METTL8 links mt-tRNA m3C modification to the HIF1α/RTK/Akt axis to sustain GBM stemness and tumorigenicity.

Epitranscriptomic RNA modifications are crucial for the maintenance of glioma stem cells (GSCs), the most malignant cells in glioblastoma (GBM). 3-methylcytosine (m3C) is a new epitranscriptomic mark on RNAs and METTL8 represents an m3C writer that is dysregulated in cancer. Although METTL8 has an established function in mitochondrial tRNA (mt-tRNA) m3C modification, alternative splicing of METTL8 can also generate isoforms that localize to the nucleolus where they may regulate R-loop formation. The molecular basis for METTL8 dysregulation in GBM, and which METTL8 isoform(s) may influence GBM cell fate and malignancy remain elusive. Here, we investigated the role of METTL8 in regulating GBM stemness and tumorigenicity. In GSC, METTL8 is exclusively localized to the mitochondrial matrix where it installs m3C on mt-tRNAThr/Ser(UCN) for mitochondrial translation and respiration. High expression of METTL8 in GBM is attributed to histone variant H2AZ-mediated chromatin accessibility of HIF1α and portends inferior glioma patient outcome. METTL8 depletion impairs the ability of GSC to self-renew and differentiate, thus retarding tumor growth in an intracranial GBM xenograft model. Interestingly, METTL8 depletion decreases protein levels of HIF1α, which serves as a transcription factor for several receptor tyrosine kinase (RTK) genes, in GSC. Accordingly, METTL8 loss inactivates the RTK/Akt axis leading to heightened sensitivity to Akt inhibitor treatment. These mechanistic findings, along with the intimate link between METTL8 levels and the HIF1α/RTK/Akt axis in glioma patients, guided us to propose a HIF1α/Akt inhibitor combination which potently compromises GSC proliferation/self-renewal in vitro. Thus, METTL8 represents a new GBM dependency that is therapeutically targetable.

Assessing the influence of dopamine and mindfulness on the formation of routines in visual search.

Given experience in cluttered but stable visual environments, our eye-movements form stereotyped routines that sample task-relevant locations, while not mixing-up routines between similar task-settings. Both dopamine signaling and mindfulness have been posited as factors that influence the formation of such routines, yet quantification of their impact remains to be tested in healthy humans. Over two sessions, participants searched through grids of doors to find hidden targets, using a gaze-contingent display. Within each session, door scenes appeared in either one of two colors, with each color signaling a differing set of likely target locations. We derived measures for how well target locations were learned (target-accuracy), how routine were sets of eye-movements (stereotypy), and the extent of interference between the two scenes (setting-accuracy). Participants completed two sessions, where they were administered either levodopa (dopamine precursor) or placebo (vitamin C), under double-blind counterbalanced conditions. Dopamine and trait mindfulness (assessed by questionnaire) interacted to influence both target-accuracy and stereotypy. Increasing dopamine improved accuracy and reduced stereotypy for high mindfulness scorers, but induced the opposite pattern for low mindfulness scorers. Dopamine also disrupted setting-accuracy invariant to mindfulness. Our findings show that mindfulness modulates the impact of dopamine on the target-accuracy and stereotypy of eye-movement routines, whereas increasing dopamine promotes interference between task-settings, regardless of mindfulness. These findings provide a link between non-human and human models regarding the influence of dopamine on the formation of task-relevant eye-movement routines and provide novel insights into behavior-trait factors that modulate the use of experience when building adaptive repertoires.

The continuance intention to vaccinate against COVID-19: An empirical study from Malaysia.

BACKGROUND: Vaccination has been one of the most effective preventive strategies to contain the COVID-19 pandemic. However, as the COVID-19 vaccines' effect wanes off after some time and given their reduced level of protection against mutation strains of the virus, the calls for boosters and second boosters signal the need for continuous vaccination for the foreseeable future. As Malaysia transitions into the endemic phase, the nation's ability to co-exist with the virus in the endemic phase will hinge on people's continuance intention to be vaccinated against the virus. Adapting the expectations confirmation model (ECM) to the public health context and in a developing country, this study integrates the ECM with the health belief model (HBM) and the theory of reasoned action (TRA) to examine the inter-relationships of the predictors of people's continuance intention to vaccinate against COVID-19. METHODOLOGY: Data were collected using self-administered questionnaires from 1,914 respondents aged 18 and above by a marketing consulting firm via its online panel. The partial least squares structural equation modeling (PLS-SEM) technique was used to analyze the data. RESULTS: Out of the 1,914 respondents, 55.9% reported having a continuance intention to vaccinate against COVID-19, similar to other developing countries. The multivariate analysis revealed that perceived usefulness and satisfaction significantly influenced individuals' continuance intention to vaccinate against COVID-19. Additionally, attitude was found to play a key role in influencing behavioral change among individuals towards their perceptions of continuously getting vaccinated against COVID-19. CONCLUSIONS: By integrating three theoretical frameworks (i.e., HBM, TRA and ECM), this study showed that behavioral characteristics could provide insights towards continuance vaccination intention. Hence, policymakers and key stakeholders can develop effective public health strategies or interventions to encourage vaccine booster uptake by targeting behavioral factors such as perceived usefulness, attitude, satisfaction, and subjective norms.

Intensity-dependent effects of tDCS on motor learning are related to dopamine.

Non-invasive brain stimulation techniques, such as transcranial direct current stimulation (tDCS), are popular methods for inducing neuroplastic changes to alter cognition and behaviour. One challenge for the field is to optimise stimulation protocols to maximise benefits. For this to happen, we need a better understanding of how stimulation modulates cortical functioning/behaviour. To date, there is increasing evidence for a dose-response relationship between tDCS and brain excitability, however how this relates to behaviour is not well understood. Even less is known about the neurochemical mechanisms which may drive the dose-response relationship between stimulation intensities and behaviour. Here, we examine the effect of three different tDCS stimulation intensities (1 mA, 2 mA, 4 mA anodal motor cortex tDCS) administered during the explicit learning of motor sequences. Further, to assess the role of dopamine in the dose-response relationship between tDCS intensities and behaviour, we examined how pharmacologically increasing dopamine availability, via 100 mg of levodopa, modulated the effect of stimulation on learning. In the absence of levodopa, we found that 4 mA tDCS improved and 1 mA tDCS impaired acquisition of motor sequences relative to sham stimulation. Conversely, levodopa reversed the beneficial effect of 4 mA tDCS. This effect of levodopa was no longer evident at the 48-h follow-up, consistent with previous work characterising the persistence of neuroplastic changes in the motor cortex resulting from combining levodopa with tDCS. These results provide the first direct evidence for a role of dopamine in the intensity-dependent effects of tDCS on behaviour.

Mechanistic insights and the clinical prospects of targeted therapies for glioblastoma: a comprehensive review.

Glioblastoma (GBM) is a fatal brain tumour that is traditionally diagnosed based on histological features. Recent molecular profiling studies have reshaped the World Health Organization approach in the classification of central nervous system tumours to include more pathogenetic hallmarks. These studies have revealed that multiple oncogenic pathways are dysregulated, which contributes to the aggressiveness and resistance of GBM. Such findings have shed light on the molecular vulnerability of GBM and have shifted the disease management paradigm from chemotherapy to targeted therapies. Targeted drugs have been developed to inhibit oncogenic targets in GBM, including receptors involved in the angiogenic axis, the signal transducer and activator of transcription 3 (STAT3), the PI3K/AKT/mTOR signalling pathway, the ubiquitination-proteasome pathway, as well as IDH1/2 pathway. While certain targeted drugs showed promising results in vivo, the translatability of such preclinical achievements in GBM remains a barrier. We also discuss the recent developments and clinical assessments of targeted drugs, as well as the prospects of cell-based therapies and combinatorial therapy as novel ways to target GBM. Targeted treatments have demonstrated preclinical efficacy over chemotherapy as an alternative or adjuvant to the current standard of care for GBM, but their clinical efficacy remains hindered by challenges such as blood-brain barrier penetrance of the drugs. The development of combinatorial targeted therapies is expected to improve therapeutic efficacy and overcome drug resistance.

Reactive Oxygen Species Modulation in the Current Landscape of Anticancer Therapies.

Significance: Reactive oxygen species (ROS) are generated during mitochondrial oxidative metabolism, and are tightly controlled through homeostatic mechanisms to maintain intracellular redox, regulating growth and proliferation in healthy cells. However, ROS production is perturbed in cancers where abnormal accumulation of ROS leads to oxidative stress and genomic instability, triggering oncogenic signaling pathways on one hand, while increasing oxidative damage and triggering ROS-dependent death signaling on the other. Recent Advances: Our review illuminates how critical interactions between ROS and oncogenic signaling, the tumor microenvironment, and DNA damage response (DDR) pathways have led to interest in ROS modulation as a means of enhancing existing anticancer strategies and developing new therapeutic opportunities. Critical Issues: ROS equilibrium exists via a delicate balance of pro-oxidant and antioxidant species within cells. "Antioxidant" approaches have been explored mainly in the form of chemoprevention, but there is insufficient evidence to advocate its routine application. More progress has been made via the "pro-oxidant" approach of targeting cancer vulnerabilities and inducing oxidative stress. Various therapeutic modalities have employed this approach, including direct ROS-inducing agents, chemotherapy, targeted therapies, DDR therapies, radiotherapy, and immunotherapy. Finally, emerging delivery systems such as "nanosensitizers" as radiotherapy enhancers are currently in development. Future Directions: While approaches designed to induce ROS have shown considerable promise in selectively targeting cancer cells and dealing with resistance to conventional therapies, most are still in early phases of development and challenges remain. Further research should endeavor to refine treatment strategies, optimize drug combinations, and identify predictive biomarkers of ROS-based cancer therapies.

Exploring the intra-individual reliability of tDCS: A registered report.

Transcranial direct current stimulation (tDCS), a form of non-invasive brain stimulation, has become an important tool for the study of in-vivo brain function due to its modulatory effects. Over the past two decades, interest in the influence of tDCS on behaviour has increased markedly, resulting in a large body of literature spanning multiple domains. However, the effect of tDCS on human performance often varies, bringing into question the reliability of this approach. While reviews and meta-analyses highlight the contributions of methodological inconsistencies and individual differences, no published studies have directly tested the intra-individual reliability of tDCS effects on behaviour. Here, we conducted a large scale, double-blinded, sham-controlled registered report to assess the reliability of two single-session low-dose tDCS montages, previously found to impact response selection and motor learning operations, across two separate time periods. Our planned analysis found no evidence for either protocol being effective nor reliable. Post-hoc explorative analyses found evidence that tDCS influenced motor learning, but not response selection learning. In addition, the reliability of motor learning performance across trials was shown to be disrupted by tDCS. These findings are amongst the first to shed light specifically on the intra-individual reliability of tDCS effects on behaviour and provide valuable information to the field.

Dopamine Increases Accuracy and Lengthens Deliberation Time in Explicit Motor Skill Learning.

Although animal research implicates a central role for dopamine in motor skill learning, a direct causal link has yet to be established in neurotypical humans. Here, we tested if a pharmacological manipulation of dopamine alters motor learning, using a paradigm which engaged explicit, goal-directed strategies. Participants (27 females; 11 males; aged 18-29 years) first consumed either 100 mg of levodopa (n = 19), a dopamine precursor that increases dopamine availability, or placebo (n = 19). Then, during training, participants learnt the explicit strategy of aiming away from presented targets by instructed angles of varying sizes. Targets jumped mid-movement by the instructed aiming angle. Task success was thus contingent upon aiming accuracy and not speed. The effect of the dopamine manipulations on skill learning was assessed during training and after an overnight follow-up. Increasing dopamine availability at training improved aiming accuracy and lengthened reaction times, particularly for larger, more difficult aiming angles, both at training and, importantly, at follow-up, despite prominent session-by-session performance improvements in both accuracy and speed. Exogenous dopamine thus seems to result in a learnt, persistent propensity to better adhere to task goals. Results support the proposal that dopamine is important in engagement of instrumental motivation to optimize adherence to task goals, particularly when learning to execute goal-directed strategies in motor skill learning.

CURATE.AI COR-Tx platform as a digital therapy and digital diagnostic for cognitive function in patients with brain tumour postradiotherapy treatment: protocol for a prospective mixed-methods feasibility clinical trial.

INTRODUCTION: Conventional interventional modalities for preserving or improving cognitive function in patients with brain tumour undergoing radiotherapy usually involve pharmacological and/or cognitive rehabilitation therapy administered at fixed doses or intensities, often resulting in suboptimal or no response, due to the dynamically evolving patient state over the course of disease. The personalisation of interventions may result in more effective results for this population. We have developed the CURATE.AI COR-Tx platform, which combines a previously validated, artificial intelligence-derived personalised dosing technology with digital cognitive training. METHODS AND ANALYSIS: This is a prospective, single-centre, single-arm, mixed-methods feasibility clinical trial with the primary objective of testing the feasibility of the CURATE.AI COR-Tx platform intervention as both a digital intervention and digital diagnostic for cognitive function. Fifteen patient participants diagnosed with a brain tumour requiring radiotherapy will be recruited. Participants will undergo a remote, home-based 10-week personalised digital intervention using the CURATE.AI COR-Tx platform three times a week. Cognitive function will be assessed via a combined non-digital cognitive evaluation and a digital diagnostic session at five time points: preradiotherapy, preintervention and postintervention and 16-weeks and 32-weeks postintervention. Feasibility outcomes relating to acceptability, demand, implementation, practicality and limited efficacy testing as well as usability and user experience will be assessed at the end of the intervention through semistructured patient interviews and a study team focus group discussion at study completion. All outcomes will be analysed quantitatively and qualitatively. ETHICS AND DISSEMINATION: This study has been approved by the National Healthcare Group (NHG) DSRB (DSRB2020/00249). We will report our findings at scientific conferences and/or in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04848935.

Individual Differences in Decision Strategy Relate to Neurochemical Excitability and Cortical Thickness.

The speed-accuracy trade-off (SAT), whereby faster decisions increase the likelihood of an error, reflects a cognitive strategy humans must engage in during the performance of almost all daily tasks. To date, computational modeling has implicated the latent decision variable of response caution (thresholds), the amount of evidence required for a decision to be made, in the SAT. Previous imaging has associated frontal regions, notably the left prefrontal cortex and the presupplementary motor area (pre-SMA), with the setting of such caution levels. In addition, causal brain stimulation studies, using transcranial direct current stimulation (tDCS), have indicated that while both of these regions are involved in the SAT, their role appears to be dissociable. tDCS efficacy to impact decision-making processes has previously been linked with neurochemical concentrations and cortical thickness of stimulated regions. However, to date, it is unknown whether these neurophysiological measures predict individual differences in the SAT, and brain stimulation effects on the SAT. Using ultra-high field (7T) imaging, here we report that instruction-based adjustments in caution are associated with both neurochemical excitability (the balance between GABA+ and glutamate) and cortical thickness across a range of frontal regions in both sexes. In addition, cortical thickness, but not neurochemical concentrations, was associated with the efficacy of left prefrontal and superior medial frontal cortex (SMFC) stimulation to modulate performance. Overall, our findings elucidate key neurophysiological predictors, frontal neural excitation, of individual differences in latent psychological processes and the efficacy of stimulation to modulate these.SIGNIFICANCE STATEMENT The speed-accuracy trade-off (SAT), faster decisions increase the likelihood of an error, reflects a cognitive strategy humans must engage in during most daily tasks. The SAT is often investigated by explicitly instructing participants to prioritize speed or accuracy when responding to stimuli. Using ultra-high field (7T) magnetic resonance imaging (MRI), we found that individual differences in the extent to which participants adjust their decision strategies with instruction related to neurochemical excitability (ratio of GABA+ to glutamate) and cortical thickness in the frontal cortex. Moreover, brain stimulation to the left prefrontal cortex and the superior medial frontal cortex (SMFC) modulated performance, with the efficacy specifically related to cortical thickness. This work sheds new light on the neurophysiological basis of decision strategies and brain stimulation.

Presenting characteristics, histological subtypes and outcomes of adult central nervous system tumours: retrospective review of a surgical cohort.

Introduction: The most recent local study on the incidence of histological subtypes of all brain and spinal tumours treated surgically was published in 2000. In view of the outdated data, we investigated the presenting characteristics, histological subtypes and outcomes of adult patients who underwent surgery for brain or spinal tumours at our institution. Methods: A single-centre retrospective review of 501 patients who underwent surgery for brain or spinal tumours from 2016 to 2020 was conducted. The inclusion criteria were (a) patients who had a brain or spinal tumour that was histologically verified and (b) patients who were aged 18 years and above at the time of surgery. Results: Four hundred and thirty-five patients (86.8%) had brain tumours and 66 patients (13.2%) had spinal tumours. Patients with brain tumours frequently presented with cranial nerve palsy, headache and weakness, while patients with spinal tumours frequently presented with weakness, numbness and back pain. Overall, the most common histological types of brain and spinal tumours were metastases, meningiomas and tumours of the sellar region. The most common complications after surgery were cerebrospinal fluid leak, diabetes insipidus and urinary tract infection. In addition, 15.2% of the brain tumours and 13.6% of the spinal tumours recurred, while 25.7% of patients with brain tumours and 18.2% of patients with spinal tumours died. High-grade gliomas and metastases had the poorest survival and highest recurrence rates. Conclusion: This study serves as a comprehensive update of the epidemiology of brain and spinal tumours and could help guide further studies on brain and spinal tumours.

Dopamine Alters the Effect of Brain Stimulation on Decision-Making.

Noninvasive brain stimulation techniques, such as transcranial direct current stimulation (tDCS), show promise in treating a range of psychiatric and neurologic conditions. However, optimization of such applications requires a better understanding of how tDCS alters cognition and behavior. Existing evidence implicates dopamine in tDCS alterations of brain activity and plasticity; however, there is as yet no causal evidence for a role of dopamine in tDCS effects on cognition and behavior. Here, in a preregistered, double-blinded study, we examined how pharmacologically manipulating dopamine altered the effect of tDCS on the speed-accuracy trade-off, which taps ubiquitous strategic operations. Cathodal tDCS was delivered over the left prefrontal cortex and the superior medial frontal cortex before participants (N = 62, 24 males, 38 females) completed a dot-motion task, making judgments on the direction of a field of moving dots under instructions to emphasize speed, accuracy, or both. We leveraged computational modeling to uncover how our interventions altered latent decisional processes driving the speed-accuracy trade-off. We show that dopamine in combination with tDCS (but not tDCS alone nor dopamine alone) not only impaired decision accuracy but also impaired discriminability, which suggests that these manipulations altered the encoding or representation of discriminative evidence. This is, to the best of our knowledge, the first direct evidence implicating dopamine in the way tDCS affects cognition and behavior.SIGNIFICANCE STATEMENT tDCS can improve cognitive and behavioral impairments in clinical conditions; however, a better understanding of its mechanisms is required to optimize future clinical applications. Here, using a pharmacological approach to manipulate brain dopamine levels in healthy adults, we demonstrate a role for dopamine in the effects of tDCS in the speed-accuracy trade-off, a strategic cognitive process ubiquitous in many contexts. In doing so, we provide direct evidence implicating dopamine in the way tDCS affects cognition and behavior.

Clinical effectiveness of rehabilitation in ambulatory care for patients with persisting symptoms after COVID-19: a systematic review.

BACKGROUND: Lingering symptoms after acute COVID-19 present a major challenge to ambulatory care services. Since there are reservations regarding their optimal management, we aimed to collate all available evidence on the effects of rehabilitation treatments applicable in ambulatory care for these patients. METHODS: On 9 May 2022, we systematically searched articles in COVID-19 collections, Embase, MEDLINE, Cochrane Library, Web of Science, CINAHL, PsycArticles, PEDro, and EuropePMC. References were eligible if they reported on the clinical effectiveness of a rehabilitation therapy applicable in ambulatory care for adult patients with persisting symptoms continuing 4 weeks after the onset of COVID-19. The quality of the studies was evaluated using the CASP cohort study checklist and the Cochrane Risk of Bias Assessment Tool. Summary of Findings tables were constructed and the certainty of evidence was assessed using the GRADE framework. RESULTS: We included 38 studies comprising 2,790 participants. Physical training and breathing exercises may reduce fatigue, dyspnoea, and chest pain and may improve physical capacity and quality of life, but the evidence is very weak (based on 6 RCTs and 12 cohort studies). The evidence underpinning the effect of nutritional supplements on fatigue, dyspnoea, muscle pain, sensory function, psychological well-being, quality of life, and functional capacity is very poor (based on 4 RCTs). Also, the evidence-base is very weak about the effect of olfactory training on sensory function and quality of life (based on 4 RCTs and 3 cohort studies). Multidisciplinary treatment may have beneficial effects on fatigue, dyspnoea, physical capacity, pulmonary function, quality of life, return to daily life activities, and functional capacity, but the evidence is very weak (based on 5 cohort studies). The certainty of evidence is very low due to study limitations, inconsistency, indirectness, and imprecision. CONCLUSIONS: Physical training, breathing exercises, olfactory training and multidisciplinary treatment can be effective rehabilitation therapies for patients with persisting symptoms after COVID-19, still with high uncertainty regarding these effects. These findings can guide ambulatory care practitioners to treat these patients and should be incorporated in clinical practice guidelines. High-quality studies are needed to confirm our hypotheses and should report on adverse events.

Masturbation Among Malaysian Young Adults: Associated Sexual and Psychological Well-Being Outcomes.

Despite being a common sexual practice, not much is known about masturbation within the Malaysian context. The current study examined the masturbation practices of a convenience sample of Malaysian young adults, and how one's reported experience of masturbating and frequency of masturbation is associated with sexual and psychological well-being. Satisfaction with sex life, satisfaction with life, depression, anxiety, and stress were measured as outcome variables. Responses from 621 participants (M = 22.1 years, SD = 2.4 years) that were collected through an online questionnaire were analyzed. Results revealed that most participants (77.7%) had masturbated at least once in their life. Sexual satisfaction and psychological well-being did not differ between those who reported masturbating before and those who did not. Among those with masturbation experience, higher frequency of masturbation was associated with less sexual satisfaction and more symptoms of anxiety and stress. Masturbation frequency was not associated with life satisfaction or reports of depressive symptoms. Gender, frequency of partnered sex, availability of a sexual partner, and religiosity did not moderate the relationships between masturbation frequency with sexual satisfaction and psychological well-being. Although the limitations of the current study impede generalizability, masturbation was found to be a common behavior among the current sample. Causal inferences cannot be drawn from the significant associations found in the current study, as the findings indicate such relationships may be bidirectional. Supplementary Information: The online version contains supplementary material available at 10.1007/s12119-023-10101-2.

COVID-19 vaccine hesitancy and its drivers: An empirical study of the vaccine hesitant group in Malaysia.

BACKGROUND: Sporadic outbreaks of COVID-19 remain a threat to public healthcare, especially if vaccination levels do not improve. As Malaysia begins its transition into the endemic phase, it is essential to identify the key determinants of COVID-19 vaccination intention amongst the pockets of the population who are still hesitant. Therefore, focusing on a sample of individuals who did not register for the COVID-19 vaccination, the current study integrated two widely used frameworks in the public health domain-the health belief model (HBM) and the theory of reasoned action (TRA)-to examine the inter-relationships of the predictors of vaccination intention amongst these individuals. METHODOLOGY: Primary data from 117 respondents who did not register for the COVID-19 vaccination were collected using self-administered questionnaires to capture predictors of vaccination intention amongst individuals in a Malaysian context. The partial least squares structural equation modeling (PLS-SEM) technique was used to analyze the data. RESULTS: Subjective norms and attitude play key mediating roles between the HBM factors and vaccination intention amongst the unregistered respondents. In particular, subjective norms mediate the relationship between cues to action and vaccination intention, highlighting the significance of important others to influence unregistered individuals who are already exposed to information from mass media and interpersonal discussions regarding vaccines. Trust, perceived susceptibility, and perceived benefits indirectly influence vaccination intention through attitude, indicating that one's attitude is vital in promoting behavioral change. CONCLUSION: This study showed that the behavioral factors could help understand the reasons for vaccine refusal or acceptance, and shape and improve health interventions, particularly among the vaccine-hesitant group in a developing country. Therefore, policymakers and key stakeholders can develop effective strategies or interventions to encourage vaccination amongst the unvaccinated for future health pandemics by targeting subjective norms and attitude.

Pornography consumption and sexual health among emerging adults from Malaysia: an observational study.

BACKGROUND: Despite the high prevalence, few studies have examined pornography consumption among emerging adults in Malaysia. The current study examined the attitudes, motivations, and behaviours related to pornography consumption and their association with sexual health. METHODS: Using a cross-sectional survey that was conducted online, a convenience sample of 319 Malaysians aged 18-30years (M =23.05, s.d.=2.55) reported their attitudes and behaviours related to pornography consumption, including the degree of problematic consumption, and completed measures of sexual health. These included sexual satisfaction, awareness of sexual feelings, sexual self-reflection, sexual assertiveness, embarrassment during partnered sex, and genital image. To capture pornography genre preferences, participants also reported the keywords that they typically use to search for pornography. These open-ended responses were thematically coded. RESULTS: Between 60 and 70% of participants reported positive attitudes toward pornography and 81.2% (N =259) reported lifetime intentional exposure to pornography. Gender differences were present in pornography consumption attitudes, motivations, preferences, and behaviours. Problematic pornography consumption, and not consumption frequency, was associated with poorer sexual satisfaction. Among women and not men, more frequent consumption was associated with more sexual self-reflection and positive feelings about their genitals. Sexual embarrassment was higher among women who consume pornography more problematically and among men who consumed pornography more frequently. CONCLUSIONS: Pornography consumption attitudes and behaviours appear rather universal. However, the benefits of pornography consumption frequency and disadvantages associated with problematic consumption appear to be more relevant for women's than men's sexual health, specifically sexual self-reflection, genital image, and sexual embarrassment.

FAM3C in circulating tumor-derived extracellular vesicles promotes non-small cell lung cancer growth in secondary sites.

Rationale: Metastasis is a complex process with a molecular underpinning that remains unclear. We hypothesize that cargo proteins conducted by extracellular vesicles (EVs) released from tumors may confer growth and metastasis potential on recipient cells. Here, we report that a cytokine-like secreted protein, FAM3C, contributes to late-stage lung tumor progression. Methods: EV protein profiling was conducted with an unbiased proteomic mass spectrometry analysis on non-small cell lung cancer (NSCLC) and normal lung fibroblast cell lines. Expression of FAM3C was confirmed in a panel of NSCLC cell lines, and correlated to the invasive and metastatic potentials. Functional phenotype of endogenous FAM3C and tumor-derived EVs (TDEs) were further investigated using various biological approaches in RNA and protein levels. Metastasis potential of TDEs secreted by FAM3C-overexpressing carcinoma cells was validated in mouse models. Results: Transcriptomic meta-analysis of pan-cancer datasets confirmed the overexpression of FAM3C - a gene encoding for interleukin-like EMT inducer (ILEI) - in NSCLC tumors, with strong association with poor patient prognosis and cancer metastasis. Aberrant expression of FAM3C in lung carcinoma cells enhances cellular transformation and promotes distant lung tumor colonization. In addition, higher FAM3C concentrations were detected in EVs extracted from plasma samples of NSCLC patients compared to those of healthy subjects. More importantly, we defined a hitherto-unknown mode of microenvironmental crosstalk involving FAM3C in EVs, whereby the delivery and uptake of FAM3C via TDEs enhances oncogenic signaling - in recipient cells that phenocopies the cell-endogenous overexpression of FAM3C. The oncogenicity transduced by FAM3C is executed via a novel interaction with the Ras-related protein RalA, triggering the downstream activation of the Src/Stat3 signaling cascade. Conclusions: Our study describes a novel mechanism for FAM3C-driven carcinogenesis and shed light on EV FAM3C as a driver for metastatic lung tumors that could be exploited for cancer therapeutics.

Effect of perioperative seizures on mortality and recurrence in patients with brain metastases.

Objective: To identify the independent risk factors for 30-day perioperative seizures, as well as to evaluate the effect of perioperative seizures on overall mortality and tumor recurrence among patients who underwent surgical resection of brain metastases. Methods: Patients who underwent surgical resection of brain metastases at our institution between 2011 and 2019 were included. 30-day perioperative seizures were defined as the presence of any preoperative or postoperative seizures diagnosed by a neurosurgeon or neurologist within 30 days of metastases resection. Independent risk factors for 30-day perioperative seizures were evaluated using multivariate logistic regression models. Kaplan-Meier plots and Cox regression models were constructed to evaluate the effects of 30-day perioperative seizures on overall mortality and tumor recurrence. Subgroup analyses were conducted for 30-day preoperative and 30-day postoperative seizures. Results: A total of 158 patients were included in the analysis. The mean (SD) age was 59.3 (12.0) years, and 20 (12.7%) patients had 30-day perioperative seizures. The presence of 30-day preoperative seizures (OR=41.4; 95% CI=4.76, 924; p=0.002) was an independent risk factor for 30-day postoperative seizures. Multivariate Cox regression revealed that any 30-day perioperative seizure (HR=3.25; 95% CI=1.60, 6.62; p=0.001) was independently and significantly associated with overall mortality but not tumor recurrence (HR=1.95; 95% CI=0.78, 4.91; p=0.154). Conclusions: Among patients with resected brain metastases, the presence of any 30-day perioperative seizure was independently associated with overall mortality. This suggests that 30-day perioperative seizures may be a prognostic marker of poor outcome. Further research evaluating this association as well as the effect of perioperative antiepileptic drugs in patients with resected brain metastases may be warranted.

Montreal cognitive assessment as a screening instrument for cognitive impairment in systemic lupus erythematosus patients without overt neuropsychiatric manifestations.

OBJECTIVES: The Montreal Cognitive Assessment (MoCA) is an increasingly used screening tool for cognitive impairment. The aim of this study was to examine how MoCA performed in identifying cognitive impairment (CI) domains in SLE patients compared with formal standardized neuropsychological testing (NPT). Factors related to SLE disease, immunologic and psychological state associated with CI were also explored. METHODS: This cross-sectional study recruited 50 SLE patients without overt neuropsychiatric manifestations from April 2017 to May 2018. The patients were evaluated with MoCA, formal NPT and the Depression, Anxiety, and Stress Scales (DASS) 42-item self-report questionnaire. Values of sensitivity and specificity were computed for different cut-offs of MoCA within each cognitive domain of NPT and descriptive analysis was used to identify the factors affecting cognitive function. RESULTS: The median score for MoCA was 27.5 (range 22-30). Using a MoCA cutoff of <26, 18 (36%) were identified to have CI using NPT compared to 8 (16%) using MoCA. The most frequently affected cognitive domain was executive functioning with 15 affected patients. Sensitivities and specificities of the MoCA range from 50% to 100% and 5.7% to 16.7%, respectively, across cognitive domains. A lower MoCA cutoff of <25 improve sensitivity of identifying impairment in executive functioning from 60% to 80%. In univariate analysis, DASS scores, disease activity, presence of antiphospholipid antibodies, presence of concurrent autoimmune disease, current, and cumulative corticosteroid therapy did not predict cognitive performance. CONCLUSION: MoCA may be a useful screening tool to identify the most frequently affected cognitive domain which is executive functioning using a lower cutoff of <25 in SLE patients without overt neuropsychiatric manifestations.

Healthcare Facilities as Potential Reservoirs of Antimicrobial Resistant Klebsiella pneumoniae: An Emerging Concern to Public Health in Bangladesh.

The emergence of virulent extended spectrum ß-lactamase producing Klebsiella pneumoniae (ESBL-KP) including carbapenem-resistant Klebsiella pneumoniae (CRKP) in hospital-acquired infections has resulted in significant morbidity and mortality worldwide. We investigated the antibiotic resistance and virulence factors associated with ESBL-KP and CRKP in tertiary care hospitals in Bangladesh and explored their ability to form biofilm. A total of 67 ESBL-KP were isolated from 285 Klebsiella pneumoniae isolates from environmental and patient samples from January 2019 to April 2019. For ESBL-KP isolates, molecular typing was carried out using enterobacterial repetitive intergenic consensus polymerase chain reaction (ERIC-PCR), antibiotic susceptibility testing, PCR for virulence and drug-resistant genes, and biofilm assays were also performed. All 67 isolates were multidrug-resistant (MDR) to different antibiotics at high levels and 42 isolates were also carbapenem-resistant. The most common ß-lactam resistance gene was blaCTX-M-1 (91%), followed by blaTEM (76.1%), blaSHV (68.7%), blaOXA-1 (29.9%), blaGES (14.9%), blaCTX-M-9 (11.9%), and blaCTX-M-2 (4.5%). The carbapenemase genes blaKPC (55.2%), blaIMP (28.4%), blaVIM (14.9%), blaNDM-1 (13.4%), and blaOXA-48 (10.4%) and virulence-associated genes such as fimH (71.6%), ugeF (58.2%), wabG (56.7%), ureA (47.8%) and kfuBC (28.4%) were also detected. About 96.2% of the environmental and 100% of the patient isolates were able to form biofilms. ERIC-PCR-based genotyping and hierarchical clustering of K. pneumoniae isolates revealed an association between environmental and patient samples, indicating clonal association with possible transmission of antimicrobial resistance genes. Our findings can help in improving patient care and infection control, and the development of public health policies related to hospital-acquired infections.