Insights into diagnostic errors in endocrinology: a prospective, case-based, international study.

BACKGROUND: Diagnostic errors in internal medicine are common. While cognitive errors have previously been identified to be the most common contributor to errors, very little is known about errors in specific fields of internal medicine such as endocrinology. This prospective, multicenter study focused on better understanding the causes of diagnostic errors made by general practitioners and internal specialists in the area of endocrinology. METHODS: From August 2019 until January 2020, 24 physicians completed five endocrine cases on an online platform that simulated the diagnostic process. After each case, the participants had to state and explain why they chose their assumed diagnosis. The data gathering process as well as the participants' explanations were quantitatively and qualitatively analyzed to determine the causes of the errors. The diagnostic processes in correctly and incorrectly solved cases were compared. RESULTS: Seven different causes of diagnostic error were identified, the most frequent being misidentification (mistaking one diagnosis with a related one or with more frequent and similar diseases) in 23% of the cases. Other causes were faulty context generation (21%) and premature closure (17%). The diagnostic confidence did not differ between correctly and incorrectly solved cases (median 8 out of 10, p = 0.24). However, in incorrectly solved cases, physicians spent less time on the technical findings (such as lab results, imaging) (median 250 s versus 199 s, p < 0.049). CONCLUSIONS: The causes for errors in endocrine case scenarios are similar to the causes in other fields of internal medicine. Spending more time on technical findings might prevent misdiagnoses in everyday clinical practice.

Tourette Syndrome Treatment Updates: a Review and Discussion of the Current and Upcoming Literature.

PURPOSE OF REVIEW: This study aims to examine the treatments currently available for Tourette syndrome (TS) and to discuss evolving therapies, spanning behavioral, pharmacologic, complementary and alternative medicine, and neuromodulation approaches. RECENT FINDINGS: Behavioral therapies have undergone several modifications to improve accessibility, including transitioning to a virtual format which is particularly important in the current pandemic. There are several recent or ongoing pharmacologic studies that have shown promise including the selective D1 receptor antagonist ecopipam and various cannabinoid compounds. Adaptive DBS may enable the physiologic markers of tics to determine stimulation parameters and improve tic outcomes related to neuromodulation. In recent years, there has been a wealth of research across multiple treatment domains in the TS field. This review highlights exciting and new potential options for the future treatment of patients with TS.

Can telemedicine address neurologic health disparities in rural Guatemala: a health promotor educational intervention study.

The global burden of neurologic disease is high and its impact manifests in health disparities observed in rural communities of limited resources like those surrounding San Lucas Tolimán, Guatemala. Telehealth may be one method to close these gaps by offering a virtual neurology curriculum. The goal of this project was to determine the pervasiveness of neurologic disease in San Lucas Tolimán and to increase interest and knowledge in neurology topics for local health promotors. A neurologic needs assessment was performed during the initial site visit. This information was subsequently used to create monthly health promotor neurology-based workshops and remote consultations delivered via a telehealth platform over the following year. The 29 health promotors were surveyed before and after the neurology course to measure self-reported knowledge of variable topics as well as their interest in neurology and how effective the remote lectures were. The needs assessment identified at least 68 different patients with neurologic diseases, the most common being headaches and seizures. The health promotors' knowledge of several neurologic diseases as well as their comfort level diagnosing a condition based on a description of neurologic symptoms significantly increased following the year-long neurology course. The lectures were convenient, easy to see and hear virtually, and increased the health promotors' interest in neurology. Telehealth is an acceptable and feasible method of delivering educational neurology topics relevant to rural communities. Future, longer-term studies are needed to determine if telehealth interventions such as these impact neurologic patient outcomes.

Although the global burden of neurologic disease remains high, rural communities throughout the world suffer from health disparities including inadequate resources and knowledge gaps. These barriers often prevent patients from receiving effective neurologic care. In collaboration with the health promoters in the rural communities surrounding San Lucas Tolimán, Guatemala, we designed a year-long educational curriculum addressing neurologic conditions and providing neurological consultations. The goal was to increase the health promoters' interest in and knowledge of clinical neurology. The delivery of virtual monthly lecture series with a telemedicine component offers a sustainable and feasible approach to achieving these goals.

Glioblastoma and Internal Carotid Artery Calcium Score: A Possible Novel Prognostic Partnership?

Purpose: Clinical evidence suggests an association between comorbidities and outcome in patients with glioblastoma (GBM). We hypothesised that the internal carotid artery (ICA) calcium score could represent a promising prognostic biomarker in a competing risk analysis in patients diagnosed with GBM. Methods: We validated the use of the ICA calcium score as a surrogate marker of the coronary calcium score in 32 patients with lung cancer. Subsequently, we assessed the impact of the ICA calcium score on overall survival in GBM patients treated with radio-chemotherapy. Results: We analysed 50 GBM patients. At the univariate analysis, methyl-guanine-methyltransferase gene (MGMT) promoter methylation (p = 0.048), gross total tumour resection (p = 0.017), and calcium score (p = 0.011) were significant prognostic predictors in patients with GBM. These three variables also maintained statistical significance in the multivariate analysis. Conclusions: the ICA calcium score could be a promising prognostic biomarker in GBM patients.

Contemporary HIV-1 consensus Env with AI-assisted redesigned hypervariable loops promote antibody binding.

An effective HIV-1 vaccine must elicit broadly neutralizing antibodies (bnAbs) against highly diverse Envelope glycoproteins (Env). Since Env with the longest hypervariable (HV) loops is more resistant to the cognate bnAbs than Env with shorter HV loops, we redesigned hypervariable loops for updated Env consensus sequences of subtypes B and C and CRF01_AE. Using modeling with AlphaFold2, we reduced the length of V1, V2, and V5 HV loops while maintaining the integrity of the Env structure and glycan shield, and modified the V4 HV loop. Spacers are designed to limit strain-specific targeting. All updated Env are infectious as pseudoviruses. Preliminary structural characterization suggests that the modified HV loops have a limited impact on Env's conformation. Binding assays show improved binding to modified subtype B and CRF01_AE Env but not to subtype C Env. Neutralization assays show increases in sensitivity to bnAbs, although not always consistently across clades. Strikingly, the HV loop modification renders the resistant CRF01_AE Env sensitive to 10-1074 despite the absence of a glycan at N332.

Cognitive outcomes following unilateral magnetic resonance-guided focused ultrasound thalamotomy for essential tremor: findings from two cohorts.

Magnetic resonance-guided, focused ultrasound thalamotomy is a neurosurgical treatment for refractory essential tremor. This study examined cognitive outcomes following unilateral magnetic resonance-guided, focused ultrasound thalamotomy, targeting the ventral intermediate nucleus of the thalamus for essential tremor. The research was conducted at two sites: Sunnybrook Research Institute in Toronto, Canada, and West Virginia University School of Medicine Rockefeller Neuroscience Institute in West Virginia, USA. The study focused on cognitive changes at both the group and individual levels. Patients with refractory essential tremor completed cognitive testing before and after magnetic resonance-guided, focused ultrasound thalamotomy at both sites. The cognitive testing assessed domains of attention, processing speed, working memory, executive function, language and learning/memory. Postoperative changes in cognition were examined using paired t-tests and Wilcoxon signed-rank tests, as appropriate. Reliable change indices were calculated to assess clinically significant changes at the individual level. A total of 33 patients from Toronto and 22 patients from West Virginia were included. Following magnetic resonance-guided, focused ultrasound thalamotomy, there was a significant reduction in tremor severity in both cohorts. At the group level, there were no significant declines in postoperative cognitive performance in either cohort. The reliable change analyses revealed some variability at the individual level, with most patients maintaining stable performance or showing improvement. Taken together, the results from these two independent cohorts demonstrate that unilateral magnetic resonance-guided, focused ultrasound thalamotomy significantly reduces tremor severity without negatively impacting cognition at both the group and individual levels, highlighting the cognitive safety of magnetic resonance-guided focused ultrasound thalamotomy for essential tremor.

Applications of Transcranial Magnetic Stimulation for Understanding and Treating Dystonia.

Transcranial magnetic stimulation (TMS)-based studies have led to an advanced understanding of the pathophysiology of dystonia. This narrative review summarizes the TMS data contributed to the literature so far. Many studies have shown that increased motor cortex excitability, excessive sensorimotor plasticity, and abnormal sensorimotor integration are the core pathophysiological substrates for dystonia. However, an increasing body of evidence supports a more widespread network dysfunction involving many other brain regions. Repetitive TMS pulses (rTMS) in dystonia have therapeutic potential as they can induce local and network-wide effects through modulation of excitability and plasticity. The bulk of rTMS studies has targeted the premotor cortex with some promising results in focal hand dystonia. Some studies have targeted the cerebellum for cervical dystonia and the anterior cingulate cortex for blepharospasm. We believe that therapeutic potential could be leveraged better when rTMS is implemented in conjunction with standard-of-care pharmacological treatments. However, due to several limitations in the studies conducted to date, including small samples, heterogeneous populations, variability in the target sites, and inconsistencies in the study design and control arm, it is hard to draw a definite conclusion. Further studies are warranted to determine optimal targets and protocols yielding the most beneficial outcomes that will translate into meaningful clinical changes.

Double blind, nonrandomized crossover study of active recharge biphasic deep brain stimulation for primary dystonia.

BACKGROUND: Deep brain stimulation (DBS) of the globus pallidus interna (GPi) is an effective therapy for select patients with primary dystonia. DBS programming for dystonia is often challenging due to variable time to symptomatic improvement or stimulation induced side effects (SISE) such as capsular or optic tract activation which can prolong device optimization. OBJECTIVE: To characterize the safety and tolerability of active recharge biphasic DBS (bDBS) in primary dystonia and to compare it to conventional clinical DBS (clinDBS). METHODS: Ten subjects with primary dystonia and GPi DBS underwent a single center, double blind, nonrandomized crossover study comparing clinDBS versus bDBS. The testing occurred over two-days. bDBS and clinDBS were administered on separate days and each was activated for 6 h. Rating scales were collected by video recording and scored by four blinded movement disorders trained neurologists. RESULTS: The bDBS paradigm was safe and well-tolerated in all ten subjects. There were no persistent SISE reported. The mean change in the Unified Dystonia Rating Scale after 4 h of stimulation was greater in bDBS when compared to clinDBS (-6.5 vs 0.3, p < 0.04). CONCLUSION: In this pilot study, we demonstrated that biphasic DBS is a novel stimulation paradigm which can be administered safely. The biphasic waveform revealed a greater immediate improvement. Further studies are needed to determine whether this immediate improvement persists with chronic stimulation or if clinDBS will eventually achieve similar levels of improvement to bDBS over time.

Use of the dTAG system in vivo to degrade CDK2 and CDK5 in adult mice and explore potential safety liabilities.

The degradation tag (dTAG) system for target protein degradation can remove proteins from biological systems without the drawbacks of some genetic methods, such as slow kinetics, lack of reversibility, low specificity, and the inability to titrate dosage. These drawbacks can make it difficult to compare toxicity resulting from genetic and pharmacological interventions, especially in vivo. Because the dTAG system has not been studied extensively in vivo, we explored the use of this system to study the physiological sequalae resulting from CDK2 or CDK5 degradation in adult mice. Mice with homozygous knock-in of the dTAG sequence onto CDK2 and CDK5 were born at Mendelian ratios despite decreased CDK2 or CDK5 protein levels in comparison with wild-type mice. In bone marrow cells and duodenum organoids derived from these mice, treatment with the dTAG degrader dTAG-13 resulted in rapid and robust protein degradation but caused no appreciable change in viability or the transcriptome. Repeated delivery of dTAG-13 in vivo for toxicity studies proved challenging; we explored multiple formulations in an effort to maximize degradation while minimizing formulation-related toxicity. Degradation of CDK2 or CDK5 in all organs except the brain, where dTAG-13 likely did not cross the blood brain barrier, only caused microscopic changes in the testis of CDK2dTAG mice. These findings were corroborated with conditional CDK2 knockout in adult mice. Our results suggest that the dTAG system can provide robust protein degradation in vivo and that loss of CDK2 or CDK5 in adult mice causes no previously unknown phenotypes.

TikTok Tourette's: Are We Witnessing a Rise in Functional Tic-Like Behavior Driven by Adolescent Social Media Use?

Perceptions of Tourette syndrome (TS) and tic disorders are often driven by social media. During the COVID-19 pandemic, social media consumption greatly increased, particularly in the adolescent population. In parallel with increased social media consumption, there has also been an increase in tic severity and functional tic-like behavior (FTLB). Given that many of the tic videos posted on social media are misleading, perpetuate false beliefs about TS, or reinforce tic-like behaviors, there is increasing concern that these videos are driving the rapid increase in FTLBs. Several studies have reviewed newly presenting cases of FTLB and have found shared characteristics, including that a higher proportion of affected individuals are female, there is a low proportion with a history of childhood or family tics, and symptom onset is typically acute and develops in the teenage years. In addition, the quality of the tics seen in association with FTLB mirrors many of the tics seen on popular social media channels, with higher rates of coprophenomena, tic attacks, and involvement of the trunk and extremities than is seen with typical tics. FTLBs are likely a specific subgroup of functional tics largely influenced by the portrayal of and growing popularity of functional tics posted on social media during the COVID-19 pandemic. However, several factors, including increased anxiety, social isolation, and social media use in general during the pandemic are likely also contributing factors to the surge of FTLBs seen recently. In this era of increased social media consumption, it will become increasingly important for clinicians to educate patients about where and how medical information is spread, to ensure the best possible diagnosis, treatment, and outcomes for patients.

Computed Tomography-assessed Skeletal Muscle Index and Skeletal Muscle Radiation Attenuation in Patients With Ovarian Cancer Treated With Primary Surgery Followed by Platinum-based Chemotherapy: A Single-center Italian Study.

AIM: To assess the prognostic relevance of baseline and post-treatment skeletal muscle index (SMI) and skeletal muscle radiation attenuation (SMRA) at the level of third lumbar vertebra in patients with ovarian cancer who underwent primary surgery and platinum-based chemotherapy. PATIENTS AND METHODS: This retrospective investigation analyzed 134 patients who underwent staging computed tomography, surgery, chemotherapy and post-treatment computed tomography. RESULTS: At univariate analysis, stage (p<0.0001), histotype (p=0.01), residual disease (p<0.0001) and treatment response (p<0.0001) correlated with progression-free survival (PFS), whereas age (p=0.004), stage (p=0.006), residual disease (p<0.0001) and treatment response (p<0.0001) were associated with overall survival (OS). Neither baseline nor post-treatment SMI and SMRA had prognostic relevance. At multivariate analysis, residual disease and treatment response correlated with PFS (p<0.0001 and p<0.0001) and OS (p=0.007 and p<0.0001), whilst age was an independent prognostic variable for OS (p=0.02). CONCLUSION: Baseline and post-treatment SMI and SMRA did not correlate with patient outcome in this clinical setting.

Past, Present, and Future of Deep Brain Stimulation: Hardware, Software, Imaging, Physiology and Novel Approaches.

Deep brain stimulation (DBS) has advanced treatment options for a variety of neurologic and neuropsychiatric conditions. As the technology for DBS continues to progress, treatment efficacy will continue to improve and disease indications will expand. Hardware advances such as longer-lasting batteries will reduce the frequency of battery replacement and segmented leads will facilitate improvements in the effectiveness of stimulation and have the potential to minimize stimulation side effects. Targeting advances such as specialized imaging sequences and "connectomics" will facilitate improved accuracy for lead positioning and trajectory planning. Software advances such as closed-loop stimulation and remote programming will enable DBS to be a more personalized and accessible technology. The future of DBS continues to be promising and holds the potential to further improve quality of life. In this review we will address the past, present and future of DBS.

Intrinsic and acquired drug resistance to LSD1 inhibitors in small cell lung cancer occurs through a TEAD4-driven transcriptional state.

Small-cell lung cancer (SCLC) is a heterogeneous disease, consisting of intratumoral and intertumoral neuroendocrine (ASCL1 and/or NEUROD1), mesenchymal-like, and YAP-driven transcriptional states. Lysine-specific demethylase 1 (LSD1; also known as KDM1A) inhibitors have recently been progressed to clinical trials in SCLC based on a promising preclinical antitumor activity. A potential clinical limitation of LSD1 inhibitors is the heterogeneous drug responses that have been observed in SCLC cell lines and patient-derived models. Based on these observations, we studied molecular and transcriptional signatures that predict patient response to this class of drug. Employing SCLC patient-derived transcriptional signatures, we define that SCLC cell lines sensitive to LSD1 inhibitors are enriched in neuroendocrine transcriptional markers, whereas cell lines enriched in a mesenchymal-like transcriptional program demonstrate intrinsic resistance to LSD1 inhibitors. We have identified a reversible, adaptive resistance mechanism to LSD1 inhibitors through epigenetic reprogramming to a TEAD4-driven mesenchymal-like state. Our data suggest that only a segment of SCLC patients, with a defined neuroendocrine differentiation state, will likely benefit from LSD1 inhibitors. It provides novel evidence for the selection of a TEAD4-driven mesenchymal-like subpopulation resistant to LSD1 inhibitors in SCLC patients that may require effective drug combinations to sustain effective clinical responses.

Usefulness of MRI-based radiomic features for distinguishing Warthin tumor from pleomorphic adenoma: performance assessment using T2-weighted and post-contrast T1-weighted MR images.

Purpose: Differentiating Warthin tumor (WT) from pleomorphic adenoma (PA) is of primary importance due to differences in patient management, treatment and outcome. We sought to evaluate the performance of MRI-based radiomic features in discriminating PA from WT in the preoperative setting. Methods: We retrospectively evaluated 81 parotid gland lesions (48 PA and 33 WT) on T2-weighted (T2w) images and 52 of them on post-contrast fat-suppressed T1-weighted (pcfsT1w) images. All MRI examinations were carried out on a 1.5-Tesla MRI scanner, and images were segmented manually using the software ITK-SNAP (www.itk-snap.org). Results: The most discriminative feature on pcfsT1w images was GLCM_InverseVariance, yielding area under the curve (AUC), sensitivity and specificity of 0.9, 86 % and 87 %, respectively. Skewness was the feature extracted from T2w images with the highest specificity (88 %) in discriminating WT from PA. Conclusion: Radiomic analysis could be an important tool to improve diagnostic accuracy in differentiating PA from WT.

A randomized clinical trial of burst vs. spaced physical therapy for Parkinsons disease.

INTRODUCTION: The optimal timing for physical therapy (PT) delivery in Parkinson's disease (PD) is unknown. Our objective was to determine whether spacing physical therapy visits over a longer period of time is beneficial for maintenance of physical function in PD. METHODS: A single center, single-blinded, randomized controlled trial of PD participants. Participants (n = 30) were randomized to either burst (two PT sessions weekly for 6 weeks) or spaced (one PT session every 2 weeks for 6 months) PT. 11 participants in each arm completed the study and were analyzed. The primary outcome measure was the Timed Up and Go (TUG) test at baseline and 6 months. The burst group had an additional outcome measure timepoint at the completion of PT at 6 weeks. RESULTS: Neither group achieved a minimal clinically significant benefit in the TUG score (3.5s) at 6 months. The spaced PT TUG scores were maintained when comparing baseline (7.8 ± 1.5s) and 6 month timepoints (7.8 ± 2.6s, p = 0.594). The burst group TUG scores comparing baseline (9.8 ± 3.8s) to 6 weeks (9.1 ± 3.0s) also was maintained (p = 0.365). The burst group worsened, however, when measuring the period from 6 weeks to 6 months (12.1 ± 7.6s, p = 0.034). CONCLUSIONS: The spaced PT group had stability of the TUG mobility measure at 6 months, while the burst group had a significant worsening once PT was discontinued after 6 weeks. It is feasible to test these approaches in a future larger comparative effectiveness study.

Impact of Early Introduction to the Neurosciences on West Virginia High School Students via the Brain Bee.

BACKGROUND: The science, technology, engineering, and math (STEM) fields are often underrepresented due to lack of interest or exposure. The Brain Bee is a neuroscience competition for high school students meant to inspire future leaders in the neurosciences. A regional Brain Bee competition hosted in West Virginia was led by medical students and neurology residents with the goal of increasing high school student interest in the neurosciences. ACTIVITY: The West Virginia Brain Bee competition consisted of a neuroanatomy practical, a written exam, and a clinical assessment. Other fun neuroscience educational activities were also offered to students throughout the competition day. Students were surveyed before and after the competition day. RESULTS: Student interest in pursuing a neuroscience career increased (3.24 to 3.58, p = 0.043), and confidence in neuroscience knowledge increased (2.88 to 3.12, p = 0.036). Qualitative assessment revealed the importance of role models and a supportive environment for student learning. CONCLUSION: The West Virginia Brain Bee increased high school student interest in and confidence of neuroscience knowledge. This competition may be a meaningful way to connect high school students with potential mentors in the neurosciences and may also help foster an interest in pursuing a career in the neurosciences in the future.

Training in Neurology: Neuro Day: An Innovative Curriculum Connecting Medical Students With Patients.

OBJECTIVE: To determine whether increased patient interaction, exposure to the neurologic examination, and access to positive neurology mentors increase interest in neurology for first-year medical students. METHODS: Neuro Day was a 2-part experience for first-year medical students. The first part consisted of a flipped classroom to teach the standard neurologic examination. The second part involved patient encounters modeled off of the traditional patient rounds. Students rotated from room to room, listening to patients' experiences with different neurologic diseases and eliciting pathologic neurologic examinations. Students were surveyed before and after Neuro Day. RESULTS: The result of the binomial test indicated that the proportion of medical students interested in neurology significantly increased from 78% to 85% (95% confidence interval [CI] 0.79-0.92; p = 0.034) after participating in Neuro Day. The proportion of students' knowledge of clinical neurology increased from 45% to 63.1% (95% CI 0.54-0.72; p < 0.0001), comfort with performing a neurologic examination increased from 30% to 78.4% (95% CI 0.70-0.86; p < 0.0001), and fear of studying neurology decreased from 46% to 26% (95% CI 0.17-0.34; p < 0.0001) following Neuro Day. One hundred percent of students indicated that they would recommend Neuro Day to their peers. CONCLUSION: Neuro Day is a feasible and effective model to incorporate into medical education. There was increased interest in and decreased fear of neurology. We anticipate that this paradigm can be used in the future to encourage students to consider a career in neurology.

Transcranial Magnetic Stimulation in Tremor Syndromes: Pathophysiologic Insights and Therapeutic Role.

Transcranial magnetic stimulation (TMS) is a painless, non-invasive, and established brain stimulation technique to investigate human brain function. Over the last three decades, TMS has shed insight into the pathophysiology of many neurological disorders. Tremor is an involuntary, rhythmic oscillatory movement disorder commonly related to pathological oscillations propagated via the cerebello-thalamo-cortical pathway. Although tremor is the most common movement disorder and recent imaging studies have enhanced our understanding of the critical pathogenic networks, the underlying pathophysiology of different tremor syndromes is complex and still not fully understood. TMS has been used as a tool to further our understanding of tremor pathophysiology. In addition, repetitive TMS (rTMS) that can modulate brain functions through plasticity effects has been targeted to the tremor network to gain potential therapeutic benefits. However, evidence is available for only a few studies that included small patient samples with limited clinical follow-up. This review aims to discuss the role of TMS in advancing the pathophysiological understanding as well as emerging applications of rTMS for treating individual tremor syndromes. The review will focus on essential tremor, Parkinson's disease tremor, dystonic tremor syndrome, orthostatic tremor, and functional tremor.