Major Depressive Disorder (MDD) is a prevalent, chronic, disabling, and multidimensional mental disorder. Cognitive dysfunction represents a core diagnostic and symptomatic criterion of MDD, and is a ...principal determinant of functional non-recovery. Cognitive impairment has been observed to persist despite remission of mood symptoms, suggesting dissociability of mood and cognitive symptoms in MDD. Recurrent impairments in several domains including, but not limited to, executive function, learning and memory, processing speed, and attention and concentration, are associated with poor psychosocial and occupational outcomes. Attempts to restore premorbid functioning in individuals with MDD requires regular screenings and assessment of objective and subjective measures of cognition by clinicians. Easily accessible and cost-effective tools such as the THINC-integrated tool (THINC-it) are suitable for use in a busy clinical environment and appear to be promising for routine usage in clinical settings. However, antidepressant treatments targeting specific cognitive domains in MDD have been insufficiently studied. While select antidepressants, e.g., vortioxetine, have been demonstrated to have direct and independent pro-cognitive effects in adults with MDD, research on additional agents remains nascent. A comprehensive clinical approach to cognitive impairments in MDD is required. The current narrative review aims to delineate the importance and relevance of cognitive dysfunction as a symptomatic target for prevention and treatment in the phenomenology of MDD.
Gut-focused hypnotherapy is an effective treatment for irritable bowel syndrome but is not widely available. This study assessed whether providing hypnotherapy by Skype might partially overcome this ...problem. Using a 50-point or more reduction in the IBS Symptom Severity Score as the primary outcome measure, 65% of subjects responded to Skype hypnotherapy with all other outcomes significantly improving. The primary outcome figure for face-to-face hypnotherapy was 76%. When other outcome scores for Skype and face-to-face treatment were compared, the mean changes were these: symptom severity (−94.1 vs. −129.2), noncolonic score (−52.3 vs. −64.8), quality of life (+56.4 vs. +66.2), anxiety (−3.3 vs. −3.0), depression (−1.7 vs. −2.5), and a 30% or more pain reduction (44% vs. 62%). Skype hypnotherapy is effective but slightly less so than face-to-face treatment. However, many patients would have been unable to access treatment without the Skype option.
Orexins are neuropeptides that are postulated to play a central role in the regulation of the sleep-wake cycle, appetite, affect, and reward circuitry. The objectives of the current review are to ...comprehensively evaluate (1) the potential role of orexins in the pathophysiology of major depressive disorders (MDD) and (2) the orexin system as a novel target in the treatment of MDD. Dysfunction of the sleep-wake cycle is observed as a central feature of MDD pathophysiology. Orexin system disturbances produce sleep-wake dysfunction, as observed in MDD. Orexin antagonists have been shown to treat insomnia effectively without disrupting normal sleep architecture in both preclinical (e.g., animal models) and clinical studies. Orexin antagonists are generally safe, well-tolerated, and associated with an acceptable long-term adverse effect profile with relatively low propensity for tolerance or dependence. Orexin antagonists have also been shown to possess antidepressant-like properties in some animal models of MDD. Extant evidence indicates that orexin-modulating treatments exert pleiotropic effects on multiple neural systems implicated in the phenomenology of mood disorders and suggests orexins as a promising target for investigation and intervention in mood disorders. To date, no human clinical trials evaluating the antidepressant effects of orexin antagonists in MDD have been completed. Given the promising results from preclinical studies, clinical trials are merited to evaluate the antidepressant effects of orexin antagonists in MDD.
•Orexins are neuropeptides that are postulated to play a central role in the regulation of the sleep-wake cycle, appetite, affect, and reward circuitry•Dysfunction of the sleep-wake cycle is observed as a central feature of MDD pathophysiology•Orexin system disturbances produce sleep-wake dysfunction, as observed in MDD•Orexin antagonists are generally safe, well-tolerated, and associated with an acceptable long-term adverse effect profile with relatively low propensity for tolerance or dependence and has shown to possess antidepressant properties•The objectives are to evaluate (1) the potential role of orexins in the pathophysiology of major depressive disorders (MDD) and (2) the orexin system as a novel target in the treatment of MDD
Smartphone emergency medical identification (SEMID) applications are built-in health information-storing functions that are accessible without a passcode. The utility of these applications in the ...real-time resuscitation of trauma patients is unknown.
We prospectively evaluated all trauma activation patients ≥16 y and unable to provide a medical history for any reason for the presence of a smartphone at our urban level I center between October 2020 and September 2021. Available smartphones were queried for SEMID utilization, categories of information contained, and real-time clinical relevance.
One hundred and forty three patients with a median age of 39 y interquartile range 28-59 and Injury Severity Score of 16 2-29 were included. 30 (21%) patients arrived with a smartphone, 27 (90%) of which were accessible. 8 (30%) of those individuals utilized a SEMID application, and SEMID information was relevant for patient care in 6 cases (75%). The extracted information included: identifiers (75%), emergency contacts (50%), height/weight (38%), allergies (38%), age (38%), medications (25%), medical history (13%), and blood type (13%).
Approximately one in five altered trauma patients have smartphones present at arrival, some of which contain medical information pertinent for immediate care. There is a pressing need for education and our institution has developed a publicly-facing campaign with shareable materials to improve SEMID awareness and utilization. Other centers are likely to find similar benefit.
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During development, morphogens pattern tissues by instructing cell fate across long distances. Directly visualizing morphogen transport in situ has been inaccessible, so the molecular mechanisms ...ensuring successful morphogen delivery remain unclear. To tackle this longstanding problem, we developed a mouse model for compromised sonic hedgehog (SHH) morphogen delivery and discovered that endocytic recycling promotes SHH loading into signaling filopodia called cytonemes. We optimized methods to preserve in vivo cytonemes for advanced microscopy and show endogenous SHH localized to cytonemes in developing mouse neural tubes. Depletion of SHH from neural tube cytonemes alters neuronal cell fates and compromises neurodevelopment. Mutation of the filopodial motor myosin 10 (MYO10) reduces cytoneme length and density, which corrupts neuronal signaling activity of both SHH and WNT. Combined, these results demonstrate that cytoneme-based signal transport provides essential contributions to morphogen dispersion during mammalian tissue development and suggest MYO10 is a key regulator of cytoneme function.
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•Dispatched cleavage promotes sonic hedgehog endocytic recycling and cytoneme loading•Cytonemes contribute to sonic hedgehog deployment during neurodevelopment•Myosin 10 promotes formation of neuronal cytonemes for SHH and WNT transport•Cytoneme dysfunction compromises neuronal cell fate specification
During neural tube development, cytonemes, specialized signaling filopodia, contribute to the dispersion of sonic hedgehog and WNT to ensure appropriate cell fate determination across ventral and dorsal morphogen signaling gradients. Dispatched facilitates endocytic recycling of sonic hedgehog to promote ligand entry into cytonemes.
Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) have a favorable prognosis. As a result, de-escalation clinical trials are under way. However, ...approximately 10% of patients will experience distant recurrence even with standard-of-care treatment. Here, we sought to identify novel biomarkers to better risk-stratify HPV-positive patients with OPSCC.
Gene expression profiling by RNA sequencing (RNA-seq) and quantitative polymerase chain reaction was performed on HPV-positive OPSCC primary tumor specimens from patients with and without distant metastasis (DM).
RNA-seq analysis of 39 HPV-positive OPSCC specimens revealed that patients with DM had 2-fold higher E6 gene expression levels than did patients without DM (P=.029). This observation was confirmed in a validation cohort comprising 93 patients with HPV-positive OPSCC. The mean normalized E6 expression level in the 17 recurring primary specimens was 13 ± 2 compared with 8 ± 1 in the remaining 76 nonrecurring primaries (P=.001). Receiver operating characteristic analysis established an E6 expression level of 7.3 as a cutoff for worse recurrence-free survival (RFS). Patients from this cohort with high E6 gene expression (E6-high) (n=51, 55%) had more cancer-related deaths (23% vs 2%, P<.001) and DM (26% vs 5%, P<.001) than did patients with low E6 gene expression (E6-low) (n=42, 45%). Kaplan-Meier survival analysis revealed that E6-high had worse RFS (95% vs 69%, P=.004) and cancer-specific survival (97% vs 79%, P=.007). E6-high maintained statistical significance in multivariate regression models balancing surgery, chemotherapy, nodal stage, and smoking status. Gene set enrichment analysis demonstrated that tumors with high E6 expression were associated with P53, epidermal growth factor receptor, activating transcription factor-2, and transforming growth factor-β signaling pathways.
High E6 gene expression level identifies HPV-positive OPSCC patients with 5-fold greater risk of distant disease recurrence and worse cancer-specific survival. Validation in a multi-institutional prospective clinical trial is required to assess the utility of E6 gene expression as a clinically useful prognostic biomarker.
Ectopic activation of the Wnt signaling pathway is highly oncogenic for many human tissues. Here, we show that ectopic Wnt signaling increases the effective stem cell activity in mouse mammary glands ...in vivo. Furthermore, Wnt effectors induce the accumulation of mouse mammary epithelial progenitors (assayed by Hoechst dye exclusion, a surrogate stem cell marker, side population cells) both in vivo and in vitro. The longevity of stem cells makes them good candidate tumor precursors, and we propose that Wnt-induced progenitor amplification is likely to be key to tumor initiation. In support of this notion, mammary glands from a tumor-resistant strain of mice (carrying a null mutation in syndecan-1) contain fewer side population cells. When this strain is crossed to mice that overexpress effectors of the β-catenin/T cell factor Wnt pathway, the amplification of progenitors is reduced, together with all subsequent events of tumor development. We propose that the growth dynamic of the stem cell fraction is a major determinant of tumor susceptibility.
There are no widely adopted ethical standards for the use of imagery in global health publications. We reviewed imagery used by global health actors in grey literature related to antimicrobial ...resistance (AMR) and vaccination and analysed whether the imagery used was relevant, ethical, and equitable.
Reports produced by key global health actors on AMR and vaccination were retrieved through searches on 1) Google using key MESH terms; and 2) the website of each actor. Reports containing at least one image of person/s, published between 2015 and 2022 were included. Guidelines from Photographers Without Borders, European Non-governmental confederation for relief and development (CONCORD) Code of Conduct on Images and Messages, and the National Press Photographers Association were used to develop an analysis framework. Consensus was reached iteratively on the (qualitative and quantitative) indicators used in the final framework.
In 118 reports from 14 global health actors, there were 1115 images, of which 859 included people (370 healthcare professionals (HCPs), 402 adult non-HCPs, and 393 children). Of HCP images, 301/370 (81%) included non- whites, 273/370 (74%) included women, and 247/370 (67%) included non-white women. Of the non-HCP images, 346/402 (86%) included non-whites, 321/402 (80%) included women, and 278/402 (69%) included non-white women. Of images including children, 359/393 (91%) included non-whites. Qualitative analysis identified issues of relevance, integrity, consent, and representation from high income versus low-and middle-income countries (LMIC). Inequities in staging, digital manipulation, and breaches of confidentiality were noted in images depicting LMICs.
Biased representation of LMICs drives misleading and irrelevant disease associations and power imbalances. This work highlights how imagery in global health contributes to representations that are inequitable and unethical.
Through the process of inquiry, we have created an ethical framework for appropriate imagery use in global health grey literature to help key actors avoid these biases.
Endoplasmic reticulum (ER) plays an essential role in cell function and survival. Accumulation of unfolded or misfolded proteins in the lumen of the ER activates the unfolded protein response (UPR), ...resulting in ER stress and subsequent apoptosis. The alkylphosphocholine erufosine is a known Akt-mTOR inhibitor in oral squamous cell carcinoma (OSCC). In the present study, we evaluate erufosine's role to induce ER and mitochondrial stress leading to autophagy, apoptosis, and ROS induction. The cellular toxicity of erufosine was determined in two OSCC cell lines and gene expression and enrichment analyses were performed. A positive enrichment of ER stress upon erufosine exposure was observed, which was verified at protein levels for the ER stress sensors and their downstream mediators. Knockdown and pharmacological inhibition of the ER stress sensors PERK and XBP1 revealed their involvement into erufosine's cellular effects, including proliferation, apoptosis, and autophagy induction. Autophagy was confirmed by increased acidic vacuoles and LC3-B levels. Upon erufosine exposure, calcium influx into the cytoplasm of the two OSCC cell lines was seen. Apoptosis was confirmed by nuclear staining, Annexin-V, and immunoblotting of caspases. The induction of mitochondrial stress upon erufosine exposure was predicted by gene set enrichment analysis (GSEA) and shown by erufosine's effect on mitochondrial membrane potential, ATP, and ROS production in OSCC cells. These data show that ER and mitochondrial targeting by erufosine represents a new facet of its mechanism of action as well as a promising new framework in the treatment of head and neck cancers.
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