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Louise Tan, a Year 12 student from Ballyclare in County Antrim, Northern Ireland, recently attended the joint NDS and NDORMS Virtual Work Experience. In this guest blog, Louise reflects on her experience.
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Cortico-thalamic tremor circuits and their associations with deep brain stimulation effects in essential tremor.
Essential tremor (ET) is one of the most common movement disorders in adults. Deep brain stimulation (DBS) of the ventralis intermediate nucleus (VIM) of the thalamus and/or the posterior subthalamic area (PSA) has been shown to provide significant tremor suppression in patients with ET, but with significant inter-patient variability and habituation to the stimulation. Several non-invasive neuromodulation techniques targeting other parts of the central nervous system, including cerebellar, motor cortex, or peripheral nerves, have also been developed for treating ET, but the clinical outcomes remain inconsistent. Existing studies suggest that pathology in ET may emerge from multiple cortical and subcortical areas, but its exact mechanisms remain unclear. By simultaneously capturing neural activities from motor cortices and thalami, and hand tremor signals recorded via accelerometers in fifteen human subjects who have undergone lead implantations for DBS, we systematically characterized the efferent and afferent cortico-thalamic tremor networks. Through the comparisons of these network characteristics and tremor amplitude between DBS OFF and ON conditions, we further investigated the associations between different tremor network characteristics and the magnitude of DBS effect. Our findings implicate the thalamus, specifically the contralateral hemisphere, as the primary generator of tremor in ET, with a significant contribution of the ipsilateral hemisphere as well. Although there is no direct correlation between the cortico-tremor connectivity and tremor power or reduced tremor by DBS, the strength of connectivity from the motor cortex to the thalamus and vice versa at tremor frequency predicts baseline tremor power and effect of DBS. Interestingly, there is no correlation between these two connectivity pathways themselves, suggesting that, independent of the subcortical pathway, the motor cortex appears to play a relatively distinct role, possibly mediated through an afferent/feedback loop in the propagation of tremor. DBS has a greater clinical effect in those with stronger cortico-thalamo-tremor connectivity involving the contralateral thalamus, which is also associated with bigger and more stable tremor measured with an accelerometer. Interestingly, stronger cross-hemisphere coupling between left and right thalami is associated with more unstable tremor. Together this study provides important insights into a better understanding of the cortico-thalamic tremor generating network and its implication for the development of patient-specific therapeutic approaches for ET.
Using freedom of information requests to access novel data sources in health professions education research.
Educators and researchers are reliant upon access to data to drive teaching methods, curricular improvements, and progress in medical education research. However, data are not always accessible, due to resource constraints, institutional policies, and privacy concerns. Researchers have attempted to access novel data sources through surveys, semistructured interviews, and databases; however, these methodologies are limited. To improve access to data, Freedom of Information (FOI) Acts grant researchers the ability to formally request data that any public institute holds. Researchers have been reluctant to use this tool due to negative perceptions, despite its unique benefits. To increase awareness of this underutilized methodology, we summarize the process of FOI Act requests, its strengths and weaknesses, and the ways in which health professions education can leverage FOI requests within research. We provide examples of the use of FOI requests as a research method within adjacent fields and nascent use within the field of health professions research. In doing so, we hope to highlight how FOI requests can be a useful tool in health professions education researchers and its potential to increase access to unique data sources.
Diagnosis and management of rectal syphilis-case report.
The incidence and prevalence of syphilis are rising worldwide. Rectal syphilis is a rare condition with few reported cases in the literature and therefore often missed from differential diagnosis of atypical anorectal ulceration. We report a case of a 64-year-old male who presented with change in the bowel habit and a palpable rectal mass on examination. Colonoscopy revealed a small, ulcerated lesion in the rectum. However, histopathological analysis and radiological assessments were inconclusive. A cutaneous ulceration prompted a repeat biopsy and staining for spirochaetes, which was diagnostic of syphilitic proctitis. He was successfully treated with first line antibiotics via the Genitourinary Medicine clinic. With its increasing incidence, syphilis should be considered as a potential diagnosis of atypical anorectal ulceration. A complete sexual history including relevant risk factors should be taken and a full clinical examination performed actively looking for signs and symptoms of disease.
A call for objectivity: Radiologists' proposed wishlist for response evaluation in solid tumors (RECIST 1.1).
The Response Evaluation in Solid Tumors (RECIST) 1.1 provides key guidance for performing imaging response assessment and defines image-based outcome metrics in oncology clinical trials, including progression free survival. In this framework, tumors identified on imaging are designated as either target lesions, non-target disease or new lesions and a structured categorical response is assigned at each imaging time point. While RECIST provides definitions for these categories, it specifically and objectively defines only the target disease. Predefined thresholds of size change provide unbiased metrics for determining objective response and disease progression of the target lesions. However, worsening of non-target disease or emergence of new lesions is given the same importance in determining disease progression despite these being qualitatively assessed and less rigorously defined. The subjective assessment of non-target and new disease contributes to reader variability, which can impact the quality of image interpretation and even the determination of progression free survival. The RECIST Working Group has made significant efforts in developing RECIST 1.1 beyond its initial publication, particularly in its application to targeted agents and immunotherapy. A review of the literature highlights that the Working Group has occasionally employed or adopted objective measures for assessing non-target and new lesions in their evaluation of RECIST-based outcome measures. Perhaps a prospective evaluation of these more objective definitions for non-target and new lesions within the framework of RECIST 1.1 might improve reader interpretation. Ideally, these changes could also better align with clinically meaningful outcome measures of patient survival or quality of life.
Expanding Human Breg for Cellular Therapy in Transplantation: Time for Translation.
Regulatory B cells (Breg) are instrumental in protecting allografts in transplantation. Breg signatures are identified in operationally tolerant human kidney transplant recipients and can predict organ survival and acute rejection. Animal models of transplantation and autoimmunity support the use of Breg as an adoptive cellular therapy. Detailed mechanistic studies have identified multiple signaling pathways utilized by Breg in their induction, expansion, and downstream function. These preclinical studies provide the guiding principles, which will inform protocols by which to expand this crucial immunoregulatory population before clinical use. There is an urgent need for novel therapies to improve long-term transplant outcomes and to minimize immunosuppression-related morbidity including life-threatening infection and cancer. Systematic evaluation of the signals, which drive Breg expansion, will be key to transforming the as of yet unharnessed potential of this potent immunoregulatory cell. In this review, we explore the potential avenues of translating Breg subsets from cell culture at the laboratory bench to cell therapy at the patient's bedside. We will discuss the standardization of Breg phenotypes to aid in precursor population selection and quality control of a Breg-cell therapy product. We will evaluate avenues by which to optimize protocols to drive human Breg expansion to levels sufficient for cellular therapy. Finally, we will examine the steps required in process development including scalable culture systems and quality control measures to deliver a viable Breg-cell therapy product for administration to a transplant recipient.
Single cell and spatial transcriptomics highlight the interaction of club-like cells with immunosuppressive myeloid cells in prostate cancer.
Prostate cancer treatment resistance is a significant challenge facing the field. Genomic and transcriptomic profiling have partially elucidated the mechanisms through which cancer cells escape treatment, but their relation toward the tumor microenvironment (TME) remains elusive. Here we present a comprehensive transcriptomic landscape of the prostate TME at multiple points in the standard treatment timeline employing single-cell RNA-sequencing and spatial transcriptomics data from 120 patients. We identify club-like cells as a key epithelial cell subtype that acts as an interface between the prostate and the immune system. Tissue areas enriched with club-like cells have depleted androgen signaling and upregulated expression of luminal progenitor cell markers. Club-like cells display a senescence-associated secretory phenotype and their presence is linked to increased polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) activity. Our results indicate that club-like cells are associated with myeloid inflammation previously linked to androgen deprivation therapy resistance, providing a rationale for their therapeutic targeting.
Improvement of the outcome of the saphenous vein graft when connected to the internal thoracic artery.
BACKGROUND: Since 2000, we have been grafting the right coronary artery system (RCAs) using the proximal portion of the right internal thoracic artery (RITA) as the inflow of the saphenous vein graft (SVG) to increase the number of patients undergoing beating heart complete myocardial revascularization. METHODS: From 2000 to 2022, 928 consecutive patients underwent SVG on the RCAs. In 546 patients (58.8%), the inflow was the RITA (I-graft group), and in 382 patients (41.2%), the inflow was the aorta (Ao-graft group). The inclusion criteria were age ≤75 years, ejection fraction >35%, only one SVG per patient, bilateral internal thoracic arteries as a Y-graft on the left system (three-vessel disease, n = 817, 88.0%) or left internal thoracic artery on the left anterior descending artery and RITA + SVG on the RCAs (two-vessel disease, n = 111, 12.0%). Propensity matching identified 306 patients per group. After a median follow-up of 8 (5-10) years, graft patency was assessed by coronary computed tomographic angiography in 132 patients (64 in the I-graft group and 68 in the Ao-graft group). RESULTS: Early results were similar in both groups. The I-graft group had higher 10-year survival and freedom from main adverse cardiac events (90.0 ± 2.0 vs. 80.6 ± 3.8, p = 0.0162, and 81.3 ± 2.7 vs. 64.7 ± 5.6, p = 0.0206, respectively). When RITA was the inflow, SVG had a higher estimated 10-year patency rate (82.8% ± 6.5 vs. 58.8% ± 7.4, p = 0.0026) and a smaller inner lumen diameter (2.7 ± 0.4 vs. 3.4 ± 0.6 mm, p
Ten years survival benefit and appropriateness of surgical versus percutaneous revascularization in synergy between percutaneous coronary intervention with taxus and cardiac surgery randomized trial.
OBJECTIVES: Average treatment effects from randomized trials do not reflect the heterogeneity of an individual's response to treatment. This study evaluates the appropriate proportions of patients for coronary artery bypass grafting, or percutaneous intervention based on the predicted/observed ratio of 10-year all-cause mortality in the SYNTAX population. METHODS: The study included 1800 randomized patients and 1275 patients in the nested percutaneous (n = 198) or surgical (n = 1077) registries. The primary end-point was 10-year all-cause mortality. The SYNTAX score II-2020 was validated internally in the randomized cohort and externally in the registry cohort. Proportions of patients with survival benefits from coronary artery bypass grafting or percutaneous intervention were determined using SYNTAX score II-2020. RESULTS: Ten-year mortality was 23.8% for coronary artery bypass grafting 28.6% for percutaneous intervention in the randomized cohort, 27.6% for coronary artery bypass grafting, and 55.4% for percutaneous intervention in the registries. In the coronary artery bypass grafting registry, the SYNTAX score II-2020 predicted 10-year mortality with helpful calibration and discrimination (C-index : 0.70, intercept : 0.00, slope : 0.76). The proportion of patients deriving a predicted survival benefit from coronary artery bypass grafting over percutaneous intervention was 82.4% (2143/2602) and 17.7% (459/2602) for the entire SYNTAX trial population; translating into a 4.7 to 1 appropriate ratio of treatment allocation to coronary artery bypass grafting and percutaneous intervention. CONCLUSIONS: Choosing a revascularization modality should depend on an individual's long-term prognosis rather than average treatment effects. Additionally, patients should be informed about their predicted prognosis. TRIAL REGISTRATION: Registered on clinicaltrial.govSYNTAXES: NCT03417050 (https://clinicaltrials.gov/ct2/show/NCT03417050);SYNTAX: NCT00114972 (https://www.clinicaltrials.gov/ct2/show/NCT00114972).
Muscarinic receptors mediate motivation via preparatory neural activity in humans.
Motivation depends on dopamine, but might be modulated by acetylcholine which influences dopamine release in the striatum, and amplifies motivation in animal studies. A corresponding effect in humans would be important clinically, since anticholinergic drugs are frequently used in Parkinson's disease, a condition that can also disrupt motivation. Reward and dopamine make us more ready to respond, as indexed by reaction times (RT), and move faster, sometimes termed vigour. These effects may be controlled by preparatory processes that can be tracked using electroencephalography (EEG). We measured vigour in a placebo-controlled, double-blinded study of trihexyphenidyl (THP), a muscarinic antagonist, with an incentivised eye movement task and EEG. Participants responded faster and with greater vigour when incentives were high, but THP blunted these motivational effects, suggesting that muscarinic receptors facilitate invigoration by reward. Preparatory EEG build-up (contingent negative variation [CNV]) was strengthened by high incentives and by muscarinic blockade, although THP reduced the incentive effect. The amplitude of preparatory activity predicted both vigour and RT, although over distinct scalp regions; frontal activity predicted vigour, whereas a larger, earlier, central component predicted RT. The incentivisation of RT was partly mediated by the CNV, though vigour was not. Moreover, the CNV mediated the drug's effect on dampening incentives, suggesting that muscarinic receptors underlie the motivational influence on this preparatory activity. Taken together, these findings show that a muscarinic blocker impairs motivated action in healthy people, and that medial frontal preparatory neural activity mediates this for RT.
Muscarinic receptors mediate motivation via preparatory neural activity in humans
Motivation depends on dopamine, but might be modulated by acetylcholine which influences dopamine release in the striatum, and amplifies motivation in animal studies. A corresponding effect in humans would be important clinically, since anticholinergic drugs are frequently used in Parkinson’s disease, a condition that can also disrupt motivation. Reward and dopamine make us more ready to respond, as indexed by reaction times (RT), and move faster, sometimes termed vigour. These effects may be controlled by preparatory processes that can be tracked using electroencephalography (EEG). We measured vigour in a placebo-controlled, double-blinded study of trihexyphenidyl (THP), a muscarinic antagonist, with an incentivised eye movement task and EEG. Participants responded faster and with greater vigour when incentives were high, but THP blunted these motivational effects, suggesting that muscarinic receptors facilitate invigoration by reward. Preparatory EEG build-up (contingent negative variation [CNV]) was strengthened by high incentives and by muscarinic blockade, although THP reduced the incentive effect. The amplitude of preparatory activity predicted both vigour and RT, although over distinct scalp regions; frontal activity predicted vigour, whereas a larger, earlier, central component predicted RT. The incentivisation of RT was partly mediated by the CNV, though vigour was not. Moreover, the CNV mediated the drug’s effect on dampening incentives, suggesting that muscarinic receptors underlie the motivational influence on this preparatory activity. Taken together, these findings show that a muscarinic blocker impairs motivated action in healthy people, and that medial frontal preparatory neural activity mediates this for RT.
A narrative review of the current available literature on the intersection between the climate crisis and paediatric surgical care.
The climate crisis exacerbates health inequities, including in paediatric surgery, creating a vicious cycle. We sought to review (a) existing evidence on the connection between paediatric surgery and climate and (b) how this addresses the vicious cycle. A PubMed search was conducted on 23-08-2023. Articles not commenting on "climate change" and "paediatric surgery" were excluded. Included papers were categorised into emerging themes. Out of 151 search results, seven articles were included. The emerging themes related to "Effect of climate on paediatric surgical illness" (n = 3), "Effect of surgery on climate" (n = 2), and "Mitigating impact of paediatric surgery" (n = 2). Five articles were observational studies, and two were literature reviews, all papers published after 2020. We found limited primary research focusing on the intersection between climate change and paediatric surgery. Articles tend to focus on quantifying impact and mitigation, which does not lend itself to climate justice. The syndemic model of health focuses on the complex interconnections and pathways through which health conditions interact within populations to exacerbate adverse health outcomes. We suggest future research needs to be reframed, with the interconnection between health inequities, the climate crisis, and the wider health system addressed together.
The Use of Virtual Patients to Provide Feedback on Clinical Reasoning: A Systematic Review.
PURPOSE: Virtual patients (VPs) are increasingly used in health care professions education to support clinical reasoning (CR) development. However, the extent to which feedback is given across CR components is unknown, and guidance is lacking on how VPs can optimize CR development. This systematic review sought to identify how VPs provide feedback on CR. METHOD: Seven databases (MEDLINE, EMBASE, CINAHL, ERIC, PsycINFO, Scopus, and ProQuest Dissertations) were searched in March 2023 using terms (e.g., medical education, virtual patient, case-based learning, computer simulation) adapted from a previous systematic review. All studies that described VP use for developing CR in medical professionals and provided feedback on at least 1 CR component were retrieved. Screening, data extraction, and quality assessment were performed. Narrative synthesis was performed to describe the approaches used to measure and provide feedback on CR. RESULTS: A total of 6,526 results were identified from searches, of which 72 met criteria, but only 35 full-text articles were analyzed because the reporting of interventions in abstracts (n = 37) was insufficient. The most common CR components developed by VPs were leading diagnosis (23 [65.7%]), management or treatment plan (23 [65.7%]), and information gathering (21 [60%]). The CR components were explored by various approaches, from redefined questions to free text and concept maps. CONCLUSIONS: Studies describing VP use for giving CR feedback have mainly focused on easy-to-assess CR components, whereas few studies have described VPs designed for assessing CR components, such as problem representation, hypothesis generation, and diagnostic justification. Despite feedback being essential for learning, few VPs provided information on the learner's use of self-regulated learning processes. Educators designing or selecting VPs for CR use must consider the needs of learner groups and how different CR components can be explored and should make the instructional design of VPs explicit in published work.
Deep brain stimulation of the motor thalamus relieves experimentally induced air hunger.
RESEARCH QUESTION: We previously reported that Deep Brain Stimulation (DBS) of motor thalamus (MT), in a patient with post-stroke tremor, relieved breathlessness associated with chronic obstructive pulmonary disease. This raised the question of whether MT DBS mitigates the ascending dyspnoea signal. We therefore sought to conduct a fully powered cohort study of experimentally induced air hunger (AH), an uncomfortable urge to breathe in patients with MT DBS ON and OFF. METHODS: 16 patients (3 females) with DBS of the ventral intermediate nucleus (VIM) as treatment for tremor, underwent hypercapnic AH tests, with DBS "ON" and "OFF". Patients rated AH on a visual analogue scale (VAS) every 15 s. Hypercapnia and ventilation were matched for ON and OFF states (mean±sd 43±4 and 43±4 mmHg for end-tidal PCO2, 13.7 and 13.4 L·min-1 for ventilation). Participants ventilation was constrained to baseline levels by breathing from a 3-litre inspiratory reservoir with fixed flow of fresh gas while targeting their resting breathing frequency to a metronome. RESULTS: Overall steady state AH was 52±28%VAS for "ON" and 67±20%VAS for "OFF" (p=0.002; two-tailed paired t-test). The mean reduction in AH during VIM DBS was -14.4%VAS. MT DBS relieved AH in thirteen patients, heightened AH in two and caused no change in one. CONCLUSION: MT DBS for tremor relief also mitigates the AH component of dyspnoea. We posit that DBS of the MT heightens the gating control of the thalamus modulating the ascending air hunger signal. Extent of relief suggests that thalamic DBS may prove to be a viable therapy for intractable dyspnoea.
Spinal Cord Stimulation Improves Quality of Life for Patients With Chronic Pain-Data From the UK and Ireland National Neuromodulation Registry.
INTRODUCTION: Spinal cord stimulation (SCS) is a well-established treatment for chronic pain and is supported by numerous studies. However, some recent articles have questioned its efficacy. This article examines a cohort of >1800 patients with SCS from the UK and Ireland National Neuromodulation Registry. It is intended to provide a "real-world" assessment of efficacy and compare its effects with other procedures performed for painful indications. MATERIALS AND METHODS: Quality of life (QoL) data (EuroQoL five-level [EQ5D]) and demographic data were extracted from the National Neuromodulation Registry for all patients (N = 1811) who underwent SCS for chronic pain in 27 centers in the UK between February 2018 and July 2022. These were compared with data from the published literature for other commonly performed elective surgical procedures. RESULTS: The EQ5D utility index increased by a mean of 0.202 in the 1236 patients with paired pre- and postoperative utility scores. The median utility was 0.263 (interquartile range [IQR] = 0.384; n = 1811) preoperatively, whereas at six months after the operation, it was 0.550 (IQR = 0.396; n = 1025), p < 0.0001, Wilcoxon rank sum test. The median utility score at 12 months postoperation was 0.548 (IQR = 0.417; n = 970). There was no difference in utility scores at six months and 12 months after implantation (p = 0.15, Wilcoxon rank sum test). There was a significant improvement in QoL in all five domains of the five-level EQ5D tool at six months after baseline (p < 0.01, for all subcategories), and this was sustained at one year after implantation. The baseline utility was lower than in patients who underwent elective surgery for other painful conditions, and the absolute (and proportionate) increase in utility produced by SCS was greater than that achieved with most other interventions. CONCLUSIONS: SCS increases the QoL in patients requiring surgery for pain. Similar results were seen regardless of SCS indication. When comparing analogous data bases, SCS produces a greater percentage improvement in EQ5D utility than do many other elective surgical procedures for painful conditions, including spinal surgery and some joint replacements.
Figure 1 from Associations between Dietary Patterns and Incident Colorectal Cancer in 114,443 Individuals from the UK Biobank: A Prospective Cohort Study
<p>Sequential stratification/adjustments to the model comparing the risk of incident colorectal cancer associated with DP1 and DP2. Top, sequential changes to the HRs for quintiles 5 versus 1 for DP1 and DP2. Bottom, sequential changes to the HRs for DP1 and DP2 <i>z</i>-scores in continuous form. The <i>X</i>-axis represents HRs on the log-scale. CIs were obtained using the floating absolute risk method (<a href="#bib34" target="_blank">34</a>). χ<sup>2</sup> and <i>P</i> values were calculated by likelihood ratio tests to assess the heterogeneity in the associations with sequential adjustments for covariates. Behavioral factors included smoking status, physical activity level (MET-hours/week), and total energy intake (ln-kJ). SES* comprises TDI and educational attainment. Models were stratified by covariates violating the proportional hazards assumption: physical activity, family history of colorectal cancer, education, and BMI. SES, socioeconomic status.</p>
Supplementary Table S8 from Associations between Dietary Patterns and Incident Colorectal Cancer in 114,443 Individuals from the UK Biobank: A Prospective Cohort Study
<p>Table S8 Hazard ratios and 95% confidence intervals of all variables in the fully-adjusted model for DP2</p>
Supplementary Figure S4 from Associations between Dietary Patterns and Incident Colorectal Cancer in 114,443 Individuals from the UK Biobank: A Prospective Cohort Study
<p>Figure S4 DP2 associations with CRC by anatomic subsite</p>