Methamphetamine use disorder (MUD) is a chronic brain disorder that involves frequent failures of inhibitory control and relapses into methamphetamine intake. However, it remains unclear whether the impairment of inhibitory control in MUD is proactive, reactive or both. To address this issue, the current study used the conditional stop-signal task to assess proactive and reactive inhibitory control in 35 MUD patients with long-term abstinence and 35 matched healthy controls. The results showed that MUD patients with long-term abstinence had greater preparation costs than healthy controls, but did not differ in performance, implying a less efficient utilization of proactive inhibitory control. In contrast, MUD patients exhibited intact reactive inhibitory control; reactive but not proactive inhibitory control was associated with high sensation seeking in MUD patients with long-term abstinence. These findings suggest that proactive and reactive inhibitory control may be two different important endophenotypes of addiction in MUD patients with long-term abstinence. The current study provides new insight into the uses of proactive and reactive inhibitory control to effectively evaluate and precisely treat MUD patients with long-term abstinence. Methamphetamine use disorder (MUD) is a chronic relapsing disorder according to the Diagnostic and Statistical Manual of Mental Disorders , with frequent failures of self-control of methamphetamine intake despite methamphetamine abusers being well aware of the serious negative consequences. Theoretical models of addiction suggest that impaired inhibitory control is a key psychological mechanism underlying the development and maintenance of substance addiction ,2. MethaInhibitory control can be categorized into two types: proactive and reactive. These types have different measurement methods and evaluation indexes, and their psychological and neural mechanisms are also different. The stop-signal task is one of the commonly used tasks for assessing inhibitory control that instructs participants to respond to go-signals , but to withhold a response when a stop signal is presented . To study proactive inhibitory control, researchers have modified the classic stop-signal task by adding a condition in which participants do not need to prepare for inhibition. The index of proactive inhibitory control is preparation cost, i.e., the difference in response time between the prepared and unprepared conditions ,10. The Proactive inhibitory control may be an important protective factor that enables individuals with addiction to resist the temptation of addiction-related stimuli. For MUD patients, proactive inhibitory control is essential to their ability to refrain from using drugs when they experience unavoidable contact with methamphetamine-predictive cues or environments known to trigger use , rather than relying only on reactive inhibitory control  ,15. TherIn MUD, previous studies of inhibitory control focused on reactive inhibitory control ,19. HoweIn addition, one of the key factors of impaired inhibitory control in MUD patients is excessive sensation seeking. Previous studies found that inhibition was associated with sensation seeking at the self-report and cognitive/behavioral levels and was often implicated in externalizing behaviors, such as drug addiction ,26,27. HThe goals of the current study were to investigate the function of reactive and proactive inhibitory control in MUD patients with long-term abstinence as well as the relationship between sensation seeking  and inhibitory control. The conditional stop-signal task was applied to measure both reactive and proactive inhibitory control, and the sensation-seeking personality trait was measured using the Sensation Seeking Scale. We hypothesized that similar to abstinence in people with cannabis use disorder or pathological gambling problem, MUD patients with long-term abstinence would utilize more proactive inhibitory control to accomplish goal-directed behaviors than HCs. Based on previous literature indicating that reactivity inhibitory control could be recovered with long-term abstinence ,24, we hAll participants were examined by the physicians and psychologists of rehabilitation centers using standardized scales and interview techniques. The inclusion criteria for all participants were as follows: age 18 or older; no history of or current neurological disorders or severe mental disorders; no chronic somatic diseases or brain injury; and no substance use disorders  or behaviors  according to the DSM-V.Thirty-five MUD patients according to the DSM-V diagnostic criteria from two compulsory addiction rehabilitation centers in Hebei Province, China, were included in this study. All the MUD patients were primarily monosubstance-dependent users and met the severe criteria. These MUD patients had abstained from methamphetamine intake for an average of 264.89 (SD = 167.35) days and had previously taken an average dose of 265.57 (SD = 428.87) grams. In abstinence treatment, drug rehabilitation centers help MUD patients suppress/stay away from addiction-related stimuli by conducting expert lectures, popularizing science and speaking on behalf of successful drug rehabilitation, which benefits MUD patients’ awareness of the dangers of drugs and their initiative to stay away from drugs. And each subject’s lifetime methamphetamine dosage was estimated by recalling the sum of the daily dosage multiplied by the number of days used in each month from the first to the most recent methamphetamine use.Thirty-five HCs from nearby communities were recruited through referrals from center staff, word-of-mouth, and print advertisements. They were matched for age, gender and education level with the MUD patients. The HCs were carefully assessed for a history of substance use and were excluded from the study if they met any criteria for substance use disorders.All participants received a participation incentive of 45 Chinese yuan (CNY) and were transferred to MA patients’ savings cards and to HCs’ Alipay accounts. The study was approved by the Institutional Review Board of the Institute of Psychology, Chinese Academy of Sciences, and conducted in accordance with the Declaration of Helsinki. Demographic characteristics of the participants are presented in Depression. The Chinese version of the Beck Depression Inventory—version 2 (BDI-II)  was usedTrait anxiety. The Chinese version of the State-Trait Anxiety Inventory—T (STAI-T)  was usedSensation seeking. The Chinese version of the Sensation Seeking Scale  was usedAll of the questionnaires were presented in and data were collected by the Python-based software PsychoPy2 .Inhibitory control was assessed by the conditional stop-signal task (C-SST), a paradigm modified from tasks applied in Chikazoe et al.  and ZhenThe formal task included two certain blocks and two uncertain blocks . Each blData were analyzed using Statistical Package for the Social Sciences 26.0 statistical software  and MATLAB R2017a . For the demographic and questionnaire data, independent sample t-tests were used to compare group differences (HC group vs. MUD group).For the behavioral data on the C-SST, each index of cognitive ability was calculated. Preparation cost, the index of proactive inhibitory control, was estimated by subtracting the mean Certain-Go RT from the mean Uncertain-Go RT for each participant. This difference reflected the delay in response when individuals were required to anticipate and prepare for inhibiting an ongoing response . The crip-value of 0.05 after correction by the false discovery rate (FDR).The group differences in baseline RT, preparation cost, critical SSD, SSRT and PSS were analyzed with independent t tests. Two 2 (group: MUD vs. HC) × 4 (context: Certain-Go vs. Ignore-Go vs. Uncertain-Go vs. Stop) mixed-design analyses of variance (ANOVAs) were used to assess RT and accuracy. The Greenhouse–Geisser epsilon correction was used in case the assumption of sphericity was violated, and the Bonferroni procedure was applied for posthoc comparisons. Two non-parametric two-way ANOVAs (Scheirer–Ray–Hare tests) were used to investigate the effects of group and gender on preparation cost and SSRT by R. Pearson correlation analyses were conducted for all participants, HCs and MUD patients to investigate the relationship between proactive and reactive inhibitory control in the dual mechanisms of cognitive control as well as the relationship between inhibitory control and sensation seeking. The significance threshold was a ps > 0.05). As expected, the total scores on the personality traits of sensation seeking showed that patients in the MUD group scored higher than the HC group (ps < 0.05). Specifically, MUD patients showed stronger sensation seeking in the Disinhibition of Desire (p < 0.05) and Thrill and Adventure Seeking subscales (p < 0.01).The results of the questionnaires are presented in p < 0.01), but there were no group differences in the baseline RT, critical SSD, SSRT or PSS (ps > 0.05)  A.F  = 213.11, p < 0.001, ps < 0.001). It suggested that the slowing in SSRT indeed reflected inhibitory control rather the differences in the properties of the “Stop” signal itself. The interaction between group and context was significant, F  = 6.20, p < 0.01, ps > 0.05). In the HC group, Certain-Go RT and Ignore-Go RT < Fail-to-Stop RT < Uncertain-Go RT (ps < 0.001); there was no significant difference between Certain-Go RT and Ignore-Go RT (p > 0.05). In the MUD group, the RT on the trials increased in the following order: Certain-Go, Ignore-Go and Fail-to-Stop (ps < 0.001).The mixed-design ANOVA on RT found a significant main effect of context, 2 = 0.76 B. PosthoF  = 2626.24, p < 0.001, ps < 0.01); there was no significant difference in accuracy on the Certain-Go and Uncertain-Go trials (p > 0.05). The accuracy on the Stop trials was approximately 50% and significantly different from the other three conditions (p < 0.001), indicating that the SSD was manipulated effectively. No significant main effect of group or interaction of group and context was found.The mixed-design ANOVA on accuracy found a significant main effect of context, 2 = 0.98 C. PosthoH (1) = 7.25, p = 0.007; however, the main effect of gender, H (1) = 0.04, p = 0.838 and the interaction between group and gender were not significant, H (1) = 1.98, p = 0.159. For SSRT, we found a significant main effect of gender, H (1) = 3.87, p = 0.049, wherein male was worse than female; however, the main effect of group, H (1) = 0.07, p = 0.796, and the interaction between group and gender were not significant, H (1) = 0.51, p = 0.473.To investigate gender differences in the inhibitory control of MUD, two non-parametric two-way ANOVAs of preparation cost and SSRT were applied in current study. For preparation cost, we found a significant main effect of group, r = 0.38, p = 0.005; FDR-corrected)    A and MUDrrected) C. There rrected) B.r = −0.44, p = 0.038; FDR-corrected)   C, indicarrected) A,B.r = 0.42, p = 0.045; FDR-corrected)  , indicatThe present study used the conditional stop-signal task to investigate changes in inhibitory control. To our knowledge, this is the first behavioral study to simultaneously compare proactive and reactive inhibitory control in MUD patients with long-term abstinence and to explore the relationship between the two types of inhibitory control and the personality trait of sensation seeking. The results suggest that MUD patients with long-term abstinence utilized more proactive inhibitory control than HCs and that their reactive inhibitory control was intact. No significant differences were found in “Go” processing and PSS effects between MUD patients with long-term abstinence and HCs, ruling out the possibility that the inefficient proactive inhibitory control in MUD patients may emerge due to executive functioning and performance monitoring. Additionally, we found that inhibitory control in MUD patients with long-term abstinence was associated with sensation seeking.The current study found that MUD patients with long-term abstinence had a larger preparation cost than HCs, while their performance (accuracy of response to the “Go” stimulus) was the same. Proactive inhibitory control is a goal-driven “early selection” process, preparing for the possibility of behavioral suppression ,13. MUD The group difference in proactive inhibitory control between MUD patients with long-term abstinence and HCs may be due to the following reasons. First, the difference in abstinence motivation may have led to the group difference in proactive inhibitory control. Previous research found that active alcohol-dependent patients exhibited less utilization of proactive inhibitory control, however, resulting in poorer performance . This maSecond, abstinence may increase the salience of inhibition anticipation in patients with addiction, reflecting a stronger allocation of top-down attention control . PatientIn the current study, not only the SSRT but also the performance (accuracy) of MUD patients with long-term abstinence did not differ from that of HCs. The core features that distinguish reactive inhibitory control from proactive inhibitory control are a stimulus-driven “late correction” process and a rapid cancelation of behavioral responses upon the sudden appearance of a “Stop” signal ,13. WorsAs expected, no group differences were found in reactive inhibitory control. A possible explanation may be that the prolonged abstinence facilitated the functional recovery of reactive inhibitory control. Previous behavioral results in MUD patients have found that their reactive inhibitory control was worse with shorter periods of abstinence ,21, but As hypothesized, investigations into the personality traits related to addiction revealed that MUD patients with long-term abstinence exhibited higher levels of sensation seeking than HCs. Moreover, in MUD patients, sensation seeking was associated with reactive inhibitory control, but not proactive inhibitory control. Sensation seeking is a personality trait as well as a potential endophenotype for various addictive behaviors ,52 and cFurthermore, the current study indicated that the processing of proactive and reactive inhibitory control was independent and complementary for MUD patients with long-term abstinence. On the one hand, the independence of the two types of inhibitory control was reflected in the following aspects. First, while there was a group difference in proactive inhibitory control, reactive inhibitory control did not show a group difference, suggesting that abnormalities in the two types of inhibitory control can occur independently. Second, no significant correlation was found between proactive and reactive inhibitory control in the HCs, suggesting that the two types of inhibitory control may be implemented independently in this population. Third, in MUD patients with long-term abstinence, a correlation was found between only reactive inhibitory control and sensation seeking, whereas no such correlation was found for proactive inhibitory control, further indicating the independence of the two types of inhibitory control. Fourth, previous neuroimaging studies found that proactive inhibitory control specifically activates the bilateral superior parietal lobule, reflecting the top-down influence over motor control ,59. WhilOne limitation of this study is the lack of a specific division to distinguish short-term and long-term abstinence in addiction population. Previous studies found that proactive and reactive inhibitory control in patients with addiction was altered depending on the duration of abstinence. However, due to the lack of active MUD patients, it is difficult to investigate the dynamics of or distinction between proactive and reactive inhibitory control among addiction patients with active use, short-term abstinence, and long-term abstinence that are addicted to the same substance. Thus, the characteristics of proactive and reactive inhibitory control in MUD patients warrant investigation with a longitudinal study. A second limitation is that the research paradigm lacks addiction-related cues. As addiction cues provide a specific context for addicted patients, an examination of their inhibitory control to addiction-related stimuli is needed. Therefore, addiction-related cues should be added to the paradigm in future studies to examine differences in proactive and reactive inhibitory control over addiction-related and non-addiction-related cues in MUD patients. Third, the current study did not find gender differences in inhibitory control of MUD. Although gender differences are observed in drug response, addictive behavior and mental health of MA patients ,62,63, nThe difficult recovery of proactive inhibitory control may be an important reason for the high relapse rate of addiction. Previous studies have found that reactive inhibitory control could be recovered with long-term abstinence therapy ,23,24, bThe present study provides evidence of the behavioral characteristics of proactive and reactive inhibitory control in MUD patients with long-term abstinence, suggesting that the effectiveness of proactive inhibitory control in MUD patients with long-term abstinence was low, but that their reactive inhibitory control remained intact, possibly related to recovery after long-term abstinence. In addition, a correlation between sensation seeking and inhibitory control was found in MUD patients with long-term abstinence. These results may provide evidence that proactive and reactive inhibitory control are critical endophenotypes and viable targets in abstinent patients with addiction and that high sensation seeking is a risk factor for addiction, but these conclusions are preliminary. Additionally, recovery from MUD may also require interventions beyond abstinence, such as cognitive-behavioral therapy, motivational enhancement therapy and contingency management ,69, depe


The Amundsen Sea Embayment of the West Antarctic Ice Sheet contains Thwaites and Pine Island Glaciers, two of the most rapidly changing glaciers in Antarctica. To date, Pine Island and Thwaites Glaciers have only been observed by independent airborne radar sounding surveys, but a combined cross‐basin analysis that investigates the basal conditions across the Pine Island‐Thwaites Glaciers boundary has not been performed. Here, we combine two radar surveys and correct for their differences in system parameters to produce unified englacial attenuation and basal relative reflectivity maps spanning both Pine Island and Thwaites Glaciers. Relative reflectivities range from −24.8 to +37.4 dB with the highest values beneath fast‐flowing ice at the ice sheet margin. By comparing our reflectivity results with previously derived radar specularity and trailing bed echoes at Thwaites Glacier, we find a highly diverse subglacial landscape and hydrologic conditions that evolve along‐flow. Together, these findings highlight the potential for joint airborne radar analysis with ground‐based seismic and geomorphological observations to understand variations in the bed properties and cross‐catchment interactions of ice streams and outlet glaciers. We analyze two simultaneous 2004/2005 airborne radar surveys of Pine Island and Thwaites Glaciers conducted using different soundersWe produce catchment‐wide englacial attenuation and basal reflectivity maps for Pine Island and Thwaites GlaciersRadar analysis reveals a critical frozen basal patch that currently separates the two neighboring glaciers BedrockAirborne radar echo sounding is one of the powerful geophysical methods used to investigate the subglacial environment at a catchment‐scale  and Thwaites Glacier (TG), two of the most rapidly changing  system  processed  the initial correlation between ice thickness and power is greater than 0.7, (b) the minimum correlation is <0.01, and (c) the fractional uncertainty in the estimated attenuation rate is <10% for a fitting correlation width of 0.1. . To identify the minimum radius that satisfied these conditions, a binary search is performed over the range of fitting radii. These steps are repeated for each transect, discarding points where the fitting conditions are not satisfied. The most commonly failed condition was the 10% uncertainty in attenuation rate. The resulting englacial attenuation rates and uncertainty are shown in Figures 3We examine the internal consistency of our empirical attenuation estimates for the PASIN and HiCARS data by comparing the initial bed power prior to any corrections Figure  to the f3.1Our empirical attenuation correction assumes the observed correlation between bed echo power and ice thickness is entirely attributable to attenuation. However, in principle, the ideal correlation target for the attenuation fitting may not be zero  the empirical fitting uncertainty Figure  from theFigure 4−1) near the ice sheet margin  ice along the central ice trunk up to the slower (∼100–200 m yr−1) moving head of PIG's tributary 3  “marginal zone” where TG's velocity exceeds 500 m yr−1; (b) “lower basin” where surface velocity is between 200 and 500 m yr−1; (c) “upper basin” where surface velocity is between 100 and 199 m yr−1; (d) “tributary head” with velocities range between 50 and 99 m yr−1; and (e) “ice sheet interior” where ice velocity drops below 50 m yr−1.In TG, in contrast to PIG, we observe a more spatially variable reflectivity pattern. High relative reflectivity regions >20 dB are mainly confined in the retrograde bed within 100 km upstream of the grounding line Figure . As ice Figure 4.3Along the boundary of PIG and TW, a ∼400‐m high basal plateau , indicating the bed interface is likely near or at a frozen condition , which describes the ratio of specular bed energy to the total of specular and diffuse power in the along‐track direction , which describes the distribution of bed energy as a function of fast time as a proxy for off‐nadir scattering  specularity content  is more sensitive to material contrast, meanwhile, both S and T are more sensitive to changes in feature geometry, such as bed roughness . In other words, a bedform or drainage feature that is smooth along the direction of flight, but surrounded by rougher materials on either side would result in both high S and T. For the clearest indication for subglacial water, we look for signals with a combination of high R, high S, and low T, which suggest an isotropically smooth and flat ice‐bed interface.In principle, reflectivity , diffuse (S < 0.3), and isotropic (no trailing bed echoes), (b) dim (R < 0 dB), diffuse, and isotropic, (c) bright, specular (S > 0.3), and anisotropic (have trailing bed echoes), (d) dim, specular, and anisotropic; (e) bright, specular, and isotropic; and (f) dim (R < 0 dB), specular, and isotropic.The final combined bed classification for TG based on R, S, and T as the glacier transitions from the ice sheet interior zone to the tributary head and upper and lower basins, indicating a progressively wetter ice‐bed interface with a basal roughness that displays stronger directionality along‐flow as ice velocity increases , we observe a reversal in S and T to lower values while R remains high, suggesting a shift in bed morphology back to a more isotropic roughness, similar to that observed in the ice sheet interior zone . Both studies provide independent evidence for the existence of sediment‐mantled, crag‐and‐tail bedforms in TG's upper basin. In particular, the 40 km seismic reflection profile . Here, the radar displays alternating regions of high R, S, and T (similar to those observed in the crag‐and‐tail regions in the upper basin), now separated by areas with high R, high S, and low T, indicative of subglacial water ponding or saturated thin till layer with an isotropically smooth, mirror‐like interface. These results are consistent with a previous specularity study that suggests that the lower basin consists of a field of distributed subglacial canals surrounded by an area of deforming till  in the marginal zone of TG  that is largely unsaturated and maybe frozen in localized places.−1 in the interior to 500 m yr−1 in the lower basin zone. We interpret this evolution to be the along‐flow transition of ribbed moraines (or other similar transverse bedforms) to drumlin‐like features.The glacier bed progressively becomes wetter and smoothens along‐flow as ice velocity increases from <50 m yr−1, are characterized by a highly heterogeneous bed with distinct bands of varying basal wetness and roughness. In the upper basin, we believe these bands of varying radar reflectivity and scattering character likely correspond to crag‐and‐tails and their changing dilated/consolidated till cover previously observed by seismic and swath radar studies. In the lower basin, we observe a clear indication of meltwater ponding, which likely reflects the presence of distributed canals in an area of deformable subglacial tills.The upper and lower basin zones of TG, that is, the region where surface velocity is between 100 and 500 m yr−1) is likely characterized by a system of subglacial channels cutting across an isotropically rough region. The presence of channels can transport a significant amount of water without raising the background specularity content.The bed at the marginal zone (where velocity >500 m yrWe analyze a total of 1,081 unfocused SAR radargrams, covering ∼54,000 line‐km from two simultaneous airborne radar surveys of PIG and TG to produce estimates of englacial attenuation and basal reflectivity. These results provide a cross‐system, cross‐catchment 2004–2005 baseline against which other geophysical studies can be compared. Our analysis of the sensitivity of the relative reflectivity patterns to breakdowns in the assumption of uncorrelated ice thickness and reflectivity highlights the interpretive robustness of relative rather than absolute reflectivity patterns. We also combine the relative reflectivity estimates with previously published results on specularity content and trailing bed echoes at TG. Together, these results display several noteworthy subglacial features across TG:Finally, with our new cross‐system, cross‐catchment reflectivities, we also identify a potential frozen bed patch in the Byrd Subglacial Basin that currently separates the ice mass of PIG's southern basin and the eastern tributary of TG. Overall, our study suggests that combining airborne radar analysis with ground validation from seismic and geomorphological observations provides a powerful toolset for understanding variations in subglacial hydrology and roughness and how they impact cross‐catchment interactions of ice streams and glaciers.


The use of a robotic arm has been well-described in the literature for the placement of pedicle screws in spine surgery as well as implants for sacroiliac joint fusion. There are no reports describing the use of a robotic arm to place screws in osseous fixation pathways (OFPs) employed in the treatment of pelvic ring and acetabular fractures outside of a single center in China. Using a Sawbones model, the authors describe a technique for using a robotic arm widely available in Europe and the Americas for placement of 6.5 mm cannulated screws into two OFPs commonly used in the treatment of pelvic and acetabular fractures.Using the Mazor X Stealth Edition (MSXE) robot from Medtronic, the authors were able to place a pin into the pelvis onto which the robot was docked. The authors were then able to designate the area of interest using navigated instruments, and in combination with the MSXE “scan and plan” marker, obtain cross-sectional imaging using the O-Arm and successfully register the MSXE robot. We then used the provided software to plan trajectories for the lateral compression type 2 (LC-II) screw pathway as well as a pathway for a trans-ilio-trans-sacral screw. We describe in detail the steps for setup, planning and placement of 6.5 mm cannulated screws using the MSXE robotic arm into these two OFPs.Visual inspection and plain x-rays demonstrated successful placement of the screws into the two planned OFPs. No breach of cortical bone was seen on either visual inspection of the model or demonstrated on post-procedure x-rays.It is possible to use the Mazor X Stealth Edition robot to place screws into the LC-II and trans-ilio-transsacral screw pathways in a Sawbones model. This is only a feasibility study, and should in no way be taken to suggest that clinical application of this technique should be attempted. Placement of 6.5 mm cannulated screws for the fixation of pelvic and acetabular fractures is standard practice in orthopaedic trauma surgery. Contemporary techniques for placement of screws in pelvic and acetabular surgery employ extensive use of fluoroscopy exposing the surgeon, residents, patients and operating room staff to high levels of ionizing radiation . PlacemeThe fluoroscopic views necessary for the placement of various screws for fixation of pelvic and acetabular fractures have been described . The useThe simulated bone model was placed supine on a radiolucent table and taped in place Fig. . For theA pin must be placed into the pelvis to allow for attachment of the robot to the pelvis. There are several options for pin placement, all of which are off label, as is the entire technique we describe. Regardless of the chosen starting point, it is important to note that the pin must be placed perpendicular to the floor and parallel with the walls of the OR (“straight up and down”) to allow for proper attachment of the robot. Options for the start point include: The inferior aspect of the anterior inferior iliac spine (AIIS), anticipating an LC-II osseus fixation pathway (OFP) screw more superiorly; the superior aspect of the AIIS, anticipating an LC-II screw more inferiorly; the anterior superior iliac spine (ASIS); the iliac crest superior and posterior to the ASIS. For the purposes of this feasibility study, the pin was placed in the anterior to posterior direction at the iliac crest anteriorly and just superior to the iliac spine.For the purposes of this feasibility study, we used a “scan and plan” technique, meaning that O-arm imaging and robot registration was performed after the model was secured to the operating table immediately prior to the procedure rather than planned from a pre-procedure CT. With this robot, the markers used for registration of the robot are different with “scan and plan” using an O-Arm spin after positioning the model on the OR table vs obtaining an actual CT with a standardized protocol in advance of the simulated procedure. Registration was carried out according to manufacturer’s directions under the supervision of the robot technician. The pin was placed as described above, and the robot was docked to the model. The model was covered by a blue-colored operative gown, and a visual scan was done by the robotic arm to prevent collision with the simulated soft tissues. The robot was attached to a pin placed into the pelvis Fig. . The navArm. At the time of this writing, only high-dose scanning was available as a setting when using a 40 cm (vs 20 cm) window for the O-Arm. Such a high setting with use of a sawbones model led to overexposure of the scan, but we were able to adjust the contrast and brightness settings of the MXSE software to visualize the simulated bony anatomy to a degree needed to plan, execute and evaluate screw placement. Of note, the four metallic spherical markers must be contained within the 2D window on all O-Arm fluoroscopic views for the purposes of registration. Even though the 40 cm window extends beyond the fluoroscopic views in 2D, registration was not possible if they are not contained within the fluoroscopic views even if they are contained within the 40 cm scan. Once the spin was complete, the images were transferred to the MXSE robot, and a successful registration of the robot was achieved.It is important to note that on the O-Arm settings, the model (patient) was indicated to be in the SUPINE position.It is equally important to note that for the MXSE robot software, the model (patient) was indicated to be in the PRONE position. At the time of this writing, no supine option is available with the MXSE software.This software limitation can be overcome as discussed in the next section.Once the O-Arm spin has been acquired and transferred to the MXSE robot we began to plan the screws. One of the first steps for the planning for spine surgery involves the robot technician outlining each spinal segment. We found that it is best to define the entire scan as a single “S1” segment that includes all bony anatomy of interest obtained from the O-Arm spin. This selection allowed us to utilize all the scanned anatomy for planning purposes.A key concept of the current feasibility technique involves “scan and plan” once the patient (model) has been transferred to the table. With unstable sacral, sacroiliac, pelvic ring and/or acetabular fractures, any positioning and reduction techniques would need to be employed and maintained during and after the O-Arm spin to avoid mal-positioning of instruments or implants due to shifting of the bony anatomy following acquisition of the cross-sectional imaging. It is currently unknown whether a pre-operative CT scan could be used to plan screw trajectories prior to transfer to the OR table.The next and one of the most critical steps is that, due to software limitations at the time of this writing, it is necessary to “trick the robot.” Part of the robot technician’s job is to tell the robotic software which direction of the scan is anterior, and which direction is posterior. One of the key findings of our feasibility study is that if the model is in the supine position, the robotic arm will not work correctly if the robotic planning software designates true anterior and true posterior. The work-around for lack of “supine” as an option for “patient position” is simply to tell the robot that anterior is posterior, and posterior is anterior. The robot technician can setup the case just as she usually would. Then, on the axial views, switch anterior to posterior by rotating that axis 180 degrees. Of note, this also leads to the right side being marked as the left side by the robotic software and vise a versa. There is no currently other available software work-around available as far as the authors are aware. Simple visual inspection when moving the robotic arm to a planned start point for a screw will immediately reveal if right and left sides have been inadvertently interchanged during planning, and the plan can be easily revised to correct any such mistakes in the plan. Once the planned LC-II trajectory was entered into the robot, the robotic arm was sent to the planned trajectory. Direct visualization down the canula demonstrated proper positioning of the robotic arm for placement of the instruments and screw for this osseus fixation pathway with the anterior inferior iliac spine positioned exactly in the center of the robotic canula Fig. .Fig. 2ViOnce the robotic arm has been sent to the trajectory for the first screw, cannulas are placed to allow an opening burr to open the outer cortex of the bone Fig. . Use of An LC-II screw was first placed, followed by a trans-sacral screw into the first sacral segment. Repeat O-Arm spin demonstrated accurate placement of the screws. Each screw was contained completely within the sawbones model on the repeat spin. Visual inspection of the model confirmed no cases of cortical violation or screw malposition. Plain radiographs demonstrate screw containment within the bone model Fig.  and posiIt is important to note that this feasibility study serves only as an initial step to see if the MXSE robotic arm could be used to place screws into two commonly used osseus fixation pathways in a sawbones model. This study should not be interpreted in any way that the robot could or should be used in cases with actual patients in the ways described. Our study serves only to demonstrate the possible feasibility of the use of the robotic arm in off-label applications. Further cadaveric studies are needed with multiple screws placed in more than these two trajectories to further explore robotic arm assisted surgery for placement of screws in these and other osseus fixation pathways with rigorous measurements to evaluate accuracy of actual screw placement vs the planned trajectories. Other surgical techniques for the use of CT navigation for placement of similar screws typically rely on navigation of the 2.8- or 3.2-mm guidewire. The authors of the current study have observed that, especially as screw lengths increase, accurate navigation of the guidewire becomes unreliable and can lead to perforation of the model despite software indicating that the wire is contained within the bone. Maximizing the use of native instrumentation in the form of an opening burr followed by a navigated tap from the manufacturer may lead to more reliable screw placement in comparison with attempting to navigate guidewires, but further study is needed.There are several potential advantages to a robotic arm surgical technique for placement of the screws. If data from pedicle screw placement can be extrapolated to the pelvis and acetabulum, it would not be unreasonable to expect that the use of the robotic arm would lead to accuracy as least as good as – if not better – than screws placed with fluoroscopy. Additionally, the use of robotic arm guidance may enable safe and accurate placement of implants in cases where fluoroscopic techniques prove inadequate due to obesity, overlying bowel gas or other factors that prevent adequate fluoroscopic imaging from being obtained.It is technically possible to place trans-sacral and LC-II style screws with the off-label use of the MXSE robotic arm. Further study is needed to clarify if other osseus fixation pathways are technically possible as well as characterize the accuracy of implant placement vs planned trajectories. In no way should this feasibility study imply that these techniques should be applied to actual patient care or used outside of an experimental, laboratory setting.


Voltage-gated calcium channels (VGCCs) play critical roles in cardiac and skeletal muscle contractions, hormone and neurotransmitter release, as well as slower processes such as cell proliferation, differentiation, migration and death. Mutations in VGCCs lead to numerous cardiac, muscle and neurological disease, and their physiological function is tightly regulated by kinases, phosphatases, G-proteins, calmodulin and many other proteins. Fifteen years ago, RGK proteins were discovered as the most potent endogenous regulators of VGCCs. They are a family of monomeric GTPases , in the superfamily of Ras GTPases, and they have two known functions: regulation of cytoskeletal dynamics including dendritic arborization and inhibition of VGCCs. Here we review the mechanisms and molecular determinants of RGK-mediated VGCC inhibition, the physiological impact of this inhibition, and recent evidence linking the two known RGK functions. In nerve and muscle cells, the principal entryways for Ca2+ are voltage-gated calcium channels (VGCCs). These are large multisubunit membrane proteins, whose mutations have been implicated in autism, epilepsy, migraine, cardiovascular and skeletal muscle disease, blindness, deafness, pain and other conditions.Ca1 subunit or Cavα1. Cavα1 has intracellular N- and C-termini and four homologous repeats (I–IV), each with six transmembrane segments (S1–S6) and a pore-forming loop. Each S4 segment contains positively charged amino acids and forms the channel’s voltage sensor, whose movement upon depolarization leads to channel opening , which binds to the β subunit of VGCCs (Cavβ). As we discuss later, Cavβ is critical for VGCC function and inhibition by RGKs.The principal component of VGCCs is a large  pore-forming α opening . The volvα1 subunits are encoded by 10 different genes with over 70 splice variants. Cavα1 determines and defines the unique biophysical and pharmacological properties of VGCCs  and do not have an AID in their I-II loop and do not require any auxiliary subunits for proper expression or function ..o, 1].v1.2 channels. Thus, in the presence of Rem, as well as the dominant negative dynamin mutant that rescues channel surface expression, gating currents were still reduced. This indicates that voltage sensor movement is obstructed in the presence of Rem and establishes a new mechanism of RGK inhibition of VGCCs. Similar reduction of voltage sensor movement may be exerted by Rad, but not Rem, on native Cav1.1 skeletal muscle channels [v1.2 currents in cardiac myocytes from Rad knockout mice found that Cav1.2 activation is shifted to more negative voltages (channels are easier to open), which is consistent with a retarding effect of Rad on voltage sensor movement. It remains to be determined how universal this effect is [In the case of reducing voltage sensor movement, Yang et al.  used a cchannels . Howeverffect is .v1.2 channels. As will be discussed later, this difference is thought to result from their inability to bind to the channel’s N-terminus [o [v1.2 gating currents and tail currents , revealed that channel Po is reduced in the presence of Rem [v2.2 channels by rendering them nonconducting, the molecular mechanism of which is yet to be studied [o reduction.Interestingly, Gem and Rem2 do not seem to inhibit voltage sensor movement in Ca studied . It woul3vβ is required for all forms of inhibition. However, RGK-Cavβ binding is important for some but not all forms of inhibition, as we discuss below.RGK inhibition of VGCCs is multifaceted, affecting the surface expression and biophysical properties of membrane-resident channels. But regardless of the mechanism, the presence of Ca3.1vβ both in vitro and in cells [vβ. This binding was initially proposed to inhibit VGCCs by competing Cavβ away from the calcium channel complex and sequestering Cavβ into the nucleus [vβ with it, it was still able to inhibit VGCCs [vβ3 interaction has been developed using homology modeling [vβ crystal structures [3 GK domain at a site distinct from the AID-binding pocket, with residues D194, D270 and D272 in β3 and R196, V223 and H225 in Gem critical for this interaction  to achieve two effects: (i) the mutation was mild enough to allow sufficient Cavβ3-Cavα1 binding to promote channel surface expression in Xenopus oocytes, in this case Cav2.1; (ii) at the same time, the weakened Cavβ3-Cavα1 binding allowed us to later wash away this mutant Cavβ from a macropatch preparation, leaving β-less channels on the plasma membrane [vβ3 was perfused onto the macropatch first, Gem could now strongly inhibit the channels in a partially reversible manner. Thus, Cavβ is absolutely required for Gem inhibition of Cav2.1 channels [2+ channels, which do not associate with Cavβ nor require Cavβ for their activity [Beguin et al.  first de by RGKs . This tucurately ,4. To ovmembrane . In suppchannels . Consistactivity ,22,24.vβ required for inhibition because it anchors RGKs to the channel? To answer this question, we simultaneously mutated, based on model predictions and previous biochemical studies [vβ3 to abolish their mutual interaction (creating Gem_mut3 and β3_mut3) [v2.1 channel inhibition in whole oocytes and in macropatches. Strikingly, Gem_mut3 was able to inhibit Cav2.1 channels expressed with β3_mut3, suggesting that the Gem-Cavβ3 interaction is not necessary for current inhibition. To reconcile this result with the finding that the presence of Cavβ is required for inhibition (as described above), we proposed a “β priming model” where Cavβ is required to unmask an inhibitory site on Cavα1. This model implies that Gem can bind Cavα1 directly. Indeed, we found that Gem coimmunoprecipitated with Cav2.1, even in the absence of Cavβ, suggesting direct Gem-Cav2.1 binding. Interestingly, Crump et al. [v1.2 is relatively resistant to RGK inhibition, hinting that RGK-Cav1.2 interactions may occur. Thus, while Cavβ is necessary for some forms of RGK inhibition, Cavβ-RGK binding may not be. Subsequent studies have identified both Cavβ- and Cavα1-binding dependent mechanisms of RGK inhibition [Is Ca studies ,40, threβ3_mut3) . We thenp et al.  had foun3.3v1.2 with a triple mutant Cavβ2a that cannot interact with RGKs. Upon Rem coexpression, currents were still inhibited, albeit to a lesser extent than in the presence of WT Cavβ, suggesting that Rem inhibits Cav1.2 channels using both Cavβ-binding and Cavα1-binding dependent mechanisms. Further experiments revealed that the reduction of surface expression and of channel Po were critically dependent on binding to Cavβ. Thus, translocation of a chemically sensitive Rem construct to the plasma membrane dramatically reduced channel Po only in the presence of a WT Cavβ, but not the triple mutant Cavβ. In contrast, the immobilization of voltage sensors seems to be dependent on Rem-Cav1.2 binding, as it persisted in the presence of the triple mutant Cavβ. Rad can also immobilize voltage sensor movement, and both Rad and Rem exert this effect by binding to the Cav1.2 N-terminus [v1.2, rely only on Cavβ-binding dependent mechanisms of inhibition: reduction in surface expression and channel Po [v2.2 channels, Rem used only Cavβ-binding dependent mechanisms to inhibit Cav2.2 [vα1 and cell type specific.To further investigate the effects of RGKs’ multiple interactions with VGCCs, Colecraft and colleagues  expresse44.1v1.2, but not Cav2.2 [v1.2. Remarkably, overexpression of the Cav1.2 N-terminus can relieve Rem-mediated channel inhibition, albeit only incompletely since the Cavβ-binding dependent mechanisms remain in place.FRET, co-localization analyses and co-IP experiments show that Rem and Rad (but not Rem2 and Gem) bind to the N-terminus of Ca4.2v1.2 C-terminus and any of the four (tagged) RGKs. However, Pang et al. [v1.2 in vitro. In addition, they showed that calmodulin overexpression can partially relieve RGK-mediated inhibition, suggesting that RGKs may be competing with calmodulin for the Cavα1 C-terminus. The same group also found that Cav1.2 with a truncated C-terminus is relatively resistant to RGK inhibition [vβ- and Cavα1-binding mechanisms.Yang et al.  performeg et al.  suggestehibition . While t4.3v2.1 insensitive to RGK inhibition by replacing its IIS1–IIS3 region with that of a T-type channel (Cav3.1) [vβ, which is bound on the nearby I–II loop. Remarkably, T-type channels became RGK sensitive when their I–II loop, together with the IIS1–IIS3 region, were replaced with those of Cav2.1 [vβ could bind to this chimeric channel and modulate its gating, suggesting that Cavβ is not sufficient for conferring RGK sensitivity and that the IIS1-IIS3 region of Cavα1 is critical.We were able to render Ca(Cav3.1) . This fif Cav2.1 . This wa4.4v2.1 channels in Xenopus oocytes. In addition, we performed extensive deletion analyses and found a 12 amino acid (aa) C-terminal region of Gem that, when purified and applied to macropatches, can inhibit Cav2.1 [v1.2 and Cav2.2 channels [v2.1 channels. Interestingly, mutating this 12 aa site in full-length Gem is not sufficient to abolish inhibition, suggesting the existence of one or more additional inhibitory sites. As discussed below, a candidate inhibitory site has been found in the core region of Gem [Several groups have demonstrated that truncating the RGK C-terminus abolishes their ability to inhibit VGCCs -24,30,34t Cav2.1 . Intereschannels ,23. Thusn of Gem .v1.2 and Cav2.2 channels if they were fused to the membrane targeting sequence of an unrelated protein [v1.2 channels, albeit incompletely [vβ acting as a membrane anchor for Rem.A more universal function for the RGK C-terminus in channel inhibition lies in the fact that it contains a polybasic motif used for membrane anchorage of RGKs ,22,46. D protein . Interesmpletely . Perhapsv2.1-channel inhibition [A complicating factor in determining the precise role of the RGK C-terminus in VGCC inhibition is that it also contains calmodulin and 14-3-3 binding sites, phosphorylation sites and a nuclear localization signal . The rolhibition , while thibition ).v2.1 can proceed without it .4.5v1.1 channels from muscle. Thus, replacing the N-terminus of Rad with that of Rem, which has no effect on Cav1.1 voltage sensors, abolished the inhibition of voltage sensor movement by the mutant Rad. On the other hand, the N-terminus of Rem harbors a protein kinase D1 phosphorylation site that, when phosphorylated, may relieve Rem inhibition of Cav1.2 and contribute to β-adrenergic signaling in the heart [v2.1 or Cav2.2 inhibition, respectively [Beqollari et al.  recentlyhe heart . Finallyectively ,45.4.6v2.1 channels; it requires at least membrane anchorage [v2.1 inhibition is lost. At the same time, Gem binding to Cavβ and Gem binding to Cavα1 are preserved. Thus, it appears that there are at least two inhibitory sites in Gem, one in the core region and one in the C-terminus, both contributing independently to Gem inhibition of Cav2.1 [We and others have shown that the core region of Gem, without the N- and C-termini, is incapable of inhibiting Canchorage . But sevnchorage . When muf Cav2.1 .4.7S17N), which decrease GTP binding, to examine the role of GTP binding in RGK inhibition of VGCCs. RadS105N and GemS89N mutants, which were preferentially GDP-bound, and RemT94N and Rem2S129N, display reduced binding to Cavβ [S89N (T94N, on the other hand, could still inhibit Cav1.2 channels expressed in HEK293 cells, but without impacting voltage sensor movement [T94N could not inhibit Cav1.2 currents, presumably because heart cells can inactivate GDP-bound Rem or prevent it from inhibiting Cav1.2 channels [S105N, which could not inhibit Cav1.2 channels in HEK 293 cells but increased native calcium currents in heart cells [S129N inhibited sympathetic neuron currents as strongly as WT Rem2. In addition, dialyzing sympathetic neurons that normally express Rem2, with GDPβs, a non-hydrolysable form of GDP, had no effect on current inhibition.RGKs can be GTP- or GDP-bound, and there are differences in the efficacy with which the two forms inhibit VGCCs. Several groups used mutations homologous to a mutation in Ras (Ras to Cavβ ,21,31. Fchannels . Similarrt cells . Thus, R5The physiological significance of VGCC inhibition by RGKs has been recently questioned . This is5.12+ channel currents and action potential duration in cardiac cells and causes longer QT intervals and arrhythmias [−/− mice have a smaller twitch amplitude, underlined by calcium current densities that are ~15% reduced compared to WT cardiomyocytes and activation that is shifted ~4 mV to more depolarized voltages [It has been shown that dominant negative suppression of endogenous Rad in the heart increases L-type Cahythmias . Calciumhythmias . In addivoltages . Finallyvoltages . These f5.2Xenopus oocytes, where the levels of Gem expression could be carefully titrated by injecting different amounts of Gem RNA.Using RT-PCR and microarray analyses, Scamps et al.  demonstrv1.2 that slows channel inactivation [vβ binding. Intriguingly, both the reduced dendritic arborization and its reversal by Gem overexpression were observed with TS Cav1.2 channels that also had mutations blocking the channels’ pore. Thus, Gem has to bind to the VGCC complex, but its alteration of dendritic arborization uses a mechanism that is independent of VGCC channel inhibition. The authors proposed that Gem binding or recruitment to the TS channel was impaired, leading to an increased activity of Rho-kinase and a resultant inhibition of dendritic arborization, whereas in WT cells, Gem recruitment and binding to the channel is more efficient, Rho-kinase inhibition is stronger, and a more vibrant dendritic arborization is observed.Recently, several reports have focused on the role of RGK proteins, in particular Rem2  and Gem tivation . In a setivation  showed tv1.2 currents [2+ ions may be excluded in the reduced dendritic arborization of TS cells, it cannot be disregarded in contributing to the overall autistic phenotype in TS patients. A recent combination of systems and computational approaches suggested Ca2+ as a central factor in the pathophysiology of autism [While this study and a similar one that studied Rem2  show a mcurrents . Thus, wf autism .vβ as well as RGK inhibition of VGCCs is over 550 million years old. All three residues in both RGKs and Cavβs involved in Cavβ-RGK binding are nearly 100% conserved, and fruit flies as well as zebrafish RGK proteins can inhibit calcium channels of rat sympathetic neurons [Finally, a recent study from the Ikeda group suggested that both RGK binding to Ca neurons . Thus, t6v channels they are paired with. It remains to be determined which cellular or experimental factors contribute to the observed discrepancies in the modes of RGK inhibition. These factors may include GTPase activating proteins such as nm23 and proteins that interact with VGCC subunits. New RGK binding partners may be identified through yeast two hybrid or other screens. Considering the newly described role of RGK proteins in shaping neuronal morphology [v channels have shown promising results [As much as the field of RGK regulation of VGCCs has grown, there are many tantalizing unanswered questions. Like chameleons, RGK proteins alter the mode of their inhibition of VGCCs depending on the cellular context and the Carphology ,51, it wrphology . Further results , studies


Schistosomiasis is a parasitic disease that is endemic in 78 countries and affects almost 240 million people worldwide. It has been acknowledged that an integrated approach that goes beyond drug treatment is needed to achieve control and eventual elimination of the disease. Improving hygiene has been encouraged by World Health Organisation, and one aspect of good hygiene is using soap during water-contact activities, such as bathing and doing laundry. This hygiene practice might directly reduce the skin exposure to cercariae at transmission sites. A systematic review was carried out to investigate the efficacy of soap against schistosome cercariae and to identify the knowledge gaps surrounding this topic.th and 8th July of 2021. Records returned from these databases were screened to remove duplicates, and the remaining records were classified by reading titles, abstracts, and full texts to identify the included studies. The results were categorised into two groups based on two different protective mechanisms of soap .Six online databases were searched between 5Limited research has been conducted on the efficacy of soap against schistosome cercariae and only 11 studies met the criteria to be included in this review. The review demonstrates that soap has the potential of protecting people against schistosome cercariae and there are two protective aspects: (1) soap affects cercariae adversely; (2) soap on the skin prevents cercariae from penetrating the skin, developing into adult worms and producing eggs. Both aspects of protection were influenced by many factors, but the differences in the reported experimental conditions, such as the cercarial endpoint measurement used and the cercaria numbers used per water sample, lead to low comparability between the previous studies. This review indicates that more evidence is needed to inform hygiene advice for people living in schistosomiasis endemic areas. Schistosomiasis affects millions of people living in low- and middle-income countries lacking safe access to water, sanitation and hygiene (WASH). Infection occurs through skin-contact with water containing schistosome cercariae which are released from the snail intermediate hosts. The disease is mainly controlled through drug treatment with praziquantel in humans, but reinfection is possible if contact with cercaria-contaminated water continues. Despite all the efforts that have been made, this disease remains a major public health problem in disease-endemic regions. The use of soap during water contact, as part of good hygiene practice, may be an effective complementary control method as it might reduce the penetration of schistosome cercariae into the skin, thereby reducing the likelihood of reinfection. We conducted a systematic review to summarise previous research into the efficacy of soap against schistosome cercariae, and to identify current knowledge gaps to inform future studies. The information gathered from this review can provide policymakers with preliminary scientific evidence  to further emphasise the importance of effective soap usage in reducing the spread of schistosomiasis. Schistosoma that affects approximately 240 million people worldwide [Schistosoma eggs into freshwater via the faeces or urine of infected individuals depending on the Schistosoma species. The eggs then hatch into miracidia which infect the intermediate hosts, specific freshwater snails. The compatible infected snails passing the prepatent period release cercariae, which can penetrate human skin, develop into adult worms and produce eggs inside humans.Schistosomiasis is a parasitic disease caused by trematode worms of the genus orldwide . It is eSeveral interventions can be adopted to control schistosomiasis transmission, such as preventive chemotherapy and snail control. Preventive chemotherapy, namely mass drug administration with praziquantel (Merck KGaA), has been the primary control measure in the last few decades since it is cost-effective and safe ,3,4. HowDespite the efforts and progress made, schistosomiasis remains a major public health problem in disease-endemic regions. In the new road map for neglected tropical diseases, the World Health Organisation (WHO) has proposed a target of eliminating schistosomiasis as a public health problem by 2030, aiming to reduce the proportion of heavy intensity infections to less than 1% . In the Hygiene can be defined as personal and household-level practices  which are aimed at achieving cleanliness, maintaining health and preventing disease ,11. One et al. have suggested that this role might have two aspects [The use of soap might play a vital role in controlling schistosomiasis and Grimes  aspects . The firPhytolacca dodecandra) berries are a typical local soap in Ethiopia, and these small berries can be used to wash clothes after being grounded either in dried or fresh condition and placed in water [S. mansoni infection in females after soap containing ground Endod berries was distributed to people washing clothes, though the prevalence in males increased insignificantly [S. haematobium infection, with a high reported soap-use rate of 98.4% during laundry in the rural communities of Zanzibar [S. haematobium—S. mansoni focus in Niger found that the use of soap did not prevent children from being infected, though almost all women claimed to use soap when washing their children at the transmission sites [S. mansoni and S. haematobium infection and the use of handwashing facilities equipped with available soap and water [Some field studies have been carried out in disease-endemic regions to investigate the effectiveness of soap use in preventing schistosomiasis, but the results remain inconclusive, since some observed a positive effect and some did not. Endod  to control the spread of schistosomiasis.th and 8th July of 2021 in six databases: Web of Science, Scopus, PubMed, The British Library, Google Scholar, and China National Knowledge Infrastructure (CNKI). All languages and document types were included, and databases were searched from inception to the present day. All databases were searched for any combination of common schistosomiasis-related terms  and hygiene-related terms  in the title. A full list of search terms and search strategies for each database can be found in Our systematic review followed the guidelines of the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). This review was not registered, and the protocol was not prepared. Papers were searched between 5A classification system was developed to screen and classify the records. First, duplicate records were removed and assigned the code 1. Remaining records were classified by screening titles, and when the titles were not relevant to the scope of this review, the records were removed and assigned the code 2. Afterwards, the records were classified by reading their abstracts. Records were excluded and assigned the codes 3–5 when their abstracts showed the studies were (1) not experiment-based studies (2) not about the use of soap (3) not about the effect of soap against cercariae. The full texts of the remaining records were read. When the papers met the same criteria for screening abstracts, those papers were assigned the codes 6–8. Chapter titles of books were screened; however no relevant studies were found. The remaining papers were included in this review and assigned the codes 9–10 based on the two protective aspects of soap. Additional studies which were referenced in the already included papers in a way indicating that these studies met the objective of this review were also retrieved for the full texts to be read, included and assigned the corresponding codes. A flow diagram  were adaFull texts were acquired from Imperial College London Library and the British Library. Non-English papers were translated using Google Translate first to decide whether the study should be included. Then, translations of those included papers were checked by native speakers.Two tables  were devSome washing powders and detergents were tested in the included papers. These are described as powder soap in the sections below.90 was used as the dose for 100% mortality in one study; (3) only one individual compound existed in both soaps tested in one study; (4) in two studies stating “immediate cercaricidal effect/death”, the exposure time was assumed to be three seconds based on our estimation that at least three seconds are required to determine cercarial death. Regarding the soap concentration in ppm during handwashing, a rough estimate was performed as below. One study has found that it takes 0.4–9 mL of liquid soap for each handwash [Parts per million (ppm) is used to compare the soap concentrations in the sections below, since the majority of soap concentrations in included papers were presented in ppm. The major assumption made in our data analysis is that the liquid density is 1 g/mL when converting concentrations in mg/L or mol/L to ppm. There are several other assumptions made to include the data about the effect of soap on cercaria mortality as follows  were used depending on the cercaria endpoint assessed and one model simulation for the effect on cercaria mortality was performed using SPSS software . For the soap protection on skin against cercaria penetration, the protection which is the reduction in worms recovered from soap-treated mice/rats compared with the control was calculated to show the results. All the figures except The result of our classification process is shown in the flow diagram . A totalSchistosoma spp. and could be potentially used as a molluscicide [Three major types of soap were investigated in the included studies: locally produced soap, commercial soap, and experimental soap . Endod, uscicide .Based on the findings from the included studies in this review, the role of soap against schistosome cercariae has two aspects: (1) soap has adverse effects on cercariae; (2) soap gives protection against cercaria penetration into the skin, developing into adult worms and producing eggs. Different adverse endpoints of cercariae were assessed including mortality, motility, morphological change, infectivity and viability. For the first three endpoints, microscopes were the tool for observing cercariae. For infectivity and viability, mice/rats were exposed to cercariae by immersing their tails in water, and the percentage of cercaria penetration and the worm burden or other indices were determined after exposure.The results suggest that soap is less toxic to schistosome cercariae than other chemicals, such as niclosamide and chlorine ,46. For 2 of 0.68. The exposure time required to achieve 100% cercarial mortality is reduced with increasing soap concentration [As shown in ntration ,38,42,44−2 dilution of Dettol which should mean that adding 1 part of Dettol to 99 parts of water [The motility and morphology of cercariae can also be affected by exposure to soap. Pacheco and Jansen presented cercaria motility in three different phases including sinking to the bottom, slower movement and immobilization which was also used to determine death . Even thof water .In studies examining the effect of soap on cercarial viability, cercariae exposed to different concentrations of soap diluted in water were used to infect mice via tail immersion, and worm burden and egg load were determined. Worm burden (load) and egg load refer to the worms and eggs recovered from hosts after exposure to cercariae ,37. Otheet al. tested endod and this soap totally suppressed the cercarial viability at 12 ppm after treating for 2 hours, and the worm burden and egg load were also significantly reduced at lower concentrations  at reducing cercaria penetration and worm burden [−2 provided total protection under the same time interval [Katz m burden . The resm burden . Howeverinterval .et al. conducted field experiments and compared with laboratory results [A limitation of the findings presented in previous studies is that most these experimental studies were performed in controlled laboratory conditions. Only one study by Katz  results . There wThis systematic review demonstrates that soap has the potential to harm schistosome cercariae and provide skin with protection, thereby reducing the likelihood of infection during water-contact activities. Different adverse endpoints of cercariae were used in previous studies , and several types of soap were tested .Soap’s toxicity to cercariae was associated with soap concentration and soap exposure time. However, for the studies on cercaria mortality, most studies did not mention how they evaluated the cercaria death and the number of cercariae used in these studies ranged from 10 to more than 300, which may lead to the differences in the reported results. Compared with the experiments that investigated the concentrations required to kill cercariae in water, lower soap doses were needed to make cercariae lose their capability of penetrating and developing into adult worms.The protection provided by soap on the skin (represented by rodent tails) has also been revealed by several studies. However, it should be noted that the rodent tails were not rinsed in some experiments, which does not comply with the real-world scenario where rinsing is an essential step involved in almost every soap-related activity. High protection after rinsing was only found in two experimental soaps rather than commercial soaps, and no study investigated if protection on skin from commercial soaps could exist after rinsing, suggesting the importance of future research in this area.The two protective aspects of soap both varied among different studies, which might be due to different cercarial endpoints assessed, soap ingredients, and experimental conditions . For skin protection, there are more influencing factors, such as the rinse duration, the skin-soap contact time, the amount of soap applied, the skin surface area exposed, and the time interval. However, most of the factors mentioned above have not been systematically studied and need further investigation.S. mansoni, and only two studies used S. haematobium and S. mattheei. Also, there are no studies using more than one species. Therefore, the sensitivity of different species of cercariae to soap remains unclear. In addition, only one study was carried out in the natural environment and it is unknown in some studies whether the snails used were laboratory-cultivated or naturally infected. Future studies need to conduct experiments using both cercariae produced by “wild” snails and water samples collected from disease-endemic areas with varying water qualities.Most studies in this review tested The effects of the plant endod and essential oils were investigated in a few studies. Endod showed a lower toxicity to cercariae compared with the commercial powder soaps, and there was a wide range of protection on mouse tails from different soaps containing essential oils and one soap formulation containing essential oils showed 100% protection even after rinsing the tails. Future studies could focus on incorporating plant extracts into soap to investigate whether the new product is effective at reducing the infection risk.The potential benefit of soap as a schistosomiasis control measure is currently limited due to the low access to soap by people living in some schistosomiasis-endemic regions. According to the WHO, the proportion of the population with basic handwashing facilities including soap and water at home was only 4.83% in rural Ethiopia and 9.23% in rural Zambia in 2020 . BecauseOverall, however, there is insufficiently detailed knowledge about the impact of soap use against schistosome cercariae, which makes it difficult to propose reliable hygiene guidelines for preventing schistosomiasis, such as specific guidance on which soap types, amounts, and exposure times will be most protective. With the increasing awareness of the important role of WASH in schistosomiasis prevention, further research is needed to optimise the benefits of soap use and help to incorporate this as an intervention into multi-faceted schistosomiasis control strategies.S1 MethodsSearch terms and strategies of each database.(DOCX)Click here for additional data file.S1 PRISMA 2020 checklist(DOCX)Click here for additional data file.S2 PRISMA 2020 checklist(DOCX)Click here for additional data file.S1 TableClassification process and codes, a list of excluded and included studies, experimental setups and extracted data.(XLSX)Click here for additional data file.