Should rTMS be considered a first-line treatment for major depressive episodes in adults?

Treatment-resistant depression (TRD) is an epidemic with rising social, economic, and political costs. In a patient whose major depressive episode (MDE) persists through an adequate antidepressant trial, insurance companies often cover alternative treatments which may include repetitive transcranial magnetic stimulation (rTMS). RTMS is an FDA-cleared neuromodulation technique for TRD which is safe, efficacious, noninvasive, and well-tolerated. Recent developments in the optimization of rTMS algorithms and targeting have increased the efficacy of rTMS in treating depression, improved the clinical convenience of these treatments, and decreased the cost of a course of rTMS. In this opinion paper, we make a case for why conventional FDA-cleared rTMS should be considered as a first-line treatment for all adult MDEs. RTMS is compared to other first-line treatments including psychotherapy and SSRIs. These observations suggest that rTMS has similar efficacy, fewer side-effects, lower risk of serious adverse events, comparable compliance, the potential for more rapid relief, and cost-effectiveness. This suggestion, however, would be strengthened by further research with an emphasis on treatment-naive subjects in their first depressive episode, and trials directly contrasting rTMS with SSRIs or psychotherapy.

Improving the introduction of telemedicine in pre-hospital emergency medicine: understanding users and how acceptability, usability and effectiveness influence this process.

INTRODUCTION: Increasing numbers of ambulance calls, vacant positions and growing workloads in Emergency Medicine (EM) are increasing the pressure to find adequate solutions. With telemedicine providing health-care services by bridging large distances, connecting remote providers and even patients while using modern communication technologies, such a technology seems beneficial. As the process of developing an optimal solution is challenging, a need to quantify involved processes could improve implementation. Existing models are based on qualitative studies although standardised questionnaires for factors such as Usability, Acceptability and Effectiveness exist. METHODS: A survey was provided to participants within a German county. It was based on telemedical surveys, the System Usabilty Scale (SUS) and earlier works describing Usability, Acceptability and Effectiveness. Meanwhile a telemedical system was introduced in the investigated county. A comparison between user-groups aswell as an exploratory factor analysis (EFA) was performed. RESULTS: Of n = 91 included participants n = 73 (80,2%) were qualified as emergency medical staff (including paramedics n = 36 (39,56%), EMTs n = 28 (30,77%), call handlers n = 9 (9,89%)) and n = 18 (19,8%) as emergency physicians. Most participants approved that telemedicine positively impacts EM and improved treatment options with an overall Usabilty Score of 68,68. EFA provided a 3-factor solution involving Usability, Acceptability and Effectiveness. DISCUSSION: With our results being comparable to earlier studies but telemedicine only having being sparsely introduced, a positive attitude could still be attested. While our model describes 51,28% of the underlying factors, more research is needed to identify further influences. We showed that Usability is correlated with Acceptability (strong effect), Usability and Effectiveness with a medium effect, likewise Acceptability and Effectiveness. Therefore available systems need to improve. Our approach can be a guide for decision makers and developers, that a focus during implementation must be on improving usability and on a valid data driven implementation process.

Accelerated Theta Burst Stimulation: Safety, Efficacy, and Future Advancements.

Theta burst stimulation (TBS) is a noninvasive brain stimulation technique that can be used to modulate neural networks underlying psychiatric and neurological disorders. TBS can be delivered intermittently or continuously. The conventional intermittent TBS protocol is approved by the U.S. Food and Drug Administration to treat otherwise treatment-resistant depression, but the 6-week duration limits the applicability of this therapy. Accelerated TBS protocols present an opportunity to deliver higher pulse doses in shorter periods of time, thus resulting in faster and potentially more clinically effective treatment. However, the acceleration of TBS delivery raises questions regarding the relative safety, efficacy, and durability compared with conventional TBS protocols. In this review paper, we present the data from accelerated TBS trials to date that support the safety and effectiveness of accelerated protocols while acknowledging the need for more durability data. We discuss the stimulation parameters that seem to be important for the efficacy of accelerated TBS protocols and possible avenues for further optimization.

Comparing effects and application of telemedicine for different specialties in emergency medicine using the Emergency Talk Application (U-Sim ETA Trial).

Telemedicine as a technology can support processes in the field of emergency medicine (EM) including therapies and diagnostics, but technically is often based on hardware solutions for local EM structures, especially when involving the field of pre-hospital EM. By developing an open-source, data protection compliant solution (EU GDPR and HIPAA) as well as using standardized web and open-source based technology the Emergency Talk Application (ETA) can be used as a technology that can connect emergency medical providers and include already available regional structures. By actively involving patients and connecting these with emergency or urgent care physicians ETA can be used not only as a teleconsultation system for paramedics and physicians, but in a wider network. Randomised simulation trial, comparing EM scenarios from the field of internal medicine, trauma and neurology. Participants were qualified as certified paramedics or emergency physicians (EP). Paramedics performed as ambulances crews and involved an EP if needed via ETA as Tele-Emergency Physicians (TEP). EP participated from a device of their choice, while being able to stay within their clinical workspace. From 141 scenarios 129 used ETA. Significant differences were found for the length of scenarios, duration of time the TEP was on scene, TEP arrival after scenario start, duration until TEP was called and the duration until a diagnosis was made. Also a strong positive and significant correlation between duration of the scenario and the time a TEP was bound could be described. Telemedicine is a technology that is increasingly used in the field of EM. Improving the use of telemedicine by using up-to date technology while allowing an integration of available technical and human resources is a challenge in the field of emergency medicine especially with its regional but also broad medical variety. When using one technical solution, understanding that different cases need a different medical and also telemedical approach can help in the understanding and improving therapies, diagnostics but also the involved processes and solutions. Such results are not only relevant for healthcare providers but especially by law and decision makers as to which type of solution could be introduced in each regional setting.

Developing telemedicine in Emergency Medical Services: A low-cost solution and practical approach connecting interfaces in emergency medicine.

Background: In Germany, the number of calls for Emergency Medical Services (EMS) are increasing, while the number of general practitioners and hospitals are decreasing, resulting in a growing demand and workload for emergency physicians and paramedics. Furthermore, an aging population with increasingly complex medical histories, present emergencies in which a more detailed assessment and therapies are urgently needed. Therefore, common EMS systems need to find solutions to handle these problems. Methods: We used a user-focused five-step approach to define a technological solution: Research of current systems, definition of goals and requirements, development of concept, test series and evaluation, evaluation of costs and benefits. Results: Development of a holistic telemedical concept to connect in-hospital clinical emergency physicians and paramedics on the scene, by implementing and connecting systems that are already partially being used in common EMS in Germany. By using live audio and video communication, including vital signs between the two, a system can be established by keeping costs low, affordable and at the same time protecting patient data in line with General Data Protection Regulation. Conclusion: Implementing technologies in a practical specialty like Emergency Medicine with a user-focused approach demonstrates that the hurdle for integration into established routines can improve current processes. Evaluation of costs and usability is a main driver to define success of such concepts and can improve if such systems can be developed to be used in larger networks.

Investigating Drivers of Antireward in Addiction Behavior with Anatomically Specific Single-Cell Gene Expression Methods.

Increasing rates of addiction behavior have motivated mental health researchers and clinicians alike to understand antireward and recovery. This shift away from reward and commencement necessitates novel perspectives, paradigms, and hypotheses along with an expansion of the methods applied to investigate addiction. Here, we provide an example: A systems biology approach to investigate antireward that combines laser capture microdissection (LCM) and high-throughput microfluidic reverse transcription quantitative polymerase chain reactions (RT-qPCR). Gene expression network dynamics were measured and a key driver of neurovisceral dysregulation in alcohol and opioid withdrawal, neuroinflammation, was identified. This combination of technologies provides anatomic and phenotypic specificity at single-cell resolution with high-throughput sensitivity and specific gene expression measures yielding both hypothesis-generating datasets and mechanistic possibilities that generate opportunities for novel insights and treatments.

Corazonin Neurons Contribute to Dimorphic Ethanol Sedation Sensitivity in Drosophila melanogaster.

Exposure to alcohol has multiple effects on nervous system function, and organisms have evolved mechanisms to optimally respond to the presence of ethanol. Sex differences in ethanol-induced behaviors have been observed in several organisms, ranging from humans to invertebrates. However, the molecular mechanisms underlying the dimorphic regulation of ethanol-induced behaviors remain incompletely understood. Here, we observed sex differences in ethanol sedation sensitivity in Drosophila Genome Reference Panel (DGRP) lines of Drosophila melanogaster compared to the absence of dimorphism in standard laboratory wildtype and control lines. However, in dose response experiments, we were able to unmask dimorphic responses for the control mutant line w 1118 by lowering the testing ethanol concentration. Notably, feminization of the small population of Corazonin (Crz) neurons in males was sufficient to induce female-like sedation sensitivity. We also tested the role of the transcription factor apontic (apt) based on its known expression in Crz neurons and its regulation of sedation responses. Interestingly, loss of function apt mutations increased sedation times in both males and females as compared to controls. No significant difference between male and female apt mutants was observed, suggesting a possible role of apt in the regulation of dimorphic ethanol-induced responses. Thus, our results shed light into the mechanisms regulating sex-differences in ethanol-induced behaviors at the cellular and molecular level, suggesting that the genetic sex in a small neuronal population plays an important role in modulating sex differences in behavioral responses to ethanol.

A general protocol for the expression and purification of the intact transmembrane transporter FeoB.

Ferrous iron (Fe2+) transport is an essential process that supports the growth, intracellular survival, and virulence of several drug-resistant pathogens, and the ferrous iron transport (Feo) system is the most important and widespread protein complex that mediates Fe2+ transport in these organisms. The Feo system canonically comprises three proteins (FeoA/B/C). FeoA and FeoC are both small, accessory proteins localized to the cytoplasm, and their roles in the Fe2+ transport process have been of great debate. FeoB is the only wholly-conserved component of the Feo system and serves as the inner membrane-embedded Fe2+ transporter with a soluble G-protein-like N-terminal domain. In vivo studies have underscored the importance of Feo during infection, emphasizing the need to better understand Feo-mediated Fe2+ uptake, although a paucity of research exists on intact FeoB. To surmount this problem, we designed an overproduction and purification system that can be applied generally to a suite of intact FeoBs from several organisms. Importantly, we noted that FeoB is extremely sensitive to excess salt while in the membrane of a recombinant host, and we designed a workflow to circumvent this issue. We also demonstrated effective protein extraction from the lipid bilayer through small-scale solubilization studies. We then applied this approach to the large-scale purifications of Escherichia coli and Pseudomonas aeruginosa FeoBs to high purity and homogeneity. Lastly, we show that our protocol can be generally applied to various FeoB proteins. Thus, this workflow allows for isolation of suitable quantities of FeoB for future biochemical and biophysical characterization.

A fusion of the Bacteroides fragilis ferrous iron import proteins reveals a role for FeoA in stabilizing GTP-bound FeoB.

Iron is an essential element for nearly all organisms, and under anoxic and/or reducing conditions, Fe2+ is the dominant form of iron available to bacteria. The ferrous iron transport (Feo) system is the primary prokaryotic Fe2+ import machinery, and two constituent proteins (FeoA and FeoB) are conserved across most bacterial species. However, how FeoA and FeoB function relative to one another remains enigmatic. In this work, we explored the distribution of feoAB operons encoding a fusion of FeoA tethered to the N-terminal, G-protein domain of FeoB via a connecting linker region. We hypothesized that this fusion poises FeoA to interact with FeoB to affect function. To test this hypothesis, we characterized the soluble NFeoAB fusion protein from Bacteroides fragilis, a commensal organism implicated in drug-resistant infections. Using X-ray crystallography, we determined the 1.50-Å resolution structure of BfFeoA, which adopts an SH3-like fold implicated in protein-protein interactions. Using a combination of structural modeling, small-angle X-ray scattering, and hydrogen-deuterium exchange mass spectrometry, we show that FeoA and NFeoB interact in a nucleotide-dependent manner, and we mapped the protein-protein interaction interface. Finally, using guanosine triphosphate (GTP) hydrolysis assays, we demonstrate that BfNFeoAB exhibits one of the slowest known rates of Feo-mediated GTP hydrolysis that is not potassium-stimulated. Importantly, truncation of FeoA from this fusion demonstrates that FeoA-NFeoB interactions function to stabilize the GTP-bound form of FeoB. Taken together, our work reveals a role for FeoA function in the fused FeoAB system and suggests a function for FeoA among prokaryotes.

Neuropsychiatric Features of Punding and Hobbyism in Parkinson's Disease.

BACKGROUND: Little is known about the cognitive and neuropsychiatric profile associated with punding and hobbyism in Parkinson's disease (PD). OBJECTIVE: To compare the clinical and neuropsychological features of PD patients with punding and hobbyism to PD controls. METHODS: The Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) was used as a screening tool, and a structured interview was used to diagnose punding/hobbyism. Clinical and neuropsychological assessment was conducted with validated questionnaires/scales. RESULTS: Twenty-one patients with PD and punding (PD + pu) were compared to 26 with hobbyism (PD + h) and 25 PD controls. PD + pu patients showed higher levels of anxiety, non-motor symptoms and motor symptoms, and lower Frontal Assessment Battery scores. The PD + h group exhibited similar levels of anxiety and motor fluctuations to the PD + pu group. CONCLUSION: PD + pu showed increased anxiety and frontal lobe dysfunction, similar to PD + h. Hobbyism could be a prodromal phase with increased risk of leading to punding.

Modification of hurling helmets causing penetrating upper limb injury: A case series demonstrating opportunity for improved player safety.

BACKGROUND: The games of hurling and camogie involve fast ball movement and a substantial physical contact with opposing players. The wearing of protective helmets with faceguards became obligatory 10 years ago and resulted in a significant reduction of craniofacial injuries. However since then a trend has emerged of players modifying helmets to improve comfort and vision. As officials are not yet required to perform pre-match checks, many players enter competition with defective protective equipment which poses a risk to both themselves and others. METHODS: We present 4 cases of penetrating upper limb injury in hurlers sustained as a result of helmet faceguards. These injuries were sustained during competitive play and the affected patients presented with portions of the faceguards embedded in their wounds. Each patient required admission to hospital and exploration of their wounds under general anaesthetic. CONCLUSIONS: This case series demonstrates the dangers of modification and damage to protective helmet faceguards used in hurling and camogie. We encourage helmet manufacturers to re-engage with players to ensure that current safety equipment meets the functional demands of the modern player while adhering to approved manufacturing standards. Mandatory helmet checks before competitive games would reduce the likelihood of penetrating upper limb injury to players.

Single Cell Scale Neuronal and Glial Gene Expression and Putative Cell Phenotypes and Networks in the Nucleus Tractus Solitarius in an Alcohol Withdrawal Time Series.

Alcohol withdrawal syndrome (AWS) is characterized by neuronal hyperexcitability, autonomic dysregulation, and severe negative emotion. The nucleus tractus solitarius (NTS) likely plays a prominent role in the neurological processes underlying these symptoms as it is the main viscerosensory nucleus in the brain. The NTS receives visceral interoceptive inputs, influences autonomic outputs, and has strong connections to the limbic system and hypothalamic-pituitary-adrenal axis to maintain homeostasis. Our prior analysis of single neuronal gene expression data from the NTS shows that neurons exist in heterogeneous transcriptional states that form distinct functional subphenotypes. Our working model conjectures that the allostasis secondary to alcohol dependence causes peripheral and central biological network decompensation in acute abstinence resulting in neurovisceral feedback to the NTS that substantially contributes to the observed AWS. We collected single noradrenergic and glucagon-like peptide-1 (GLP-1) neurons and microglia from rat NTS and measured a subset of their transcriptome as pooled samples in an alcohol withdrawal time series. Inflammatory subphenotypes predominate at certain time points, and GLP-1 subphenotypes demonstrated hyperexcitability post-withdrawal. We hypothesize such inflammatory and anxiogenic signaling contributes to alcohol dependence via negative reinforcement. Targets to mitigate such dysregulation and treat dependence can be identified from this dataset.

Similarities in alcohol and opioid withdrawal syndromes suggest common negative reinforcement mechanisms involving the interoceptive antireward pathway.

Alcohol and opioids are two major contributors to so-called deaths of despair. Though the effects of these substances on mammalian systems are distinct, commonalities in their withdrawal syndromes suggest a shared pathophysiology. For example, both are characterized by marked autonomic dysregulation and are treated with alpha-2 agonists. Moreover, alcohol and opioids rapidly induce dependence motivated by withdrawal avoidance. Resemblances observed in withdrawal syndromes and abuse behavior may indicate common addiction mechanisms. We argue that neurovisceral feedback influences autonomic and emotional circuits generating antireward similarly for both substances. Amygdala is central to this hypothesis as it is principally responsible for negative emotion, prominent in addiction and motivated behavior, and processes autonomic inputs while generating autonomic outputs. The solitary nucleus (NTS) has strong bidirectional connections to the amygdala and receives interoceptive inputs communicating visceral states via vagal afferents. These visceral-emotional hubs are strongly influenced by the periphery including gut microbiota. We propose that gut dysbiosis contributes to alcohol and opioid withdrawal syndromes by contributing to peripheral and neuroinflammation that stimulates these antireward pathways and motivates substance dependence.

Breast lipofilling as a treatment for breast hypoplasia in Becker naevus syndrome: a case report.

A Becker's naevus is a rare, pigmented, cutaneous hamartoma, which when associated with other cutaneous or musculoskeletal anomalies is termed Becker naevus syndrome. Female patients commonly seek medical attention for breast hypoplasia. Here, we describe our experience in the surgical management of unilateral breast hypoplasia in a patient with Becker naevus syndrome, using high-volume autologous fat grafting. This is, to our knowledge, the second report in the literature describing the aforementioned management technique in this patient cohort.

Patellar stabilization surgeries in cases of recurrent patellar instability: a retrospective clinical and radiological audit.

BACKGROUND: Patellar instability is a disabling condition that limits the functional ability and physical aspirations of patients. There are multiple anatomical structures which stabilize the patella and surgical treatment is tailored to repair the underlying aetiology. AIMS: To evaluate the clinical and radiological outcome of patellar stabilization procedures in patients with recurrent patellar instability. METHODS: We analysed 34 patients (36 knees) (mean age, 26.6) with recurrent patellar instability who underwent patellar stabilization surgery from June 2009 to September 2014. Type of procedure was dependent on the concomitant aetiological factors; tibial tuberosity osteotomy (61.76%), medial patellofemoral ligament reconstruction (67.64%), lateral release (5.88%) and trochleoplasty (2.94%). Mean follow-up was 3 years (range 9 months-6 years). RESULTS: At follow-up, 77% of patients were satisfied with the overall outcome of the procedure. The mean IKDC was 66.7, Lysholm 74.9. Mean patellar height decreased significantly (P < .05) to anatomical values. Pre-operatively, the mean tibial tuberosity-trochlear groove distance was 14.66 mm (55.6% at borderline/abnormal level) and 81% showed evidence of trochlear dysplasia. Complications were found in 3 patients (8.33%), 2 of which had further episodes of instability. CONCLUSIONS: Patellar stabilization surgery is an effective method of treating patellar instability, resulting in stability of the knee in 94.4%. Despite this, patient dissatisfaction rates are quite high suggesting that this patient group, whilst mostly stable, remains significantly symptomatic from their knee. These positive results which are reflected in the recent literature represent a strong case for consideration of primary surgical stabilization in cases of patellar instability.

Diurnal Patterns of Gene Expression in the Dorsal Vagal Complex and the Central Nucleus of the Amygdala - Non-rhythm-generating Brain Regions.

Genes that establish the circadian clock have differential expression with respect to solar time in central and peripheral tissues. Here, we find circadian-time-induced differential expression in a large number of genes not associated with circadian rhythms in two brain regions lacking overt circadian function: the dorsal vagal complex (DVC) and the central nucleus of the amygdala (CeA). These regions primarily engage in autonomic, homeostatic, and emotional regulation. However, we find striking diurnal shifts in gene expression in these regions of male Sprague Dawley rats with no obvious patterns that could be attributed to function or region. These findings have implications for the design of gene expression studies as well as for the potential effects of xenobiotics on these regions that regulate autonomic and emotional states.

Combining Laser Capture Microdissection and Microfluidic qPCR to Analyze Transcriptional Profiles of Single Cells: A Systems Biology Approach to Opioid Dependence.

Profound transcriptional heterogeneity in anatomically adjacent single cells suggests that robust tissue functionality may be achieved by cellular phenotype diversity. Single-cell experiments investigating the network dynamics of biological systems demonstrate cellular and tissue responses to various conditions at biologically meaningful resolution. Herein, we explain our methods for gathering single cells from anatomically specific locations and accurately measuring a subset of their gene expression profiles. We combine laser capture microdissection (LCM) with microfluidic reverse transcription quantitative polymerase chain reactions (RT-qPCR). We also use this microfluidic RT-qPCR platform to measure the microbial abundance of gut contents.