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Hematologic cancers are among the most common cancers in adults and children. Despite significant improvements in therapies, many patients still succumb to the disease. Therefore, novel therapies are needed. The Wiskott-Aldrich syndrome protein (WASp) family regulates actin assembly in conjunction with the Arp2/3 complex, a ubiquitous nucleation factor. WASp is expressed exclusively in hematopoietic cells and exists in two allosteric conformations: autoinhibited or activated. Here, we describe the development of EG-011, a first-in-class small molecule activator of the autoinhibited form of WASp. EG-011 possesses in vitro and in vivo antitumor activity as a single agent in lymphoma, leukemia, and multiple myeloma, including models of secondary resistance to PI3K, BTK, and proteasome inhibitors. The in vitro activity was confirmed in a lymphoma xenograft. Actin polymerization and WASp binding were demonstrated using multiple techniques. Transcriptome analysis highlighted homology with drugs inducing actin polymerization.

This narrative review examines the existing literature on minimally invasive image-guided sampling techniques of mediastinal lesions gathered from international databases (Medline, PubMed, Scopus, and Google Scholar). Original studies, systematic reviews with meta-analyses, randomized controlled trials, and case reports published between January 2009 and November 2023 were included. Four authors independently conducted the search to minimize bias, removed duplicates, and selected and evaluated the studies. The review focuses on the recent advancements in mediastinal sampling techniques, including EBUS-TBNA, EUS-FNA and FNB, IFB, and nodal cryobiopsy. The review highlights the advantages of an integrated approach using these techniques for diagnosing and staging mediastinal diseases, which, when used competently, significantly increase diagnostic yield and accuracy.

The Artificial Intelligence (AI) research community has used ad-hoc benchmarks to measure the " intelligence " level of Large Language Models (LLMs). In humans, intelligence is closely linked to the functional integrity of the prefrontal lobes, which are essential for higher-order cognitive processes. Previous research has found that LLMs struggle with cognitive tasks that rely on these prefrontal functions, highlighting a significant challenge in replicating human-like intelligence. In December 2022, OpenAI released ChatGPT, a new chatbot based on the GPT-3.5 model that quickly gained popularity for its impressive ability to understand and respond to human instructions, suggesting a significant step towards intelligent behaviour in AI. Therefore, to rigorously investigate LLMs' level of " intelligence ," we evaluated the GPT-3.5 and GPT-4 versions through a neuropsychological assessment using tests in the Italian language routinely employed to assess prefrontal functioning in humans. The same tests were also administered to Claude2 and Llama2 to verify whether similar language models perform similarly in prefrontal tests. When using human performance as a reference, GPT-3.5 showed inhomogeneous results on prefrontal tests, with some tests well above average, others in the lower range, and others frankly impaired. Specifically, we have identified poor planning abilities and difficulty in recognising semantic absurdities and understanding others' intentions and mental states. Claude2 exhibited a similar pattern to GPT-3.5, while Llama2 performed poorly in almost all tests. These inconsistent profiles highlight how LLMs' emergent abilities do not yet mimic human cognitive functioning. The sole exception was GPT-4, which performed within the normative range for all the tasks except planning. Furthermore, we showed how standardised neuropsychological batteries developed to assess human cognitive functions may be suitable for challenging LLMs' performance., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Amnesia is a frequent claim in major crimes, and it is estimated that the complete or partial absence of memory following a crime ranges from 25% to 50% of total cases. Although some cases may constitute a genuine form of amnesia, due to organic-neurological defects or psychological causes, and possibly combined with a dissociative or repressive coping style after an extreme experience, malingering is still fairly common in offenders. Therefore, one of the main goals in medico-legal proceedings is to find methods to determine the credibility of crime-related amnesia. At present, a number of lie and memory detection techniques can assist the forensic assessment of the reliability of declarative proof, and have been devised and improved over the past century: for example, modern polygraphs, event-related potentials, thermal imaging, functional magnetic resonance imaging, kinematic, and facial analysis. Other ad hoc psychological tests, such as the so-called Symptom Validity Test (SVT) and Performance Validity Test (PVT), as well as the autobiographical Implicit Association Test (aIAT), can also be used. To date, however, there is little evidence or case reports that document their real usefulness in forensic practice. Here, we report two cases of crime-related amnesia, whereby both defendants, who were found guilty of homicide, appeared to exhibit dissociative amnesia but where the application of SVTs, PVTs, and aIAT detected a malingered amnesia., (© 2023 Cognitive Science Society LLC.)

Posttraumatic stress disorder (PTSD) is one of the most serious and incapacitating mental diseases that can result from trauma exposure. The exact prevalence of this disorder is not known as the literature provides very different results, ranging from 2.5% to 74%. The aim of this umbrella review is to provide an estimation of PTSD prevalence and to clarify whether the prevalence depends on the assessment methods applied (structured interview v . self-report questionnaire) and on the nature of the traumatic event (interpersonal v . not-interpersonal). A systematic search of major databases and additional sources (Google Scholar, EBSCO, Web of Science, PubMed, Galileo Discovery) was conducted. Fifty-nine reviews met the criteria of this umbrella review. Overall PTSD prevalence was 23.95% (95% confidence interval 95% CI 20.74-27.15), with no publication bias or significant small-study effects, but a high level of heterogeneity between meta-analyses. Sensitivities analyses revealed that these results do not change after removing meta-analysis also including data from underage participants (23.03%, 95% CI 18.58-27.48), nor after excluding meta-analysis of low quality (24.26%, 95% CI 20.46-28.06). Regarding the impact of diagnostic instruments on PTSD prevalence, the results revealed a lack of significant differences in PTSD prevalence when structured v . self-report instruments were applied ( p = 0.0835). Finally, PTSD prevalence did not differ following event of intentional (25.42%, 95% CI 19.76-31.09) or not intentional (22.48%, 95% CI 17.22-27.73) nature ( p = 0.4598). The present umbrella review establishes a robust foundation for future research and provides valuable insights on PTSD prevalence.

Purpose: Breast cancer is the most frequently diagnosed tumour, representing nearly 30% of all new cases in women. Radiotherapy (RT) plays a crucial role in the management of breast cancer. The objective of this study is to assess modesty in patients undergoing RT for breast cancer and take their suggestions and ideas into consideration to enhance the quality of treatment in this regard., Methods: The study enrolled 555 breast cancer patients undergoing adjuvant RT in three Italian centres. Patients completed a self-test questionnaire assessing their comfort level concerning modesty during therapy and their relationship with strangers and healthcare professionals. The impact of religious views and potential changes in sexuality were also examined., Results: Results showed that modesty was a common concern across the overall cohort of patients, with discomfort in being undressed during RT correlating with discomfort experienced in other daily life situations. Most patients felt more at ease with same sex healthcare workers. Age was also a major factor with younger patients generally feeling more comfortable with healthcare workers of the same age group. Interestingly, the surgical technique used (mastectomy vs. quadrantectomy) did not significantly influence modesty perceptions. Patients provided valuable suggestions to improve privacy and modesty during RT., Conclusion: This study demonstrates that modesty is an important issue for women undergoing RT, which can be influenced by personal characteristics and hospital-related factors. A reflection about the need to address modesty concerns and to incorporate dedicated interventions for protecting patients' physical and emotional well-being is warranted. Initiatives to improve communication, involvement, and body image support should also be integrated into the care path of patients to better their overall therapeutic experience. This study paves the way for broader research and interventions in daily cancer care., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Medical thoracoscopy is a minimally invasive and safe procedure mostly performed for unexplained exudative pleural effusions but may be considered for pneumothorax (PNX)., Methods: This retrospective study included participants affected by PNX who underwent medical thoracoscopy with talc poudrage at a single academic hospital from 2008 to 2021. The primary endpoint was the observation of complete radiographical lung re-expansion and absence of air supply from the chest drain within 7 days of medical thoracoscopy. The secondary endpoint was achieving no recurrence of ipsilateral PNX at 24 months post-discharge., Results: A total of 95 patients affected by primary spontaneous PNX (PSP), secondary spontaneous PNX (SSP), iatrogenic, and traumatic PNX were enrolled. An additional procedure was required by 17.89% of patients, and only one patient with SSP required subsequent surgery. Recurrence of PNX occurred on the same side within 24 months after discharge in 9.47% of patients, with a median time to recurrence of 13.5 months. The PSP group was significantly more likely to achieve the primary endpoint. Pleural morphology was significantly associated with reaching the primary endpoint, while receiving a cumulative dose of talc greater than or equal to 4 g during hospitalization was associated with a lower risk of meeting it. Receiving a cumulative dose of talc greater than or equal to 4 g led in all cases to the achievement of the secondary endpoint. Patients with iatrogenic and traumatic PNX had an excellent prognosis in both the short- and long-term evaluation., Conclusion: Medical thoracoscopy is an effective procedure for treating PNX in the acute setting in selected cases while preventing long-term relapses. Large prospective clinical studies are needed to support and better define the role of medical thoracoscopy in current clinical practice., (© 2024. The Author(s).)

This narrative review aims to provide an overview of medical pleurodesis techniques, and their indications and potential adverse effects. Pleurodesis is a procedure performed with the aim of obliterating the pleural space. It has indications in the management of both malignant and benign pleural effusions and pneumothorax. Various nonsurgical techniques exist to perform pleurodesis. The scope of this work is to review the different nonsurgical techniques and their indications. This narrative review was performed checking scientific databases for medical literature, focusing especially on the data derived from randomised controlled trials. Pleurodesis is an effective method to manage pleural effusions and pneumothorax, and minimally invasive techniques are now frequently used with good results. Further research is needed to assess the efficacy of new treatments and the possibility of using different techniques in association., Competing Interests: Conflict of interest: Each author declares that he or she has no commercial associations (e.g. consultancies, stock ownership, equity interest, patent/licensing arrangement) that might pose a conflict of interest in connection with the submitted article., (Copyright ©ERS 2024.)

The ACTA2 gene codes for alpha-smooth muscle actin, a critical component of the contractile apparatus of the vascular smooth muscle cells. Autosomal dominant variants in the ACTA2 gene have been associated to familial non-syndromic thoracic aortic aneurysm/dissection (TAAD). They are thought to act through a dominant-negative mechanism. These variants display incomplete penetrance and variable expressivity, complicating the validation of ACTA2 variants pathogenicity by family segregation studies. In this study, we developed a yeast based assay to test putative TAAD-associated ACTA2 variants. We identified five new heterozygous ACTA2 missense variants in TAAD patients through next generation sequencing. We decided to test their pathogenicity in Saccharomyces cerevisiae, since yeast actin is very similar to human alpha-smooth muscle actin, and the residues at which the TAAD-associated variants occur in ACTA2 are well conserved. A wild type yeast strain was transformed with a vector expressing the different mutant alleles, to model the heterozygous condition of patients. Then, we evaluated yeast growth by spot test and cytoskeletal and mitochondrial morphology by fluorescence microscopy. We found that mutant yeast strains displayed only mild growth defects but a significant increase in the percentage of cells with abnormal mitochondrial distribution and abnormal organization of the actin cytoskeleton compared to controls. All variants appeared to interfere with the activity of wild type actin in yeast, suggesting a dominant-negative pathogenic mechanism. Our results demonstrate the utility of using the yeast actin model system to validate the pathogenicity of TAAD-associated ACTA2 variants., (© 2024. The Author(s), under exclusive licence to European Society of Human Genetics.)

Introduction: The Exacerbation of Chronic Obstructive Pulmonary Disease (ECOPD), especially if leading to hospitalization, increases the risk of death. Our scoping review aims to identify updated mortality risk factors for both short- and long-term periods., Areas Covered: A comprehensive search, covering the period from January 2013 to February 2024, was performed to identify eligible studies that consider factors associated with death in hospitalized ECOPD. We considered short-term mortality, up to one year (including in-hospital mortality, IHM) and long-term mortality over one year, without time limits. We excluded studies concerning the intensive care area., Expert Opinion: We considered 38 studies, 32 and 8 reporting data about short- and long-term mortality, respectively. Two studies consider both periods. Several factors, some already known, others newly identified, have been evaluated and discussed. Some of these were related to the characteristics and severity of COPD (age, body mass index, lung impairment), and some considered the response to ECOPD. In this last context, we focused on the increasing role of biomarkers in predicting the mortality of patients, particularly IHM. Our factors associated with a worse prognosis may be helpful in clinical practice to identify patients at risk and, subsequently, determine a personalized approach.

In this study, we propose an approach to detect deception during investigative interviews by integrating response latency and error analysis with the unexpected question technique. Sixty participants were assigned to an honest (n = 30) or deceptive group (n = 30). The deceptive group was instructed to memorize the false biographical details of a fictitious identity. Throughout the interviews, participants were presented with a randomized sequence of control, expected, and unexpected open-ended questions about identity. Responses were audio recorded for detailed examination. Our findings indicate that deceptive participants showed markedly longer latencies and higher error rates when answering expected (requiring deception) and unexpected questions (for which premeditated deception was not possible). Longer response latencies were also observed in participants attempting deception when answering control questions (which necessitated truthful answers). Moreover, a within-subject analysis highlighted that responding to unexpected questions significantly impaired individuals' performance compared to answering control and expected questions. Leveraging machine-learning algorithms, our approach attained a classification accuracy of 98% in distinguishing deceptive and honest participants. Additionally, a classification analysis on single response levels was conducted. Our findings underscore the effectiveness of merging response latency metrics and error rates with unexpected questioning as a robust method for identity deception detection in investigative interviews. We also discuss significant implications for enhancing interview strategies., (© 2024. The Author(s).)

Background: SARS-CoV-2 infection has raised concerns about long-term health repercussions. Exercise ventilatory inefficiency (EVin) has emerged as a notable long-term sequela, potentially impacting respiratory and cardiovascular health. This study aims to assess the long-term presence of EVin after 34 months and its association with cardiorespiratory health in post-COVID patients., Methods: In a longitudinal study on 32 selected post-COVID subjects, we performed two cardiopulmonary exercise tests (CPETs) at 6 months (T0) and 34 months (T1) after hospital discharge. The study sought to explore the long-term persistence of EVin and its correlation with respiratory and cardiovascular responses during exercise. Measurements included also V̇O 2peak, end-tidal pressure of CO 2 (PET CO2 ) levels, oxygen uptake efficiency slope (OUES) and other cardiorespiratory parameters, with statistical significance set at p < 0.05. The presence of EVin at both T0 and T1 defines a persisting EVin (pEVin)., Results: Out of the cohort, five subjects (16%) have pEVin at 34 months. Subjects with pEVin, compared to those with ventilatory efficiency (Evef) have lower values of PET CO2 throughout exercise, showing hyperventilation. Evef subjects demonstrated selective improvements in DL CO and oxygen pulse, suggesting a recovery in cardiorespiratory function over time. In contrast, those with pEvin did not exhibit these improvements. Notably, significant correlations were found between hyperventilation (measured by PET CO2 ), oxygen pulse and OUES, indicating the potential prognostic value of OUES and Evin in post-COVID follow-ups., Conclusions: The study highlights the clinical importance of long-term follow-up for post-COVID patients, as a significant group exhibit persistent EVin, which correlates with altered and potentially unfavorable cardiovascular responses to exercise. These findings advocate for the continued investigation into the long-term health impacts of COVID-19, especially regarding persistent ventilatory inefficiencies and their implications on patient health outcomes., (© 2024. The Author(s).)

One potential application of forensic "brain reading" is to test whether a suspect has previously experienced a crime scene. Here, we investigated whether it is possible to decode real life autobiographic exposure to spatial locations using fMRI. In the first session, participants visited four out of eight possible rooms on a university campus. During a subsequent scanning session, subjects passively viewed pictures and videos from these eight possible rooms (four old, four novel) without giving any responses. A multivariate searchlight analysis was employed that trained a classifier to distinguish between "seen" versus "unseen" stimuli from a subset of six rooms. We found that bilateral precuneus encoded information that can be used to distinguish between previously seen and unseen rooms and that also generalized to the two stimuli left out from training. We conclude that activity in bilateral precuneus is associated with the memory of previously visited rooms, irrespective of the identity of the room, thus supporting a parietal contribution to episodic memory for spatial locations. Importantly, we could decode whether a room was visited in real life without the need of explicit judgments about the rooms. This suggests that recognition is an automatic response that can be decoded from fMRI data, thus potentially supporting forensic applications of concealed information tests for crime scene recognition., (© 2024 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background and Objective: Medical thoracoscopy (MT) is an endoscopic technique performed by interventional pulmonologists with a favorable safety profile and few contraindications, providing diagnostic and therapeutic intervention in a single sitting. This narrative review was designed to summarize the therapeutic role of MT based on the latest results from the available literature., Methods: Pertinent literature published in English, relative to human studies, between 2010-2022 was searched in Medline/PubMed and Cochrane databases. Publications regarded as relevant were considered for inclusion in this review; additional references were added based on the authors' knowledge and judgment. The review considered population studies, meta-analyses, case series, and case reports., Key Content and Findings: MT has mostly been described and is currently used globally in the diagnostic approach to exudative pleural effusion of undetermined origin. Carefully evaluating the literature, it is clear that there is initial evidence to support the use of MT in the therapeutic approach of malignant pleural effusion, pneumothorax, empyema, and less frequently hemothorax and foreign body retrieval., Conclusions: MT is an effective procedure for treating the clinical entities presented in this document; it must be carried out in selected patients, managed in centers with high procedural expertise. Further evidence is needed to assess the optimal indications and appropriate patients' profiles for therapeutic MT. The endpoints of length of hospital stay, surgical referral, complications and mortality will have to be considered in future studies to validate it as a therapeutic intervention to be applied globally., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1745/coif). The series “Malignant and Benign Pleural Effusions” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare., (2024 Journal of Thoracic Disease. All rights reserved.)

BTK and PI3K inhibitors are among the drugs approved for the treatment of patients with lymphoid neoplasms. Although active, their ability to lead to long-lasting complete remission is rather limited, especially in the lymphoma setting. This indicates that tumor cells often develop resistance to the drugs. We started from a marginal zone lymphoma cell line, Karpas-1718, kept under prolonged exposure to the PI3Kδ inhibitor idelalisib until acquisition of resistance, or with no drug. Cells underwent transcriptome, miRNA and methylation profiling, whole-exome sequencing, and pharmacologic screening, which led to the identification of the overexpression of ERBB4 and its ligands HBEGF and NRG2 in the resistant cells. Cellular and genetic experiments demonstrated the involvement of this axis in blocking the antitumor activity of various BTK/PI3K inhibitors, currently used in the clinical setting. Addition of recombinant HBEGF induced resistance to BTK/PI3K inhibitors in parental cells and in additional lymphoma models. Combination with the ERBB inhibitor lapatinib was beneficial in resistant cells and in other lymphoma models already expressing the identified resistance factors. An epigenetic reprogramming sustained the expression of the resistance-related factors, and pretreatment with demethylating agents or EZH2 inhibitors overcame the resistance. Resistance factors were also shown to be expressed in clinical specimens. In conclusion, we showed that the overexpression of ERBB4 and its ligands represents a novel mechanism of resistance for lymphoma cells to bypass the antitumor activity of BTK and PI3K inhibitors and that targeted pharmacologic interventions can restore sensitivity to the small molecules., (©2023 American Association for Cancer Research.)

Nqo15 is a subunit of respiratory complex I of the bacterium Thermus thermophilus , with strong structural similarity to human frataxin (FXN), a protein involved in the mitochondrial disease Friedreich's ataxia (FRDA). Recently, we showed that the expression of recombinant Nqo15 can ameliorate the respiratory phenotype of FRDA patients' cells, and this prompted us to further characterize both the Nqo15 solution's behavior and its potential functional overlap with FXN, using a combination of in silico and in vitro techniques. We studied the analogy of Nqo15 and FXN by performing extensive database searches based on sequence and structure. Nqo15's folding and flexibility were investigated by combining nuclear magnetic resonance (NMR), circular dichroism, and coarse-grained molecular dynamics simulations. Nqo15's iron-binding properties were studied using NMR, fluorescence, and specific assays and its desulfurase activation by biochemical assays. We found that the recombinant Nqo15 isolated from complex I is monomeric, stable, folded in solution, and highly dynamic. Nqo15 does not share the iron-binding properties of FXN or its desulfurase activation function.

Introduction: Autobiographical memory is the capacity to recollect memories of personally experienced events. The detection of such memories plays a key role in criminal trials. Among behavioral memory-detection methods, the autobiographical Implicit Association Test (aIAT) has gained popularity for its flexibility and suitability for forensic applications. The aIAT is a reaction time-based methodology aiming to assess whether information about an event is encoded in the respondent's mind. Here, we introduced the eye-D index, a measure based on the topography of fixations while performing the aIAT, as an additional measure to detect autobiographical memories covertly., Methods: In this study, participants were involved in a mock-crime experiment in which they could act as Guilty or Innocent. One week later all participants underwent the aIAT combined with eye-tracking to investigate the presence of the crime-related memory., Results: Guilty participants showed a higher number of fixations towards the category labels in the block in which true sentences shared the same response key with crime-related sentences, as compared to the block in which true sentences were paired with sentences describing an alternative version. Innocent participants showed the opposite pattern. This unbalanced allocation of attention to the category labels was quantified by the eye-D index and was found to be highly correlated to the standard aIAT-D index., Discussion: This suggests that more fixations to the category labels could indicate increased cognitive load and monitoring of response conflicts. These preliminary results highlight eye-tracking as a tool to detect autobiographical memories covertly while performing the aIAT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Zangrossi, Gatto, Lanfranchi, Scarpazza, Celli and Sartori.)

Background: Recent clinical trials demonstrated longer survival in extended small cell lung cancer (SCLC) patients treated with immunotherapy in addition to chemotherapy. However, the magnitude of benefit is modest and the impact in real-world setting has to be fully established., Methods: We collected clinical data and radiological imaging of patients affected by extended or relapsing SCLC and consecutively treated according to clinical practice between 2016 and 2023. As primary end-point, we compared pre-defined outcome indicators before and after the introduction of chemo-immunotherapy (May 2020): 6-month and 12-month progression free survival (PFS) rate, 12-month and 18-month overall survival (OS). Among those who were treated after May 2020, patients who did not receive immunotherapy according to treating physician's choice were included in the analysis to minimize clinical selection bias., Results: The analysis included 214 patients: 132 (61.7%) were treated in an Academic cancer center and 82 (38.3%) in two community hospitals; 104 were treated before May 2020. Median PFS of the overall study population was 4.8 months (95% confidence interval [95% CI]: 4.4-5.4), median OS was 7.1 months (95% CI: 6.3-7.7). Estimated PFS and OS were significantly longer in patients treated after May 2020 with hazard ratio (HR) for PFS and OS of 0.61 (95% CI: 0.46-0.81, p < 0.001) and 0.70 (95% CI: 0.52-0.93, p = 0.015), respectively. 6-month PFS rate increased from 27% to 40% (p = 0.04) while 12-months PFS raised from 1% to 11% (p = 0.003). 12-month and 18-month OS rate increased from 15% to 28% (p = 0.03) and from 2.1% to 12% (p = 0.009), respectively. After May 2020 the median number of hospitalization days per patient decreased significantly and the incidence of severe AEs was similar. Among patients treated with chemo-immunotherapy, the onset of immune-related AEs was associated with improved PFS and OS (HR 0.55, 95% CI: 0.35-0.89, p = 0.012 and HR 0.47, 95%CI 0.28-0.77, p = 0.002, respectively)., Conclusions: The real-world analysis shows a meaningful improvement of outcome indicators after the introduction of chemo-immunotherapy, with reduction of the duration of hospitalization, thus supporting the use of chemo-immunotherapy and the need for further biomarker research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Bonanno, Calvetti, Dal Maso, Pavan, Bao, De Nuzzo, Frega, Sartori, Ferro, Pasello, Morandi, Aprile and Guarneri.)

The DNA damage response (DDR) is the cellular process of preserving an intact genome and is often deregulated in lymphoma cells. The ataxia telangiectasia and Rad3-related (ATR) kinase is a crucial factor of DDR in the response to DNA single-strand breaks. ATR inhibitors are agents that have shown considerable clinical potential in this context. We characterized the activity of the ATR inhibitor elimusertib (BAY 1895344) in a large panel of lymphoma cell lines. Furthermore, we evaluated its activity combined with the clinically approved PI3K inhibitor copanlisib in vitro and in vivo. Elimusertib exhibits potent anti-tumour activity across various lymphoma subtypes, which is associated with the expression of genes related to replication stress, cell cycle regulation and, as also sustained by CRISPR Cas9 experiments, CDKN2A loss. In several tumour models, elimusertib demonstrated widespread anti-tumour activity stronger than ceralasertib, another ATR inhibitor. This activity is present in both DDR-proficient and DDR-deficient lymphoma models. Furthermore, a combination of ATR and PI3K inhibition by treatment with elimusertib and copanlisib has in vitro and in vivo anti-tumour activity, providing a potential new treatment option for lymphoma patients., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

Human accuracy in detecting deception with intuitive judgments has been proven to not go above the chance level. Therefore, several automatized verbal lie detection techniques employing Machine Learning and Transformer models have been developed to reach higher levels of accuracy. This study is the first to explore the performance of a Large Language Model, FLAN-T5 (small and base sizes), in a lie-detection classification task in three English-language datasets encompassing personal opinions, autobiographical memories, and future intentions. After performing stylometric analysis to describe linguistic differences in the three datasets, we tested the small- and base-sized FLAN-T5 in three Scenarios using 10-fold cross-validation: one with train and test set coming from the same single dataset, one with train set coming from two datasets and the test set coming from the third remaining dataset, one with train and test set coming from all the three datasets. We reached state-of-the-art results in Scenarios 1 and 3, outperforming previous benchmarks. The results revealed also that model performance depended on model size, with larger models exhibiting higher performance. Furthermore, stylometric analysis was performed to carry out explainability analysis, finding that linguistic features associated with the Cognitive Load framework may influence the model's predictions., (© 2023. The Author(s).)

The Transactivating response (TAR) element DNA-binding of 43 kDa (TDP-43) is mainly implicated in the regulation of gene expression, playing multiple roles in RNA metabolism. Pathologically, it is implicated in amyotrophic lateral sclerosis and in a class of neurodegenerative diseases broadly going under the name of frontotemporal lobar degeneration (FTLD). A common hallmark of most forms of such diseases is the presence of TDP-43 insoluble inclusions in the cell cytosol. The molecular mechanisms of TDP-43-related cell toxicity are still unclear, and the contribution to cell damage from either loss of normal TDP-43 function or acquired toxic properties of protein aggregates is yet to be established. Here, we investigate the effects on cell viability of FTLD-related TDP-43 mutations in both yeast and mammalian cell models. Moreover, we focus on nucleolin ( NCL ) gene, recently identified as a genetic suppressor of TDP-43 toxicity, through a thorough structure/function characterization aimed at understanding the role of NCL domains in rescuing TDP-43-induced cytotoxicity. Using functional and biochemical assays, our data demonstrate that the N-terminus of NCL is necessary, but not sufficient, to exert its antagonizing effects on TDP-43, and further support the relevance of the DNA/RNA binding central region of the protein. Concurrently, data suggest the importance of the NCL nuclear localization for TDP-43 trafficking, possibly related to both TDP-43 physiology and toxicity.

Friedreich ataxia (FRDA) is a rare, inherited neurodegenerative disease caused by an expanded GAA repeat in the first intron of the FXN gene, leading to transcriptional silencing and reduced expression of frataxin. Frataxin participates in the mitochondrial assembly of FeS clusters, redox cofactors of the respiratory complexes I, II and III. To date it is still unclear how frataxin deficiency culminates in the decrease of bioenergetics efficiency in FRDA patients' cells. We previously demonstrated that in healthy cells frataxin is closely attached to the mitochondrial cristae, which contain both the FeS cluster assembly machinery and the respiratory chain complexes, whereas in FRDA patients' cells with impaired respiration the residual frataxin is largely displaced in the matrix. To gain novel insights into the function of frataxin in the mitochondrial pathophysiology, and in the upstream metabolic defects leading to FRDA disease onset and progression, here we explored the potential interaction of frataxin with the FeS cluster-containing respiratory complexes I, II and III. Using healthy cells and different FRDA cellular models we found that frataxin interacts with these three respiratory complexes. Furthermore, by EPR spectroscopy, we observed that in mitochondria from FRDA patients' cells the decreased level of frataxin specifically affects the FeS cluster content of complex I. Remarkably, we also found that the frataxin-like protein Nqo15 from T. thermophilus complex I ameliorates the mitochondrial respiratory phenotype when expressed in FRDA patient's cells. Our data point to a structural and functional interaction of frataxin with complex I and open a perspective to explore therapeutic rationales for FRDA targeted to this respiratory complex., (© 2023. The Author(s).)

Background: Recently, the Rome proposal updated the definition of exacerbation of COPD (ECOPD). However, such severity grade has not yet demonstrated intermediate-term clinical relevance., Research Question: What is the association between the Rome severity classification and short-term and intermediate-term clinical outcomes?, Study Design and Methods: We retrospectively grouped hospitalized patients with ECOPD according to the Rome severity classification (ie, mild, moderate, severe). Baseline, clinical, microbiologic, gas analysis, and laboratory variables were collected. In addition, data about the length of hospital stay and mortality (in-hospital and a follow-up time line from 6 months until 3 years) were assessed., Results: Of the 347 hospitalized patients, 39% were categorized as mild, 31% were categorized as moderate, and 30% were categorized as severe. Overall, patients with severe ECOPD had an extended length of hospital stay. Although in-hospital mortality was similar among groups, patients with severe ECOPD presented a worse prognosis in all follow-up time points. The Kaplan-Meier curves show the role of the severe classification in the cumulative survival at 1 and 3 years (Gehan-Breslow-Wilcoxon test, P = .032 and P = .004, respectively). The multivariable Cox regression analysis showed a higher risk of death at 1 year when patients presented a severe (hazard ratio, 1.99; 95% CI, 1.49-2.65) or moderate grade (hazard ratio, 1.47; 95% CI, 1.10-1.97) compared with a mild grade. Older patients (aged ≥ 80 years), patients requiring long-term oxygen therapy, or patients reporting previous ECOPD episodes had a higher mortality risk. A BMI between 25 and 29 kg/m 2 was associated with a lower risk., Interpretation: The Rome classification makes it possible to discriminate patients with a worse prognosis (severe or moderate) until a 3-year follow-up., Competing Interests: Financial/Nonfinancial Disclosures None declared., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Usual interstitial pneumonia (UIP) is the radiologic and histologic hallmark of idiopathic pulmonary fibrosis (IPF) and the commonest histologic pattern of other progressive fibrosing interstitial lung diseases (e.g., fibrotic hypersensitivity pneumonia). Analogous to lung cancer, activation of epithelial-to-mesenchymal transition (EMT) is one of the main molecular pathways recently identified by transcriptomic studies in IPF. Fibroblastic foci (FF) are considered the active/trigger component of UIP pattern. The proto-oncogene C-MET is a key gene among molecules promoting EMT against which several inhibitors are currently available or promising in ongoing studies on lung cancer., Methods: Twenty surgical cases of diffuse fibrosing interstitial lung diseases (fILD) with UIP pattern and FF-rich (17 IPF and 3 patients with fibrotic hypersensitivity pneumonia, fHP) were retrospectively selected. FF were manually microdissected and analysed for c-MET gene alterations (FISH amplification and gene hot-spot mutations Sanger sequencing) and tested with a c-MET companion diagnostic antibody (clone SP44 metmab) by immunohistochemistry., Results: FF are characterized by upregulation of c-MET as shown by overexpression of the protein in 80% of cases, while no gene amplification by FISH or mutations were detected. C-MET upregulation of FF was observed either in IPF and fHP, with a tropism for the epithelial cell component only., Conclusion: Upregulation of c-MET in FF of ILD with UIP pattern further confirms the key role of the proto-oncogene c-MET in its pathogenesis, possibly representing an interesting and easily-detectable molecular target for selective therapy using specific inhibitors in future clinical trials, similar to lung cancer. It is reasonable to speculate that molecular alterations in FF can also be detected in FF by transbronchial cryobiopsy., (Copyright © 2023 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

Objective: The study explored the change in handwritten signature in neurodegenerative diseases by using of a rater-based approach., Methods: Four independent observers were required to compare a pair of signatures (on average, 5 years elapsed between the two signatures) made by 103 patients (mean age 72 years) with Alzheimer's disease (AD) or frontotemporal dementia (FTD) and by 31 healthy participants (HC; mean age 73 years), judging their change according to a 0-1 rating scale (0 = similar or 1 = different). If a signature change was detected, the rater had also to report which signature features (spatial layout, omitted/added/switched letters or names, shape of letter, pen-flow) changed on the same 0-1 scale. For the AD and FTD groups, one signature was collected prior to the diagnosis of dementia, the other subsequent., Results: A signature change was reported by raters in 36% of AD patients, 44% of FTD, and 17% of HC, with significant differences between both clinical groups and HC (vs. AD, p = .01; vs. FTD, p = .001). There was not a distinctive marker of the signature change (i.e., feature change) in patients with dementia. Moreover, the signature changes in neurological patients were unrelated to their clinical and demographic characteristics (age, sex, education, time elapsed between the two signatures, Mini-mental State Examination score)., Conclusion: The findings suggest a resistance of handwritten signature in neurodegenerative diseases and in physiological aging, also suggesting that the signature may be an unreliable indicator of the cognitive status in AD and FTD, at least if subjectively evaluated., (© 2023. The Author(s).)

Loss of function of the STRADA gene, an upstream mTOR inhibitor, causes a rare neurodevelopmental disorder characterized by polyhydramnios, megalencephaly, and symptomatic epilepsy (PMSE syndrome). Patients display a homogeneous phenotype including early-onset drug-resistant epilepsy, severe psychomotor delay, multisystemic comorbidities, and increased risk of premature death. The administration of sirolimus, an mTOR inhibitor, is helpful in controlling seizures in this syndrome. We report the electroclinical phenotype of two novel patients and the development of a yeast model to validate the pathogenicity of missense variants. Patient 1 harbored a missense STRADA variant and had a peculiar electroclinical phenotype with a relatively mild epilepsy course. Patient 2 harbored a truncating STRADA variant and showed a typical PMSE phenotype and a favorable response to early treatment with sirolimus. When we modeled the p.(Ser264Arg) STRADA change in its yeast homolog SPS1, it impaired SPS1 function. The results underlie the importance of a timely molecular diagnosis in these patients and show that yeast is a simple yet effective model to validate the pathogenicity of missense variants., Competing Interests: Declaration of competing interest Leonardo Salviati reports financial support was provided by Città della Speranza Pediatric Research Institute. The remaining authors declare that there are no conflicts of interests regarding the publication of this article., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Breast cancer (BC) is the most common neoplasm in women worldwide and one of the leading causes of female death. The triple-negative subtype, characterized by the absence of hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2), tends to occur in younger patients, be more aggressive and less differentiated. Furthermore, this subtype is considered the most immunogenic and associated with higher levels of tumor cell infiltration, mainly lymphocytes. Tumor-infiltrating lymphocytes (TILs) play a crucial role in the interaction of the host's immune system and cancer cells. The microenvironment is critical in tumor development and progression. Assessment of infiltrating lymphocytes can provide valuable information about the immune response and, given the lack of biomarkers to guide treatment decisions and predict outcomes in triple-negative tumors and can be considered as a potential biomarker. Some evidence suggests that higher levels of these lymphocytes are associated with better responses to systemic treatment, longer progression-free survival and overall survival (OS). However, treatment escalation or de-escalation strategies for triple-negative BC (TNBC) currently do not consider the presence or density of TILs for therapeutic decisions. TILs appear to be useful predictive and prognostic indicators. Further clinical studies are needed to confirm these relationships and integrate TILs as a biomarker consistently into clinical practice. This article summarizes key concepts relating to the role of the immune infiltrate in BC, along with the current status and future prospects regarding TILs as a predictive and prognostic biomarker., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tbcr.amegroups.org/article/view/10.21037/tbcr-23-43/coif). C.H.B. has received grants or contracts to the institution from Nektar, Pfizer, Polyphor, Amgen, Daiichi Sankyo, Sanofi, Exelixis, Regeneron, Novartis, GSK, Janssen, OBI Pharma, Lilly, Seagen, Roche, BMS, MSD, Merck Serono, AstraZeneca, Novocure, Aveo Oncology, Takeda, TRIO, PharmaMar, Celgene, PPD, Syneos Health, Labcorp, ICON, IQVIA, Parexel, Nuvisan, PSI, Worldwide, Gilead Sciences, Bayer, Servier; consulting fees from Boehringer-Ingelheim, GSK, Novartis, Pfizer, Roche/Genentech, Eisai, Bayer, MSD, AstraZeneca, Zodiac, Lilly, Sanofi, Daiichi; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Boehringer-Ingelheim, GSK, Novartis, Pfizer, Roche/Genentech, Eisai, Bayer, MSD, Astra Zeneca, Zodiac, Lilly, Sanofi, Daiichi; support for attending meetings and/or travel from Novartis, Pfizer, Roche/Genentech, MSD, Astra Zeneca, Lilly, Daiichi; participation on a Data Safety Monitoring Board or Advisory Board from Roche; stock from Thummi and MEDSIR. T.R. has received speaker’s honoraria from Daiichi-Sankyo, AstraZeneca, Gilead Libbs, Pfizer, MSD and Novartis; consulting fees for advisory boards from AstraZeneca, Lilly, MSD and Novartis; research funding from AstraZeneca, FAPESP, Libbs, PRONOM/MS. G.S. has received speaker’s honoraria from Daiichi-Sankyo, AstraZeneca, and Novartis; and consulting fees for advisory boards, and support for attending meetings from AstraZeneca. M.G. has received speaker’s honoraria from Daiichi-Sankyo, AstraZeneca and Novartis; consulting fees for advisory boards from AstraZeneca and Novartis; research funding from AstraZeneca and Libbs. The other authors have no conflicts of interest to declare., (2024 Translational Breast Cancer Research. All rights reserved.)

Large language models (LLMs) are demonstrating impressive performance on many reasoning and problem-solving tasks from cognitive psychology. When tested, their accuracy is often on par with average neurotypical adults, challenging long-standing critiques of associative models. Here we analyse recent findings at the intersection of LLMs and cognitive science. Here we discuss how modern LLMs resurrect associationist principles, with abilities like long-distance associations enabling complex reasoning. While limitations remain in areas like causal cognition and planning, phenomena like emergence suggest room for growth. Providing examples and increasing the dimensions of the network are methods that further improve LLM abilities, mirroring facilitation effects in human cognition. Analysis of LLMs errors provides insight into human cognitive biases. Overall, we argue LLMs represent a promising development for cognitive modelling, enabling new explorations of the mechanisms underlying intelligence and reasoning from an associationist point of view. Carefully evaluating LLMs with the tools of cognitive psychology will further understand the building blocks of the human mind., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Sartori and Orrù.)

The transcriptional factor ETS1 is upregulated in 25% of diffuse large B cell lymphoma (DLBCL). Here, we studied the role of ETS1 phosphorylation at threonine 38, a marker for ETS1 activation, in DLBCL cellular models and clinical specimens. p-ETS1 was detected in activated B cell-like DLBCL (ABC), not in germinal centre B-cell-like DLBCL (GCB) cell lines and, accordingly, it was more common in ABC than GCB DLBCL diagnostic biopsies. MEK inhibition decreased both baseline and IgM stimulation-induced p-ETS1 levels. Genetic inhibition of phosphorylation of ETS1 at threonine 38 affected the growth and the BCR-mediated transcriptome program in DLBCL cell lines. Our data demonstrate that ETS1 phosphorylation at threonine 38 is important for the growth of DLBCL cells and its pharmacological inhibition could benefit lymphoma patients., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Objective This proof-of-concept paper provides evidence to support machine learning (ML) as a valid alternative to traditional psychometric techniques in the development of short forms of longer parent psychological tests. ML comprises a variety of feature selection techniques that can be efficiently applied to identify the set of items that best replicates the characteristics of the original test. Methods In the present study, we integrated a dataset of 329 participants from published and unpublished datasets used in previous research on the Structured Inventory of Malingered Symptomatology (SIMS) to develop a short version of the scale. The SIMS is a multi-axial self-report questionnaire and a highly efficient psychometric measure of symptom validity, which is frequently applied in forensic settings. Results State-of-the-art ML item selection techniques achieved a 72% reduction in length while capturing 92% of the variance of the original SIMS. The new SIMS short form now consists of 21 items. Conclusions The results suggest that the proposed ML-based item selection technique represents a promising alternative to standard psychometric correlation-based methods (i.e. item selection, item response theory), especially when selection techniques (e.g. wrapper) are employed that evaluate global, rather than local, item value.

Cancer cells favor the generation of myeloid cells with immunosuppressive and inflammatory features, including myeloid-derived suppressor cells (MDSCs), which support tumor progression. The anti-apoptotic molecule, cellular FLICE (FADD-like interleukin-1β-converting enzyme)-inhibitory protein (c-FLIP), which acts as an important modulator of caspase-8, is required for the development and function of monocytic (M)-MDSCs. Here, we assessed the effect of immune checkpoint inhibitor (ICI) therapy on systemic immunological landscape, including FLIP-expressing MDSCs, in non-small cell lung cancer (NSCLC) patients. Longitudinal changes in peripheral immunological parameters were correlated with patients' outcome. In detail, 34 NSCLC patients were enrolled and classified as progressors (P) or non-progressors (NP), according to the RECIST evaluation. We demonstrated a reduction in pro-inflammatory cytokines such as IL-8, IL-6, and IL-1β in only NP patients after ICI treatment. Moreover, using t -distributed stochastic neighbor embedding ( t -SNE) and cluster analysis, we characterized in NP patients a significant increase in the amount of lymphocytes and a slight contraction of myeloid cells such as neutrophils and monocytes. Despite this moderate ICI-associated alteration in myeloid cells, we identified a distinctive reduction of c-FLIP expression in M-MDSCs from NP patients concurrently with the first clinical evaluation (T1), even though NP and P patients showed the same level of expression at baseline (T0). In agreement with the c-FLIP expression, monocytes isolated from both P and NP patients displayed similar immunosuppressive functions at T0; however, this pro-tumor activity was negatively influenced at T1 in the NP patient cohort exclusively. Hence, ICI therapy can mitigate systemic inflammation and impair MDSC-dependent immunosuppression., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.)

During the first two waves of the COVID-19 emergency in Italy, internal medicine high-dependency wards (HDW) have been organized to manage patients with acute respiratory failure (ARF). There is heterogeneous evidence about the feasibility and outcomes of non-invasive respiratory supports (NIRS) in settings outside the intensive care unit (ICU), including in patients deemed not eligible for intubation (i.e., with do-not-intubate, DNI status). Few data are available about the different NIRS modalities applied to ARF patients in the newly assembled internal medicine HDW. The main aim of our study was to describe a real-life experience in this setting of cure, focusing on feasibility and outcomes. We retrospectively collected data from COVID-19 patients with ARF needing NIRS and admitted to internal medicine HDW. Patients were treated with different modalities, that is high-flow nasal cannula (HFNC), continuous positive airway pressure (CPAP), or non-invasive mechanical ventilation (NIMV). Switching among different NIRS during the hospitalization and the success rate (weaning with the same NIRS) or failure (endotracheal intubation-ETI or in-hospital death) were recorded. Three hundred thirty four ARF patients (median age 74 years), of which 158 (54%) had a DNI status, were included. CPAP, NIMV, and HFNC's success rates were 54, 33, and 13%, respectively. Although DNI status was strongly associated with death (Gehan-Breslow-Wilcoxon test p < 0.001), an acceptable success rate was observed in these patients using CPAP (47%). Multivariate regression models showed older age (odds ratio-OR 4.74), chronic ischemic heart disease (OR 2.76), high respiratory rate after 24 h (OR 7.13), and suspected acute respiratory distress syndrome-ARDS (OR 21.1) as predictors of mortality risk or ETI. Our real-life experience shows that NIRS was feasible in internal medicine HDW with an acceptable success rate. Although DNI patients had a worse prognosis, the use of NIRS represented a reasonable chance of treatment., (© 2023. The Author(s).)

Background and Aim: endobronchial ultrasound has gained widespread popularity in the last decade, becoming the primary technique for minimally invasive evaluation of the mediastinum and staging of lung cancer. Several tertiary and quaternary care institutes use this method, performed by trained and accredited specialists. Its main indications are (I) diagnosis and staging of lung cancer, (II) mediastinal lymphadenopathy diagnosis (III) sampling peripheral pulmonary lesions., Conclusions: this manuscript aims to describe the operational potential of both convex endobronchial ultrasound probe and radial endobronchial ultrasound probe technology, focusing on lung cancer. This narrative review is complemented with by the description of peculiar clinical cases in which endobronchial ultrasound played a pivotal role in reaching the diagnosis.

Urinary extracellular vesicles (UEV) mainly derive from cells of the urogenital tract and their cargo (proteins, nucleic acids, lipids, etc.) reflects their cells of origin. Na chloride cotransporter (NCC) is expressed at the kidney level in the distal convoluted tubule, is involved in salt reabsorption, and is the target of the diuretic thiazides. NCC protein has been recognized and quantified in UEV in previous studies; however, UEV NCC mRNA has never been studied. This study aimed to identify and analyze NCC mRNA levels in primary aldosteronism (PA). The rationale for this investigation stems from previous observations regarding NCC (protein) as a possible biomarker for the diagnosis of PA. To evaluate modulations in the expression of NCC, we analyzed NCC mRNA levels in UEV in PA and essential hypertensive (EH) patients under different conditions, that is, before and after saline infusion, anti-aldosterone pharmacological treatment, and adrenal surgery. NCC mRNA was measured by RT-qPCR in all the samples and was regulated by volume expansion. Its response to mineralocorticoid receptor antagonist was correlated with renin, and it was increased in PA patients after adrenalectomy. NCC mRNA is evaluable in UEV and it can provide insights into the pathophysiology of distal convolute tubule in different clinical conditions including PA., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Introduction: The false consensus effect consists of an overestimation of how common a subject opinion is among other people. This research demonstrates that individual endorsement of questions may be predicted by estimating peers' responses to the same question. Moreover, we aim to demonstrate how this prediction can be used to reconstruct the individual's response to a single item as well as the overall response to all of the items, making the technique suitable and effective for malingering detection., Method: We have validated the procedure of reconstructing individual responses from peers' estimation in two separate studies, one addressing anxiety-related questions and the other to the Dark Triad. The questionnaires, adapted to our scopes, were submitted to the groups of participants for a total of 187 subjects across both studies. Machine learning models were used to estimate the results., Results: According to the results, individual responses to a single question requiring a "yes" or "no" response are predicted with 70-80% accuracy. The overall participant-predicted score on all questions (total test score) is predicted with a correlation of 0.7-0.77 with actual results., Discussion: The application of the false consensus effect format is a promising procedure for reconstructing truthful responses in forensic settings when the respondent is highly likely to alter his true (genuine) response and true responses to the tests are missing., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Orrù, Ordali, Monaro, Scarpazza, Conversano, Pietrini, Gemignani and Sartori.)

Background and Objective: Chronic obstructive pulmonary disease (COPD) and heart failure (HF) mutually increase the risk of being present in the same patient, especially if older. Whether or not this coexistence may be associated with a worse prognosis is debated. Therefore, employing data derived from the REPOSI register, we evaluated the clinical features and outcomes in a population of elderly patients admitted to internal medicine wards and having COPD, HF or COPD + HF., Methods: We measured socio-demographic and anthropometric characteristics, severity and prevalence of comorbidities, clinical and laboratory features during hospitalization, mood disorders, functional independence, drug prescriptions and discharge destination. The primary study outcome was the risk of death., Results: We considered 2,343 elderly hospitalized patients (median age 81 years), of whom 1,154 (49%) had COPD, 813 (35%) HF, and 376 (16%) COPD + HF. Patients with COPD + HF had different characteristics than those with COPD or HF, such as a higher prevalence of previous hospitalizations, comorbidities (especially chronic kidney disease), higher respiratory rate at admission and number of prescribed drugs. Patients with COPD + HF (hazard ratio HR 1.74, 95% confidence intervals CI 1.16-2.61) and patients with dementia (HR 1.75, 95% CI 1.06-2.90) had a higher risk of death at one year. The Kaplan-Meier curves showed a higher mortality risk in the group of patients with COPD + HF for all causes (p = 0.010), respiratory causes (p = 0.006), cardiovascular causes (p = 0.046) and respiratory plus cardiovascular causes (p = 0.009)., Conclusion: In this real-life cohort of hospitalized elderly patients, the coexistence of COPD and HF significantly worsened prognosis at one year. This finding may help to better define the care needs of this population., (© 2023. The Author(s).)

ALG8 protein-truncating variants (PTVs) have previously been described in patients with polycystic liver disease and in some cases cystic kidney disease. Given a lack of well-controlled studies, we determined whether individuals heterozygous for ALG8 PTVs are at increased risk of cystic kidney disease in a large, unselected health system-based observational cohort linked to electronic health records in Pennsylvania (Geisinger-Regeneron DiscovEHR MyCode study). Out of 174,172 patients, 236 were identified with ALG8 PTVs. Using ICD-based outcomes, patients with these variants were significantly at increased risk of having any kidney/liver cyst diagnosis (Odds Ratio 2.42, 95% confidence interval: 1.53-3.85), cystic kidney disease (3.03, 1.26-7.31), and nephrolithiasis (1.89, 1.96-2.97). To confirm this finding, blinded radiology review of computed tomography and magnetic resonance imaging studies was completed in a matched cohort of 52 thirty-plus year old ALG8 PTV heterozygotes and related non-heterozygotes. ALG8 PTV heterozygotes were significantly more likely to have cystic kidney disease, defined as four or more kidney cysts (57.7% vs. 7.7%), or bilateral kidney cysts (69.2% vs. 15.4%), but not one or more liver cyst (11.5% vs. 7.7%). In publicly available UK Biobank data, ALG8 PTV heterozygotes were at significantly increased risk of ICD code N28 (other disorders of kidney/ureter) (3.85% vs. 1.33%). ALG8 PTVs were not associated with chronic kidney disease or kidney failure in the MyCode study or the UK Biobank data. Thus, PTVs in ALG8 result in increased risk of a mild cystic kidney disease phenotype., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Initial evidence supports the hypothesis that patients with non-cystic fibrosis bronchiectasis (NCFB) have a higher risk of lung cancer. We systematically reviewed the available literature to define the characteristics of lung malignancies in patients with bronchiectasis and the characteristics of patients who develop bronchiectasis-associated lung cancer., Method: This study was performed based on the PRISMA guidelines. The review protocol was registered in PROSPERO., Results: The frequency rates of lung cancer in patients with NCFB ranged from 0.93% to 8.0%. The incidence rate was 3.96. Cancer more frequently occurred in the elderly and males. Three studies found an overall higher risk of developing lung cancer in the NCFB population compared to the non-bronchiectasis one, and adenocarcinoma was the most frequently reported histological type. The effect of the co-existence of NCFB and COPD was unclear., Conclusions: NCFB is associated with a higher risk of developing lung cancer than individuals without NCFB. This risk is higher for males, the elderly, and smokers, whereas concomitant COPD's effect is unclear.

Idiopathic and acquired pedophilia are two different disorders with two different etiologies. However, the differential diagnosis is still very difficult, as the behavioral indicators used to discriminate the two forms of pedophilia are underexplored, and clinicians are still devoid of clear guidelines describing the clinical and neuroscientific investigations suggested to help them with this difficult task. Furthermore, the consequences of misdiagnosis are not known, and a consensus regarding the legal consequences for the two kinds of offenders is still lacking. The present study used the Delphi method to reach a global consensus on the following six topics: behavioral indicators/red flags helpful for differential diagnosis; neurological conditions potentially leading to acquired pedophilia; neuroscientific investigations important for a correct understanding of the case; consequences of misdiagnosis; legal consequences; and issues and future perspectives. An international and multidisciplinary board of scientists and clinicians took part in the consensus statements as Delphi members. The Delphi panel comprised 52 raters with interdisciplinary competencies, including neurologists, psychiatrists, neuropsychologists, forensic psychologists, expert in ethics, etc. The final recommendations consisted of 63 statements covering the six different topics. The current study is the first expert consensus on a delicate topic such as pedophilia. Important exploitable consensual recommendations that can ultimately be of immediate use by clinicians to help with differential diagnosis and plan and guide therapeutic interventions are described, as well as future perspectives for researchers., (© 2023. The Author(s).)

Peripheral pulmonary lesions (PPLs) are frequent incidental findings in subjects when performing chest radiographs or chest computed tomography (CT) scans. When a PPL is identified, it is necessary to proceed with a risk stratification based on the patient profile and the characteristics found on chest CT. In order to proceed with a diagnostic procedure, the first-line examination is often a bronchoscopy with tissue sampling. Many guidance technologies have recently been developed to facilitate PPLs sampling. Through bronchoscopy, it is currently possible to ascertain the PPL's benign or malignant nature, delaying the therapy's second phase with radical, supportive, or palliative intent. In this review, we describe all the new tools available: from the innovation of bronchoscopic instrumentation (e.g., ultrathin bronchoscopy and robotic bronchoscopy) to the advances in navigation technology (e.g., radial-probe endobronchial ultrasound, virtual navigation, electromagnetic navigation, shape-sensing navigation, cone-beam computed tomography). In addition, we summarize all the PPLs ablation techniques currently under experimentation. Interventional pulmonology may be a discipline aiming at adopting increasingly innovative and disruptive technologies.

Inhibitors of phosphatidylinositol 3-kinase (PI3K) and Bruton tyrosine kinase (BTK) represent a recognized option for the treatment of patients affected by indolent B cell lymphomas. However, small molecules as single agents show limited success in their ability in inducing complete responses, with only partial remission achieved in most patients, suggesting the need for combination therapies. IRAK4 is a protein kinase downstream of the Toll-like receptor signaling (TLR), a driver pathway of secondary tumor° resistance in both hematological and solid tumor malignancies. Activation of IRAK4 upon TLRs and IL-1 receptor (IL-1R) stimulation and through the adaptor protein MYD88 initiates a signaling cascade that induces cytokine and survival factor expression mediated by the transcription factor NF-κB. MYD88-L265P encoding mutations occur in diffuse large B-cell lymphomas, in lymphoplasmacytic lymphomas and in few marginal zone lymphomas (MZL). The IRAK4 inhibitor emavusertib (CA-4948) has shown early safety and clinical activity in lymphoma and leukemia patients. In this preclinical study, we assessed emavusertib effectiveness in MZL, both as single agent and in combination with targeted agents, with a particular focus on its capability to overcome resistance to BTK and PI3K inhibitors. We showed that the presence of MYD88 L265P mutation in bona fide MZL cell lines confers sensitivity to the IRAK4 inhibitor emavusertib as single agent. Emavusertib-based combinations improved the sensitivity of MZL cells to BTK and PI3K inhibitors, including cells with a secondary resistance to these agents. Emavusertib exerted its activity via inhibition of NF-κB signaling and induction of apoptosis. Considering the early safety data from clinical trials, our study identifies the IRAK4 inhibitor emavusertib as a novel compound to be explored in trials for patients with MYD88-mutated indolent B cell lymphomas as single agent and as combination partner with BTK or PI3K inhibitors in unselected populations of patients.