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Abstract Triazole antifungals function as ergosterol biosynthesis inhibitors and are frontline therapy for invasive fungal infections, such as invasive aspergillosis. The primary mechanism of action of triazoles is through the specific inhibition of a cytochrome P450 14-α-sterol demethylase enzyme, Cyp51A/B, resulting in depletion of cellular ergosterol. Here, we uncover a clinically relevant secondary mechanism of action for triazoles within the ergosterol biosynthesis pathway. We provide evidence that triazole-mediated inhibition of Cyp51A/B activity generates sterol intermediate perturbations that are likely decoded by the sterol sensing functions of HMG-CoA reductase and Insulin-Induced Gene orthologs as increased pathway activity. This, in turn, results in negative feedback regulation of HMG-CoA reductase, the rate-limiting step of sterol biosynthesis. We also provide evidence that HMG-CoA reductase sterol sensing domain mutations previously identified as generating resistance in clinical isolates of Aspergillus fumigatus partially disrupt this triazole-induced feedback. Therefore, our data point to a secondary mechanism of action for the triazoles: induction of HMG-CoA reductase negative feedback for downregulation of ergosterol biosynthesis pathway activity. Abrogation of this feedback through acquired mutations in the HMG-CoA reductase sterol sensing domain diminishes triazole antifungal activity against fungal pathogens and underpins HMG-CoA reductase-mediated resistance.

Abstract Coleman’s theorem states that continuous internal symmetries cannot be spontaneously broken in two-dimensional quantum field theories (QFTs). In this work we consider surface (i.e. two-dimensional) defects in d-dimensional conformal field theories (CFTs) invariant under a continuous internal symmetry group G. We study under which conditions it is possible for a surface defect to break spontaneously a continuous internal symmetry. We find that spontaneous symmetry breaking (SSB) is impossible under reasonable assumptions on the defect Renormalization Group (RG) flow. Counterexamples are possible only for exotic RG flows, that do not terminate at a fixed-point. We discuss an example of this kind. We also illustrate our no-go result with an effective field theory analysis of generic defect RG flows. We find a generic weakly coupled defect universality class (with no SSB), where correlation functions decay logarithmically. Our analysis generalizes the recent discovery by Metlitski of the extraordinary-log boundary universality class in the O(N) model.

Background: While current wound treatment strategies often focus on antimicrobials and topical agents, the role of nutrition in wound healing and aesthetic outcomes is crucial but frequently overlooked. This review assesses the impact of specific nutrients and preoperative nutritional status on surgical outcomes. Methods: A comprehensive search was conducted in PubMed, Scopus, Web of Science, and the Cochrane Library, from the inception of the study to October 2023. The study focused on the influence of macronutrients and micronutrients on aesthetic outcomes, the optimization of preoperative nutritional status, and the association between nutritional status and postoperative complications. Inclusion criteria were English language peer-reviewed articles, systematic reviews, meta-analyses, and clinical trials related to the impact of nutrition on skin wound healing and aesthetic outcomes. Exclusion criteria included non-English publications, non-peer-reviewed articles, opinion pieces, and animal studies. Results: Omega-3 fatty acids and specific amino acids were linked to enhanced wound-healing and immune function. Vitamins A, B, and C and zinc positively influenced healing stages, while vitamin E showed variable results. Polyphenolic compounds showed anti-inflammatory effects beneficial for recovery. Malnutrition was associated with increased postoperative complications and infections, whereas preoperative nutritional support correlated with reduced hospital stays and complications. Conclusion: Personalized nutritional plans are essential in surgical care, particularly for enhanced recovery after surgery protocols. Despite the demonstrated benefits of certain nutrients, gaps in research, particularly regarding elements such as iron, necessitate further studies. Nutritional assessments and interventions are vital for optimal preoperative care, underscoring the need for more comprehensive guidelines and research in nutritional management for surgical patients.

Genome-wide fragmentation patterns in cell-free DNA (cfDNA) in plasma are strongly influenced by cellular origin due to variation in chromatin accessibility across cell types. Such differences between healthy and cancer cells provide the opportunity for development of novel cancer diagnostics. Here, we investigated whether analysis of cfDNA fragment end positions and their surrounding DNA sequences reveals the presence of tumor-derived DNA in blood. We performed genome-wide analysis of cfDNA from 521 samples and analyzed sequencing data from an additional 2147 samples, including healthy individuals and patients with 11 different cancer types. We developed a metric based on genome-wide differences in fragment positioning, weighted by fragment length and GC content [information-weighted fraction of aberrant fragments (iwFAF)]. We observed that iwFAF strongly correlated with tumor fraction, was higher for DNA fragments carrying somatic mutations, and was higher within genomic regions affected by copy number amplifications. We also calculated sample-level means of nucleotide frequencies observed at genomic positions spanning fragment ends. Using a combination of iwFAF and nine nucleotide frequencies from three positions surrounding fragment ends, we developed a machine learning model to differentiate healthy individuals from patients with cancer. We observed an area under the receiver operative characteristic curve (AUC) of 0.91 for detection of cancer at any stage and an AUC of 0.87 for detection of stage I cancer. Our findings remained robust with as few as 1 million fragments analyzed per sample, demonstrating that analysis of fragment ends can become a cost-effective and accessible approach for cancer detection and monitoring.

A case-control study was conducted between 1 December 2021 and 31 January 2022 to identify factors, which increase risk for coronavirus disease 2019 (COVID-19) among athletes in the National Basketball Association (NBA). Behavioral factors and stadium attendance significantly decreased time to COVID-19 infection, but local COVID-19 rates were not associated in a multivariable model.

The spread of misinformation and conspiracies has been an ongoing issue since the early stages of the internet era, resulting in the emergence of the field of infodemiology (i.e., information epidemiology), which investigates the transmission of health-related information. Due to the high volume of online misinformation in recent years, there is a need to continue advancing methodologies in order to effectively identify narratives and themes. While machine learning models can be used to detect misinformation and conspiracies, these models are limited in their generalizability to other datasets and misinformation phenomenon, and are often unable to detect implicit meanings in text that require contextual knowledge. To rapidly detect evolving conspiracist narratives within high volume online discourse while identifying nuanced themes requiring the comprehension of subtext, this study describes a hybrid methodology that combines natural language processing (i.e., topic modeling and sentiment analysis) with qualitative content coding approaches to characterize conspiracy discourse related to 5G wireless technology and COVID-19 on Twitter (currently known as X). Discourse that focused on correcting 5G conspiracies was also analyzed for comparison. Sentiment analysis shows that conspiracy-related discourse was more likely to use language that was analytic, combative, past-oriented, referenced social status, and expressed negative emotions. Corrections discourse was more likely to use words reflecting cognitive processes, prosocial relations, health-related consequences, and future-oriented language. Inductive coding characterized conspiracist narratives related to global elites, anti-vax sentiment, medical authorities, religious figures, and false correlations between technology advancements and disease outbreaks. Further, the corrections discourse did not address many of the narratives prevalent in conspiracy conversations. This paper aims to further bridge the gap between computational and qualitative methodologies by demonstrating how both approaches can be used in tandem to emphasize the positive aspects of each methodology while minimizing their respective drawbacks.

Type 2 diabetes (T2D) has a complex pathophysiology which makes modeling the disease difficult. We aimed to develop a novel model for simulating T2D in vitro, including hyperglycemia, hyperlipidemia, and variably elevated insulin levels targeting muscle cells. We investigated insulin resistance (IR), cellular respiration, mitochondrial morphometry, and the associated function in different T2D-mimicking conditions in rodent skeletal (C2C12) and cardiac (H9C2) myotubes. The physiological controls included 5 mM of glucose with 20 mM of mannitol as osmotic controls. To mimic hyperglycemia, cells were exposed to 25 mM of glucose. Further treatments included insulin, palmitate, or both. After short-term (24 h) or long-term (96 h) exposure, we performed radioactive glucose uptake and mitochondrial function assays. The mitochondrial size and relative frequencies were assessed with morphometric analyses using electron micrographs. C2C12 and H9C2 cells that were treated short- or long-term with insulin and/or palmitate and HG showed IR. C2C12 myotubes exposed to T2D-mimicking conditions showed significantly decreased ATP-linked respiration and spare respiratory capacity and less cytoplasmic area occupied by mitochondria, implying mitochondrial dysfunction. In contrast, the H9C2 myotubes showed elevated ATP-linked and maximal respiration and increased cytoplasmic area occupied by mitochondria, indicating a better adaptation to stress and compensatory lipid oxidation in a T2D environment. Both cell lines displayed elevated fractions of swollen/vacuolated mitochondria after T2D-mimicking treatments. Our stable and reproducible in vitro model of T2D rapidly induced IR, changes in the ATP-linked respiration, shifts in energetic phenotypes, and mitochondrial morphology, which are comparable to the muscles of patients suffering from T2D. Thus, our model should allow for the study of disease mechanisms and potential new targets and allow for the screening of candidate therapeutic compounds.

Since 8th March 2020 up to the time of writing, we have been producing near real-time weekly estimates of SARS-CoV-2 transmissibility and forecasts of deaths due to COVID-19 for all countries with evidence of sustained transmission, shared online. We also developed a novel heuristic to combine weekly estimates of transmissibility to produce forecasts over a 4-week horizon. Here we present a retrospective evaluation of the forecasts produced between 8th March to 29th November 2020 for 81 countries. We evaluated the robustness of the forecasts produced in real-time using relative error, coverage probability, and comparisons with null models. During the 39-week period covered by this study, both the short- and medium-term forecasts captured well the epidemic trajectory across different waves of COVID-19 infections with small relative errors over the forecast horizon. The model was well calibrated with 56.3% and 45.6% of the observations lying in the 50% Credible Interval in 1-week and 4-week ahead forecasts respectively. The retrospective evaluation of our models shows that simple transmission models calibrated using routine disease surveillance data can reliably capture the epidemic trajectory in multiple countries. The medium-term forecasts can be used in conjunction with the short-term forecasts of COVID-19 mortality as a useful planning tool as countries continue to relax public health measures.

INTRODUCTION: In 2019, the state of Massachusetts signed into law the first statewide sales restrictions of flavored ENDS/tobacco products for both physical and online shops in response to a previous executive order to curb E-Cigarette, or Vaping Product, Use Associated Lung Injury (EVALI) cases that were surging throughout the nation. METHODOLOGY: This study obtained licensure data from the Massachusetts Department of Revenue, to observe the changes in retail licensure comparing the pre ban (October 2018-August 2019) and post ban periods (October 2020- August 2021). A series of linear regression tests were conducted on both periods using census tract data to explore potential associations with sociodemographic covariates, including median age, median household income, and population proportion by gender, age, and race/ethnicity groups. RESULTS: Analysis of the Massachusetts post-ban period (October 2020-August 2021) found that new tobacco retail licenses issued decreased by 52.9% (n = 968) when compared to the pre-ban period (October 2018-August 2019) of 1831. A significant positive association was discovered between change in new retailer count and proportion male population (2.48 ± 1.05, P = .018) as well as proportion Hispanic population (1.19 ± .25, P < .001) at the census tract level. CONCLUSION/DISCUSSION: Our analysis indicates that, following the temporary MA flavor sales ban, the total number of licenses decreased, though decreases were more pronounced for new licenses when compared to continuing licenses. Higher increases in new tobacco retailer density were significantly associated with concentration of male and Hispanic populations.

BackgroundAcute Kidney Injury (AKI) incidence has continued to rise and is recognized as a major risk factor for kidney disease progression and cardiovascular complications. Early recognition of factors associated with post-AKI complications is fundamental to stratifying patients that could benefit from closer follow-up and management after an episode of AKI. Recent studies have shown that proteinuria is a prevalent sequela after AKI and a strong predictor of complications post-AKI. This study aims to evaluate the frequency and timing of the development of de-novo proteinuria after an AKI episode in patients with known kidney function and no prior history of proteinuria.MethodsWe retrospectively analyzed data from adult AKI patients with pre- and post-kidney function information between Jan 2014 and March 2019. The presence of proteinuria determined before and after index AKI encounter was based on ICD-10 code and/or urine dipstick and UPCR during the follow-up period.ResultsOf 9697 admissions with AKI diagnoses between Jan 2014 and March 2019, 2120 eligible patients with at least one assessment of Scr and proteinuria before AKI index admission were included in the analysis. The median age was 64 (IQR 54-75) years, and 57% were male. 58% (n-1712) patients had stage 1 AKI, 19% (n = 567) stage 2 AKI, and 22% (n = 650) developed stage 3 AKI. De novo proteinúria was found in 62% (n = 472) of patients and was already present by 90 days post-AKI in 59% (209/354). After adjusting for age and comorbidities, severe AKI (stage 2/3 AKI) and diabetes, were independently associated with increased risk for De novo proteinuria.ConclusionSevere AKI is an independent risk factor for subsequent de novo proteinuria post-hospitalization. Further prospective studies are needed to determine whether strategies to detect AKI patients at risk of proteinuria and early therapeutics to modify proteinuria can delay the progression of kidney disease.

IntroductionThe state of California has enacted progressive anti-tobacco policies, including Proposition 56 in 2016. In response, the alternative and emerging tobacco product (ATP) industry has increased its political activity. This study explores the association between the proportion of people voting against Proposition 56 and tobacco/ATP retail density.MethodsWe conducted a retrospective analysis using data on licensed California tobacco retailers, which were then cross-referenced for categorization using Yelp. Proportion voting against Proposition 56 was obtained from the Secretary of State's website. A series of linear regression tests were performed between population-normalized retailer density and voting proportion at the county level before and after adjusting for covariates such as age, gender, race/ethnicity and median household income.ResultsThe total number of licensed tobacco retailers increased by 29.31% from 2015 to 2019. Association between proportion voting against Proposition 56 and retail density was significant during voting and during periods of policy implementation and post-implementation (2016-2018) for non-specialized tobacco retailers. For specialized/ATP retailers, significance was only detected during the post-implementation period (2018-2019) after normalization. Proportion voting against Proposition 56 was also a significant predictor of increase in total number of non-specific (β=0.48, p=0.008) as well as specialized tobacco and/or ATP retail storefronts (β=0.21, p=0.001) from 2016 to 2018.ConclusionsThis study provides initial evidence of the association between tobacco retail density and voting patterns for anti-tobacco policy. Future research should examine the role of tobacco retail density on variation in local support for state tobacco control initiatives, including tailoring outreach to specific voting census blocks in communities with heavy retail presence.

BackgroundThere were an estimated 100,306 drug overdose deaths between April 2020 and April 2021, a three-quarter increase from the prior 12-month period. There is an approximate 6-month reporting lag for provisional counts of drug overdose deaths from the National Vital Statistics System, and the highest level of geospatial resolution is at the state level. By contrast, public social media data are available close to real-time and are often accessible with precise coordinates.ObjectiveThe purpose of this study is to assess whether county-level overdose mortality burden could be estimated using opioid-related Twitter data.MethodsInternational Classification of Diseases (ICD) codes for poisoning or exposure to overdose at the county level were obtained from CDC WONDER. Demographics were collected from the American Community Survey. The Twitter Application Programming Interface was used to obtain tweets that contained any of the 36 terms with drug names. An unsupervised classification approach was used for clustering tweets. Population-normalized variables and polynomial population-normalized variables were produced. Furthermore, z scores of the Getis Ord Gi clustering statistic were produced, and both these scores and their polynomial counterparts were explored in regression modeling of county-level overdose mortality burden. A series of linear regression models were used for predictive modeling to explore the interpretability of the analytical output.ResultsModeling overdose mortality with normalized demographic variables alone explained only 7.4% of the variability in county-level overdose mortality, whereas this was approximately doubled by the use of specific demographic and Twitter data covariates based on a backward selection approach. The highest adjusted R2 and lowest AIC (Akaike Info Criterion) were obtained for the model with normalized demographic variables, normalized z scores from geospatial analyses, and normalized topic counts (adjusted R2=0.133, AIC=8546.8). The z scores of the Getis Ord Gi statistic appeared to have improved utility over population-normalization alone. In this model, median age, female population, and tweets about web-based drug sales were positively associated with opioid mortality. Asian race and Hispanic ethnicity were significantly negatively associated with county-level burdens of overdose mortality.ConclusionsSocial media data, when transformed using certain statistical approaches, may add utility to the goal of producing closer to real-time county-level estimates of overdose mortality. Prediction of opioid-related outcomes can be advanced to inform prevention and treatment decisions. This interdisciplinary approach can facilitate evidence-based funding decisions for various substance use disorder prevention and treatment programs.

INTRODUCTION: Previous studies have identified numerous adverse events experienced with the use of ENDS or E-cigarettes. However, much remains unknown about adverse event frequency, duration, and response experienced by users. The purpose of this study was to inductively characterize ENDS-attributed adverse events among young adults. METHODS: Sixteen focus groups were held with 114 young adults (aged 18-29 years) who have reported lifetime ENDS use in April 2021. Discussion topics included current and previous tobacco, nicotine, and cannabis use; specific symptoms and frequency and duration of and response to symptoms of ENDS-attributed adverse events; and the impact of other conditions such as COVID-19 on ENDS use. Data were inductively analyzed using a team-based approach. RESULTS: More than 40 ENDS-attributed adverse events were reported in focus groups among approximately three quarters of all study participants, with headache, coughing, lightheadedness, nausea, dry or sore throat, and dizziness the most common. In general, adverse events were transient, with most resolving in a few hours, although some tended to last for longer. The frequency of adverse events varied most between every time ENDS were used and when someone vaped excessively. Finally, behavioral responses varied by adverse events, with difficulty in breathing, chest pain, and lung discomfort more likely to result in quitting permanently. CONCLUSIONS: Overall, the results of this study show that not only do adverse events vary greatly, but they also vary across multiple dimensions of user experience.

BackgroundAccess to tobacco products, including vape products, from local brick-and-mortar stores influences the exposure, uptake, and use of these products in local communities.MethodsLicensed tobacco retailers in California were classified as specialized tobacco/vape stores or non-specialized stores by obtaining categories published on Yelp. California smoking and vaping prevalence data were obtained from the 500 cities project and ESRI community analyst tool respectively. A series of simple linear regression tests were performed, at the zip code level, between the retailer count in each store category and smoking/vaping population. The Getis-Ord Gi* and Anselin Local Moran's I statistics were used for characterization of tobacco retail density hotspots and cold spots.ResultsThe association between CA smoking/vaping population and number of tobacco retailers was statistically significant for all store categories. Variability in smoking population was best explained by variability in non-specialized storefronts(R2=0.84). Spatial variability in tobacco-only storefronts explained the least proportion of variability in the overall smoking population. Similar results were obtained specific to vaping population, although the proportion of population explained by variability in the number of non-specialized storefronts was comparatively lower(R2=0.80).ConclusionsLocalities with greater numbers of non-specialized tobacco retailers had higher rates of smoking/vaping populations, and this association was much stronger for localities with greater numbers of specialized retailers. Non-specialized storefronts may represent convenient access points for nicotine products, while specialized storefronts may represent critical access points for initiation. Hence, regulations that address the entirety of the tobacco/vaping retail environment by limiting widespread access from non-specialized stores and reducing appeal generated by specialized retailers should be incorporated in future tobacco regulatory science and policymaking.

BackgroundCarbapenem-resistant Enterobacterales (CRE) are an urgent global health threat. Inferring the dynamics of local CRE dissemination is currently limited by our inability to confidently trace the spread of resistance determinants to unrelated bacterial hosts. Whole-genome sequence comparison is useful for identifying CRE clonal transmission and outbreaks, but high-frequency horizontal gene transfer (HGT) of carbapenem resistance genes and subsequent genome rearrangement complicate tracing the local persistence and mobilization of these genes across organisms.MethodsTo overcome this limitation, we developed a new approach to identify recent HGT of large, near-identical plasmid segments across species boundaries, which also allowed us to overcome technical challenges with genome assembly. We applied this to complete and near-complete genome assemblies to examine the local spread of CRE in a systematic, prospective collection of all CRE, as well as time- and species-matched carbapenem-susceptible Enterobacterales, isolated from patients from four US hospitals over nearly 5 years.ResultsOur CRE collection comprised a diverse range of species, lineages, and carbapenem resistance mechanisms, many of which were encoded on a variety of promiscuous plasmid types. We found and quantified rearrangement, persistence, and repeated transfer of plasmid segments, including those harboring carbapenemases, between organisms over multiple years. Some plasmid segments were found to be strongly associated with specific locales, thus representing geographic signatures that make it possible to trace recent and localized HGT events. Functional analysis of these signatures revealed genes commonly found in plasmids of nosocomial pathogens, such as functions required for plasmid retention and spread, as well survival against a variety of antibiotic and antiseptics common to the hospital environment.ConclusionsCollectively, the framework we developed provides a clearer, high-resolution picture of the epidemiology of antibiotic resistance importation, spread, and persistence in patients and healthcare networks.

The fungal kingdom represents an extraordinary diversity of organisms with profound impacts across animal, plant, and ecosystem health. Fungi simultaneously support life, by forming beneficial symbioses with plants and producing life-saving medicines, and bring death, by causing devastating diseases in humans, plants, and animals. With climate change, increased antimicrobial resistance, global trade, environmental degradation, and novel viruses altering the impact of fungi on health and disease, developing new approaches is now more crucial than ever to combat the threats posed by fungi and to harness their extraordinary potential for applications in human health, food supply, and environmental remediation. To address this aim, the Canadian Institute for Advanced Research (CIFAR) and the Burroughs Wellcome Fund convened a workshop to unite leading experts on fungal biology from academia and industry to strategize innovative solutions to global challenges and fungal threats. This report provides recommendations to accelerate fungal research and highlights the major research advances and ideas discussed at the meeting pertaining to 5 major topics: (1) Connections between fungi and climate change and ways to avert climate catastrophe; (2) Fungal threats to humans and ways to mitigate them; (3) Fungal threats to agriculture and food security and approaches to ensure a robust global food supply; (4) Fungal threats to animals and approaches to avoid species collapse and extinction; and (5) Opportunities presented by the fungal kingdom, including novel medicines and enzymes.

Background Recently revised WHO guidelines on malaria chemoprevention have opened the door to more tailored implementation. Countries face choices on whether to replace old drugs, target additional age groups, and adapt delivery schedules according to local drug resistance levels and malaria transmission patterns. Regular routine assessment of protective efficacy of chemoprevention is key. Here, we apply a novel modelling approach to aid the design and analysis of chemoprevention trials and generate measures of protection that can be applied across a range of transmission settings. Methods and findings We developed a model of genotype-specific drug protection, which accounts for underlying risk of infection and circulating genotypes. Using a Bayesian framework, we fitted the model to multiple simulated scenarios to explore variations in study design, setting, and participant characteristics. We find that a placebo or control group with no drug protection is valuable but not always feasible. An alternative approach is a single-arm trial with an extended follow-up (>42 days), which allows measurement of the underlying infection risk after drug protection wanes, as long as transmission is relatively constant. We show that the currently recommended 28-day follow-up in a single-arm trial results in low precision of estimated 30-day chemoprevention efficacy and low power in determining genotype differences of 12 days in the duration of protection (power = 1.4%). Extending follow-up to 42 days increased precision and power (71.5%) in settings with constant transmission over this time period. However, in settings of unstable transmission, protective efficacy in a single-arm trial was overestimated by 24.3% if recruitment occurred during increasing transmission and underestimated by 15.8% when recruitment occurred during declining transmission. Protective efficacy was estimated with greater precision in high transmission settings, and power to detect differences by resistance genotype was lower in scenarios where the resistant genotype was either rare or too common. Conclusions These findings have important implications for the current guidelines on chemoprevention efficacy studies and will be valuable for informing where these studies should be optimally placed. The results underscore the need for a comparator group in seasonal settings and provide evidence that the extension of follow-up in single-arm trials improves the accuracy of measures of protective efficacy in settings with more stable transmission. Extension of follow-up may pose logistical challenges to trial feasibility and associated costs. However, these studies may not need to be repeated multiple times, as the estimates of drug protection against different genotypes can be applied to different settings by adjusting for transmission intensity and frequency of resistance., Author(s): Andria Mousa 1,*, Gina Cuomo-Dannenburg 2, Hayley A. Thompson 3, R. Matthew Chico 1, Khalid B. Beshir 1, Colin J. Sutherland 1, David Schellenberg 1, Roly Gosling 1,4, Michael [...]

Artificial intelligence (AI) has the potential to transform various aspects of our lives, but its development has been accompanied by several social and ethical concerns. To comprehend the implications and underlying mechanisms, it is essential to acquire a broad understanding of its benefits and drawbacks. To this purpose, AI literacy is a fundamental driver for more aware attitudes towards AI development and implications. However, AI literacy research is still in its infancy. To contribute to advances in the sector, this paper presents the results of a study aimed at assessing students’ AI literacy in the context of higher education, focusing on doctoral students. A survey on AI literacy was performed in four dimensions: cognitive, operational, critical and ethical. The results show that while participants had little AI knowledge, they were overconfident of the technology’s capabilities. The study highlights the need for a more comprehensive approach to AI literacy that encompasses a deeper understanding of its ethical, social and economic implications.

Intimate partner violence (IPV) is one of the most common forms of violence against women. Gender-based violence is a major issue for women throughout their lifespan and comorbid mental health complaints are documented. The estimated worldwide prevalence is nearly 1 in 3, with female survivors reporting physical and/or sexual assault by an intimate partner at some time in their life. Scientific panels are currently addressing interest in both understanding risk factors and improving support services for this population. Up to now, previous research made poor efforts to explore the effectiveness of psychological interventions, in particular psychotherapy, in addressing mental health problems among women survivors of intimate partner violence. Our search aimed to summarize the available literature about psychological treatments for post-traumatic stress disorder (PTSD) in female survivors with a focus on the effectiveness of cognitive-behavioral therapy in addressing those symptoms. Twenty-six studies providing cognitive-behavioral therapies, psychodrama, interpersonal therapy, and active psychological intervention were included in a systematic review. Meta-analysis was restricted to thirteen studies that implemented cognitive behavioral therapies with similar treatment components. A strong reduction of PTSD severity was found (g = 1.52; 95 %-CI = 1.33, 1.71; p < 0.01) with moderate to large heterogeneity between studies (I2= 64 %; Q = 80.81). Evidence for publication bias was observed (Egger's test; t = 2.396; p = 0.02). Results suggest cognitive behavioral therapy is effective for PTSD symptoms improvement in women survivors of intimate partner violence. The core interventions’ components included psychoeducation, relaxation with diaphragmatic breathing, trauma exposure, imagery, and problem-solving.

Background: This systematic review and meta-analysis aimed to synthesize the evidence of efficacy and tolerability of adjunctive topiramate treatment for patients with obsessive-compulsive disorder. Methods: A systematic search was conducted on MEDLINE, Cochrane Central Register of Controlled Trials, and OpenGrey to identify randomized controlled trials assigning participants with OCD to pharmacological intervention with topiramate. Study inclusion and data extraction were undertaken by two reviewers independently. The primary outcome was the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scale score, as a continuous variable within-subject OCD illness severity before and after treatment. The weighted mean difference (WMD) with 95 % confidence interval was calculated between the topiramate group and the control group. Results: Five studies were selected for inclusion in the systematic review, 4 of which were also included in the quantitative synthesis of data. The WMD in the Y-BOCS score between topiramate and placebo subjects was -0.49 (-2.28, 1.30) (p = 0.00); The results show a trend towards an effect of topiramate, but the estimate was not significant. Subgroup analysis revealed a significant effect at 12 weeks but not at 16 weeks (p = 0.00). Limitations: Low quality of the studies included and small sample size. Conclusion: There is a small positive signal for an anti-obsessive/compulsive effect in OCD patients which should encourage further research with larger, randomized, and placebo-controlled trials to assess topiramate's potential role in OCD treatment comprehensively.

In exploring the evolutionary trajectories of both pathogenesis and karyotype dynamics in fungi, we conducted a large-scale comparative genomic analysis spanning the Cryptococcus genus, encompassing both global human fungal pathogens and nonpathogenic species, and related species from the sister genus Kwoniella. Chromosome-level genome assemblies were generated for multiple species, covering virtually all known diversity within these genera. Although Cryptococcus and Kwoniella have comparable genome sizes (about 19.2 and 22.9 Mb) and similar gene content, hinting at preadaptive pathogenic potential, our analysis found evidence of gene gain (via horizontal gene transfer) and gene loss in pathogenic Cryptococcus species, which might represent evolutionary signatures of pathogenic development. Genome analysis also revealed a significant variation in chromosome number and structure between the 2 genera. By combining synteny analysis and experimental centromere validation, we found that most Cryptococcus species have 14 chromosomes, whereas most Kwoniella species have fewer (11, 8, 5, or even as few as 3). Reduced chromosome number in Kwoniella is associated with formation of giant chromosomes (up to 18 Mb) through repeated chromosome fusion events, each marked by a pericentric inversion and centromere loss. While similar chromosome inversion-fusion patterns were observed in all Kwoniella species with fewer than 14 chromosomes, no such pattern was detected in Cryptococcus. Instead, Cryptococcus species with less than 14 chromosomes showed reductions primarily through rearrangements associated with the loss of repeat-rich centromeres. Additionally, Cryptococcus genomes exhibited frequent interchromosomal translocations, including intercentromeric recombination facilitated by transposons shared between centromeres. Overall, our findings advance our understanding of genetic changes possibly associated with pathogenicity in Cryptococcus and provide a foundation to elucidate mechanisms of centromere loss and chromosome fusion driving distinct karyotypes in closely related fungal species, including prominent global human pathogens.

Therapist responsiveness is an emerging construct in psychotherapy research that still lacks a clear definition and, consequently, a unique operationalization. Indeed, there is a great overlap between therapist responsiveness and other variables, such as attunement, flexibility, and empathy. This overlap inevitably hinders the assessment of the therapist’s responsiveness, although it is crucial for the effectiveness of the treatments. Therefore, the current systematic review aims at exploring the different methodologies of measurement and analysis of therapist responsiveness, including both direct and indirect instruments. The results confirmed difficulties and divergences in the operationalization of the construct, as shown by the great heterogeneity found in the choice and use of the tools. Furthermore, this review provides guidance for future research, clinical practice, and training of therapists.

Background: Diverticular disease (DD) represents a common gastrointestinal condition that poses a heavy burden on healthcare systems worldwide. A high degree of uncertainty surrounds the therapeutic approaches for the control of symptoms in patients with symptomatic uncomplicated diverticular disease (SUDD) and primary and secondary prevention of diverticulitis and its consequences. Objectives: To review the current knowledge and discuss the unmet needs regarding the management of SUDD and the prevention of acute diverticulitis. Eligibility criteria: Randomized trials, observational studies, and systematic reviews on lifestyle/dietary interventions and medical treatment (rifaximin, mesalazine, and probiotics) of SUDD or prevention of acute diverticulitis. Sources of evidence: The literature search was performed from inception to April 2023, without language restriction, following the modified Preferred Reporting Items for Systematic review and Meta-Analyses (PRISMA) reporting guidelines. References of the papers selected were checked to identify additional papers of potential interest. The final list of references was evaluated by a panel of experts, who were asked to check for any lack of relevant studies. Charting methods: Information on patient population, study design, intervention, control group, duration of the observation, and outcomes assessed was collected by two authors independently. Results: The review shows a high degree of uncertainty about therapeutic interventions, both dietary/lifestyle and pharmacological, in patients with SUDD, because of the scarcity and weakness of existing evidence. Available studies are generally of low quality, heterogeneous, and outdated, precluding the possibility to draw robust conclusions. Similarly, acute diverticulitis prevention has been seldom investigated, and there is a substantial lack of evidence supporting the role of dietary/lifestyle or pharmacological approaches to reduce the risk of diverticulitis. Conclusion: The lack of robust evidence regarding therapeutic options for gastrointestinal symptoms in SUDD patients and for primary and secondary prevention of acute diverticulitis remains an important unmet need in the management of DD.

BackgroundRecently revised WHO guidelines on malaria chemoprevention have opened the door to more tailored implementation. Countries face choices on whether to replace old drugs, target additional age groups, and adapt delivery schedules according to local drug resistance levels and malaria transmission patterns. Regular routine assessment of protective efficacy of chemoprevention is key. Here, we apply a novel modelling approach to aid the design and analysis of chemoprevention trials and generate measures of protection that can be applied across a range of transmission settings.Methods and findingsWe developed a model of genotype-specific drug protection, which accounts for underlying risk of infection and circulating genotypes. Using a Bayesian framework, we fitted the model to multiple simulated scenarios to explore variations in study design, setting, and participant characteristics. We find that a placebo or control group with no drug protection is valuable but not always feasible. An alternative approach is a single-arm trial with an extended follow-up (>42 days), which allows measurement of the underlying infection risk after drug protection wanes, as long as transmission is relatively constant. We show that the currently recommended 28-day follow-up in a single-arm trial results in low precision of estimated 30-day chemoprevention efficacy and low power in determining genotype differences of 12 days in the duration of protection (power = 1.4%). Extending follow-up to 42 days increased precision and power (71.5%) in settings with constant transmission over this time period. However, in settings of unstable transmission, protective efficacy in a single-arm trial was overestimated by 24.3% if recruitment occurred during increasing transmission and underestimated by 15.8% when recruitment occurred during declining transmission. Protective efficacy was estimated with greater precision in high transmission settings, and power to detect differences by resistance genotype was lower in scenarios where the resistant genotype was either rare or too common.ConclusionsThese findings have important implications for the current guidelines on chemoprevention efficacy studies and will be valuable for informing where these studies should be optimally placed. The results underscore the need for a comparator group in seasonal settings and provide evidence that the extension of follow-up in single-arm trials improves the accuracy of measures of protective efficacy in settings with more stable transmission. Extension of follow-up may pose logistical challenges to trial feasibility and associated costs. However, these studies may not need to be repeated multiple times, as the estimates of drug protection against different genotypes can be applied to different settings by adjusting for transmission intensity and frequency of resistance.

Background: Mpox virus (MPXV) has recently spread outside of sub-Saharan Africa. This large multicentre study was conducted in Lombardy, the most densely populated Italian region accounting for more than 40% of Italian cases. The present study aims to: i) evaluate the presence and the shedding duration of MPXV DNA in different body compartments correlating the MPXV viability with the time to onset of symptoms; ii) provide evidence of MPXV persistence in different body compartment as a source of infection and iii) characterize the MPXV evolution by whole genome sequencing (WGS) during the outbreak occurred in Italy. Material and methods: The study included 353 patients with a laboratory-confirmed diagnosis of MPXV infection screened in several clinical specimens in the period May 24th - September 1st, 2022. Viral isolation was attempted from different biological matrices and complete genome sequencing was performed for 61 MPXV strains. Results: MPXV DNA detection was more frequent in the skin (94.4%) with the longest median time of viral clearance (16 days). The actively-replicating virus in cell culture was obtained for 123/377 (32.6%) samples with a significant higher viral quantity on isolation positive samples (20 vs 31, p

Objectives To investigate pregnancy outcomes in women with autoimmune rheumatic diseases (ARD) in the Italian prospective cohort study P-RHEUM.it.Methods Pregnant women with different ARD were enrolled for up to 20 gestational weeks in 29 Rheumatology Centres for 5 years (2018–2023). Maternal and infant information were collected in a web-based database.Results We analysed 866 pregnancies in 851 patients (systemic lupus erythematosus was the most represented disease, 19.6%). Maternal disease flares were observed in 135 (15.6%) pregnancies. 53 (6.1%) pregnancies were induced by assisted reproduction techniques, 61 (7%) ended in miscarriage and 11 (1.3%) underwent elective termination. Obstetrical complications occurred in 261 (30.1%) pregnancies, including 2.3% pre-eclampsia. Two cases of congenital heart block were observed out of 157 pregnancies (1.3%) with anti-Ro/SSA. Regarding treatments, 244 (28.2%) pregnancies were treated with glucocorticoids, 388 (44.8%) with hydroxychloroquine, 85 (9.8%) with conventional synthetic disease-modifying anti-rheumatic drugs and 122 (14.1%) with biological disease-modifying anti-rheumatic drugs. Live births were 794 (91.7%), mostly at term (84.9%); four perinatal deaths (0.5%) occurred. Among 790 newborns, 31 (3.9%) were small-for-gestational-age and 169 (21.4%) had perinatal complications. Exclusive maternal breast feeding was received by 404 (46.7%) neonates. The Edinburgh Postnatal Depression Scale was compiled by 414 women (52.4%); 89 (21.5%) scored positive for emotional distress.Conclusions Multiple factors including preconception counselling and treat-to-target with pregnancy-compatible medications may have contributed to mitigate disease-related risk factors, yielding limited disease flares, good pregnancy outcomes and frequency of complications which were similar to the Italian general obstetric population. Disease-specific issues need to be further addressed to plan preventative measures.

Most of the described species in kingdom Fungi are contained in two phyla, the Ascomycota and the Basidiomycota (subkingdom Dikarya). As a result, our understanding of the biology of the kingdom is heavily influenced by traits observed in Dikarya, such as aerial spore dispersal and life cycles dominated by mitosis of haploid nuclei. We now appreciate that Fungi comprises numerous phylum-level lineages in addition to those of Dikarya, but the phylogeny and genetic characteristics of most of these lineages are poorly understood due to limited genome sampling. Here, we addressed major evolutionary trends in the non-Dikarya fungi by phylogenomic analysis of 69 newly generated draft genome sequences of the zoosporic (flagellated) lineages of true fungi. Our phylogeny indicated five lineages of zoosporic fungi and placed Blastocladiomycota, which has an alternation of haploid and diploid generations, as branching closer to the Dikarya than to the Chytridiomyceta. Our estimates of heterozygosity based on genome sequence data indicate that the zoosporic lineages plus the Zoopagomycota are frequently characterized by diploid-dominant life cycles. We mapped additional traits, such as ancestral cell-cycle regulators, cell-membrane- and cell-wall-associated genes, and the use of the amino acid selenocysteine on the phylogeny and found that these ancestral traits that are shared with Metazoa have been subject to extensive parallel loss across zoosporic lineages. Together, our results indicate a gradual transition in the genetics and cell biology of fungi from their ancestor and caution against assuming that traits measured in Dikarya are typical of other fungal lineages.

IntroductionThe urgent need to acquire medical supplies amidst the COVID-19 pandemic has led to bypassing of controls that govern the global pharmaceutical supply chain, increasing the risk of corruption. Hence, promoting anti-corruption, transparency, and accountability (ACTA) in supply chain and procurement has never been more important. The adoption of digital tools, if designed and implemented appropriately, can reduce the risks of corruption.Areas coveredFollowing PRISMA guidelines, we conducted an interdisciplinary systematic review of health/medicine, humanities/social sciences, engineering, and computer science literature, with the aims of identifying technologies used for pharmaceutical supply chain and procurement optimization and reviewing whether they address ACTA mechanisms to strengthen pharmaceutical governance. Our review identified four distinct categories of digital solutions: e-procurement and open contracting; track-and-trace technology; anti-counterfeiting technology; and blockchain technology.Expert opinionFindings demonstrate an increase in research of technologies to improve pharmaceutical supply chain and procurement functions; however, most technologies are not being leveraged to directly address ACTA or global health outcomes. Some blockchain and RFID technologies incorporated ACTA mechanisms and mentioned specific policy/governance frameworks, but more purposeful linkage is needed. Findings point to the need for targeted policy development and governance to activate these innovative technologies to improve global health .

Fungi survive in diverse ecological niches by secreting proteins and other molecules into the environment to acquire food and interact with various biotic and abiotic stressors. Fungal secretome content is, therefore, believed to be tightly linked to fungal ecologies. We sampled 132 genomes from the early-diverging terrestrial fungal lineage zygomycetes (Mucoromycota and Zoopagomycota) and characterized their secretome composition. Our analyses revealed that phylogeny played an important role in shaping the secretome composition of zygomycete fungi with trophic mode contributing a smaller amount. Reconstruction of the evolution of secreted digestive enzymes revealed lineage-specific expansions, indicating that Mucoromycota and Zoopagomycota followed different trajectories early in their evolutionary history. We identified the presence of multiple pathogenicity-related proteins in the lineages known as saprotrophs, suggesting that either the ecologies of these fungi are incompletely known, and/or that these pathogenicity-related proteins have important functions associated with saprotrophic ecologies, both of which invite further investigation.