Multidimensional digital biomarker phenotypes for mild cognitive impairment: considerations for early identification, diagnosis and monitoring.

Mild Cognitive Impairment (MCI) poses a challenge for a growing population worldwide. Early identification of risk for and diagnosis of MCI is critical to providing the right interventions at the right time. The paucity of reliable, valid, and scalable methods for predicting, diagnosing, and monitoring MCI with traditional biomarkers is noteworthy. Digital biomarkers hold new promise in understanding MCI. Identifying digital biomarkers specifically for MCI, however, is complex. The biomarker profile for MCI is expected to be multidimensional with multiple phenotypes based on different etiologies. Advanced methodological approaches, such as high-dimensional statistics and deep machine learning, will be needed to build these multidimensional digital biomarker profiles for MCI. Comparing patients to these MCI phenotypes in clinical practice can assist clinicians in better determining etiologies, some of which may be reversible, and developing more precise care plans. Key considerations in developing reliable multidimensional digital biomarker profiles specific to an MCI population are also explored.

Body Mindsets are Associated With Pain and Threat-Related Risk Factors for Pain in Survivors of Childhood Cancer.

Pain is a common consequence of childhood cancer. While most research has examined biomedical predictors of post-cancer pain, biopsychosocial conceptualisations such as the cancer threat interpretation (CTI) model hold promise for guiding comprehensive pain management strategies. Guided by the CTI model, this cross-sectional study evaluated correlates of post-cancer pain in childhood cancer survivors including threat-related risk factors (bodily threat monitoring, fear of cancer recurrence, help-seeking) and mindsets about the body. In the preceding three months, 21.8% of the survivors reported chronic pain (>3 months), and 14.3% experienced pain most days. Greater bodily threat monitoring, more fear of cancer recurrence, and more help-seeking were associated with more pain. There was heterogeneity in the mindsets that survivors of childhood cancer hold about their bodies. Holding the mindset that the 'body is an adversary' was associated with more pain, greater bodily threat monitoring, and more fear of cancer recurrence. Holding the mindset that the 'body is responsive' was associated with less bodily threat monitoring, while the mindset that the 'body is capable' was associated with greater help-seeking. A path model demonstrated a significant combined indirect effect of the 'body is an adversary' mindset on pain through bodily threat monitoring and fear of cancer recurrence. Overall, this study supported that a sub-group of childhood cancer survivors experience persistent and interfering pain and provided cross-sectional support for threat-related correlates for pain aligning with the CTI model. Body mindsets were associated with pain and threat-related correlates and may represent a novel target to support survivors with pain. PERSPECTIVE: This article presents associations of body mindsets, threat-related risk factors, and pain in survivors of childhood cancer (aged 11-25), guided by the Cancer Threat Interpretation model. The study indicates that body mindsets may be novel targets to embed in comprehensive post-cancer pain management approaches to support young survivors with pain.

Interferometric Imaging Using Shared Quantum Entanglement.

Quantum entanglement-based imaging promises significantly increased resolution by extending the spatial separation of optical collection apertures used in very-long-baseline interferometry for astronomy and geodesy. We report a tabletop entanglement-based interferometric imaging technique that utilizes two entangled field modes serving as a phase reference between two apertures. The spatial distribution of a simulated thermal light source is determined by interfering light collected at each aperture with one of the entangled fields and performing joint measurements. This experiment demonstrates the ability of entanglement to implement interferometric imaging.

Digital outpatient health solutions as a vehicle to improve healthcare sustainability-a United Kingdom focused policy and practice perspective.

Introduction: In the midst of a global climate emergency and with health care systems across the world facing extreme pressure, interest in digital approaches as a potential part-solution to these challenges has increased rapidly. The evidence base to support the role that digitalization can play in moving towards more sustainable models of healthcare is growing, as is the awareness of this key area of healthcare reform amongst policy makers, clinicians and the public. Method and Results: In this policy and practice review we explore four domains of healthcare sustainability-environmental, economic, and patient and clinician, delineating the potential impact that digitally enabled healthcare can have on each area. Real-world examples are provided to illustrate the impact individual digital interventions can have on each pillar of sustainability and demonstrate the scale of the potential benefits which can be achieved. Discussion: Digitally enabled healthcare solutions present an approach which offer numerous benefits, including environmental sustainability, economic benefits, and improved patient experience. There are also potential drawbacks such as the risk of digital exclusion and the need for integration with existing technology platforms. Overall, it is essential to strike a balance between the benefits and potential drawbacks of digital healthcare solutions to ensure that they are equitable, effective, and sustainable.

Conservative Management of Postoperative Urinary Leak and Intra-Abdominal Abscess.

Ureteral injury is a rare occurrence in medical practice. Most cases encountered stem from blunt trauma or are iatrogenic, occurring during open abdominal or pelvic surgery and laparoscopic procedures. Prompt diagnosis of ureteral injury allows clinicians to avoid complications including ureteral strictures, abscess, renal failure, sepsis, and loss of the ipsilateral kidney. Treatment depends on whether the ureteral injury was discovered intraoperatively or if it was a delayed diagnosis. Several procedures can be used, including ureteroureterostomy, ureteroileal interposition, and nephrectomy. Stenting can also be a viable option as it can reestablish urinary drainage. Herein, we present the case of a 43-year-old male who presented with complaints of progressive abdominal pain that was subsequently diagnosed as a left ureteral injury and how the use of a ureteral stent allowed him to have a full recovery with optimized normal ureteral function.

Long-Term Retained Lippes Loop Intrauterine Device Causes Vesicouterine Fistula.

This case report discusses a 77-year-old female patient who presented to an outpatient clinic with urinary symptoms and recurrent UTIs. Imaging revealed a foreign body, which was later confirmed as a retained intrauterine device (IUD) that had caused a vesicouterine fistula (VUF). The patient had a medical history of cervical cancer treated with radiation therapy, during which her IUD's string could not be located, leading to the decision to proceed with radiation therapy without removing the IUD. The patient opted to manage her condition medically rather than undergo surgical removal due to concerns about worsening the vesicouterine fistula. This case highlights the potential risks and complications of retained IUDs, and the importance of careful consideration and communication among clinical teams and patients when managing these situations.

Moving Forward from Moral Injury: A Mixed Methods Study Investigating the Use of 3MDR for Treatment-Resistant PTSD.

BACKGROUND: Exposure to trauma and potentially morally injurious events may lead to moral injury (MI). The link between MI and posttraumatic stress disorder (PTSD) may have particularly relevant implications for treatment-resistant PTSD (TR-PTSD). Multi-modal Motion-Assisted Memory Desensitization and Reconsolidation (3MDR), a technology-assisted exposure-based trauma therapy that has been used in the treatment of PTSD, may also be an acceptable modality for patients in the treatment of TR-PTSD and MI. This proof-of-concept study aimed to investigate (1) whether MI co-occurs in military members (MMs) and veterans with TR-PTSD, and (2) the perspectives of MMs and veterans with TR-PTSD utilizing 3MDR for MI. METHODS: This study employed a mixed-methods clinical trial. Military Members and veterans participated in this study (N = 11) through self-reported questionnaires, video recordings of treatment sessions, and semi-structured interviews post-session and post-intervention, with longitudinal follow-up to 6 months. RESULTS: MI scores correlated with self-reported measures of mental health symptoms related to PTSD. The thematic analysis revealed three emergent themes: (1) Realities of War, (2) Wrestling Scruples, and (3) Moral Sensemaking. CONCLUSION: MI was highly correlated with TR-PTSD and themes regarding MI. This result, while preliminary, allows for the postulation that MI may be contributing to the continuation of PTSD symptoms in TR-PTSD, and that 3MDR may be an acceptable modality for addressing these symptoms in MMs and veterans.

FALCON systematically interrogates free fatty acid biology and identifies a novel mediator of lipotoxicity.

Cellular exposure to free fatty acids (FFAs) is implicated in the pathogenesis of obesity-associated diseases. However, there are no scalable approaches to comprehensively assess the diverse FFAs circulating in human plasma. Furthermore, assessing how FFA-mediated processes interact with genetic risk for disease remains elusive. Here, we report the design and implementation of fatty acid library for comprehensive ontologies (FALCON), an unbiased, scalable, and multimodal interrogation of 61 structurally diverse FFAs. We identified a subset of lipotoxic monounsaturated fatty acids associated with decreased membrane fluidity. Furthermore, we prioritized genes that reflect the combined effects of harmful FFA exposure and genetic risk for type 2 diabetes (T2D). We found that c-MAF-inducing protein (CMIP) protects cells from FFA exposure by modulating Akt signaling. In sum, FALCON empowers the study of fundamental FFA biology and offers an integrative approach to identify much needed targets for diverse diseases associated with disordered FFA metabolism.

FALCON systematically interrogates free fatty acid biology and identifies a novel mediator of lipotoxicity.

Cellular exposure to free fatty acids (FFA) is implicated in the pathogenesis of obesity-associated diseases. However, studies to date have assumed that a few select FFAs are representative of broad structural categories, and there are no scalable approaches to comprehensively assess the biological processes induced by exposure to diverse FFAs circulating in human plasma. Furthermore, assessing how these FFA- mediated processes interact with genetic risk for disease remains elusive. Here we report the design and implementation of FALCON (Fatty Acid Library for Comprehensive ONtologies) as an unbiased, scalable and multimodal interrogation of 61 structurally diverse FFAs. We identified a subset of lipotoxic monounsaturated fatty acids (MUFAs) with a distinct lipidomic profile associated with decreased membrane fluidity. Furthermore, we developed a new approach to prioritize genes that reflect the combined effects of exposure to harmful FFAs and genetic risk for type 2 diabetes (T2D). Importantly, we found that c-MAF inducing protein (CMIP) protects cells from exposure to FFAs by modulating Akt signaling and we validated the role of CMIP in human pancreatic beta cells. In sum, FALCON empowers the study of fundamental FFA biology and offers an integrative approach to identify much needed targets for diverse diseases associated with disordered FFA metabolism. Highlights: FALCON (Fatty Acid Library for Comprehensive ONtologies) enables multimodal profiling of 61 free fatty acids (FFAs) to reveal 5 FFA clusters with distinct biological effectsFALCON is applicable to many and diverse cell typesA subset of monounsaturated FAs (MUFAs) equally or more toxic than canonical lipotoxic saturated FAs (SFAs) leads to decreased membrane fluidityNew approach prioritizes genes that represent the combined effects of environmental (FFA) exposure and genetic risk for diseaseC-Maf inducing protein (CMIP) is identified as a suppressor of FFA-induced lipotoxicity via Akt-mediated signaling.

Cannabis-Based Medicinal Products in the Management of Emotionally Unstable Personality Disorder (EUPD): A Narrative Review and Case Series.

Emotionally unstable personality disorder (EUPD) is a common mental health disorder, manifesting with a range of chronic and debilitating symptoms, including impaired social functioning, unstable mood, and risky impulsive or self-injurious behaviour. Whilst the exact aetiology has not been fully elucidated, implicated factors seem to include genetic factors, environmental causes such as trauma, and neurotransmitter deficits. The literature suggests that impaired functioning of the endocannabinoid system in key brain regions responsible for emotional processing and stress response may underlie the manifestation of EUPD symptoms. The National Institute for Health and Care Excellence (NICE) 2009 guidelines state that "no drugs have established efficacy in treating or managing EUPD", and yet, patients are commonly prescribed medication which includes antipsychotics, antidepressants, and mood stabilisers. Here we present a case series of seven participants diagnosed with EUPD and treated with cannabis-based medicinal products (CBMPs). Participants were given an initial assessment and followed up one month after CBMPs prescription. Improvement in symptoms was assessed by the completion of ratified rating scales by the participant and psychiatrist. Our results indicate that CBMPs were effective and well tolerated, as six participants reported a noticeable improvement in their symptoms and functioning. Although promising, further research is needed to ascertain the long-term tolerability, efficacy, and dosing strategy for CBMPs in EUPD.

"Flower Power": Controlled Inhalation of THC-Predominant Cannabis Flos Improves Health-Related Quality of Life and Symptoms of Chronic Pain and Anxiety in Eligible UK Patients.

In November 2018, the UK's Home Office established a legal route for eligible patients to be prescribed cannabis-based products for medicinal use in humans (CBPMs) as unlicensed medicines. These include liquid cannabis extracts for oral administration ("oils") and dried flowers for inhalation ("flos"). Smoking of CBPMs is expressly prohibited. To date, THC-predominant cannabis flowers remain the most prescribed CBPMs in project Twenty21 (T21), the first multi-center, prospective, observational UK cannabis patient registry. This observational, prospective data review analyzes patient-reported outcome measures (PROMS) collected by T21 associated with the inhalation of KHIRON 20/1, the most prescribed CBPM in the project. PROMS collected at baseline and at subsequent 3-month follow-up included health-related quality of life (HRQoL), general mood, and sleep. Condition-specific measures of illness severity were performed with the Brief Pain Inventory Short Form (BPI-SF) and the Generalized Anxiety Disorder 7-Item Scale (GAD-7). Participants (N = 344) were mostly males (77.6%, average age = 38.3) diagnosed mainly with chronic pain (50.9%) and anxiety-related disorders (25.3%). Inhalation of KHIRON 20/1 was associated with a marked increase in self-reported HRQoL, general mood, and sleep (N = 344; p < 0.001). Condition-specific assessments showed significant improvements in pain severity (T = 6.67; p < 0.001) and interference (T = 7.19; p < 0.001) in patients using KHIRON 20/1 for chronic pain (N = 174). Similar results were found for patients diagnosed with anxiety-related disorders (N = 107; T = 12.9; p < 0.001). Our results indicate that controlled inhalation of pharmaceutical grade, THC-predominant cannabis flos is associated with a significant improvement in patient-reported pain scores, mood, anxiety, sleep disturbances and overall HRQoL in a treatment-resistant clinical population.

The Redesign and Validation of Multimodal Motion-Assisted Memory Desensitization and Reconsolidation Hardware and Software: Mixed Methods, Modified Delphi-Based Validation Study.

BACKGROUND: In recent years, the delivery of evidence-based therapies targeting posttraumatic stress disorder (PTSD) has been the focus of the Departments of Defense in countries such as Canada, the Netherlands, and the United States. More than 66% of military members continue to experience symptoms of PTSD that significantly impact their daily functioning and quality of life after completing evidence-based treatments. Innovative, engaging, and effective treatments for PTSD are needed. Multimodal motion-assisted memory desensitization and reconsolidation (3MDR) is an exposure-based, virtual reality-supported therapy used to treat military members and veterans with treatment-resistant PTSD. Given the demonstrated efficacy of 3MDR in recently published randomized control trials, there is both an interest in and a need to adapt the intervention to other populations affected by trauma and to improve accessibility to the treatment. OBJECTIVE: We aimed to further innovate, develop, and validate new and existing hardware and software components of 3MDR to enhance its mobility, accessibility, feasibility, and applicability to other populations affected by trauma, including public safety personnel (PSP), via international collaboration. METHODS: This study used a modified Delphi expert consultation method and mixed methods quasi-experimental validation with the purpose of software validation among PSP (first responders, health care providers) participants (N=35). A team of international experts from the Netherlands, the United States, and Canada met on the web on a weekly basis since September 2020 to discuss the adoption of 3MDR in real-world contexts, hardware and software development, and software validation. The evolution of 3MDR hardware and software was undertaken followed by a mixed methods software validation study with triangulation of results to inform the further development of 3MDR. RESULTS: This study resulted in the identification, description, and evolution of hardware and software components and the development of new 3MDR software. Within the software validation, PSP participants widely acknowledged that the newly developed 3MDR software would be applicable and feasible for PSP affected by trauma within their professions. The key themes that emerged from the thematic analysis among the PSP included the desire for occupationally tailored environments, individually tailored immersion, and the applicability of 3MDR beyond military populations. CONCLUSIONS: Within the modified Delphi consultation and software validation study, support for 3MDR as an intervention was communicated. PSP participants perceived that 3MDR was relevant for populations affected by trauma beyond military members and veterans. The resulting hardware and software evolution addressed the recommendations and themes that arose from PSP participants. 3MDR is a novel, structured, exposure-based, virtual reality-supported therapy that is currently used to treat military members and veterans with PTSD. Going forward, it is necessary to innovate and adapt 3MDR, as well as other trauma interventions, to increase effectiveness, accessibility, cost-effectiveness, and efficacy among other populations affected by trauma.

Technology Acceptance and Usability of a Virtual Reality Intervention for Military Members and Veterans With Posttraumatic Stress Disorder: Mixed Methods Unified Theory of Acceptance and Use of Technology Study.

BACKGROUND: Military members and veterans exhibit higher rates of injuries and illnesses such as posttraumatic stress disorder (PTSD) because of their increased exposure to combat and other traumatic scenarios. Novel treatments for PTSD are beginning to emerge and increasingly leverage advances in gaming and other technologies, such as virtual reality. Without assessing the degree of technology acceptance and perception of usability to the end users, including the military members, veterans, and their attending therapists and staff, it is difficult to determine whether a technology-based treatment will be used successfully in wider clinical practice. The Unified Theory of Acceptance and Use of Technology model is commonly used to address the technology acceptance and usability of applications in 5 domains. OBJECTIVE: Using the Unified Theory of Acceptance and Use of Technology model, the purpose of this study was to determine the technology acceptance and usability of multimodal motion-assisted memory desensitization and reconsolidation (3MDR) on a virtual reality system in the primary user group (military members and veterans with treatment-resistant PTSD, 3MDR therapists, and virtual reality environment operators). METHODS: This mixed methods embedded pilot study included military members (n=3) and veterans (n=8) with a diagnosis of combat-related PTSD, as well as their therapists (n=13) and operators (n=5) who completed pre-post questionnaires before and on completion of 6 weekly sessions of 3MDR. A partial least squares structural equation model was used to analyze the questionnaire results. Qualitative data from the interviews were assessed using thematic analysis. RESULTS: Effort expectancy, which was the most notable predictor of behavioral intention, increased after a course of 3MDR with the virtual reality system, whereas all other constructs demonstrated no significant change. Participants' expectations of the technology were met, as demonstrated by the nonsignificant differences in the pre-post scores. The key qualitative themes included feasibility and function, technical support, and tailored immersion. CONCLUSIONS: 3MDR via a virtual reality environment appears to be a feasible, usable, and accepted technology for delivering 3MDR to military members and veterans who experience PTSD and 3MDR therapists and operators who facilitate their treatment.

The nuclear receptor REV-ERBα is implicated in the alteration of ß-cell autophagy and survival under diabetogenic conditions.

Pancreatic ß-cell failure in type 2 diabetes mellitus (T2DM) is associated with impaired regulation of autophagy which controls ß-cell development, function, and survival through clearance of misfolded proteins and damaged organelles. However, the mechanisms responsible for defective autophagy in T2DM ß-cells remain unknown. Since recent studies identified circadian clock transcriptional repressor REV-ERBα as a novel regulator of autophagy in cancer, in this study we set out to test whether REV-ERBα-mediated inhibition of autophagy contributes to the ß-cell failure in T2DM. Our study provides evidence that common diabetogenic stressors (e.g., glucotoxicity and cytokine-mediated inflammation) augment ß-cell REV-ERBα expression and impair ß-cell autophagy and survival. Notably, pharmacological activation of REV-ERBα was shown to phenocopy effects of diabetogenic stressors on the ß-cell through inhibition of autophagic flux, survival, and insulin secretion. In contrast, negative modulation of REV-ERBα was shown to provide partial protection from inflammation and glucotoxicity-induced ß-cell failure. Finally, using bioinformatic approaches, we provide further supporting evidence for augmented REV-ERBα activity in T2DM human islets associated with impaired transcriptional regulation of autophagy and protein degradation pathways. In conclusion, our study reveals a previously unexplored causative relationship between REV-ERBα expression, inhibition of autophagy, and ß-cell failure in T2DM.

Sex-Dependent Prescription Patterns and Clinical Outcomes Associated With the Use of Two Oral Cannabis Formulations in the Multimodal Management of Chronic Pain Patients in Colombia.

To date, the therapeutic use of cannabinoids in chronic pain management remains controversial owing to the limited clinical evidence found in randomized clinical trials (RCTs), the heterogeneous nature of the clinical indication, and the broad range of cannabis-based medicinal products (CBMPs) used in both experimental and observational clinical studies. Here we evaluate patient-reported clinical outcomes (PROMS) in a cohort of adult patients, diagnosed with chronic pain of diverse etiology, who received adjuvant treatment with oral, cannabis-based, magistral formulations between May and September 2021 at the Latin American Institute of Neurology and Nervous System (ILANS-Zerenia) in Bogotá, Colombia. During this period, 2,112 patients completed a PROMS questionnaire aimed at capturing the degree of clinical improvement of their primary symptom and any potential side effects. Most participants were female (76.1%) with an average age of 58.7 years old, and 92.5% (1,955 patients) reported some improvement in their primary symptom (p < 0.001). Two monovarietal, full-spectrum, cannabis formulations containing either cannabidiol (CBD 30 mg/mL; THC <2 mg/mL) or a balanced composition (THC 12 mg/mL; CBD 14 mg/mL) accounted for more than 99% of all prescriptions (59.5 and 39.8%, respectively). The degree of improvement was similar between both formulations, although males reported less effectiveness in the first 4 weeks of treatment. Sex-specific differences were also found in prescription patterns, with male patients increasing the intake of the balanced chemotype overtime. For many patients (71.7%) there were no adverse side effects associated to the treatment and those most reported were mild, such as somnolence (13.0%), dizziness (8.1%) and dry mouth (4.2%), which also appeared to fade over time. Our results constitute the first real-world evidence on the clinical use of medicinal cannabis in Colombia and suggest that cannabis-based oral magistral formulations represent a safe and efficacious adjuvant therapeutic option in the management of chronic pain.

It's What and When You Eat: An Overview of Transcriptional and Epigenetic Responses to Dietary Perturbations in Pancreatic Islets.

Our ever-changing modern environment is a significant contributor to the increased prevalence of many chronic diseases, and particularly, type 2 diabetes mellitus (T2DM). Although the modern era has ushered in numerous changes to our daily living conditions, changes in "what" and "when" we eat appear to disproportionately fuel the rise of T2DM. The pancreatic islet is a key biological controller of an organism's glucose homeostasis and thus plays an outsized role to coordinate the response to environmental factors to preserve euglycemia through a delicate balance of endocrine outputs. Both successful and failed adaptation to dynamic environmental stimuli has been postulated to occur due to changes in the transcriptional and epigenetic regulation of pathways associated with islet secretory function and survival. Therefore, in this review we examined and evaluated the current evidence elucidating the key epigenetic mechanisms and transcriptional programs underlying the islet's coordinated response to the interaction between the timing and the composition of dietary nutrients common to modern lifestyles. With the explosion of next generation sequencing, along with the development of novel informatic and -omic approaches, future work will continue to unravel the environmental-epigenetic relationship in islet biology with the goal of identifying transcriptional and epigenetic targets associated with islet perturbations in T2DM.

Specialized Mechanosensory Epithelial Cells in Mouse Gut Intrinsic Tactile Sensitivity.

BACKGROUND AND AIMS: The gastrointestinal (GI) tract extracts nutrients from ingested meals while protecting the organism from infectious agents frequently present in meals. Consequently, most animals conduct the entire digestive process within the GI tract while keeping the luminal contents entirely outside the body, separated by the tightly sealed GI epithelium. Therefore, like the skin and oral cavity, the GI tract must sense the chemical and physical properties of the its external interface to optimize its function. Specialized sensory enteroendocrine cells (EECs) in GI epithelium interact intimately with luminal contents. A subpopulation of EECs express the mechanically gated ion channel Piezo2 and are developmentally and functionally like the skin's touch sensor- the Merkel cell. We hypothesized that Piezo2+ EECs endow the gut with intrinsic tactile sensitivity. METHODS: We generated transgenic mouse models with optogenetic activators in EECs and Piezo2 conditional knockouts. We used a range of reference standard and novel techniques from single cells to living animals, including single-cell RNA sequencing and opto-electrophysiology, opto-organ baths with luminal shear forces, and in vivo studies that assayed GI transit while manipulating the physical properties of luminal contents. RESULTS: Piezo2+ EECs have transcriptomic features of synaptically connected, mechanosensory epithelial cells. EEC activation by optogenetics and forces led to Piezo2-dependent alterations in colonic propagating contractions driven by intrinsic circuitry, with Piezo2+ EECs detecting the small luminal forces and physical properties of the luminal contents to regulate transit times in the small and large bowel. CONCLUSIONS: The GI tract has intrinsic tactile sensitivity that depends on Piezo2+ EECs and allows it to detect luminal forces and physical properties of luminal contents to modulate physiology.

Using Machine Learning to Predict Remission in Patients With Major Depressive Disorder Treated With Desvenlafaxine.

BACKGROUND: Major depressive disorder (MDD) is a common and burdensome condition that has low rates of treatment success for each individual treatment. This means that many patients require several medication switches to achieve remission; selecting an effective antidepressant is typically a sequential trial-and-error process. Machine learning techniques may be able to learn models that can predict whether a specific patient will respond to a given treatment, before it is administered. This study uses baseline clinical data to create a machine-learned model that accurately predicts remission status for a patient after desvenlafaxine (DVS) treatment. METHODS: We applied machine learning algorithms to data from 3,399 MDD patients (90% of the 3,776 subjects in 11 phase-III/IV clinical trials, each described using 92 features), to produce a model that uses 26 of these features to predict symptom remission, defined as an 8-week Hamilton Depression Rating Scale score of 7 or below. We evaluated that learned model on the remaining held-out 10% of the data (n = 377). RESULTS: Our resulting classifier, a trained linear support vector machine, had a holdout set accuracy of 69.0%, significantly greater than the probability of classifying a patient correctly by chance. We demonstrate that this learning process is stable by repeatedly sampling part of the training dataset and running the learner on this sample, then evaluating the learned model on the held-out instances of the training set; these runs had an average accuracy of 67.0% ± 1.8%. CONCLUSIONS: Our model, based on 26 clinical features, proved sufficient to predict DVS remission significantly better than chance. This may allow more accurate use of DVS without waiting 8 weeks to determine treatment outcome, and may serve as a first step toward changing psychiatric care by incorporating clinical assistive technologies using machine-learned models.

Time-restricted feeding prevents deleterious metabolic effects of circadian disruption through epigenetic control of ß cell function.

Circadian rhythm disruption (CD) is associated with impaired glucose homeostasis and type 2 diabetes mellitus (T2DM). While the link between CD and T2DM remains unclear, there is accumulating evidence that disruption of fasting/feeding cycles mediates metabolic dysfunction. Here, we used an approach encompassing analysis of behavioral, physiological, transcriptomic, and epigenomic effects of CD and consequences of restoring fasting/feeding cycles through time-restricted feeding (tRF) in mice. Results show that CD perturbs glucose homeostasis through disruption of pancreatic ß cell function and loss of circadian transcriptional and epigenetic identity. In contrast, restoration of fasting/feeding cycle prevented CD-mediated dysfunction by reestablishing circadian regulation of glucose tolerance, ß cell function, transcriptional profile, and reestablishment of proline and acidic amino acid­rich basic leucine zipper (PAR bZIP) transcription factor DBP expression/activity. This study provides mechanistic insights into circadian regulation of ß cell function and corresponding beneficial effects of tRF in prevention of T2DM.

Decreased Emotional Dysregulation Following Multi-Modal Motion-Assisted Memory Desensitization and Reconsolidation Therapy (3MDR): Identifying Possible Driving Factors in Remediation of Treatment-Resistant PTSD.

Multi-modal motion-assisted memory desensitization and reconsolidation therapy (3MDR), an interactive, virtual reality-assisted, exposure-based intervention for PTSD, has shown promising results for treatment-resistant posttraumatic stress disorder (TR-PTSD) among military members (MMs) and veterans in randomized controlled trials (RCT). Previous research has suggested that emotional regulation (ER) and emotional dysregulation (ED) may be factors which are correlated with symptom severity and maintenance of TR-PTSD. This embedded mixed-methods pilot study (n = 9) sought to explore the impact of 3MDR on ER and ED of MMs and veterans. Difficulties in Emotional Regulation Scale (DERS-18) data were collected at baseline, prior to each session, and at one week, one month, and three months postintervention and analyzed. Qualitative data collected from sessions, debriefs, and follow-up interviews were transcribed and descriptively analyzed. Results demonstrated statistically significant decreases in DERS-18 scores from preintervention to postintervention at each timepoint. Qualitatively, participants perceived improvements in ER within specified DERS-18 domains. We describe how 3MDR's unique and novel approach addresses ED through cognitive-motor stimulation, narration, divergent thinking, reappraisal of aversive stimuli, dual-task processing, and reconsolidation of traumatic memories. More studies are needed to better understand the underlying neurobiological mechanisms by which 3MDR addresses ER and PTSD.