Motor activity patterns can distinguish between interepisode bipolar disorder patients and healthy controls.

BACKGROUND: Bipolar disorder (BD) is linked to circadian rhythm disruptions resulting in aberrant motor activity patterns. We aimed to explore whether motor activity alone, as assessed by longitudinal actigraphy, can be used to classify accurately BD patients and healthy controls (HCs) into their respective groups. METHODS: Ninety-day actigraphy records from 25 interepisode BD patients (ie, Montgomery-Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS) < 15) and 25 sex- and age-matched HCs were used in order to identify latent actigraphic biomarkers capable of discriminating between BD patients and HCs. Mean values and time variations of a set of standard actigraphy features were analyzed and further validated using the random forest classifier. RESULTS: Using all actigraphy features, this method correctly assigned 88% (sensitivity = 85%, specificity = 91%) of BD patients and HCs to their respective group. The classification success may be confounded by differences in employment between BD patients and HCs. When motor activity features resistant to the employment status were used (the strongest feature being time variation of intradaily variability, Cohen's d = 1.33), 79% of the subjects (sensitivity = 76%, specificity = 81%) were correctly classified. CONCLUSION: A machine-learning actigraphy-based model was capable of distinguishing between interepisode BD patients and HCs solely on the basis of motor activity. The classification remained valid even when features influenced by employment status were omitted. The findings suggest that temporal variability of actigraphic parameters may provide discriminative power for differentiating between BD patients and HCs while being less affected by employment status.

Advocacy for Health Justice: An Innovative Pilot Course for MD and Master of Public Policy Students.

Problem: U.S. medical schools are searching for ways to address issues of health justice in undergraduate medical education. Physicians have not typically received training in how to be effective advocates for systemic change and individuals in policy fields are not usually equipped to understand the complex issues of health science and their intersection with the health system and society. To address this gap, medical school faculty partnered with school of public policy faculty on a collaborative learning model that engaged MD and Master of Public Policy students together to strengthen their collective knowledge of the healthcare landscape, and to build skills to work for health justice. Intervention: We hypothesized that pairing medical students with public policy students to learn about the intersections of health justice and advocacy could enhance the efficacy of each group and provide a new model of collaboration between medical and policy professionals. The students collaborated on a health justice advocacy project through which they provided consultation to an established community organization. Context: The 8-week course took place in the spring of 2021 in Los Angeles, California. Due to Covid-19 the course was taught online and included asynchronous learning modules and live Zoom sessions. The project also served as a pilot for the post-clerkship phase of a new longitudinal health justice curriculum for MD students that launched in August 2021. Impact: Analysis of student work products, course evaluations, partner interviews, and student focus groups showed that students valued learning through their interdisciplinary collaborative work which gave them new perspectives on health justice issues. The community partners indicated that the students consultative work products were useful for their initiatives, and that they found working with MD and MPP students to be a valuable way to think about how to build stronger and more inclusive coalitions to advocate for health justice. This project has the potential for national impact as it aligns with the Association of American Medical Colleges' renewed focus on the responsibility of academic medicine to partner with communities for health justice. The project also contributed to the national conversation on how to align health systems science education with the aims of health justice through our participation in the American Medical Association Accelerating Change in Medical Education Consortium. Lessons Learned: Leveraging faculty relationships with community partners was crucial for developing meaningful projects for students. Cultivating and expanding community partner networks is necessary to sustain and scale up this type of intervention. Centering the needs of communities and supporting their on-going work for health justice is essential for becoming an effective advocate. Learning communities that bring interdisciplinary students, healthcare providers, policy professionals, and community partners together to learn from one another can create key opportunities for ameliorating health inequities.

Melanoma Cellular Plasticity.

Despite the advances of modern medicine and the development of innovative and promising new therapeutic strategies for the treatment of the numerous types of cancer, far too many patients still lose the battle against these devastating diseases [...].

SOX2 in development and cancer biology.

The transcription factor SOX2 is essential for embryonic development and plays a crucial role in maintaining the stemness of embryonic cells and various adult stem cell populations. On the other hand, dysregulation of SOX2 expression is associated with a multitude of cancer types and it has been shown that SOX2 positively affects cancer cell traits such as the capacity to proliferate, migrate, invade and metastasize. Moreover, there is growing evidence that SOX2 mediates resistance towards established cancer therapies and that it is expressed in cancer stem cells. These findings indicate that studying the role of SOX2 in the context of cancer progression could lead to the development of new therapeutic options. In this review, the current knowledge about the role of SOX2 in development, maintenance of stemness, cancer progression and the resistance towards cancer therapies is summarized.

FOXD1 promotes dedifferentiation and targeted therapy resistance in melanoma by regulating the expression of connective tissue growth factor.

Metastatic melanoma is an aggressive skin cancer and associated with a poor prognosis. In clinical terms, targeted therapy is one of the most important treatments for patients with BRAFV600E -mutated advanced melanoma. However, the development of resistance to this treatment compromises its therapeutic success. We previously demonstrated that forkhead box D1 (FOXD1) regulates melanoma migration and invasion. Here, we found that FOXD1 was highly expressed in melanoma cells and was associated with a poor survival of patients with metastatic melanoma. Upregulation of FOXD1 expression enhanced melanoma cells' resistance to vemurafenib (BRAF inhibitor [BRAFi]) or vemurafenib and cobimetinib (MEK inhibitor) combination treatment whereas loss of FOXD1 increased the sensitivity to treatment. By comparing gene expression levels between FOXD1 knockdown (KD) and overexpressing (OE) cells, we identified the connective tissue growth factor (CTGF) as a downstream factor of FOXD1. Chromatin immunoprecipitation and luciferase assay demonstrated the direct binding of FOXD1 to the CTGF promoter. Similar to FOXD1, knockdown of CTGF increased the sensitivity of BRAFi-resistant cells to vemurafenib. FOXD1 KD cells treated with recombinant CTGF protein were less sensitive towards vemurafenib compared to untreated FOXD1 KD cells. Based on these findings, we conclude that FOXD1 might be a promising new diagnostic marker and a therapeutic target for the treatment of targeted therapy resistant melanoma.

A Novel Saliva Collection Method among Children and Infants: A Comparison Study between Oral Swab and Pacifier-based Saliva Collection.

AIM: This study aims to test the feasibility and effectiveness of a novel pacifier-based saliva collection method on children and infants in comparison to an oral swab-based saliva collection method. MATERIALS AND METHODS: This study was performed during spring 2018 in a clinical non-sponsored setting at Queen Silvia Children's Hospital pediatric emergency ward. Saliva collection was performed by comparing oral swab (Salimetrics® SalivaBio's Children's Swab) with a pacifier-based saliva collection method (Salivac®). All participating children used both saliva collection systems. The amount of saliva collected in 2 minutes was measured. The amount of time needed for the healthcare professional was recorded. Parental preference was evaluated by a questionnaire. RESULTS: No statistically significant difference was observed in collected saliva (174 µL for pacifier-based saliva collection and 158 µL for oral swab). The healthcare professional spent significantly less (p < 0.001) mean time with the pacifier-based saliva collection method than with the oral swab (31 vs 150 sec). A total of 48 out of the 52 caretakers preferred the pacifier-based saliva collection method compared to the oral swab. CONCLUSION: The novel pacifier-based saliva collection method proved to be a feasible, appreciated, and effective way of collecting saliva that simplifies the saliva collection method among children and infants. CLINICAL SIGNIFICANCE: The pacifier-based saliva collection method simplifies saliva testing. The closed vacutainer system minimizes the risk of saliva contamination and opens up for novel home testing strategies.

T-type calcium channel inhibition restores sensitivity to MAPK inhibitors in de-differentiated and adaptive melanoma cells.

BACKGROUND: Drug resistance remains as one of the major challenges in melanoma therapy. It is well known that tumour cells undergo phenotypic switching during melanoma progression, increasing melanoma plasticity and resistance to mitogen-activated protein kinase inhibitors (MAPKi). METHODS: We investigated the melanoma phenotype switching using a partial reprogramming model to de-differentiate murine melanoma cells and target melanoma therapy adaptation against MAPKi. RESULTS: Here, we show that partially reprogrammed cells are a less proliferative and more de-differentiated cell population, expressing a gene signature for stemness and suppressing melanocyte-specific markers. To investigate adaptation to MAPKi, cells were exposed to B-Raf Proto-Oncogene (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors. De-differentiated cells became less sensitive to MAPKi, showed increased cell viability and decreased apoptosis. Furthermore, T-type calcium channels expression increased in adaptive murine cells and in human adaptive melanoma cells. Treatment with the calcium channel blocker mibefradil induced cell death, differentiation and susceptibility to MAPKi in vitro and in vivo. CONCLUSION: In summary, we show that partial reprogramming of melanoma cells induces de-differentiation and adaptation to MAPKi. Moreover, we postulated a calcium channel blocker such as mibefradil, as a potential candidate to restore sensitivity to MAPKi in adaptive melanoma cells.

Influence of glucometric 'dynamical' variables on duodenal-jejunal bypass liner (DJBL) anthropometric and metabolic outcomes.

BACKGROUND: The endoscopically implanted duodenal-jejunal bypass liner (DJBL) is an attractive alternative to bariatric surgery for obese diabetic patients. This article aims to study dynamical aspects of the glycaemic profile that may influence DJBL effects. METHODS: Thirty patients underwent DJBL implantation and were followed for 10 months. Continuous glucose monitoring (CGM) was performed before implantation and at month 10. Dynamical variables from CGM were measured: coefficient of variation of glycaemia, mean amplitude of glycaemic excursions (MAGE), detrended fluctuation analysis (DFA), % of time with glycaemia under 6.1 mmol/L (TU6.1), area over 7.8 mmol/L (AO7.8) and time in range. We analysed the correlation between changes in both anthropometric (body mass index, BMI and waist circumference) and metabolic (fasting blood glucose, FBG and HbA1c) variables and dynamical CGM-derived metrics and searched for variables in the basal CGM that could predict successful outcomes. RESULTS: There was a poor correlation between anthropometric and metabolic outcomes. There was a strong correlation between anthropometric changes and changes in glycaemic tonic control (∆BMI-∆TU6.1: rho = - 0.67, P < .01) and between metabolic outcomes and glycaemic phasic control (∆FBG-∆AO7.8: r = .60, P < .01). Basal AO7.8 was a powerful predictor of successful metabolic outcome (0.85 in patients with AO7.8 above the median vs 0.31 in patients with AO7.8 below the median: Chi-squared = 5.67, P = .02). CONCLUSIONS: In our population, anthropometric outcomes of DJBL correlate with improvement in tonic control of glycaemia, while metabolic outcomes correlate preferentially with improvement in phasic control. Assessment of basal phasic control may help in candidate profiling for DJBL implantation.

Cellular Reprogramming-A Model for Melanoma Cellular Plasticity.

Cellular plasticity of cancer cells is often associated with phenotypic heterogeneity and drug resistance and thus remains a major challenge for the treatment of melanoma and other types of cancer. Melanoma cells have the capacity to switch their phenotype during tumor progression, from a proliferative and differentiated phenotype to a more invasive and dedifferentiated phenotype. However, the molecular mechanisms driving this phenotype switch are not yet fully understood. Considering that cellular heterogeneity within the tumor contributes to the high plasticity typically observed in melanoma, it is crucial to generate suitable models to investigate this phenomenon in detail. Here, we discuss the use of complete and partial reprogramming into induced pluripotent cancer (iPC) cells as a tool to obtain new insights into melanoma cellular plasticity. We consider this a relevant topic due to the high plasticity of melanoma cells and its association with a strong resistance to standard anticancer treatments.

Classification of Actigraphy Records from Bipolar Disorder Patients Using Slope Entropy: A Feasibility Study.

Bipolar Disorder (BD) is an illness with high prevalence and a huge social and economic impact. It is recurrent, with a long-term evolution in most cases. Early treatment and continuous monitoring have proven to be very effective in mitigating the causes and consequences of BD. However, no tools are currently available for a massive and semi-automatic BD patient monitoring and control. Taking advantage of recent technological developments in the field of wearables, this paper studies the feasibility of a BD episodes classification analysis while using entropy measures, an approach successfully applied in a myriad of other physiological frameworks. This is a very difficult task, since actigraphy records are highly non-stationary and corrupted with artifacts (no activity). The method devised uses a preprocessing stage to extract epochs of activity, and then applies a quantification measure, Slope Entropy, recently proposed, which outperforms the most common entropy measures used in biomedical time series. The results confirm the feasibility of the approach proposed, since the three states that are involved in BD, depression, mania, and remission, can be significantly distinguished.

Histone methyltransferase SETDB1 contributes to melanoma tumorigenesis and serves as a new potential therapeutic target.

Alterations in histone modifications play a crucial role in the progression of various types of cancer. The histone methyltransferase SETDB1 catalyzes the addition of methyl groups to histone H3 at lysine 9. Here, we describe how overexpression of SETDB1 contributes to melanoma tumorigenesis. SETDB1 is highly amplified in melanoma cells and in the patient tumors. Increased expression of SETDB1, which correlates with SETDB1 amplification, is associated with a more aggressive phenotype in in vitro and in vivo studies. Mechanistically, SETDB1 implements its effects via regulation of thrombospondin 1, and the SET-domain of SETDB1 is essential for the maintenance of its tumorigenic activity. Inhibition of SETDB1 reduces cell growth in melanomas resistant to targeted treatments. Our results indicate that SETDB1 is a major driver of melanoma development and may serve as a potential future target for the treatment of this disease.

Loss of neural crest-associated gene FOXD1 impairs melanoma invasion and migration via RAC1B downregulation.

Recent studies suggest that malignant melanoma heterogeneity includes subpopulations of cells with features of multipotent neural crest (NC) cells. Zebrafish and mouse models have shown that reactivation of neural crest-specific pathways during transformation determines the invasiveness of melanoma cells. In our study, we show that the neural crest-associated transcription factor FOXD1 plays a key role in the invasion and the migration capacities of metastatic melanomas both in vivo and in vitro. Gene expression profiling analysis identified both an upregulation of FOXD1 in NC and melanoma cells, as well as a downregulation of several genes related to cell invasion in FOXD1 knockdown cells, including MMP9 and RAC1B. Furthermore, we demonstrate that knockdown of RAC1B a tumor-specific isoform of RAC1, significantly impaired melanoma cell migration and invasion and could abrogate enhanced invasiveness induced by FOXD1 overexpression. We conclude that FOXD1 may influence invasion and migration via indirect regulation of MMP9 and RAC1B alternative splicing in melanoma cells.

SOX2-mediated upregulation of CD24 promotes adaptive resistance toward targeted therapy in melanoma.

Melanoma is often characterized by a constitutively active RAS-RAF-MEK-ERK pathway. For targeted therapy, BRAF inhibitors are available that are powerful in the beginning but resistance occurs rather fast. A better understanding of the mechanisms of resistance is urgently needed to increase the success of the treatment. Here, we observed that SOX2 and CD24 are upregulated upon BRAF inhibitor treatment. A similar upregulation was seen in targeted therapy-resistant, melanoma-derived induced pluripotent cancer cells (iPCCs). SOX2 and CD24 are known to promote an undifferentiated and cancer stem cell-like phenotype associated with resistance. We, therefore, elucidated the role of SOX2 and CD24 in targeted therapy resistance in more detail. We found that the upregulation of SOX2 and CD24 required activation of STAT3 and that SOX2 induced the expression of CD24 by binding to its promoter. We find that the overexpression of SOX2 or CD24 significantly increases the resistance toward BRAF inhibitors, while SOX2 knock-down rendered cells more sensitivity toward treatment. The overexpression of CD24 or SOX2 induced Src and STAT3 activity. Importantly, by either CD24 knock-down or Src/STAT3 inhibition in resistant SOX2-overexpressing cells, the sensitivity toward BRAF inhibitors was re-established. Hence, we suggest a novel mechanism of adaptive resistance whereby BRAF inhibition is circumvented via the activation of STAT3, SOX2 and CD24. Thus, to prevent adaptive resistance, it might be beneficial to combine Src/STAT3 inhibitors together with MAPK pathway inhibitors.

Parental education and family income affect birthweight, early longitudinal growth and body mass index development differently.

AIM: This study investigated the effects of two parental socio-economic characteristics, education and income, on growth and risk of obesity in children from birth to 8 years of age. METHODS: Longitudinal growth data and national register-based information on socio-economic characteristics were available for 3,030 Swedish children. The development of body mass index (BMI) and height was compared in groups dichotomised by parental education and income. RESULTS: Low parental education was associated with a higher BMI from 4 years of age, independent of income, immigrant background, maternal BMI and smoking during pregnancy. Low family income was associated with a lower birthweight, but did not independently predict BMI development. At 8 years of age, children from less educated families had a three times higher risk of obesity, independent of parental income. Children whose parents had fewer years of education but high income had significantly higher height than all other children. CONCLUSION: Parental education protected against childhood obesity, even after adjusting for income and other important parental characteristics. Income-related differences in height, despite similar BMIs, raise questions about body composition and metabolic risk profiles. The dominant role of education underscores the value of health literacy initiatives for the parents of young children.

Distinct populations of neurons respond to emotional valence and arousal in the human subthalamic nucleus.

Both animal studies and studies using deep brain stimulation in humans have demonstrated the involvement of the subthalamic nucleus (STN) in motivational and emotional processes; however, participation of this nucleus in processing human emotion has not been investigated directly at the single-neuron level. We analyzed the relationship between the neuronal firing from intraoperative microrecordings from the STN during affective picture presentation in patients with Parkinson's disease (PD) and the affective ratings of emotional valence and arousal performed subsequently. We observed that 17% of neurons responded to emotional valence and arousal of visual stimuli according to individual ratings. The activity of some neurons was related to emotional valence, whereas different neurons responded to arousal. In addition, 14% of neurons responded to visual stimuli. Our results suggest the existence of neurons involved in processing or transmission of visual and emotional information in the human STN, and provide evidence of separate processing of the affective dimensions of valence and arousal at the level of single neurons as well.

Routine colonoscopy, diabetic eye care, mammogram and pap smear screening in vascular surgery patients.

Objective An increasing emphasis on preventive medicine has been supported by the recent reforms in United States health care system. Majority of the patients seen in vascular surgery clinics are elderly with more extensive medical comorbidities compared to the general population. Thus, these patients would be expected at higher risk for common malignant pathologies such as colon, breast and cervical cancer, and nonmalignant diseases such as diabetic retinopathy. This study looked at the screening compliance of vascular patients compared to data provided by Centers for Disease Control on the national and state levels. Methods The office records of 851 consecutive patients seen in Brooklyn and Staten Island vascular clinics were examined. We queried patients regarding their last colonoscopy, diabetic eye exams, recent mammograms, and Pap smears. Our patient screening compliance was compared between the two clinics as well as to the national and New York state data provided by Centers for Disease Control. Compliance with regard to patient's age was also examined. Results Patients referred to the Staten Island office have a better colonoscopy compliance compared to the Brooklyn office ( P = .0001) and the national Centers for Disease Control average ( P = .026). Compliance for mammography and cervical cancer screening was higher in Staten Island office compared to the Brooklyn office ( P = .0001, P < .0001), respectively. Compliance was lower for Pap smear ( P = .0273) in Brooklyn when compared to the national average. Compliance for colonoscopy increased with age for both clinics ( P = .001, P < .001), while Pap smear decreased ( P < .001, P = .004). Conclusion Patients in vascular clinics in an urban setting had better adherence to screening protocol than the national and state average, with the exception of female patients for colonoscopy in our Brooklyn vascular office. There exists variability in both patient populations based on sub-specific locality and demographics including socioeconomic status. Overall, however patients in Staten Island had better compliance and adherence to the screening protocol than Brooklyn vascular clinic.

Bilateral Phlegmasia Cerulea Dolens After Warfarin Reversal for Acute Rectal Bleeding: A Case Report.

BACKGROUND: Deep vein thrombosis (DVT) is a common disease that is diagnosed in approximately 1 in 1000 adults annually. Extensive DVT can lead to life- or limb-threatening diagnoses such as phlegmasia cerulea dolens (PCD), phlegmasia alba dolens, and venous gangrene. PCD, also known as massive iliofemoral venous thrombosis, is rare, and a severe complication of DVT. CASE REPORT: We report a case of a 94-year-old bedridden woman with past medical history of dementia, hypertension, pulmonary embolism, DVT, and atrial fibrillation. The patient was admitted to the hospital for bright red blood per rectum and an elevated international normalized ratio (INR) of 5.7. On admission, her dose of warfarin was suspended and she was given 4 units of fresh frozen plasma as well as 10 mg of i.v. vitamin K. She was discharged home with an INR normalized to 1.3 and cessation of her rectal bleeding. At discharge, she was not restarted on warfarin, nor was any bridging therapy used. The patient returned to the Emergency Department a week later for worsening pain and bluish discoloration of her bilateral lower extremities. An ultrasound (US) examination showed that she had developed bilateral PCD, after INR reversal. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians commonly care for patients who present with acute DVT or treat patients on anticoagulant therapy who require cessation of medications or administration of prothrombotic agents to reverse bleeding. Cases of extensive clot burden leading to PCD have been reported in the literature, however, reports of bilateral PCD secondary to cessation of warfarin have been scarce. PCD should be considered carefully as one of the complications in warfarin reversal, as it requires immediate attention and surgical intervention to prevent limb loss.

Characterization of Artifact Influence on the Classification of Glucose Time Series Using Sample Entropy Statistics.

This paper analyses the performance of SampEn and one of its derivatives, Fuzzy Entropy (FuzzyEn), in the context of artifacted blood glucose time series classification. This is a difficult and practically unexplored framework, where the availability of more sensitive and reliable measures could be of great clinical impact. Although the advent of new blood glucose monitoring technologies may reduce the incidence of the problems stated above, incorrect device or sensor manipulation, patient adherence, sensor detachment, time constraints, adoption barriers or affordability can still result in relatively short and artifacted records, as the ones analyzed in this paper or in other similar works. This study is aimed at characterizing the changes induced by such artifacts, enabling the arrangement of countermeasures in advance when possible. Despite the presence of these disturbances, results demonstrate that SampEn and FuzzyEn are sufficiently robust to achieve a significant classification performance, using records obtained from patients with duodenal-jejunal exclusion. The classification results, in terms of area under the ROC of up to 0.9, with several tests yielding AUC values also greater than 0.8, and in terms of a leave-one-out average classification accuracy of 80%, confirm the potential of these measures in this context despite the presence of artifacts, with SampEn having slightly better performance than FuzzyEn.

Directed Dedifferentiation Using Partial Reprogramming Induces Invasive Phenotype in Melanoma Cells.

The combination of cancer-focused studies and research related to nuclear reprogramming has gained increasing importance since both processes-reprogramming towards pluripotency and malignant transformation-share essential features. Studies have revealed that incomplete reprogramming of somatic cells leads to malignant transformation indicating that epigenetic regulation associated with iPSC generation can drive cancer development [J Mol Cell Biol 2011;341-350; Cell 2012;151:1617-1632; Cell 2014;156:663-677]. However, so far it is unclear whether incomplete reprogramming also affects cancer cells and their function. In the context of melanoma, dedifferentiation correlates to therapy resistance in mouse studies and has been documented in melanoma patients [Nature 2012;490:412-416; Clin Cancer Res 2014;20:2498-2499]. Therefore, we sought to investigate directed dedifferentiation using incomplete reprogramming of melanoma cells. Using a murine model we investigated the effects of partial reprogramming on the cellular plasticity of melanoma cells. We demonstrate for the first time that induced partial reprogramming results in a reversible phenotype switch in melanoma cells. Partially reprogrammed cells at day 12 after transgene induction display elevated invasive potential in vitro and increased lung colonization in vivo. Additionally, using global gene expression analysis of partially reprogrammed cells, we identified SNAI3 as a novel invasion-related marker in human melanoma. SNAI3 expression correlates with tumor thickness in primary melanomas and thus, may be of prognostic value. In summary, we show that investigating intermediate states during the process of reprogramming melanoma cells can reveal novel insights into the pathogenesis of melanoma progression. We propose that deeper analysis of partially reprogrammed melanoma cells may contribute to identification of yet unknown signaling pathways that can drive melanoma progression.