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Post-traumatic stress disorder (PTSD) is associated with significant patient burden. While pharmacotherapies and evidence-based psychotherapy interventions (EBPI) are effective, studies consistently highlight inadequate outcomes and high treatment dropout. Psychedelic therapy (PT) has shown preliminary promise across difficult-to-treat conditions, including MDMA-assisted therapy for PTSD, however trials of classical psychedelics in PTSD are lacking. Understanding patients' experiences of EBPI could help promote safety in PT. To systematically review qualitative research on patients' subjective experience of EBPI for PTSD, and of PT, and examine areas of overlap and divergence between them. Systematic literature searches for studies published between 2010 and 2023 were conducted on OVID, PubMed, Web of Science, and PsycInfo. Included were original studies in English that presented qualitative data of patient experiences of EBPI in PTSD, or PT for any indication. Extracted data from included studies were analysed using thematic synthesis. Syntheses were completed separately for EBPI and PT, before similarities and differences between the therapies were identified. 40 research articles were included for review: 26 studies on EBPI for PTSD, and 14 studies on PT. EBPI studied were CBT, EMDR, CPT and PE. Psychedelic compounds studied were psilocybin, ibogaine, LSD, MDMA and ketamine, for treatment of substance use disorders, anxiety relating to physical illness, depression, and PTSD. Core themes from patient experiences of EBPI: 1) patient burden in PTSD treatment; 2) readiness; 3) key mechanisms of change; 4) psychological safety and trust. Themes identified in the review of PT: 1) indirect trauma processing; 2) reorganisation of self-narratives via processes of relatedness and identification; 3) key treatment characteristics. This study suggests overlap between patients' experience of EBPI and PT in terms of key mechanisms of change, the importance of psychological safety and readiness to engage in treatment. Trauma-informed care paradigms and practices may improve safety and acceptability of PT research.

Radiation therapy plays a major role in the treatment of lung cancer patients. However, cancer cells develop resistance to radiation. Tumor radioresistance is a complex multifactorial mechanism which may be dependent on DNA damage and repair, hypoxic conditions inside tumor microenvironment, and the clonal selection of radioresistant cells from the heterogeneous tumor site, and it is a major cause of treatment failure in non–small cell lung cancer (NSCLC). In the present investigation caveolin-1 ( CAV-1 ) has been observed to be highly expressed in radiation resistant A549 lung cancer cells. CRISPR-Cas9 knockout of CAV-1 reverted the cells to a radio sensitive phenotype. In addition, CAV-1 overexpression in parental A549 cells, led to radiation resistance. Further, gene expression analysis of A549 parental, radiation resistant, and caveolin-1 overexpressed cells, exhibited overexpression of DNA repair genes RAD51B, RAD18, SOX2 cancer stem cell marker, MMPs, mucins and cytoskeleton proteins in resistant and caveolin-1 over expressed A549 cells, as compared to parental A549 cells. Bioinformatic analysis shows upregulation of BRCA1, Nuclear Excision DNA repair, TGFB and JAK/STAT signaling pathways in radioresistant and caveolin-1 overexpressed cells, which may functionally mediate radiation resistance. Immunohistochemistry data demonstrated heterogeneous expression of CAV-1 gene in human lung cancer tissues, which was analogous to its enhanced expression in human lung cancer cell line model and mouse orthotopic xenograft lung cancer model. Also, TCGA PanCancer clinical studies have demonstrated amplification, deletions and missense mutation in CAV-1 gene in lung cancer patients, and that CAV-1 alteration has been linked to poor prognosis, and poor survival in lung cancer patients. Interestingly, we have also optimized ELISA assay to measure caveolin-1 protein in the blood of A549 radiation resistant human xenograft preclinical mouse model and discovered higher level of caveolin-1 (950 pg/ml) in tumor bearing animals treated with radiation, as compared to xenograft with radiosensitive lung cancer cells (450 pg/ml). Thus, we conclude that caveolin-1 is involved in radio-resistance and contributes to tumor aggression, and it has potential to be used as prognostic biomarker for radiation treatment response, and tumor progression for precision medicine in lung cancer patients.

Chronic insomnia is undertreated in the UK despite being a common mental disorder that severely affects quality of life. The lead author, a psychiatry trainee, implemented a new group cognitive–behavioural therapy for insomnia (CBT-I) service for secondary care patients in London with chronic insomnia and comorbid mental illness. Expertise was propagated by trainees teaching other trainees. Nine patients completed all sessions, all with moderate-to-severe insomnia on the Insomnia Severity Index (ISI) at baseline assessment (mean score 21.6). All patients seen at follow-up had improved, scoring in the ‘subthreshold’ or ‘no clinically significant insomnia’ ranges on the ISI (mean 6.6), and all with improvements in comorbid psychiatric symptoms and functioning. This evaluation demonstrates that group CBT-I can be easily learned and delivered by those without formal CBT or sleep medicine training. This could increase the availability and accessibility of treatment. However, bureaucratic challenges were faced, and trainee-led innovations should be better facilitated.

[This corrects the article DOI: 10.1371/journal.pone.0258951.].

Objective and design Neutrophil generation of reactive oxygen species (ROS) is enhanced by exposure to pro-inflammatory agents in a process termed priming. Priming is depending on exocytosis of neutrophil granules and p47 phox phosphorylation-dependent translocation of cytosolic NADPH oxidase components. Clathrin-mediated endocytosis was recently reported to be necessary for priming, but the mechanism linking endocytosis to priming was not identified. The present study examined the hypothesis that endocytosis regulates neutrophil priming by controlling granule exocytosis. Materials and methods Clathrin-mediated endocytosis by isolated human neutrophils was inhibited by chlorpromazine, monodansylcadaverine, and sucrose. Exocytosis of granule subsets was measured as release of granule components by ELISA or chemiluminescence. ROS generation was measured as extracellular release of superoxide as reduction of ferrocytochrome c. p38 MAPK activation and p47 phox phosphorylation were measured by immunoblot analysis. Statistical analysis was performed using a one-way ANOVA with the Tukey–Kramer multiple-comparison test. Results Inhibition of endocytosis prevented priming of superoxide release by TNFα and inhibited TNFα stimulation and priming of exocytosis of all four granule subsets. Inhibition of endocytosis did not reduce TNFα-stimulated p38 MAPK activation or p47 phox phosphorylation. Inhibition of NADPH oxidase activity blocked TNFα stimulation of secretory vesicle and gelatinase granule exocytosis. Conclusions Endocytosis is linked to priming of respiratory burst activity through ROS-mediated control of granule exocytosis.

Background MicroRNA (miR)-214-3p is emerging as an important tumor suppressor in esophageal cancer. In this study, we examined the interaction between miR-214-3p and RAB14, a membrane trafficking protein shown to exert oncogenic functions in other malignancies, in esophageal cancer cells. Methods Studies were performed in a human esophageal epithelial cell line and a panel of esophageal cancer cell lines, as well in human specimens. MiR-214-3p expression was measured by digital PCR. Biotinylated RNA pull-down and luciferase reporter assays assessed binding. The xCELLigence RTCA system measured cell migration and invasion in real time. A lentiviral expression vector was used to create an esophageal cancer cell line stably expressing miR-214-3p. Results MiR-214-3p expression was decreased in esophageal cancer cell lines and human specimens compared to non-malignant controls. RAB14 mRNA stability and protein expression were decreased following miR-214-3p overexpression. Binding between miR-214-3p and RAB14 mRNA was observed. Either forced expression of miR-214-3p or RAB14 silencing led to a marked decrease in cellular migration and invasion. Esophageal cancer cells stably expressing miR-214-3p demonstrated decreased growth in a subcutaneous murine model. Conclusions These results further support the tumor-suppressive role of miR-214-3p in esophageal cancer cells by demonstrating its ability to regulate RAB14 expression.

Background Individuals on the autism spectrum face significant disparities in health and physicians often report difficulties in providing care to autistic patients. In order to improve the quality of care autistic individuals receive, it is important to identify the barriers that physicians experience in providing care so that these may be addressed. This paper reports the initial development and preliminary evaluation of a physician-report ‘Barriers to Providing Healthcare’ measurement tool. Method An established taxonomy of healthcare barriers for autistic individuals informed the initial draft of a 22-item measurement tool. This measurement tool was distributed to physicians working in various healthcare specialties and settings. Exploratory factor analysis (EFA) was conducted to determine the construct validity of the tool; discriminant validity between, and internal consistency of, the resultant factors were assessed. Multiple regressions were used to explore variables potentially associated with barriers endorsed by physicians. Results A total of 203 physicians were included in the analyses. The EFA resulted in a 17-item tool with three distinct factors which explained 37.6% of the variance: 1) Patient-related barriers (Cronbach’s α = 0.83; e.g., the patient’s reactivity to the healthcare environment); 2) Healthcare provider (HCP)/family-related barriers (Cronbach’s α = 0.81; e.g., a lack of providers willing to work with autistic patients); and 3) System-related barriers (Cronbach’s α = 0.84; e.g., there is a lack of support for patients and families). Discriminant validity between the factors was adequate ( r  < .8). The barriers that were most frequently endorsed as occurring ‘often’ or ‘very often’ included a lack of support for patients and families (endorsed by 79.9% of physicians); communication difficulties (73.4%); and a lack of coordination between services (69.9%). The regression analyses identified no significant associated variables. Conclusion A preliminary version of a novel physician-report tool to assess barriers to providing care to autistic patients has been developed although further validation work is required. The use of this tool will help physicians to identify issues specific to different medical specialities and healthcare settings. This information may help identify the supports physicians require to recognise and implement the required accommodations. Future research which elucidates barriers to healthcare provision for autistic patients is required to support systemic change in healthcare so as to improve care experiences and health outcomes for people on the autism spectrum.

DNA methyltransferase inhibitors (DNMTis) reexpress hypermethylated genes in cancers and leukemias and also activate endogenous retroviruses (ERVs), leading to interferon (IFN) signaling, in a process known as viral mimicry. In the present study we show that in the subset of acute myeloid leukemias (AMLs) with mutations in TP53, associated with poor prognosis, DNMTis, important drugs for treatment of AML, enable expression of ERVs and IFN and inflammasome signaling in a STING-dependent manner. We previously reported that in solid tumors poly ADP ribose polymerase inhibitors (PARPis) combined with DNMTis to induce an IFN/inflammasome response that is dependent on STING1 and is mechanistically linked to generation of a homologous recombination defect (HRD). We now show that STING1 activity is actually increased in TP53 mutant compared with wild-type (WT) TP53 AML. Moreover, in TP53 mutant AML, STING1-dependent IFN/inflammatory signaling is increased by DNMTi treatment, whereas in AMLs with WT TP53, DNMTis alone have no effect. While combining DNMTis with PARPis increases IFN/inflammatory gene expression in WT TP53 AML cells, signaling induced in TP53 mutant AML is still several-fold higher. Notably, induction of HRD in both TP53 mutant and WT AMLs follows the pattern of STING1-dependent IFN and inflammatory signaling that we have observed with drug treatments. These findings increase our understanding of the mechanisms that underlie DNMTi + PARPi treatment, and also DNMTi combinations with immune therapies, suggesting a personalized approach that statifies by TP53 status, for use of such therapies, including potential immune activation of STING1 in AML and other cancers.

AimsChronic insomnia is a common mental disorder that severely impacts the quality of life of those affected, increases the risk of comorbid mental disorder and physical illness, and makes treatment of other mental disorders less effective. It is particularly common in patients under secondary care mental health services. Once chronic, insomnia rarely resolves spontaneously. Cognitive behavioural therapy for insomnia (CBT-I) is a highly effective treatment that is recommended by the UK's National Institute of Health and Care Excellence as the first-line treatment. Despite this, CBT-I is not universally available or accessible throughout the UK. Therefore, LW obtrained training at a sleep clinic and then initiated, ran and evaluated a new CBT-I service for existing community patients within her NHS trust.MethodsPatients received individual holistic assessments with a psychiatry trainee, a 5-session weekly virtual group intervention run by LW, and an individual 3-month follow-up. LW also trained other psychiatry trainees to run future groups, initially under supervision. Clinical rating scales were employed at initial assessment, following the final workshop and at follow-up.ResultsSeven patients completed all sessions, with five completing a 3-month follow-up review. All had suffered with chronic insomnia for over 5 years. All had moderate-to-severe insomnia on the Insomnia Severity Index (ISI) at assessment (mean 21.3), which had improved by the end of treatment (mean 14.3). All patients seen at follow-up either no longer had insomnia or had sub-threshold insomnia on the ISI (mean 7.2). From assessment to post-treatment to follow-up, mean scores on the Dysfunctional Beliefs and Attitudes About Sleep Scale reduced from 6.6 to 3.7 to 2.5, and mean scores on the Clinical Outcomes in Routine Evaluation–Outcome Measure reduced from 2.18 to 2.01 to 1.27. Mean scores on the Work and Social Adjustment Scale reduced from 23.6 (severe impairment) at assessment to 7.0 (low impairment) at follow-up. Two patients stopped taking sleeping tablets during the treatment, and remained off them at follow-up.ConclusionGroup CBT-I can be a highly effective treatment for insomnia for patients under CMHT services. In this service run by a psychiatry trainee without formal sleep medicine or CBT qualifications, the efficacy of the intervention on insomnia symptoms, as well as on anxiety and depressive symptoms, was similar to the efficacies found in clinical trials and in specialist sleep clinics. CBT-I can be easily learnt by psychiatry trainees and likely other professionals with psychological expertise, which could increase the availability and accessibility of this effective treatment.

Erythropoiesis is a highly coordinated process that generates mature red blood cells from hematopoietic stem‐progenitor cells (HSPCs). Erythropoietin (EPO) is a major regulator of erythropoiesis and binds to the erythropoietin receptor (EPOR), leading to increased erythroid differentiation and proliferation. MicroRNAs (miRs) are important developmental regulators, and distinct miR expression patterns are associated with specific stages of hematopoietic differentiation. Expression profiling of EPO‐stimulated human HSPCs revealed increased expression of miR‐513a‐5p in early erythroid cells. Enforced expression of miR‐513a in primary human CD34 + HSPCs promoted erythroid differentiation, as determined by cell‐surface marker expression and increased levels of erythroid molecules including hemoglobin. Similar results were observed in human TF‐1 erythroleukemia cells, where miR‐513a stimulated erythroid differentiation including increased GATA1 and hemoglobin expression and decreased GATA2 expression, even in the absence of EPO. Notably, miR‐513a promoted erythroid differentiation in EPOR knockout (KO) TF‐1 cells, but not in GATA1 KO TF‐1 cells, indicating that miR‐513a requires GATA1, but not EPOR, to stimulate erythropoiesis. Further analysis revealed that enforced expression of miR‐513a was associated with reduced c‐Jun and phospho‐c‐Jun protein levels. Overexpression of c‐Jun inhibited both EPO‐ and miR‐513a‐stimulated erythropoiesis. Conversely, c‐Jun KO TF‐1 cells had increased hemoglobin protein expression, even in the absence of EPO, phenocopying miR‐513a overexpression. In summary, this study identifies miR‐513a as a positive regulator of early human erythropoiesis and supports a role for miR‐513a in promoting erythroid differentiation by modulating c‐Jun expression and increasing GATA1 expression.