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The Edgerton crown is an iconic manifestation of drop impact splashing, with its prominent cylindrical edge decorated with detaching droplets. Herein, we identify the formation of an intriguing double-crown, when a high-viscosity drop impacts on a shallow pool of a lower-viscosity immiscible liquid. High-speed imaging shows that after the initial fine horizontal ejecta sheet, the first inner crown emerges vertically from the film liquid. This is followed by the second crown which forms near the outer base of the first crown, as the tip of the horizontally spreading viscous drop approaches the outer free surface. Axisymmetric numerical simulations, using the volume-of-fluid method with adaptive grid refinement, show that the flow squeezed out between the viscous drop and the solid surface, generates two counter-rotating vortex rings, which travel radially outwards together and drive out the second crown through the free surface. The bottom vortex emerges from the separated boundary layer at the solid wall, while the top one detaches from the underside of the viscous drop. We map out the narrow parameter regime, where this ephemeral structure emerges, in terms of viscosity ratio, impact velocity and film thickness.
Station-keeping control is a critical technology for stratospheric aerostats. For those aerostats that utilise wind field environments to achieve trajectory control, the station-keeping capability of a single aerostat is inherently limited. This limitation can lead to instances of the aerostat flying outside the designated task area, thereby diminishing the effectiveness of station-keeping control. To ensure continuous monitoring of the restricted area for long endurance, dynamic adjustments and cooperative coverage among multiple aerostats are necessary. This paper introduces an optimal coverage algorithm based on Voronoi diagrams and presents a formation control method for stratospheric aerostats that employs the virtual force method and the ${A^{\rm{*}}}$ algorithm, respectively. In a real wind field environment, ten aerostats are deployed to optimally cover the restricted area. Simulation results indicate that the coverage rate of the stratospheric aerostats within the restricted area can exceed 70%, while the network connectivity rate among the aerostats can reach 80% following guidance control during return flights. Furthermore, the stratospheric aerostats that flying out of the restricted area can return through path planning and optimal coverage algorithm, and the networking connectivity rate between aerostats is higher than that using the virtual force method.
This paper presents detailed analyses of the Reynolds stresses and their budgets in temporally evolving stratified wakes using direct numerical simulation. Ensemble averaging is employed to mitigate statistical errors in the data, and the results are presented as functions of both the transverse and vertical coordinates – at time instants across the near-wake, non-equilibrium, and quasi-two-dimensional regimes for wakes in weakly and strongly stratified environments. Key findings include the identification of dominant terms in the Reynolds stress transport equations and their spatial structures, the generation and destruction processes of the Reynolds stresses, and the energy transfer between the Reynolds stress and the mean flow. The study also clarifies the effects of the Reynolds number and the Froude number. Additionally, we assess the validity of the eddy-viscosity type models and some existing closures for the Reynolds stress model, highlighting the limitations of isotropy and return-to-isotropy hypotheses in stratified flows.
Extant literature implicates the role of glucagon-like peptide-1 (GLP-1) and GLP-1 receptor agonists (GLP-1RAs) on modulating alcohol-associated behaviours, with a particular emphasis of these agents on neural circuits subserving reward and appetite control. Herein, we explore the potential effects of GLP-1RAs on alcohol-associated behaviours in brain regions implicated in reward processing facilitating the repurposing of these agents for the treatment and prevention of problematic drinking. Understanding how GLP-1’s analogues interact with alcohol-related behaviours may underscore the development of therapeutic strategies for alcohol use disorder (AUD) and those with comorbid metabolic disorders.
Methods:
A systematic review was conducted, wherein relevant literature was identified through Web of Science, PubMed, and OVID (MedLINE, Embase, AMED, PsycInfo, JBI EBP) from database inception to October 27th, 2024. Preclinical and clinical studies examining the association between GLP-1RAs and alcohol-related behaviours were assessed.
Results:
Preclinical studies (n = 19) indicate that GLP-1RAs attenuate alcohol-related behaviours, with exenatide demonstrating significant dose-dependent effects in high alcohol-consuming phenotypes. Semaglutide and liraglutide are associated with reduced alcohol intake, though their effects were often transient. In human studies (n = 2) with AUD, semaglutide significantly reduced alcohol consumption, while exenatide showed mixed results, with reductions in alcohol drinking within high BMI subpopulations.
Discussion:
Extant preclinical and clinical literature provides preliminary support for the potential therapeutic role of GLP-1RAs in attenuating alcohol consumption and preference. There is a need for large well controlled studies evaluating the effect of GLP-1RAs as a treatment strategy for behavioural modifications in individuals living with alcohol use disorder.
Pemetrexed and immunotherapies (e.g., pembrolizumab) are approved for first-line maintenance (1LM) treatment of nonsquamous advanced/metastatic non-small-cell lung cancer (NSCLC), but real-world data on their use are limited. The objective of this study was to assess 1LM clinical outcomes, safety, and treatment patterns of immunotherapy versus immunotherapy+pemetrexed among patients with advanced/metastatic NSCLC from the EU4 (France, Germany, Italy, Spain)+UK.
Methods
Data from patients in the US, Canada, and EU4+UK with nonsquamous advanced/metastatic NSCLC without targetable mutations were collected via electronic case report form. Physician-identified patients (≥18 y) in the EU4+UK were eligible for this subgroup analysis if they achieved stable disease or complete or partial response with first-line platinum-based chemotherapy+immunotherapy (January 2019 to March 2021) and received 1LM immunotherapy or immunotherapy+pemetrexed. Patients were followed from index (1LM initiation) until last physician contact or death. Outcomes were overall survival (OS), progression-free survival (PFS), treatment patterns and duration, and adverse events.
Results
Among the selected 367 patients (male, 71.9%; mean±StDev age, 63.4±7.2 y; current/former smokers, 85.8%), 203 (55.3%) received immunotherapies, most commonly pembrolizumab (n=173; 85.2%), and 164 (44.7%) received immunotherapy+pemetrexed. Patients receiving immunotherapy had longer median adjusted OS and PFS compared to those receiving immunotherapy+pemetrexed (OS hazard ratio [HR]: 0.63; 95% confidence interval [CI]: 0.36, 0.90; PFS HR: 0.58; 95% CI: 0.38, 0.79). Patients receiving immunotherapy versus patients receiving immunotherapy+pemetrexed had longer median treatment duration (14.0 vs 10.3 mo; p<0.001) and were less likely to experience anemia (19.7% vs 33.5%; p<0.01). Results were similar in the overall study population.
Conclusions
In this real-world study, among the selected patients with nonsquamous advanced/metastatic NSCLC who achieved stable disease or complete or partial response with first-line therapy, the addition of pemetrexed to immunotherapy in 1LM did not appear to confer a clinical benefit. Identifying treatments that can improve clinical outcomes for these patients remains an area of unmet need.
The depth-integrated horizontal momentum equations and continuity equation are employed to develop a new model. The vertical velocity and pressure can be expressed exactly in terms of horizontal velocities and free-surface elevation, which are the only unknowns in the model. Dividing the water column into elements and approximating horizontal velocities using linear shape function in each element, a set of model equations for horizontal velocities at element nodes is derived by adopting the weighted residual method. These model equations can be applied for transient or steady free-surface flows by prescribing appropriate lateral boundary conditions and initial conditions. Here, only the wave–current–bathymetry interaction problems are investigated. Theoretical analyses are conducted to examine various linear wave properties of the new models, which outperform the Green–Naghdi-type models for the range of water depth to wavelength ratios and the Boussinesq-type models as they are capable of simulating vertically sheared currents. One-dimensional horizontal numerical models, using a finite-difference method, are applied to a wide range of wave–current–bathymetry problems. Numerical validations are performed for nonlinear Stokes wave and bichromatic wave group propagation in deep water, sideband instability, regular wave transformation over a submerged shoal and focusing wave group interacting with linearly sheared currents in deep water. Very good agreements are observed between numerical results and laboratory data. Lastly, numerical experiments of wave shoaling from deep to shallow water are conducted to further demonstrate the capability of the new model.
We report direct numerical simulations results of the rough-wall channel, focusing on roughness with high $k_{rms}/k_a$ statistics but small to negative $Sk$ statistics, and we study the implications of this new dataset on rough-wall modelling. Here, $k_{rms}$ is the root mean square, $k_a$ is the first-order moment of roughness height, and $Sk$ is the skewness. The effects of packing density, skewness and arrangement of roughness elements on mean streamwise velocity, equivalent roughness height ($z_0$) and Reynolds and dispersive stresses have been studied. We demonstrate that two-point correlation lengths of roughness height statistics play an important role in characterizing rough surfaces with identical moments of roughness height but different arrangements of roughness elements. Analysis of the present as well as historical data suggests that the task of rough-wall modelling is to identify geometric parameters that distinguish the rough surfaces within the calibration dataset. We demonstrate a novel feature selection procedure to determine these parameters. Further, since there is no finite set of roughness statistics that distinguish between all rough surfaces, we argue that obtaining a universal rough-wall model for making equivalent sand-grain roughness ($k_s$) predictions would be challenging, and that each rough-wall model would have its applicable range. This motivates the development of group-based rough-wall models. The applicability of multi-variate polynomial regression and feedforward neural networks for building such group-based rough-wall models using the selected features has been shown.
The cyst nematodes, subfamily Heteroderinae, are plant pathogens of worldwide economic significance. A new cyst nematode of the genus Cactodera within the Heteroderinae, Cactodera xinanensis n. sp., was isolated from rhizospheres of crops in the Guizhou and Sichuan provinces of southwest China. The new species was characterized by having the cyst with a length/width = 1.3 ± 0.1 (1.1–1.6), a fenestral diameter of 28.1 ± 4.3 (21.3–38.7) μm, vulval denticles present; second-stage juvenile with stylet 21.5 ± 0.5 (20.3–22.6) μm long, tail 59.4 ± 2.0 (55.9–63.8) μm long and hyaline region 28.7 ± 2.7 (25.0–36.3) μm long, lateral field with four incisures; the eggshell with punctations. The new species can be differentiated from other species of Cactodera by a longer tail and hyaline region of second-stage juveniles. Phylogenetic relationships within populations and species of Cactodera are given based on the analysis of the internal transcribed spacer (ITS-rRNA), the large subunit of the nuclear ribosomal RNA (28S-rRNA) D2-D3 region and the partial cytochrome oxidase subunit I (COI) gene sequences here. The ITS-rRNA, 28S-rRNA and COI gene sequences clearly differentiated Cactodera xinanensis n. sp. from other species of Cactodera. A key and a morphological identification characteristic table for the species of Cactodera are included in the study.
Idioms play an important role in language; however, little research has examined idioms in children’s natural language settings. This study explored idioms usage in maternal talk during mother-child shared book reading and its relation to children’s vocabulary development. Thirty-three Chinese children in Norway (aged 3;0–5;5) and their mothers participated. We observed shared reading at the onset of the study and assessed children’s receptive and expressive vocabulary in Chinese three times across one year. Results demonstrated that mothers used an average of 1.8 idioms and explained one-third of the idioms. Maternal idiom usage was correlated with their talk amount and lexical diversity. Individual growth modeling revealed that the number of idioms mothers used predicted the growth of children’s receptive vocabulary in Chinese. We speculate that idiom usage could be an effective and understudied marker of parental linguistic sophistication. This study underscores the importance of idiom exposure in children’s language environment.
Adolescence is a period marked by highest vulnerability to the onset of depression, with profound implications for adult health. Neuroimaging studies have revealed considerable atrophy in brain structure in these patients with depression. Of particular importance are regions responsible for cognitive control, reward, and self-referential processing. However, the causal structural networks underpinning brain region atrophies in adolescents with depression remain unclear.
Objectives
This study aimed to investigate the temporal course and causal relationships of gray matter atrophy within the brains of adolescents with depression.
Methods
We analyzed T1-weighted structural images using voxel-based morphometry in first-episode adolescent patients with depression (n=80, 22 males; age = 15.57±1.78) and age, gender matched healthy controls (n=82, 25 males; age = 16.11±2.76) to identify the disease stage-specific gray matter abnormalities. Then, with granger causality analysis, we arranged the patients’ illness duration chronologically to construct the causal structural covariance networks that investigated the causal relationships of those atypical structures.
Results
Compared to controls, smaller volumes in ventral medial prefrontal cortex (vmPFC), dorsal anterior cingulate cortex (dACC), middle cingulate cortex (MCC) and insula areas were identified in patients with less than 1 year illness duration, and further progressed to the subgenual ACC, regions of default, frontoparietal networks in longer duration. Causal network results revealed that dACC, vmPFC, MCC and insula were prominent nodes projecting exerted positive causal effects to regions of the default mode and frontoparietal networks. The dACC, vmPFC and insula also had positive projections to the reward network, which included mainly the thalamus, caudate and putamen, while MCC also exerted a positive causal effect on the insula and thalamus.
Conclusions
These findings revealed the progression of structural atrophy in adolescent patients with depression and demonstrated the causal relationships between regions involving cognitive control, reward and self-referential processes.
The occurrence of depression in adolescence, a critical period of brain development, linked with neuroanatomical and cognitive abnormalities. Neuroimaging studies have identified hippocampal abnormalities in those of adolescent patients. However, few studies have investigated the atypically developmental trends in hippocampal subfields in adolescents with depression and their relationships with cognitive dysfunctions.
Objectives
To explore the structural abnormalities of hippocampal subfields in patients with youth depression and examine how these abnormalities associated with cognitive deficits.
Methods
We included a sample of 79 first-episode depressive patients (17 males, age = 15.54±1.83) and 71 healthy controls (23 males, age = 16.18±2.85). The severity of these adolescent patients was assessed by depression scale, suicidal risk and self-harm behavior. Nine cognitive tasks were used to evaluate memory, cognitive control and attention abilities for all participants. Bilateral hippocampus were segmented into 12 subfields with T1 and T2 weighted images using Freesurfer v6.0. A mixed analysis of variance was performed to assess the differences in subfields volumes between all patients and controls, and between patients with mild and severe depression. Finally, LASSO regression was conducted to explore the associations between hippocampal subfields and cognitive abnormalities in patients.
Results
We found significant subfields atrophy in the CA1, CA2/3, CA4, dentate gyrus, hippocampal fissure, hippocampal tail and molecular layer subfields in patients. For those patients with severe depression, hippocampal subfields showed greater extensive atrophy than those in mild, particularly in CA1-4 subfields extending towards the subiculum. These results were similar across various severity assessments. Regression indicated that hippocampal subfields abnormalities had the strongest associations with memory dysfunction, and relatively week associations with cognitive control and attention. Notably, CA4 and dentate gyrus had the highest weights in the regression model.
Conclusions
As depressive severity increases, hippocampal subfield atrophy tends to spread from CA regions to surrounding areas, and primarily affects memory function in patients with youth depression. These results suggest hippocampus might be markers in progression of adolescent depression, offering new directions for early clinical intervention.
OBJECTIVES/GOALS: Incomplete mucosal healingand dysbiosis prevent long-term remission after colitis. IL4 may restore colon homeostasis through its action on immune cells and the microbiome. We will demonstrate this mechanism using genetically modified mice and molecular tools. This may result in target therapies that prolong remission in patients with IBD. METHODS/STUDY POPULATION: Mice were treated with 3% dextran sulfate sodium (DSS) in drinking water for 5 days to induce colitis. Mice were monitored daily for changes in body weight, and to monitor colitis severity. At each endpoint, mice were sacrificed and colon length was measured. For disease severity assessment, mouse colons were prepared in paraffin sections by the 'swiss-rolling' method. For flow cytometry, lamina propria mononuclear cell isolation was performed and cellular populations were stained with fluorophore-conjugated antibodies. IL4-eGFP-expressing (4get) mice were used to analyze the cellular expression of IL4 after colitis. Cell-specific IL4 deletion mice were generated using the cre-lox system. RESULTS/ANTICIPATED RESULTS: IL4-deficient mice had worse colitis compared with wild-type controls. Flow cytometry of lamina propria cells from 4get mice showed that most IL4-producing cells after colitis are eosinophils (CD11b+SiglecF+). Flow cytometry of C57bl6 mice showed an influx of IL4Ra+ monocytes (CD11b+Ly6C+) and macrophages (CD11b+F480+). IL4-stimulated bone marrow-derived macrophages demonstrated an increase in HB-EGF mRNA transcription. Myeloid-specific IL4R deleted mice had no difference in colitis severity compared with controls. Neutrophil-specific IL4R-deleted mice had increased colitis severity and mortality. Co-housing of littermate mice rescued recovery after DSS in IL4 deficient mice. DISCUSSION/SIGNIFICANCE: IL4 appears to play a role in restoring homeostasis after colitis. The mechanism depends on eosinophil-derived IL4, and action through neutrophils. However, the reparative function of IL4 can be shared with deficient mice through the microbiome. I will study the cellular and microbial mechanism by which IL4 restores homeostasis after colitis.
Amplification of velocity gradients, a key feature of turbulent flows, is affected by the non-local character of the incompressible fluid equations expressed by the second derivative (Hessian) of the pressure field. By analysing the structure of the flow in regions where the vorticity is the highest, we propose an approximate expression for the pressure Hessian in terms of the local vorticity, consistent with the existence of intense vortex tubes. Contrary to the often used simplification of an isotropic form for the pressure Hessian, which in effect inhibits vortex stretching, the proposed approximate form of the pressure Hessian enables much stronger vortex stretching. The prediction of the approximation proposed here is validated with results of direct numerical simulations of turbulent flows.
Direct numerical simulations are conducted for temporally evolving stratified wake flows at Reynolds numbers from $10\,000$ to $50\,000$ and Froude numbers from $2$ to 50. Unlike previous studies that obtained statistics from a single realization, we take ensemble averages among 80–100 realizations. Our analysis shows that data from one realization incur large convergence errors. These errors reduce quickly as the number of statistical samples increases, with the benefit of ensemble average diminishing beyond 40–60 realizations. The data with ensemble average allow us to test the previously established scalings and arrive at new scaling estimates. Specifically, the data do not support power-law scaling in the centreline velocity deficit $U_0$ beyond the near wake. Its decay rate increases continuously from 0.1 at the onset of the non-equilibrium regime until the end of our calculations without reaching any asymptote. Additionally, while no power-law scalings could be found in the wake width ($L_H$) and wake height ($L_V$) in the late wake, $L_H\sim (Nt)^{1/3}$ is a good working approximation of the wake's horizontal size, where $N$ is buoyancy frequency and $t$ is time. Besides the low-order statistics, we also report the transverse integrated terms and the vertically integrated terms in the turbulent kinetic energy budget equation as a function of the vertical and transverse coordinates. The data indicate that there are two peaks in the vertically integrated production and transport terms, and one peak when the two terms are integrated horizontally.
In response to the Omicron surge in early 2022, the HTA Philippines evaluated the acceptability of Filipinos in using self-administered antigen tests (SAAgTs) as part of COVID-19 HTAs in the Philippines.
Methods
Scoping review from literature databases was initially conducted to identify preset codes in the use of SAAgT. Preset codes were used to establish the questions for focus group discussions (FGDs). Semi-structured questionnaires were created through Delphi technique. FGDs with four stakeholder groups (i.e., nine healthcare workers [HCWs], seven representatives of at-risk groups, six economic frontliners, and seven representatives of micro–small–medium-sized enterprises) were conducted.
Results
Discomfort in being a target of stigma and being prescribed an “illness identity” when suspected or confirmed COVID-19-positive, along with lack of confidence to perform self-test, caused hesitancy in self-testing among participants. The need for subsidies for test kits from the government or employers was emphasized to increase its accessibility. Having a designated access point and reporting system for SAAgT was highlighted to avoid nepotism (padrino system attributed to debt of gratitude), inequitable distribution, and lapses in reporting. A participatory approach to education was perceived as crucial to reduce any misconceptions associated with the use of SAAgT.
Conclusions
All FGD groups expressed favorable reviews on the implementation of SAAgT because it can potentially reduce the burden of health facility-administered tests. These findings were considered by the HTA Council in the recommendation of SAAgT as part of the overarching national strategies for the diagnosis and screening of COVID-19.
To accelerate high-intensity heavy-ion beams to high energy in the booster ring (BRing) at the High-Intensity Heavy-Ion Accelerator Facility (HIAF) project, we take the typical reference particle 238U35+, which can be accelerated from an injection energy of 17 MeV/u to the maximal extraction energy of 830 MeV/u, as an example to study the basic processes of longitudinal beam dynamics, including beam capture, acceleration, and bunch merging. The voltage amplitude, the synchronous phase, and the frequency program of the RF system during the operational cycle were given, and the beam properties such as bunch length, momentum spread, longitudinal beam emittance, and beam loss were derived, firstly. Then, the beam properties under different voltage amplitude and synchronous phase errors were also studied, and the results were compared with the cases without any errors. Next, the beam properties with the injection energy fluctuation were also studied. The tolerances of the RF errors and injection energy fluctuation were dictated based on the CISP simulations. Finally, the effect of space charge at the low injection energy with different beam intensities on longitudinal emittance and beam loss was evaluated.
Compact obscured nuclei (CONs) are relatively common in the centers of local (U)LIRGs, yet their nature remains unknown. Both AGN activity and extreme nuclear starbursts have been suggested as plausible nuclear power sources. The prevalence of outflows in these systems suggest that CONs represent a key phase in the nuclear feedback cycle, in which material is ejected from the central regions of the galaxy. Here, we present results from MUSE for the confirmed local CON galaxy NGC4418. For the first time we spatially map the spectral features and kinematics of the galaxy in the optical, revealing several previously unknown structures. In particular, we discover a bilateral outflow along the minor axis, an outflowing bubble, several knot structures and a receding outflow partially obscured by the galactic disk. Based on the properties of these features, we conclude that the CON in NGC4418 is most likely powered by an AGN.
Many benign and malignant conditions are treated with fertility-threatening medical or surgical therapies. Fertility preservation is a recourse critical to discuss prior to initiation of these therapies. This chapter describes contemporary and future fertility preservation approaches while also exploring barriers in access to their use as well as key decision-making strategies helpful for clinicians caring for patients with a range of medical conditions.
The presence of a penicillin allergy label in a patient’s medical chart is associated with negative clinical and economic outcomes. Given that less than 10% of reported reactions are truly immunoglobulin E-mediated, removal of unverified penicillin allergy labels is a public health priority and an area of ongoing implementation research. The Veterans Health Administration (VHA) is the largest integrated healthcare system in the United States, with almost 9 million veterans currently enrolled. However, studies analyzing the impact of the penicillin allergy label in this population are limited to single facilities and largely focus on short-term outcomes of allergy documentation correction, usage of β-lactams, and avoidance of antibiotic-related side effects. Broader, national VHA studies focusing on health outcomes and costs are lacking. As with non-VHA facilities, penicillin allergy evaluations are limited owing to the absence of formal allergy/immunology services at most VHA facilities. Pharmacy-driven screening and referral for clinic-based penicillin skin testing is a promising and frequently discussed modality in the literature, but its scalability within the VHA is not yet proven. Broader, evidence-based strategies that can be adapted to the available resources of individual VHA facilities, including those without on-site access to allergy providers, are needed.
To fully comprehend and appreciate the impact of psychosurgery on treatment-resistant depression it is pertinent to review its initial development and subsequent history. By reviewing previous studies of psychosurgery, we can build a narrative of what was, what currently is and what might be. Assessing the complex philosophical dilemma of the mind and the impact this has on individuals’ concept of psychosurgery has helped to bridge the gap between Neurosurgery and Psychiatry.
Objectives
We aimed to examine this question, starting at the very beginnings of our concept of mind, working through to modern-day thinking, how we approach both neurosurgery and psychiatry and help to bridge the two.
Methods
A narrative review of the current literature concerning neurosurgery for mental disorders and said applications to modern psychiatry was conducted. Emphasis on philosophical thought processing in conjunction with the neurosurgical intervention was noted.
Results
Psychosurgery has its roots in the early philosophy of mind, concerned with distinguishing whether the mind is a physical entity or immaterial. Psychosurgery is reliant on a physical concept of the mind, or at the very least that the mind supervenes the physical brain. History has shown us examples of this, with the archetype of this being the story of Phineas Gage. Since its onset psychosurgery has moved in and out of vogue. After being met with early scepticism it later went on to be performed thousands of times to help cure schizophrenia. In the 1800s, Gottlieb Burkhardt pioneered initial surgical interventions on the brain with intended psychiatric outcomes, moving on to work from Egas Moniz and the development of leucotomies and famously lobotomies, to modern medical techniques of Deep Brain Stimulation.
Conclusions
Psychosurgery has faced much opposition throughout history due to the uniquely invasive nature of not just affecting us physically but also mentally and the implications that this has for us as humans and our understanding of ourselves. As both medical and cultural views of mental health have changed over time, so has our understanding of psychosurgery and its potential applications. It is possible that early attempts to implement psychosurgery, before the advent of modern medicine, did more harm to psychosurgery’s reputation than good. However, without those early forays, we may never have progressed to the modern techniques we now utilise.