YAP and TAZ differentially regulate postnatal cortical progenitor proliferation and astrocyte differentiation.

WW domain-containing transcription regulator 1 (WWTR1, referred to here as TAZ) and Yes-associated protein (YAP, also known as YAP1) are transcriptional co-activators traditionally studied together as a part of the Hippo pathway, and are best known for their roles in stem cell proliferation and differentiation. Despite their similarities, TAZ and YAP can exert divergent cellular effects by differentially interacting with other signaling pathways that regulate stem cell maintenance or differentiation. In this study, we show in mouse neural stem and progenitor cells (NPCs) that TAZ regulates astrocytic differentiation and maturation, and that TAZ mediates some, but not all, of the effects of bone morphogenetic protein (BMP) signaling on astrocytic development. By contrast, both TAZ and YAP mediate the effects on NPC fate of ß1-integrin (ITGB1) and integrin-linked kinase signaling, and these effects are dependent on extracellular matrix cues. These findings demonstrate that TAZ and YAP perform divergent functions in the regulation of astrocyte differentiation, where YAP regulates cell cycle states of astrocytic progenitors and TAZ regulates differentiation and maturation from astrocytic progenitors into astrocytes.

YAP and TAZ differentially regulate postnatal cortical progenitor proliferation and astrocyte differentiation.

WW domain-containing transcription regulator 1 (WWTR1, referred to here as TAZ) and Yes-associated protein (YAP, also known as YAP1) are transcriptional co-activators traditionally studied together as a part of the Hippo pathway, and are best known for their roles in stem cell proliferation and differentiation. Despite their similarities, TAZ and YAP can exert divergent cellular effects by differentially interacting with other signaling pathways that regulate stem cell maintenance or differentiation. In this study, we show in mouse neural stem and progenitor cells (NPCs) that TAZ regulates astrocytic differentiation and maturation, and that TAZ mediates some, but not all, of the effects of bone morphogenetic protein (BMP) signaling on astrocytic development. By contrast, both TAZ and YAP mediate the effects on NPC fate of ß1-integrin (ITGB1) and integrin-linked kinase signaling, and these effects are dependent on extracellular matrix cues. These findings demonstrate that TAZ and YAP perform divergent functions in the regulation of astrocyte differentiation, where YAP regulates cell cycle states of astrocytic progenitors and TAZ regulates differentiation and maturation from astrocytic progenitors into astrocytes.

Laser excision of urethral mesh erosion: a 10-year experience.

PURPOSE: To review our 10-year experience with laser excision for urethral mesh erosion (UME) of mid-urethral slings (MUS). METHODS: Following Institutional Review Board approval, the charts of female patients with endoscopic laser excision of UME were retrospectively reviewed. Demographics, clinical presentation, surgical history, pre- and post-operative Urinary Distress Inventory-6 scores and quality of life ratings, operative reports, and outcomes were obtained from electronic medical records. UME cure was defined as no residual mesh on office cystourethroscopy 5-6 months after the final laser excision procedure. RESULTS: From 2011 to 2021, 23 patients met study criteria; median age was 56 (range 44-79) years. Twenty (87%) had multiple prior urogynecologic procedures. Median time from MUS placement to presentation with UME-related complaints was 5.3 [interquartile range (IQR) 2.3-7.6] years. The most common presenting symptom was recurrent urinary tract infection (rUTI) (n = 10). Median operating time was 49 (IQR 37-80) minutes. Median duration of follow-up was 24 (IQR 12-84) months. Fourteen (61%) required more than 1 laser excision procedure for UME. Although 5 were asymptomatic (22%), new (n = 5) or persistent (n = 8) urinary incontinence was the most common symptom on follow-up (57%). CONCLUSION: UME presenting symptoms are highly variable, necessitating a high index of suspicion in patients with a history of MUS, especially in the case of rUTI. Endoscopic laser excision is a minimally invasive, brief, safe, outpatient procedure with a high UME cure rate.

Ultrastable N2/Water Foams Stabilized by Dilute Nanoparticles and a Surfactant at High Salinity and High Pressure.

The rapid development of unconventional oil and gas resources presents challenges for foam flooding for reservoirs with high salinity and high heterogeneity at elevated temperatures. In this study, hydrophilic anionic sulfonate-modified nanoparticles (NPs) exhibited a synergistic effect with a cationic surfactant in stabilizing N2/water foam in the presence of concentrated divalent ions from ambient temperature up to 70 °C. With low concentrations of both the sulfonated NPs (SNPs) and cationic surfactant, the foams remained stable for 4 days at 50 °C and atmospheric pressure, while the surfactant-stabilized foams collapsed completely in 1 day. This stability mechanism of foams by the SNPs and cationic surfactant is described in terms of phase behavior, bulk shear rheology of the aqueous phase, and the dilational modulus of the gas-brine interface. The high surface elastic dilational modulus E' observed upon addition of the SNP provided stability against coarsening according to the Gibbs criteria. The cryo-SEM images also showed the compact bubble structure of foams provided by the SNPs. Consequently, very minor changes in the foam bubble size were observed at 208 bar (3000 psi) and 50 °C for up to 48 h with only 0.1 wt % or 0.3 wt % SNPs and 0.01 wt % Arquad 12-50, indicating excellent foam stability. The ability of the surfactant and NPs to stabilize foams at low concentrations broadens the application of foams in subsurface reservoirs at high temperatures and salinities.

Clinical Validation of the Champagne Algorithm for Evoked Response Source Localization in Magnetoencephalography.

Magnetoencephalography (MEG) is a robust method for non-invasive functional brain mapping of sensory cortices due to its exceptional spatial and temporal resolution. The clinical standard for MEG source localization of functional landmarks from sensory evoked responses is the equivalent current dipole (ECD) localization algorithm, known to be sensitive to initialization, noise, and manual choice of the number of dipoles. Recently many automated and robust algorithms have been developed, including the Champagne algorithm, an empirical Bayesian algorithm, with powerful abilities for MEG source reconstruction and time course estimation (Wipf et al. 2010; Owen et al. 2012). Here, we evaluate automated Champagne performance in a clinical population of tumor patients where there was minimal failure in localizing sensory evoked responses using the clinical standard, ECD localization algorithm. MEG data of auditory evoked potentials and somatosensory evoked potentials from 21 brain tumor patients were analyzed using Champagne, and these results were compared with equivalent current dipole (ECD) fit. Across both somatosensory and auditory evoked field localization, we found there was a strong agreement between Champagne and ECD localizations in all cases. Given resolution of 8mm voxel size, peak source localizations from Champagne were below 10mm of ECD peak source localization. The Champagne algorithm provides a robust and automated alternative to manual ECD fits for clinical localization of sensory evoked potentials and can contribute to improved clinical MEG data processing workflows.

Atrial Fibrillation Following Patent Foramen Ovale Closure: Systematic Review and Meta-Analysis of Observational Studies and Clinical Trials.

Background and Purpose: Multiple studies evaluated whether patent foramen ovale (PFO) closure reduces the risk of ischemic stroke. One commonly reported complication of PFO closure is the development of atrial fibrillation (AF), which is itself a powerful stroke risk factor that requires specific management. This study aims to evaluate the frequency of AF in patients post-percutaneous closure of PFO and the clinical factors that predict AF detection. Methods: Studies were identified by systematically searching EMBASE and MEDLINE databases on July 11, 2019. Meta-analysis of proportions was performed, assuming a random-effects model. Results: A total of 6 randomized controlled trials and 26 observational studies were included, comprising 3737 and 9126 patients, respectively. After PFO closure, the rate of AF development was 3.7 patients per 100 patient-years of follow-up (95% CI, 2.6­4.9). The risk of AF development is concentrated in the first 45 days post-procedure (27.2 patients per 100 patient-years [95% CI, 20.1­34.81], compared with 1.3 patients per 100 patient-years [95% CI, 0.3­2.7]) after 45 days. Meta-regression by age suggested that studies with older patients reported higher rate of AF (P=0.001).In medically treated patients, the rate of AF development was 0.1 per 100 patient-years of follow-up (95% CI, 0.0­0.4). Closure of PFO is associated with increased risk of AF compared with medical management (odds ratio, 5.3 [95% CI, 2.5­11.41]; P<0.001). Conclusions: AF is more common in PFO patients who had percutaneous closure compared with those who were medically treated. The risk of AF was higher in the first 45 days post-closure and in studies that included patients with increased age.

Interhemispheric Auditory Cortical Synchronization in Asymmetric Hearing Loss.

OBJECTIVES: Auditory cortical activation of the two hemispheres to monaurally presented tonal stimuli has been shown to be asynchronous in normal hearing (NH) but synchronous in the extreme case of adult-onset asymmetric hearing loss (AHL) with single-sided deafness. We addressed the wide knowledge gap between these two anchoring states of interhemispheric temporal organization. The objectives of this study were as follows: (1) to map the trajectory of interhemispheric temporal reorganization from asynchrony to synchrony using magnitude of interaural threshold difference as the independent variable in a cross-sectional study and (2) to evaluate reversibility of interhemispheric synchrony in association with hearing in noise performance by amplifying the aidable poorer ear in a repeated measures, longitudinal study. DESIGN: The cross-sectional and longitudinal cohorts were comprised of 49 subjects (AHL; N = 21; 11 male, 10 female; mean age = 48 years) and NH (N = 28; 16 male, 12 female; mean age = 45 years). The maximum interaural threshold difference of the two cohorts spanned from 0 to 65 dB. Magnetoencephalography analyses focused on latency of the M100 peak response from auditory cortex in both hemispheres between 50 msec and 150 msec following monaural tonal stimulation at the frequency (0.5, 1, 2, 3, or 4 kHz) corresponding to the maximum and minimum interaural threshold difference for better and poorer ears separately. The longitudinal AHL cohort was drawn from three subjects in the cross-sectional AHL cohort (all male; ages 49 to 60 years; varied AHL etiologies; no amplification for at least 2 years). All longitudinal study subjects were treated by monaural amplification of the poorer ear and underwent repeated measures examination of the M100 response latency and quick speech in noise hearing in noise performance at baseline, and postamplification months 3, 6, and 12. RESULTS: The M100 response peak latency values in the ipsilateral hemisphere lagged those in the contralateral hemisphere for all stimulation conditions. The mean (SD) interhemispheric latency difference values (ipsilateral less contralateral) to better ear stimulation for three categories of maximum interaural threshold difference were as follows: NH (≤ 10 dB)-8.6 (3.0) msec; AHL (15 to 40 dB)-3.0 (1.2) msec; AHL (≥ 45 dB)-1.4 (1.3) msec. In turn, the magnitude of difference values were used to define interhemispheric temporal organization states of asynchrony, mixed asynchrony and synchrony, and synchrony, respectively. Amplification of the poorer ear in longitudinal subjects drove interhemispheric organization change from baseline synchrony to postamplification asynchrony and hearing in noise performance improvement in those with baseline impairment over a 12-month period. CONCLUSIONS: Interhemispheric temporal organization in AHL was anchored between states of asynchrony in NH and synchrony in single-sided deafness. For asymmetry magnitudes between 15 and 40 dB, the intermediate mixed state of asynchrony and synchrony was continuous and reversible. Amplification of the poorer ear in AHL improved hearing in noise performance and restored normal temporal organization of auditory cortices in the two hemispheres. The return to normal interhemispheric asynchrony from baseline synchrony and improvement in hearing following monoaural amplification of the poorer ear evolved progressively over a 12-month period.

Brain activation patterns of female multiple sclerosis patients with voiding dysfunction.

AIMS: We compared brain activation patterns between female multiple sclerosis (MS) patients with voiding dysfunction (VD) and those without. We aim to expand current knowledge of supraspinal correlates of voiding initiation within a cohort of female MS patients with and without VD. MATERIALS AND METHODS: Twenty-eight ambulatory female MS patients with stable disease and lower urinary tract dysfunction were recruited for this study. Subjects were divided into group 1, without VD (n = 14), and group 2, with VD (n = 14), defined as postvoid residual urine of ≥40% of maximum cystometric capacity or need for self-catheterization. We recorded brain activity via functional magnetic resonance imaging (fMRI) with simultaneous urodynamic testing. Average fMRI activation maps (the Student t test) were created for both groups, and areas of significant activation were identified (P < .05). A priori regions of interest (ROIs), identified by prior meta-analysis to be involved in voiding, were selected. RESULTS: Group-averaged blood-oxygen level-dependent (BOLD) activation maps demonstrated significant differences between groups 1 and 2 during initiation of voiding with group 2 showing significantly lower levels of activation in all ROIs except for the left cerebellum and right cingulate gyrus. Interestingly, group 2 displayed negative BOLD signals, while group 1 displayed positive signals in the right and left pontine micturition center, right periaqueductal gray, left thalamus, and left cingulate gyrus. The activation map of group 1 was similar to healthy controls. CONCLUSIONS: Our results support the hypothesis that distinct supraspinal activation patterns exist between female MS patients with VD and those without.

BMP-Responsive Protease HtrA1 Is Differentially Expressed in Astrocytes and Regulates Astrocytic Development and Injury Response.

Astrocytes perform a wide array of physiological functions, including structural support, ion exchange, and neurotransmitter uptake. Despite this diversity, molecular markers that label subpopulations of astrocytes are limited, and mechanisms that generate distinct astrocyte subtypes remain unclear. Here we identified serine protease high temperature requirement A 1 (HtrA1), a bone morphogenetic protein 4 signaling regulated protein, as a novel marker of forebrain astrocytes, but not of neural stem cells, in adult mice of both sexes. Genetic deletion of HtrA1 during gliogenesis accelerates astrocyte differentiation. In addition, ablation of HtrA1 in cultured astrocytes leads to altered chondroitin sulfate proteoglycan expression and inhibition of neurite extension, along with elevated levels of transforming growth factor-ß family proteins. Brain injury induces HtrA1 expression in reactive astrocytes, and loss of HtrA1 leads to an impairment in wound closure accompanied by increased proliferation of endothelial and immune cells. Our findings demonstrate that HtrA1 is differentially expressed in adult mouse forebrain astrocytes, and that HtrA1 plays important roles in astrocytic development and injury response.SIGNIFICANCE STATEMENT Astrocytes, an abundant cell type in the brain, perform a wide array of physiological functions. Although characterized as morphologically and functionally diverse, molecular markers that label astrocyte subtypes or signaling pathways that lead to their diversity remain limited. Here, after examining the expression profile of astrocytes generated in response to bone morphogenetic protein signaling, we identify high temperature requirement A 1 (HtrA1) as an astrocyte-specific marker that is differentially expressed in distinct adult mouse brain regions. HtrA1 is a serine protease that has been linked to cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, a small blood vessel disease in humans. Understanding the role of HtrA1 during development and after injury will provide insights into how distinct astrocyte populations are generated and their unique roles in injury and disease.

Human-automation interaction for multiple robot control: the effect of varying automation assistance and individual differences on operator performance.

In a human-automation interaction study, automation assistance level (AL) was investigated for its effects on operator performance in a dynamic, multi-tasking environment. Participants supervised a convoy of manned and unmanned vehicles traversing a simulated environment in three AL conditions, while maintaining situation awareness and identifying targets. Operators' situation awareness, target detection performance, workload and individual differences were evaluated. Results show increasing AL generally improved task performance and decreased perceived workload, however, differential effects due to operator spatial ability and perceived attentional control were found. Eye-tracking measures were useful in parsing out individual differences that subjective measures did not detect. At the highest AL, participants demonstrated potentially complacent behaviour, indicating task disengagement. Practitioner Summary: The effect of varying automation assistance level (AL) on operator performance on multiple tasks were examined in a within-subjects experiment. Findings indicated a moderate AL improved performance, while higher levels encouraged complacent behaviour. Effects due to individual differences suggest that effective AL depends on the underlying characteristics of the operator.

Variables associated with administration of analgesia, nurse-initiated analgesia and early analgesia in the emergency department.

OBJECTIVE: To determine the patient and clinical variables associated with administration of any analgesia, nurse-initiated analgesia (NIA, prescribed and administered by a nurse) and early analgesia (within 30 min of presentation). METHODS: We undertook a retrospective cohort study of patients who presented to a metropolitan ED in Melbourne, Australia, during July and August, 2013. The ED has an established NIA programme. Patients were included if they were aged 18 years or more and presented with a painful complaint. The study sample was randomly selected from a list of all eligible patients. Data were extracted electronically from the ED records and by explicit extraction from the medical record. Logistic regression models were constructed to assess associations with the three binary study end points. RESULTS: 1289 patients were enrolled. Patients were less likely to receive any analgesia if they presented 08:00-15:59 hours (OR 0.67, 95% CI 0.46 to 0.98) or 16:00-24:00 hours (OR 0.55, 95% CI 0.37 to 0.80) were triage category 5 (OR 0.20, 95% CI 0.08 to 0.49) or required an interpreter (OR 0.34, 95% CI 0.14 to 0.86). Patients were less likely to receive NIA or early analgesia if they were aged 56 years or more (OR 0.70 and 0.63; OR 0.57 and 0.21, respectively) or if they had received ambulance analgesia (OR 0.59, 95% CI 0.36 to 0.95; OR 0.38, 95% CI 0.20 to 0.74, respectively). CONCLUSIONS: Patients who present during the daytime, have a triage category of 5 or require an interpreter are less likely to receive analgesia. Older patients and those who received ambulance analgesia are less likely to receive NIA or early analgesia.

A Meta-Analysis of Factors Influencing the Development of Trust in Automation: Implications for Understanding Autonomy in Future Systems.

OBJECTIVE: We used meta-analysis to assess research concerning human trust in automation to understand the foundation upon which future autonomous systems can be built. BACKGROUND: Trust is increasingly important in the growing need for synergistic human-machine teaming. Thus, we expand on our previous meta-analytic foundation in the field of human-robot interaction to include all of automation interaction. METHOD: We used meta-analysis to assess trust in automation. Thirty studies provided 164 pairwise effect sizes, and 16 studies provided 63 correlational effect sizes. RESULTS: The overall effect size of all factors on trust development was g = +0.48, and the correlational effect was [Formula: see text] = +0.34, each of which represented medium effects. Moderator effects were observed for the human-related (g = +0.49; [Formula: see text] = +0.16) and automation-related (g = +0.53; [Formula: see text] = +0.41) factors. Moderator effects specific to environmental factors proved insufficient in number to calculate at this time. CONCLUSION: Findings provide a quantitative representation of factors influencing the development of trust in automation as well as identify additional areas of needed empirical research. APPLICATION: This work has important implications to the enhancement of current and future human-automation interaction, especially in high-risk or extreme performance environments.

Intelligent Agent Transparency in Human-Agent Teaming for Multi-UxV Management.

OBJECTIVE: We investigated the effects of level of agent transparency on operator performance, trust, and workload in a context of human-agent teaming for multirobot management. BACKGROUND: Participants played the role of a heterogeneous unmanned vehicle (UxV) operator and were instructed to complete various missions by giving orders to UxVs through a computer interface. An intelligent agent (IA) assisted the participant by recommending two plans-a top recommendation and a secondary recommendation-for every mission. METHOD: A within-subjects design with three levels of agent transparency was employed in the present experiment. There were eight missions in each of three experimental blocks, grouped by level of transparency. During each experimental block, the IA was incorrect three out of eight times due to external information (e.g., commander's intent and intelligence). Operator performance, trust, workload, and usability data were collected. RESULTS: Results indicate that operator performance, trust, and perceived usability increased as a function of transparency level. Subjective and objective workload data indicate that participants' workload did not increase as a function of transparency. Furthermore, response time did not increase as a function of transparency. CONCLUSION: Unlike previous research, which showed that increased transparency resulted in increased performance and trust calibration at the cost of greater workload and longer response time, our results support the benefits of transparency for performance effectiveness without additional costs. APPLICATION: The current results will facilitate the implementation of IAs in military settings and will provide useful data to the design of heterogeneous UxV teams.

Utility of stereoscopic displays for indirect-vision driving and robot teleoperation.

The effectiveness of an active shutter-glasses stereoscopic display (SD) and a passive polarised SD was evaluated in a live robot-teleoperation task and a simulated indirect-vision driving task in various terrains. Overall, participants completed their tasks significantly faster with the SDs in three-dimensional (3D) mode than with the SDs in the baseline 2D mode. They also navigated more accurately with the SDs in 3D mode. When the effectiveness of the two types of SDs was examined separately, results showed that the active shutter-glasses SD resulted in faster responses and task completion times than the passive polarised SD, though most of the differences failed to reach statistical significance. Perceived workload when interacting with the two SD systems did not differ significantly between the active versus passive display types or between the 3D and 2D modes of operation; however, participants reported more severe discomfort after interacting with the passive polarised SD.

IL2 Targeted to CD8+ T Cells Promotes Robust Effector T-cell Responses and Potent Antitumor Immunity.

IL2 signals pleiotropically on diverse cell types, some of which contribute to therapeutic activity against tumors, whereas others drive undesired activity, such as immunosuppression or toxicity. We explored the theory that targeting of IL2 to CD8+ T cells, which are key antitumor effectors, could enhance its therapeutic index. To this aim, we developed AB248, a CD8 cis-targeted IL2 that demonstrates over 500-fold preference for CD8+ T cells over natural killer and regulatory T cells (Tregs), which may contribute to toxicity and immunosuppression, respectively. AB248 recapitulated IL2's effects on CD8+ T cells in vitro and induced selective expansion of CD8+T cells in primates. In mice, an AB248 surrogate demonstrated superior antitumor activity and enhanced tolerability as compared with an untargeted IL2Rßγ agonist. Efficacy was associated with the expansion and phenotypic enhancement of tumor-infiltrating CD8+ T cells, including the emergence of a "better effector" population. These data support the potential utility of AB248 in clinical settings. Significance: The full potential of IL2 therapy remains to be unlocked. We demonstrate that toxicity can be decoupled from antitumor activity in preclinical models by limiting IL2 signaling to CD8+ T cells, supporting the development of CD8+ T cell-selective IL2 for the treatment of cancer. See related article by Kaptein et al. p. 1226.

Dominant NARS1 mutations causing axonal Charcot-Marie-Tooth disease expand NARS1-associated diseases.

Pathogenic variants in six aminoacyl-tRNA synthetase (ARS) genes are implicated in neurological disorders, most notably inherited peripheral neuropathies. ARSs are enzymes that charge tRNA molecules with cognate amino acids. Pathogenic variants in asparaginyl-tRNA synthetase (NARS1) cause a neurological phenotype combining developmental delay, ataxia and demyelinating peripheral neuropathy. NARS1 has not yet been linked to axonal Charcot-Marie-Tooth disease. Exome sequencing of patients with inherited peripheral neuropathies revealed three previously unreported heterozygous NARS1 variants in three families. Clinical and electrophysiological details were assessed. We further characterized all three variants in a yeast complementation model and used a knock-in mouse model to study variant p.Ser461Phe. All three variants (p.Met236del, p.Cys342Tyr and p.Ser461Phe) co-segregate with the sensorimotor axonal neuropathy phenotype. Yeast complementation assays show that none of the three NARS1 variants support wild-type yeast growth when tested in isolation (i.e. in the absence of a wild-type copy of NARS1), consistent with a loss-of-function effect. Similarly, the homozygous knock-in mouse model (p.Ser461Phe/Ser472Phe in mouse) also demonstrated loss-of-function characteristics. We present three previously unreported NARS1 variants segregating with a sensorimotor neuropathy phenotype in three families. Functional studies in yeast and mouse support variant pathogenicity. Thus, NARS1 is the seventh ARS implicated in dominant axonal Charcot-Marie-Tooth disease, further stressing that all dimeric ARSs should be evaluated for Charcot-Marie-Tooth disease.

Vaginoscopy With Laser Treatment of Symptomatic Upper Vaginal Mesh Exposure After Prior Mesh Sacrocolpopexy.

OBJECTIVE: To describe the technique of vaginoscopy with Holmium:YAG and Thulium laser treatment of upper vaginal mesh exposure after mesh sacrocolpopexy (MSC) as well as evaluate treatment efficacy. METHODS: Following IRB approval, a chart review of all patients who underwent laser treatment of upper vaginal mesh exposure during vaginoscopy at a single institution between 2013 and 2022 was performed. Demographic information, previous mesh placement history, presenting symptoms, physical examination and vaginoscopy findings, imaging, laser type and settings, operating time, complications, and follow-up including examination and office vaginoscopy findings were extracted from electronic medical records. RESULTS: Five patients and 6 surgical encounters were identified. All patients had a history of MSC and symptomatic mesh exposure at the vaginal apex, which was tented up and difficult to access by traditional transvaginal mesh excision. Five patients underwent vaginal mesh treatment with laser with no further vaginal mesh exposure on follow-up exam or vaginoscopy. One patient was found to have a small recurrence at 4 months and underwent a second treatment with negative findings on vaginoscopy 7.9 months post-operatively. There were no complications. CONCLUSION: Vaginoscopy using a rigid cystoscope and laser treatment of upper vaginal mesh exposure using a Holmium:YAG or Thulium laser is a safe and quick method which led to definitive symptom resolution.

Taking on Typhoid: Eliminating Typhoid Fever as a Global Health Problem.

Typhoid fever is a significant global health problem that impacts people living in areas without access to clean water and sanitation. However, collaborative international partnerships and new research have improved both knowledge of the burden in countries with endemic disease and the tools for improved surveillance, including environmental surveillance. Two typhoid conjugate vaccines (TCVs) have achieved World Health Organization prequalification, with several more in the development pipeline. Despite hurdles posed by the coronavirus disease 2019 pandemic, multiple TCV efficacy trials have been conducted in high-burden countries, and data indicate that TCVs provide a high degree of protection from typhoid fever, are safe to use in young children, provide lasting protection, and have the potential to combat typhoid antimicrobial resistance. Now is the time to double down on typhoid control and elimination by sustaining progress made through water, sanitation, and hygiene improvements and accelerating TCV introduction in high-burden locations.

Supervisory control of multiple robots in dynamic tasking environments.

A military targeting environment was simulated to examine the effects of an intelligent route-planning agent RoboLeader, which could support dynamic robot re-tasking based on battlefield developments, on the performance of robotics operators. We manipulated the level of assistance (LOAs) provided by RoboLeader as well as the presence of a visualisation tool that provided feedback to the participants on their primary task (target encapsulation) performance. Results showed that the participants' primary task benefited from RoboLeader on all LOAs conditions compared to manual performance; however, visualisation had little effect. Frequent video gamers demonstrated significantly better situation awareness of the mission environment than did infrequent gamers. Those participants with higher spatial ability performed better on a secondary target detection task than did those with lower spatial ability. Finally, participants' workload assessments were significantly lower when they were assisted by RoboLeader than when they performed the target entrapment task manually. Practitioner Summary: This study demonstrated the utility of an intelligent agent for enhancing robotics operators' supervisory control performance as well as reducing their workload during a complex urban scenario involving moving targets. The results furthered the understanding of the interplay among level-of-autonomy, multitasking performance and individual differences in military tasking environments.

Refractory Mycobacterium genavense infection secondary to thymoma-associated endogenous IL-12 inhibitor.

Case: A 39-year-old man with thymoma-associated acetylcholine receptor antibody myasthenia gravis (MG) presented with fevers, night sweats, abdominal pain and weight loss. Marked splenomegaly and intra-abdominal lymphadenopathy were found. Biopsies confirmed disseminated Mycobacterium genavense infection. Despite antimicrobials and reduced immunosuppressive medications, he worsened. We suspected a thymoma-associated cytokine inhibitory antibody. The addition of subcutaneous interferon-gamma (IFN-γ) induced clinical and radiological improvement. His antimicrobials were able to be ceased. MG remained stable. Subsequent testing demonstrated an endogenous interleukin-12 (IL-12) inhibitor, likely inhibiting the IL-12/IFN-γ axis crucial for defence against mycobacterial infections. Discussion: This case illustrates the autoimmune manifestations that can occur with thymoma. It illustrates the benefit of exogenous IFN-γ in overcoming the immune deficit. In this case, its use did not exacerbate existing autoimmune disease or trigger others. We raise awareness of the need to consider cytokine pathway defects as a contributing factor to refractory atypical infections in patients with thymoma-associated MG.