Phase 3 clinical trials of HIV treatments tend to underrepresent populations bearing a disproportionate burden of the HIV epidemic—including women, racial minorities, trans and gender-diverse people, older adults, the unhoused, people who inject drugs, those in rural areas, individuals with mental illness, and other marginalized groups. These populations commonly face significant challenges in adhering to daily HIV treatment regimens. Conducting clinical trials of long-acting treatment targeting specific unmet medical needs of these populations can improve understanding of optimal care approaches, broaden the indication for use of long-acting products, and inform treatment guidelines, all of which can influence reimbursement and access policies. Innovative trial designs and programmatic implementation can improve inclusivity for long-acting therapy. This article summarizes discussions of a multistakeholder workshop on study designs for long-acting HIV treatments. [ABSTRACT FROM AUTHOR]

Background and Aim: Helicobacter pylori infections have become resistant to many previously highly effective antimicrobial regimens resulting in clarithromycin, metronidazole, or fluoroquinolone‐containing therapies becoming unsuccessful. Pretreatment susceptibility testing is only widely available in the United States but is still rarely done. Here, we propose a framework to monitor H. pylori eradication in small clinical settings by routinely assessing the effectiveness of therapy. Methods: Because of the small sample size in individual practice's, we assume an acceptable cure rate of ≥80% (preferred cure rate ≥85%) in adherent patients, with a dichotomous outcome (cured vs. failed) and consecutive patient enrollment. To obtain results (feedback) in a timely manner, for individual practices, cure rates can be estimated after 10 patients. Large practices which acquire patients more rapidly can delay analysis until a total of 104 H. pylori‐infected patients, assuming a baseline cure rate of at least 85% with the preferred regimen. Results: We show how data from individual practices can be utilized to improve the effectiveness of H. pylori treatment decisions. The method consists of recording and accumulating the confirmation of cure data for successive small groups of patients. These data are then analyzed as binary outcomes (pass‐fail) and serve as the basis for studying and improving the effectiveness of H. pylori treatment decisions. Conclusion: A simple actuarial method can serve outpatient clinics to ensure a reliable test‐to‐cure method and avoid futile Hp regimens. [ABSTRACT FROM AUTHOR]

The relative amount of AMPA receptors expressed at the surface of neurons can be measured using superecliptic pHluorin (SEP) labeling at their N-terminus. However, the high signal variability resulting from protein overexpression in neurons and the low signal observed in intracellular vesicles make quantitative characterization of receptor trafficking difficult. Here, we establish a real-time live-cell assay of AMPAR trafficking based on fluorescence lifetime imaging (FLIM), which allows for simultaneous visualization of both surface and intracellular receptors. Using this assay, we found that elevating amyloid-beta (Ab) levels leads to a strong increase in intracellular GluA1 and GluA2-containing receptors, indicating that Aβ triggers the endocytosis of these AMPARs. In APP/PS1 Alzheimer's disease model mouse neurons, FLIM revealed strikingly different AMPAR trafficking properties for GluA1- and GluA3- containing receptors, suggesting that chronic Aβ exposure triggered the loss of both surface and intracellular GluA3-containing receptors. Interestingly, overexpression of protein phosphatase 1 (PP1) also resulted inGluA1 endocytosis as well as depressed synaptic transmission, confirming the important role of phosphorylation in regulating AMPAR trafficking. This new approach allows for the quantitative measurement of extracellular pH, small changes in receptor trafficking, as well as simultaneous measurement of surface and internalized AMPARs in living neurons, and could therefore be applied to several different studies in the future. [ABSTRACT FROM AUTHOR]

Background: There are no approved pharmacotherapies for methamphetamine use disorder. Two preliminary phase 2 randomised controlled trials have found mirtazapine, a tetracyclic antidepressant, to be effective in reducing methamphetamine use. The proposed Tina Trial is the first phase 3 placebo-controlled randomised trial to examine the effectiveness and safety of mirtazapine as an outpatient pharmacotherapy for methamphetamine use disorder. Methods: This is a multi-site phase 3 randomised, double-blind, placebo-controlled parallel trial. Participants are randomly allocated (1:1) to receive either mirtazapine (30 mg/day for 12 weeks) or matched placebo, delivered as a take-home medication. The target population is 340 people aged 18–65 years who have moderate to severe methamphetamine use disorder. The trial is being conducted through outpatient alcohol and other drug treatment clinics in Australia. The primary outcome is measured as self-reported days of methamphetamine use in the past 4 weeks at week 12. Secondary outcomes are methamphetamine-negative oral fluid samples, depressive symptoms, sleep quality, HIV risk behaviour and quality of life. Other outcomes include safety (adverse events), tolerability, and health service use. Medication adherence is being monitored using MEMS® Smart Caps fitted to medication bottles. Discussion: This trial will provide information on the safety and effectiveness of mirtazapine as a pharmacotherapy for methamphetamine use disorder when delivered as an outpatient medication in routine clinical practice. If found to be safe and effective, this trial will support an application for methamphetamine use disorder to be included as a therapeutic indication for the prescription of mirtazapine. Trial registration: Australian and New Zealand Clinical Trials Registry ACTRN12622000235707. Registered on February 9, 2022. [ABSTRACT FROM AUTHOR]

The implementation of the 2016 Peace Agreement has produced one of the most comprehensive and exhaustive peacebuilding efforts to date. The ambitious peace agreement, centred around six core themes, has expanded the scope of peacebuilding into areas that traditionally have been largely ignored or overlooked by policymakers. While the implementation process is still maintaining an overall trajectory that can be considered as success, the same process is still poised with a range of engdogenous and exogenous challenges that may undermine both the pace and the quality of peacebuilding efforts. This article surveys the current trends in the implementation phase, highlighting the key dynamics that stand in the way of an effective and timely implementation of the Colombian peace plan. In addition to exploring the emerging challenges to the liberal peacebuilding approach, this article also highlights the significance of concurrent opportunities and liabilities that stem from developmental approaches to peacebuilding. [ABSTRACT FROM AUTHOR]

Background: Thyroid hormones regulate cardiac functions mainly through direct actions in the heart and by binding to the thyroid hormone receptor (TR) isoforms α1 and β. While the role of the most abundantly expressed isoform, TRα1, is widely studied and well characterized, the role of TRβ in regulating heart functions is still poorly understood, primarily due to the accompanying elevation of circulating thyroid hormone in TRβ knockout mice (TRβ-KO). However, their hyperthyroidism is ameliorated at thermoneutrality, which allows studying the role of TRβ without this confounding factor. Methods: Here, we noninvasively monitored heart rate in TRβ-KO mice over several days using radiotelemetry at different housing temperatures (22°C and 30°C) and upon 3,3′,5-triiodothyronine (T3) administration in comparison to wild-type animals. Results: TRβ-KO mice displayed normal average heart rate at both 22°C and 30°C with only minor changes in heart rate frequency distribution, which was confirmed by independent electrocardiogram recordings in freely-moving conscious mice. Parasympathetic nerve activity was, however, impaired in TRβ-KO mice at 22°C, and only partly rescued at 30°C. As expected, oral treatment with pharmacological doses of T3 at 30°C led to tachycardia in wild-types, accompanied by broader heart rate frequency distribution and increased heart weight. The TRβ-KO mice, in contrast, showed blunted tachycardia, as well as resistance to changes in heart rate frequency distribution and heart weight. At the molecular level, these observations were paralleled by a blunted cardiac mRNA induction of several important genes, including the pacemaker channels Hcn2 and Hcn4, as well as Kcna7. Conclusions: The phenotyping of TRβ-KO mice conducted at thermoneutrality allows novel insights on the role of TRβ in cardiac functions in the absence of the usual confounding hyperthyroidism. Even though TRβ is expressed at lower levels than TRα1 in the heart, our findings demonstrate an important role for this isoform in the cardiac response to thyroid hormones. [ABSTRACT FROM AUTHOR]