Anticancer Effects of the Novel Pyrazolyl-Urea GeGe-3.

In a screen of over 200 novel pyrazole compounds, ethyl 1-(2-hydroxypentyl)-5-(3-(3-(trifluoromethyl) phenyl)ureido)-1H-pyrazole-4-carboxylate (named GeGe-3) has emerged as a potential anticancer compound. GeGe-3 displays potent anti-angiogenic properties through the presumptive targeting of the protein kinase DMPK1 and the Ca2+-binding protein calreticulin. We further explored the anticancer potential of GeGe-3 on a range of established cancer cell lines, including PC3 (prostate adenocarcinoma), SKMEL-28 (cutaneous melanoma), SKOV-3 (ovarian adenocarcinoma), Hep-G2 (hepatocellular carcinoma), MDA-MB231, SKBR3, MCF7 (breast adenocarcinoma), A549 (lung carcinoma), and HeLa (cervix epithelioid carcinoma). At concentrations in the range of 10 µM, GeGe-3 significantly restricted cell proliferation and metabolism. GeGe-3 also reduced PC3 cell migration in a standard wound closure and trans-well assay. Together, these results confirm the anticancer potential of GeGe-3 and underline the need for more detailed pre-clinical investigations into its molecular targets and mechanisms of action.

Transport and gradient formation of Wnt and Fgf in the early zebrafish gastrula.

Within embryonic development, the occurrence of gastrulation is critical in the formation of multiple germ layers with many differentiative abilities. These cells are instructed through exposure to signalling molecules called morphogens. The secretion of morphogens from a source tissue creates a concentration gradient that allows distinct pattern formation in the receiving tissue. This review focuses on the morphogens Wnt and Fgf in zebrafish development. Wnt has been shown to have critical roles throughout gastrulation, including in anteroposterior patterning and neural posterisation. Fgf is also a vital signal, contributing to involution and mesodermal specification. Both morphogens have also been found to work in finely balanced synergy for processes such as neural induction. Thus, the signalling range of Wnts and Fgfs must be strictly controlled to target the correct target cells. Fgf and Wnts signal to local cells as well as to cells in the distance in a highly regulated way, requiring specific dissemination mechanisms that allow efficient and precise signalling over short and long distances. Multiple transportation mechanisms have been discovered to aid in producing a stable morphogen gradient, including short-range diffusion, filopodia-like extensions called cytonemes and extracellular vesicles, mainly exosomes. These mechanisms are specific to the morphogen that they transport and the intended signalling range. This review article discusses how spreading mechanisms in these two morphogenetic systems differ and the consequences on paracrine signalling, hence tissue patterning.

Experiencing hallucinations in daily life: The role of metacognition.

BACKGROUND: Hallucinations have been linked to failures in metacognitive reflection suggesting an association between hallucinations and overestimation of performance, although the cross-sectional findings are inconsistent. This inconsistency may relate to the fluctuating hallucinatory experiences that are not captured in cross-sectional studies. Ecological Momentary Assessment (EMA) captures in-the-moment experiences over time so can identify causal relationships between variables such as the associations between metacognition and hallucinatory experience in daily life and overcome problems in cross-sectional designs. METHODS: Participants (N = 41) experiencing daily hallucinations completed baseline questionnaires and smartphone surveys 7 times per day for 14 days. They were prompted to identify a task they would complete in the next 4 h and to make metacognitive predictions around the likelihood of completing the task, the difficulty of the task, and how well they would complete it (standard of completion). RESULTS: 76 % finished the 14-days of assessment with an average of 42.2 % survey completion. Less accurate metacognition was associated with more hallucinations, but less accurate likelihood and standard of completion was associated with fewer hallucinations. Using a cross-lagged analysis, metacognitive predictions around the likelihood of completion (p < .001) and standard of completion (p = .01) predicted hallucination intensity at the following timepoint, and metacognitive predictions regarding likelihood of completion (p = .02) predicted hallucination control at the following timepoint. DISCUSSION: Interventions that aim to improve metacognitive ability in-the-moment may serve to reduce the intensity and increase the control of hallucinations.

Are dysfunctional attitudes elevated and linked to mood in bipolar disorder? A systematic review and meta-analysis.

OBJECTIVES: Dysfunctional attitudes (DA) are higher in depression; however, less is understood about their role in bipolar disorder (BD). This paper aimed to explore the presence of DA in BD in comparison to clinical and non-clinical groups. Also explored were the associations between DA and mood states of depression, mania or euthymia in BD. METHODS: A systematic review and meta-analysis were conducted. A total of 47 articles were included in the systematic review of which 23 were included in the meta-analysis. The quality of each study was rated. RESULTS: The meta-analysis showed significantly higher DA in BD than healthy controls (d = .70). However, no difference was observed between BD and unipolar participants (d = -.16). When reviewing mood state within BD, a significant mean difference was found between DA scores for euthymic and depressed participants (d = -.71), with those who were depressed scoring higher. Three studies found that psychological therapies significantly reduce DA in BD (d = -.38). CONCLUSIONS: These findings imply not only that DA are both a characteristic of BD that is not as prevalent in healthy populations but also that a depressed mood state is associated with increased severity. This implies that DA could possibly go 'offline' when mood symptoms are not present. Psychological therapies appear to reduce DA in BD. Implications for future research as well as practice-based implications are expanded on in the discussion.

Development and implementation of a continuing care program for patients with intellectual and developmental disabilities in family medicine.

In the United States, individuals with intellectual and developmental disabilities (IDD) consistently experience health disparities. One factor is limited access to quality healthcare services equipped to meet the needs of those with IDD, particularly as they transition to adulthood. The purpose of this work is to describe the development and implementation of Jefferson's Continuing Care Program (JCCP), which was designed to address this care gap. We share how the idea, logistics, and support for the clinic were developed; how JCCP was designed to be uniquely accessible both via physical space and clinic flow; and how those challenges encountered have been crucial for fine-tuning optimal patient care. Since its inception in 2019, JCCP has made large strides towards educating the next generation of medical providers to care for patients with IDD. Looking to the future, JCCP plans to broaden its impact by serving more patients, continuing our advocacy and education work, and continuing to adapt to the needs of our community.

The relationship between dysfunctional attitudes, maladaptive perfectionism, metacognition and symptoms of mania and depression in bipolar disorder: The role of self-compassion as a mediating factor.

BACKGROUND: Maladaptive cognitions appear to be associated with the severity of mood symptoms in bipolar disorder (BD), but findings are mixed and generally cross-sectional in design. METHOD: This study (n = 331) explored the associations between maladaptive cognitions and mood symptoms in BD over time (3 months), and the potential mediating effect of self-compassion cross-sectionally. Dysfunctional attitudes, maladaptive perfectionism and maladaptive metacognitions were explored separately with depressive and manic symptoms, and with current mood state in BD. RESULTS: The results showed maladaptive metacognitions to be the only significant predictor of depression at 3-month follow-up (ß = 0.31, p < .001), with no relationship to mania over time. Cross-sectionally, self-compassion partially mediated the relationship between all maladaptive cognitions and depression, with higher dysfunctional cognitions and lower self-compassion predicting increased severity of depressive symptoms. Only the relationship between dysfunctional attitudes and mania was partially mediated by self-compassion, however, the relationship was weak and suggestive that higher self-compassion predicted increased mania. LIMITATIONS: The study duration limited the possible analysis. Future longitudinal research is needed. Also, the study sample was not representative of the clinical population, making results less generalisable. Additionally, limited significant findings regarding manic symptoms supports the need for further research into active cognitions during this phase of BD. CONCLUSIONS: Maladaptive metacognitions were predictive of future depression severity, therefore, further exploration of metacognitive therapy for BD should be explored. Furthermore, self-compassion was shown to partially mediate the relationship between negative cognitions and mood, therefore further exploration of compassion-based therapies for BD is needed.

Wellbeing among university students during the COVID-19 pandemic: a systematic review of longitudinal studies.

OBJECTIVES: The objectives of this study were to investigate the wellbeing trajectories of university students during the COVID-19 pandemic and identify associated protective factors. Results from the study aimed to inform wellbeing-promotion strategies and crisis-response plans in university settings. STUDY DESIGN: Systematic review. METHODS: A review of articles published in English language was conducted in PubMed, PsycINFO, Scopus, Web of Science, and ERIC databases from 1 December 2019 to 15 December 2022. Longitudinal and repeated cross-sectional studies that assessed wellbeing among university students during the COVID-19 pandemic using a validated instrument were included. Article and data extraction were performed by the primary reviewer, with a random subset verified by a second reviewer. Study quality was assessed using the National Institutes of Health 'Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies'. RESULTS: Of 6651 titles screened without duplicates, 181 underwent full-text review, of which 19 were included in the current study (15 longitudinal and 4 repeated cross-sectional studies, with a total of 19,206 participants). A significant decrease in the wellbeing of university students was observed across studies during the early stages of the pandemic compared to prepandemic times; however, mixed findings were found in later phases of the pandemic, with some studies presenting an improvement in wellbeing, others no change, and two studies finding impairments. Overall, wellbeing was greater among males and was also associated with socioeconomic status, more sleep and physical activity, greater social connectedness, less alcohol use, and less social media activity. CONCLUSION: The study showed varying wellbeing trajectories across different periods of the COVID-19 pandemic. Results provide relevant information for researchers, public health professionals, and higher education institutions in charge of promoting student wellbeing and crisis preparedness. PROSPERO REGISTRATION: CRD42022383941.

Antidepressant Prescription Behavior Among Primary Care Clinician Providers After an Interprofessional Primary Care Psychiatric Training Program.

Primary care providers (PCPs) are increasingly called upon to screen for and treat depression. However, PCPs often lack the training to diagnose and treat depression. We designed an innovative 12-month evidence and mentorship-based primary care psychiatric training program entitled the University of California, Irvine (UCI) School of Medicine Train New Trainers Primary Care Psychiatry (TNT PCP) Fellowship and examined whether this training impacted clinician prescription rates for antidepressants. We retrieved information on 18,844 patients and 192 PCPs from a publicly insured health program in Southern California receiving care between 2017 and 2021. Of the 192 PCPs, 42 received TNT training and 150 did not. We considered a patient as exposed to the provider's TNT treatment if they received care from a provider after the provider completed the 1-year fellowship. We utilized the number of antidepressant prescriptions per patient, per quarter-year as the dependent variable. Linear regression models controlled for provider characteristics and time trends. Robustness checks included clustering patients by provider identification. After PCPs completed TNT training, "exposed" patients received 0.154 more antidepressant prescriptions per quarter-year relative to expected levels (p < 0.01). Clustering of standard errors by provider characteristics reduced precision of the estimate (p < 0.10) but the direction and magnitude of the results were unchanged. Early results from the UCI TNT PCP Fellowship demonstrate enhanced antidepressant prescription behavior in PCPs who have undergone TNT training. A novel, and relatively low-cost, clinician training program holds the potential to empower PCPs to optimally deliver depression treatment.

Metacognition and psychosis-spectrum experiences: A study of objective and subjective measures.

BACKGROUND: Metacognition refers to appraising one's thoughts and behaviours. Deficits in metacognition are associated with psychosis-spectrum experiences, such as hallucinations and delusions, in both clinical and non-clinical populations. Assessments of metacognitive function and abilities in clinical populations often vary in administration duration, and subjectivity of scores. This study investigates associations between different measures of metacognition and their prediction of psychosis spectrum experiences using objective and self-report measures in a cross-sectional study of psychosis-spectrum disorder (PSD) participants and controls. METHOD: Twenty-three individuals with PSD and forty-four controls were recruited online and completed in-the-moment objective ratings of metacognitive accuracy (meta-Dots Task), and retrospective self-report of metacognitive self-reflection (Beck Cognitive Insight Scale) and abilities (Metacognition Self-Assessment Scale). RESULTS: There were group differences in self-reported metacognition, with PSD participants having lower scores of metacognitive ability, but no differences in self-reflectiveness or objective metacognitive accuracy. In the PSD group, only self-reported metacognitive ability was associated with and predicted distress about, and conviction in, delusional thoughts. CONCLUSIONS: The findings demonstrate group differences in some self-reported, but not objective, measures of metacognition, and highlight that prediction of PSD experiences depends on the metacognitive construct being measured, and the type of measurement used.

Unusual experiences and their association with metacognition: investigating ASMR and Tulpamancy.

BACKGROUND: Unusual experiences in Tulpamancer and Autonomous Sensory Meridian Response (ASMR) communities are generally positive and sought after, unlike hallucinations and delusions in clinical populations. Metacognition, the ability to reflect on self-referential experiences, may aid sense-making around unusual experiences, reducing distress. This study investigated group differences in hallucination-proneness, delusion-proneness, and metacognition in these communities compared to controls, and whether metacognition predicted unusual experiences. METHODS: 243 participants reporting ASMR, Tulpamancy, or neither, with no history of psychosis, took part in an online observational study. Participants completed the Beck Cognitive Insight Scale, Metacognitions Questionnaire-30, and Brief Core Schema Scales to capture metacognition. A Tulpamancer+ (reporting ASMR) group was identified and included in analyses. ANCOVAs highlighted group differences in hallucination-proneness, with Tulpamancer+ scoring higher, and metacognitive beliefs, with Tulpamancers reporting lower metacognitive belief endorsement. There were no group differences in delusion-proneness, self-reflection, or self-schemas. Stepwise regression demonstrated metacognition does influence unusual experiences in the non-clinical population, and this influence varies across groups. CONCLUSIONS: In non-clinical populations, unusual sensory experiences are not associated with increased metacognitive beliefs, but having multiple unusual experiences is associated with higher hallucination-proneness. Results suggest improving metacognition in clinical groups may help reduce distress related to unusual sensory experiences.

Visual inspection with acetic acid screening for cervical cancer among women receiving anti-retroviral therapy for human immunodeficiency virus infection in northern Tanzania.

AIM: To evaluate visual inspection with acetic acid (VIA) screening for cervical cancer among human immunodeficiency virus (HIV)-positive patients in an East African community. METHODS: During a July 2018 cervical cancer screen-and-treat in Mwanza, Tanzania, participants were offered free cervical VIA screening, cryotherapy when indicated, and HIV testing. Acetowhite lesions and/or abnormal vascularity were designated VIA positive in accordance with current guidelines. The association between VIA results and HIV status was compared using Chi-square and Fisher exact tests. RESULTS: Eight hundred and twenty-four of 921 consented participants underwent VIA screening and 25.0% (n = 206) were VIA positive. VIA-positive nonpregnant women (n = 147) received cryotherapy and 15 (1.8%) with cancerous-appearing lesions were referred to Bugando Hospital. Sixty-six women were HIV-positive and included 25 diagnosed with HIV at the cervical cancer VIA screening and 41 with a prior diagnosis of HIV who were receiving antiretroviral therapy (ART) at the time of cervical cancer VIA screening. Sixty-four of these 66 patients, were screened with VIA. HIV infection was not associated with VIA findings. Abnormal VIA positive screening was observed in 20.3% (n = 13) of HIV-positive patients and in 24.4% (n = 145) of HIV-negative patients (p = 0.508). A nonsignificant trend of higher VIA positive screens among newly diagnosed HIV patients of 26.1% (n = 6) versus patients with preexisting HIV on ART of 17.1% (n = 7) was observed (p = 0.580). CONCLUSION: The unexpected lack of correlation between HIV infection and VIA positivity in a community with access to ART warrants additional research regarding the previously described role of ART in attenuating HPV-mediated neoplasia.

Outcomes of rib fractures in the geriatric population: A 5-year retrospective, single-institution, Australian study.

BACKGROUND: Surgical rib fixation in the general population can decrease morbidity, including length of stay and ventilator days. Elderly rib fractures convey high rates of morbidity and mortality, and it is unclear whether this population benefits from operative management. METHODS: A single-centre, retrospective study at a Level 1 Australasian trauma centre was conducted. Registry-identified patients aged ≥70 years, admitted to hospital with blunt trauma-induced rib fractures, were included. Outcome measures included demographics, pre-morbid function, acute length of stay, intensive care unit admission, injury characteristics, management and complications. RESULTS: A total of 920 presentations were identified, with 295 meeting the inclusion criteria. Falls accounted for majority (n = 148/295, 50.2%), with a median Injury Severity Score of 10 (inter-quartile range [IQR] 10-14). Severe chest trauma occurred overall in 80% (n = 243/294) and all operative patients (n = 15/15). Conservative management was used in 95% (n = 280/295). Patient-controlled analgesia was common (n = 177/295, 60.0%) and regional techniques increased in the surgical approach (n = 12/15, 80.0%) compared with conservative approach (n = 71/280, 25.4%). Despite longer acute length of stay (12 days, IQR 9-15), operative management resulted in similar complications (26.7% vs. 30.4%) and no deaths. Operative intervention was significantly associated with increased number of fractures (p < 0.001), flail segment (p = 0.001) and higher chest Abbreviated Injury Score (p < 0.001); however, it was not significantly associated with age (p = 0.90), comorbidities (0.91) or anticoagulation (p = 0.51). CONCLUSION: Surgical management of rib fractures in the elderly was performed without increased complications within this centre's multimodal approach. Standard indications for rib fixation may be applicable in the elderly population, whilst comorbidities, age and anticoagulation use alone may not be adequate reasons to withhold surgical rib fixation.

Influence of methodological and patient factors on serum NMDAR IgG antibody detection in psychotic disorders: a meta-analysis of cross-sectional and case-control studies.

BACKGROUND: Antibodies targeting the N-methyl-D-aspartate receptor (NMDAR) have been detected in patients with psychosis. However, studies measuring the IgG subclass in serum have provided variable estimates of prevalence, and it is unclear whether these antibodies are more common in patients than controls. Because these inconsistencies could be due to methodological approaches and patient characteristics, we aimed to investigate the effect of these factors on heterogeneity. METHODS: We searched Web of Science and Ovid (MEDLINE and PsycINFO) for cross-sectional and case-control studies published between Jan 1, 2000, and May 5, 2019, that reported NMDAR IgG antibody seropositivity in patients with psychosis. Pooled proportions and odds ratios (ORs) were derived using random-effects models. We estimated between-study variance (τ2) and the proportion of observed variance due to heterogeneity (I2). We then used univariable random-effects meta-regression analysis to investigate the effect of study factors on heterogeneity of proportions and ORs. Our protocol was registered on PROSPERO (CRD42018099874). FINDINGS: Of 1276 articles in the initial search, 28 studies were eligible for inclusion, including 14 cross-sectional studies and 14 case-control studies. In cross-sectional studies, NMDAR IgG antibodies were detected in 0·73% (95% CI 0·09-1·38; I2 56%; p=0·026) of patients with psychosis, and in case-control studies, patients with psychosis were not significantly more likely to be seropositive than healthy individuals (OR 1·57, 95% CI 0·78-3·16; I2 15%; p=0·20). Meta-regression analyses indicated that heterogeneity was significantly associated with assay type across both study designs, illness stage in cross-sectional studies, and study quality in case-control studies. Compared with studies using a fixed cell-based assay, cross-sectional and case-control studies using the live method yielded higher pooled prevalence estimates (0·36% [95% CI -0·23 to 0·95] vs 2·97% [0·70 to 5·25]) and higher ORs (0·65 [0·33 to 1·29] vs 4·43 [1·73 to 11·36]). In cross-sectional studies, the prevalence was higher in exclusively first-episode samples than in multi-episode or mixed samples (2·18% [0·25 to 4·12] vs 0·16% [-0·31 to 0·63]), and in case-control studies, higher ORs were reported in low-quality studies than in high-quality studies (3·80 [1·47 to 9·83] vs 0·72 [0·36 to 1·42]). INTERPRETATION: Higher estimates of NMDAR IgG antibody prevalence have been obtained with the live cell-based assay, and studies using this method find that seropositivity is more common in patients with psychosis than in controls. The effects of illness stage and study quality on heterogeneity were not consistent across study designs, and we provide clear recommendations for clinicians and researchers regarding interpreting these findings. FUNDING: None.

Implementation of human papillomavirus video education for women participating in mass cervical cancer screening in Tanzania.

BACKGROUND: Because the global disease burden of cervical cancer is greatest in Africa, the World Health Organization has endorsed visual inspection with acetic acid screening with cryotherapy triage for the screen-and-treat approach. With the lowest doctor-to-patient ratio worldwide (1:50,000), Tanzania has nearly 10,000 new cases of cervical cancer and 7000 deaths annually. OBJECTIVE: We report on the feasibility of visual inspection with acetic acid in the severely resource-limited Mwanza district and on the impact of intervening education on baseline human papillomavirus and cervical cancer knowledge. STUDY DESIGN: Two 5-day free visual inspection with acetic acid (VIA) clinics in urban Buzuruga and rural Sangabuye on the shores of Lake Victoria were approved by our university institutional review board and local Tanzanian health authorities. Participants completed a demographic survey and a 6-question (1 point per question) multiple choice test written in Kiswahili to assess baseline knowledge. A 15-minute educational video in Kiswahili (MedicalAidFilms: Understanding screening, treatment, and prevention of cervical cancer) was followed by repeated assessment using the same test, visual inspection with acetic acid screening, and optional HIV testing. Pre- and postvideo scores and change of score were analyzed via t test, analysis of variance, and multivariate regression. Significance was considered at P<.05. RESULTS: From July 2, 2018 to July 6, 2018, 825 women were screened, and 207 women (25.1%) were VIA positive (VIA+). One hundred forty-seven VIA+ nonpregnant women received same-day cryotherapy. Seven hundred sixty women participated in an educational intervention-61.6% of whom were from an urban site and 38.2% from a rural site. The mean age was 36.4 (standard deviation, 11.1). Primary languages were Kiswahili (62.2%) and Kisukuma (30.6%). Literacy was approximately 73%, and average education level was equivalent to the seventh grade (United States). Less than 20% of urban and rural women reported access to healthcare providers. Mean score of the participants before watching the video was 2.22 (standard deviation, 1.76) and was not different between VIA+ and VIA negative groups. Mean score of the participants after watching the video was 3.86 (standard deviation, 1.78). Postvideo scores significantly improved regardless of age group, clinic site, primary language, education level, literacy, or access to healthcare provider (P<.0001). Change of score after watching the video was significantly greater in participants from urban areas (1.99±2.07) than in those from rural areas (1.07±1.95) (P<.0001). Multivariate analysis identified urban site as an independent factor in change of score (P=.0211). CONCLUSION: Visual inspection with acetic acid screening for cervical cancer is feasible and accepted in northern Tanzania. Short video-based educational intervention improved baseline knowledge on the consequences of human papillomavirus infection in the studied populations. The impact was greater in the urban setting than in the rural setting.

Communicating traumatic pathology to ensure shared understanding: is there a recipe for the perfect preliminary image evaluation?

Medical imaging and emergency departments work collaboratively to interpret trauma radiographs. In addition to accurate radiographic interpretation, clear communication is crucial to ensure appropriate and timely management of musculoskeletal injuries. This two-step 'how to guide' provides the reviewer with a recipe for effectively evaluating trauma radiographs for traumatic pathology and succinctly documenting the findings. Step 1 is a systematic search of the radiograph: soft tissues, bones, alignment of joints and satisfaction of search (SBASS). Utilising SBASS increases reviewer confidence in identifying traumatic pathology of the appendicular and axial skeleton. Step 2 is a streamlined communication model for the documentation of pathological findings. The WWW acronym (What is it? Where is it? What is it doing?) can be adapted to describe simple or complex traumatic pathology.

The Association of Non-obscene Socially Inappropriate Behavior With Attention-Deficit/Hyperactivity Disorder Symptoms, Conduct Problems, and Risky Decision Making in a Large Sample of Adolescents.

Non-obscene socially inappropriate behavior (NOSI) is recognized as part of the tic disorder spectrum but has received little attention from researchers to date. A study in 87 patients with Tourette syndrome showed that comorbid attention-deficit/hyperactivity disorder (ADHD) and conduct disorder were also associated with an increase in socially inappropriate behavior. This study used data from the Millennium Cohort Study to investigate the relationship between NOSI and emotional symptoms, conduct problems, and hyperactivity/inattention as assessed by the Strengths and Difficulties Questionnaire (SDQ) in 1,280 youths, aged 14 years. Furthermore, the relationship between NOSI and decision-making processes as assessed by the Cambridge Gambling Task (CGT) was investigated. Hyperactivity/inattention and conduct problems were significantly associated with NOSI; emotional problems were not. Risk taking was significantly associated with misbehaving in lessons but not with being rude or noisy in public. The results replicate and confirm the association of NOSI with ADHD and conduct problems in a large sample, although it should be stressed that the size of the association was small. The results also suggest that some inappropriate behaviors are related to risk-taking behavior, while others are not.