Nonclinical immunogenicity risk assessment for knobs-into-holes bispecific IgG1 antibodies.

Bispecific antibodies, including bispecific IgG, are emerging as an important new class of antibody therapeutics. As a result, we, as well as others, have developed engineering strategies designed to facilitate the efficient production of bispecific IgG for clinical development. For example, we have extensively used knobs-into-holes (KIH) mutations to facilitate the heterodimerization of antibody heavy chains and more recently Fab mutations to promote cognate heavy/light chain pairing for efficient in vivo assembly of bispecific IgG in single host cells. A panel of related monospecific and bispecific IgG1 antibodies was constructed and assessed for immunogenicity risk by comparison with benchmark antibodies with known low (Avastin and Herceptin) or high (bococizumab and ATR-107) clinical incidence of anti-drug antibodies. Assay methods used include dendritic cell internalization, T cell proliferation, and T cell epitope identification by in silico prediction and MHC-associated peptide proteomics. Data from each method were considered independently and then together for an overall integrated immunogenicity risk assessment. In toto, these data suggest that the KIH mutations and in vitro assembly of half antibodies do not represent a major risk for immunogenicity of bispecific IgG1, nor do the Fab mutations used for efficient in vivo assembly of bispecifics in single host cells. Comparable or slightly higher immunogenicity risk assessment data were obtained for research-grade preparations of trastuzumab and bevacizumab versus Herceptin and Avastin, respectively. These data provide experimental support for the common practice of using research-grade preparations of IgG1 as surrogates for immunogenicity risk assessment of their corresponding pharmaceutical counterparts.

Thresholds in PROMIS Scores Anchored to Subsequent Unscheduled Health Service Use Among People Diagnosed With Cancer.

PURPOSE: To establish thresholds in the Patient-Reported Outcomes Measurement Information System (PROMIS) pain interference, physical function, fatigue, and depression scores on the basis of their association with subsequent use of the emergency department (ED) or urgent care by people diagnosed with cancer. METHODS: Retrospective data from 952 people seen at Henry Ford Cancer and insured through the Health Alliance Plan were analyzed using generalized linear mixed-effects models. The log odds of ED or urgent care use during 14 or 30 days after each patient-reported outcome (PRO) assessment were related to PRO scores, while adjusting for comorbidity, sociodemographic, and tumor characteristics. RESULTS: Pain interference and physical function were associated with subsequent ED or urgent care visits, but fatigue and depression were not, and the results for 14- and 30-day visits were similar. Thresholds anchored in the likelihood of these visits differed according to cancer stage. For people with advanced cancer, a pain interference score of 60 or higher (odds ratio [OR] 3.75, [95% CI, 1.53 to 7.87]) and a physical function score lower than 40 (OR 2.94, [95% CI, 1.22 to 7.06]) produced the largest ORs with narrowest CIs for 30-day visits. For people with nonadvanced cancer, the thresholds of 65 for pain interference (OR 2.64, [95% CI, 1.40 to 5.01]) and 35 for physical function (OR 1.87, [95% CI, 1.01 to 3.45]) produced largest ORs with narrowest CIs for 30-day visits. CONCLUSION: These anchor-based thresholds in PROMIS scores can inform clinicians' actions with the goal of preventing ED or urgent care visits.

Potent and selective binders of the E3 ubiquitin ligase ZNRF3 stimulate Wnt signaling and intestinal organoid growth.

Selective and precise activation of signaling transduction cascades is key for cellular reprogramming and tissue regeneration. However, the development of small- or large-molecule agonists for many signaling pathways has remained elusive and is rate limiting to realize the full clinical potential of regenerative medicine. Focusing on the Wnt pathway, here we describe a series of disulfide-constrained peptides (DCPs) that promote Wnt signaling activity by modulating the cell surface levels of ZNRF3, an E3 ubiquitin ligase that controls the abundance of the Wnt receptor complex FZD/LRP at the plasma membrane. Mechanistically, monomeric DCPs induce ZNRF3 ubiquitination, leading to its cell surface clearance, ultimately resulting in FZD stabilization. Furthermore, we engineered multimeric DCPs that induce expansive growth of human intestinal organoids, revealing a dependence between valency and ZNRF3 clearance. Our work highlights a strategy for the development of potent, biologically active Wnt signaling pathway agonists via targeting of ZNRF3.

The Effects of Light Therapy on Sleep, Agitation and Depression in People With Dementia: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

OBJECTIVE: To evaluate the effects of light therapy on the alleviation of sleep disturbances, agitation and depression in people with dementia. METHODS: A search was performed in PubMed, Medline, SCOPUS, Web of Science, EMBASE, CINAHL, Cochrane Library, for studies published between 2000 and 2021. RESULTS: A total of 4315 articles were screened. Sixteen articles were eligible for this review and 11 randomized controlled studies were included in the meta-analysis. Light therapy had a significant effect on reducing the number of awakenings in sleep (n = 4; 95% CI = -.56, -.05; I2 = 0%; SMD = -.31) but was not significant in reducing the wake after sleep onset (n = 3; 95% CI = -.14, .59; I2 = 0%; SMD = .23), agitation (n = 4; 95% CI = -1.02, .45; I2 = 87%; SMD = -.28) and depression (n = 6; 95% CI = -.80, .40, I2 = 85%; SMD = -.20). CONCLUSION: Light therapy appeared to be more effective in terms of alleviating sleep disturbances, rather than reducing agitation and depression, but its long-term effects remain unclear.

Antibody targeting of E3 ubiquitin ligases for receptor degradation.

Most current therapies that target plasma membrane receptors function by antagonizing ligand binding or enzymatic activities. However, typical mammalian proteins comprise multiple domains that execute discrete but coordinated activities. Thus, inhibition of one domain often incompletely suppresses the function of a protein. Indeed, targeted protein degradation technologies, including proteolysis-targeting chimeras1 (PROTACs), have highlighted clinically important advantages of target degradation over inhibition2. However, the generation of heterobifunctional compounds binding to two targets with high affinity is complex, particularly when oral bioavailability is required3. Here we describe the development of proteolysis-targeting antibodies (PROTABs) that tether cell-surface E3 ubiquitin ligases to transmembrane proteins, resulting in target degradation both in vitro and in vivo. Focusing on zinc- and ring finger 3 (ZNRF3), a Wnt-responsive ligase, we show that this approach can enable colorectal cancer-specific degradation. Notably, by examining a matrix of additional cell-surface E3 ubiquitin ligases and transmembrane receptors, we demonstrate that this technology is amendable for 'on-demand' degradation. Furthermore, we offer insights on the ground rules governing target degradation by engineering optimized antibody formats. In summary, this work describes a strategy for the rapid development of potent, bioavailable and tissue-selective degraders of cell-surface proteins.

Racial Differences in Planned Hysterectomy Procedure Route.

Background: Hysterectomies can be performed with a minimally invasive surgical (MIS) approach or a laparotomic (abdominal) approach. The objective of this study was to assess any racial differences in the likelihood of having a planned MIS hysterectomy. Materials and Methods: A prospective cohort study of women undergoing hysterectomy at Henry Ford Health System was conducted where laparotomic and MIS approaches are available to all patients. All procedures were performed between October, 2015, and August, 2017. For this study, women were asked to report demographic and insurance information and complete validated questionnaires from 2 weeks before hysterectomy and up to six additional times in the year after hysterectomy. Clinical and operative characteristics were collected from electronic health records. Logistic regression and multinomial logistic regression models were applied to assess the association between race and the surgical approach. Results: Analyses included 235 White women and 196 Black women. Black women were less likely to have any MIS planned for their hysterectomy (odds ratio [OR] = 0.46, 95% confidence interval [CI] 0.3-0.71, p < 0.05), a laparoscopic hysterectomy (relative risk ratio [RRR] = 0.46, 95% CI 0.29-0.73, p < 0.05), or a vaginal hysterectomy (RRR = 0.45, 95% CI 0.25-0.81, p = 0.01) compared with White women. After adjusting for confounders, uterine weight and indication for surgery was fibroids, these racial differences did not remain statistically significant (MIS vs. abdominal [adjusted odds ratio {aOR} = 0.93, 95% CI 0.55-1.57, p = 0.79], laparoscopic vs. abdominal [adjusted relative risk ratio {aRRR} = 0.89, 95% CI 0.52-1.51, p = 0.54], and vaginal vs. abdominal [aRRR = 1.22, 95% CI 0.61-2.45, p = 0.58]). The associations were not confounded by the baseline survey data from standardized questionnaires on depression, financial distress, and satisfaction with their decision. Conclusions: Black women were not less likely than White women to have planned an MIS hysterectomy after controlling for important confounding variables. These results emphasize the importance of considering all important confounders when examining racial differences.

The Effect of Mirror Visual Feedback on Spatial Neglect for Patients after Stroke: A Preliminary Randomized Controlled Trial.

We investigated the effects of mirror visual feedback (MVF), with reference to using a glass wall or a covered mirror, on the reduction of spatial neglect for patients with stroke. A total of 21 subacute patients with left spatial neglect after right-hemispheric stroke were randomly assigned to 3 groups: MVF, sham 1 (viewing the hemiparetic arm through the transparent glass during bilateral arm movement) and sham 2 (using a covered mirror). The 3-week treatment program for all groups consisted of 12 sessions of movement tasks for the hemiparetic arm graded according to the severity of arm impairments. Blinded assessments were administered at pre/post and a three-week follow-up. The results showed that there was no significant advantage for MVF than sham 1; however, MVF was more beneficial than sham 2, as shown by the line crossing (p = 0.022). Improvement in discriminating the left-gap figures on the left and right side of the page in the Gap Detection Test was greater in MVF than using the covered mirror (p = 0.013; p = 0.010), showing a slight advantage of MVF in alleviating allocentric symptoms. Our study confirms that MVF was superior to using a covered mirror as a method for reducing spatial neglect and in alleviating its allocentric symptoms, but no significant advantage over bilateral arm movement through transparent glass was found. Further research in comparing their therapeutic effects is warranted.

Event-Related Desynchronization During Mirror Visual Feedback: A Comparison of Older Adults and People After Stroke.

Event-related desynchronization (ERD), as a proxy for mirror neuron activity, has been used as a neurophysiological marker for motor execution after mirror visual feedback (MVF). Using EEG, this study investigated ERD upon the immediate effects of single-session MVF in unimanual arm movements compared with the ERD effects occurring without a mirror, in two groups: stroke patients with left hemiplegia and their healthy counterparts. During EEG recordings, each group performed one session of mirror therapy training in three task conditions: with a mirror, with no mirror, and with a covered mirror. An asymmetry index was calculated from the subtraction of the event-related spectrum perturbations between the C3 and C4 electrodes located over the sensorimotor cortices contralateral and ipsilateral to the moved arm. Results of the effect of task versus group in contralateral and ipsilateral motor areas showed that there was a significant effect of task condition at the contralateral motor area in the high beta band (17-35 Hz) at C3. High beta ERD showed that the suppression was greater over the contralateral hemisphere than it was over the ipsilateral hemisphere in both study groups. The magnitude of low beta (12-16 Hz) ERD in patients with stroke was more suppressed in contralesional C3 under the no mirror compared to that of the covered mirror and similarly more suppressed in ipsilesional C4 ERD under the no mirror compared to that of the mirror condition. The correlation analysis revealed that the magnitude of ERSP power correlated significantly with arm severity in the low and high beta bands in patients with stroke, and a higher asymmetry index in the low beta band was associated with higher arm functioning under the no-mirror condition. There was a shift in sensorimotor ERD toward the contralateral hemisphere as induced by MVF accompanying unimanual movement in both stroke patients and healthy controls. The use of ERD in the low beta band as a neurophysiological marker to indicate the relationships between the amount of MVF-induced ERD attenuation and motor severity, and the outcome indicator for improving stroke patients' neuroplasticity in clinical trials using MVF are warranted to be explored in the future.

Airway events in obese vs. non-obese elective surgical patients: a cross-sectional observational study.

Obesity is an increasingly prevalent comorbidity within the UK population. The aim of this study was to determine the proportion of obese patients in an elective surgical population. The second aim was to determine the choice of airway equipment and incidence of airway events in obese vs. non-obese patients. We conducted a cross-sectional observational study over two 24-h periods in March 2018 across 39 hospitals in the greater London area. Data were collected regarding 1874 patients. The incidence of obesity was 32% in the study population compared with 26% in the general UK population (p < 0.0001). Minor airway events were defined as: desaturation to Sp O2 < 90%; failed mask ventilation; supraglottic airway device problem; aspiration; airway trauma and difficult intubation; or recognised oesophageal intubation. Major airway events were defined as: unrecognised oesophageal intubation; a 'cannot intubate cannot oxygenate' emergency; the need for unplanned front-of-neck airway; cardiac arrest; or unplanned intensive care unit admission due to an airway event. In total, 89 minor and two major airway events were recorded. Obese patients were more likely to experience a minor airway event (RR 2.39, 95%CI 1.60-3.57), the most common being desaturation (Sp O2 < 90%). The use of a supraglottic airway device in obese vs. non-obese patients was associated with increased airway events (RR 3.46 [1.88-6.40]). Tracheal intubation vs. supraglottic airway device use increased with obesity class but was not associated with a decrease in airway events (RR 0.90 [0.53-1.55]). Our data suggest that obesity is more common in the elective surgical vs. general population and minor airway events are more common in obese vs. non-obese elective patients.

Effectiveness of enhanced video-based learning on removable partial denture module.

INTRODUCTION: The application of video-based learning in dentistry has been widely investigated; however, the nature of on-screen video enhancements of the video has been minimally explored in the literature. This study investigated the effectiveness of an in-class and on-demand enhanced video to support learning on removable partial dentures in terms of knowledge acquisition, perception and clinical skill performance. METHODS: Fifty-four dental students enrolled in 2018 were recruited as participants and assigned to two groups. Both groups were given the same lecture and asked to watch the same video in either the enhanced or non-enhanced version. The enhanced video was modified with the contemporaneous subtitle of the presenters' dialogue, text bullet points and summary text pages. The knowledge acquisition from the two types of video was subjected to pre- and post-tests one month after the students watched the video. A questionnaire was used to evaluate the students' perceptions of the learning experience and a performance test on practical skills was performed after six weeks. All the students responded to the test (100%). RESULTS: The enhanced video demonstration improved the students' short-term knowledge acquisition after they watched the video, with an average score of 1.59 points higher in the enhanced group than in the non-enhanced group (p < .05). The practical performance did not differ between the two groups. The students were more likely accepted the enhanced video as a replacement of the existing teaching method rather than a teaching supplement (70.3%). CONCLUSION: The application of the enhanced video demonstration resulted in a better theoretical knowledge retention but not practical performance. Students also preferred watching video to using conventional learning methods.

The Effects of Harm Events on 30-Day Readmission in Surgical Patients.

ABSTRACT: Readmission is an increasingly important focus for improvement regarding quality, value, and patient burden in our surgical patient population. We hypothesized that inpatient harm events increase the likelihood of readmission in surgical patients. We created a system-wide inpatient registry with 30-day readmission. A surgical subset was created, and harm events were tracked through the electronic health record system. Between 2015 and 2017, 37,048 surgical patient encounters met inclusion criterion. A total of 2,887 patients (7.69%) were readmitted. After multiple logistic regression of the highly significant harm measures, seven harm measures remained statistically significant (p < .05). Those with the three highest odds ratios were mucosal pressure ulcer, Clostridium difficile, and glucose <40. Incorporating harm measures to the traditional risk, predictive model for 30-day readmission improved our model performance (area under the ROC curve from 0.68 to 0.71). This study demonstrated that inpatient hospital-based harm events can be electronically monitored and used to predict 30-day readmission.

Virtual reality as a learning tool in spinal anatomy and surgical techniques.

BACKGROUND: Surgical simulation is a valuable educational tool for trainees to practice in a safe, standardized, and controlled environment. Interactive feedback-based virtual reality (VR) has recently moved to the forefront of spine surgery training, with most commercial products focusing on instrumentation. There is a paucity of learning tools directed at decompression principles. The purpose of this study was to evaluate the efficacy of VR simulation and its educational role in learning spinal anatomy and decompressive techniques. METHODS: A VR simulation module was created with custom-developed software. Orthopaedic and neurosurgical trainees were prospectively enrolled and interacted with patient-specific 3D models of lumbar spinal stenosis while wearing a headset. A surgical toolkit allowed users to perform surgical decompression, specifically removing soft tissues and bone. The module allowed users to perform various techniques in posterior decompressions and comprehend anatomic areas of stenosis. Pre- and post-module testing, and utility questionnaires were administered to provide both quantitative and qualitative evaluation of the module as a learning device. RESULTS: 28 trainees were enrolled (20-orthopaedic, 8-neurosurgery) in the study. Pre-test scores on anatomic knowledge progressively improved and showed strong positive correlation with year-in-training (Pearson's r = 0.79). Following simulation, the average improvement in post-test scores was 11.4% in junior trainees (PGYI-III), and 1.0% in senior trainees (PGYIII-Fellows). Knowledge improvement approached statistical significance amongst junior trainees (p = 0.0542). 89% of participants found the VR module useful in understanding and learning the pathology of spinal stenosis. 71% found it useful in comprehending decompressive techniques. 96% believed it had utility in preoperative planning with patient-specific models. CONCLUSIONS: Our original VR spinal decompression simulation has shown to be overwhelmingly positively received amongst trainees as both a learning module of patho-anatomy and patient-specific preoperative planning, with particular benefit for junior trainees.

Double cropping and cropland expansion boost grain production in Brazil.

Brazilian grain production increased more than fourfold from 1980 to 2016. The grain boom was achieved primarily by soybean-corn double cropping and cropland expansion-both show changing spatiotemporal patterns since the 1980s. Here, we quantified the contributions of these two strategies to corn and soybean production in Brazil using municipality-level data from 1980 to 2016. We found the contribution of double cropping to the grain boom steadily increased to 35% and the largest driving force was the increasing demand for grain export. While double cropping dominated the conventional agricultural regions, cropland expansion was still the major strategy in agricultural frontiers such as the Centre-West and Matopiba. The implementation of double cropping offset the equivalent of 76.7 million ha of Brazilian arable land for grain production from 2003 to 2016. Double cropping in Brazil has the potential to help alleviate land burdens in other pantropical countries with increasing global food demand.

Mindfulness for psychosis groups; description and preliminary evaluation of a novel routine care pathway in Hong Kong.

BACKGROUND: There is no current guidance on where Mindfulness for Psychosis groups should best be situated within care pathways. The objectives of this paper are to (1) describe a novel care pathway tested out in a psychiatric outpatient service in Hong Kong, and (2) to present feasibility outcomes on attendance and drop-out, and routine clinical outcomes. METHODS: A new mindfulness pathway was set up, for service users with psychosis who had first completed a course of Cognitive Behavioural Therapy for psychosis (CBTp). After attending an orientation 'taster' session, service users could then attended a 4-session weekly Mindfulness for Psychosis group, followed by optional monthly follow-up sessions. RESULTS: A high proportion of service users referred into the pathway (19/22; 86%) went on to attend a Mindfulness for Psychosis group after attending an orientation 'taster' session. Attendance at group sessions was high, with all participants attending at least 2/4 group sessions, and no drop-outs. Attendance at monthly follow-up groups was also high, with 84% (16/19) attending at least one monthly follow-up. Routine clinical outcome data showed a reduction in negative symptoms of psychosis, and an increase in mindfulness and mindful responding in daily life, from pre- to post group. CONCLUSIONS: Offering service users with psychosis the opportunity to attend a mindfulness for psychosis group after completing a course of CBTp was highly acceptable, as evidenced by high attendance, and low drop-out. Possible benefits in terms of improving negative symptoms may be particularly important in promoting recovery through improved everyday functioning.

A Prospective Study of Patterns of Regret in the Year After Hysterectomy.

PURPOSE: This study sought to identify patterns of self-reported regret after hysterectomy. METHODS: Women undergoing hysterectomy for a benign indication were recruited in the 2 weeks prior to surgery. Women reported demographics and completed validated questionnaires (Decisional Regret Scale, Patient Health Questionnaire-9, Decisional Conflict Scale, and the Comprehensive Score for Financial Toxicity) up to 7 times over the first year postsurgery. Medical records were reviewed for clinical and operative details. Latent class growth mixture models were applied to the repeated regret scores to identify patterns after hysterectomy. Clinical and other participant characteristics were compared across the classes. RESULTS: Three latent classes were identified among the 459 participants (422 of whom completed questionnaires at 12 months): "High Regret" (7.4%), women with a high regret score at baseline that did not improve over time; "Decreasing Regret" (13.3%), women with high baseline levels of regret but whose regret scores improved over time; and "Least Regret" (79.3%), women with the lowest baseline regret scores that remained low after surgery. These classes did not vary with respect to indication for surgery, clinical characteristics, age, or body mass index. Disproportionately more African American women (adjusted odds ratio: 1.99, 95% CI: 1.01-3.9) were in the "Decreasing Regret" versus "Least Regret" classes. Baseline satisfaction varied between the classes, with the "Least Regret" group having higher baseline satisfaction with their decision. Women with "Decreasing Regret" reported worse financial toxicity associated with surgery versus women in the "Least Regret" class (adjusted odds ratio: 0.95, 95% CI: 0.92-0.99). CONCLUSIONS: For some women, decisional regret may worsen after hysterectomy. More often, initial regret lessens over time. Future studies that identify factors strongly associated with self-reported regret could lead to improved counseling about postsurgical expectations.

Evaluation of [131I]I- and [177Lu]Lu-DTPA-A11 Minibody for Radioimmunotherapy in a Preclinical Model of PSCA-Expressing Prostate Cancer.

PURPOSE: Radioimmunotherapy uses tumor-specific antibodies to deliver therapeutic radionuclides, but hematological toxicity due to the long serum half-life of intact antibodies remains a challenge. We evaluated a smaller antibody fragment, the minibody, with faster kinetics and a potentially improved therapeutic index. PROCEDURES: The anti-prostate stem cell antigen (PSCA) minibody (A11 Mb) was radiolabeled with iodine-124 ([124I]I-A11 Mb) or conjugated with deferoxamine (DFO) and labeled with zirconium-89 ([89Zr]Zr-DFO-A11 Mb) for surrogate immunoPET to profile pharmacokinetics in a human prostate cancer xenograft model. Subsequently, minibodies labeled with two therapeutic beta emitters, directly iodinated [131I]I-A11 Mb (non-residualizing) and 177Lu chelated using DTPA ([177Lu]Lu-DTPA-A11 Mb) (residualizing), were compared for in vitro antigen-specific cytotoxicity. Full biodistribution studies (in 22Rv1-PSCA tumor bearing and hPSCA knock-in mice) were conducted for dosimetry calculations. Finally, the lead candidate [131I]I-A11 Mb was evaluated in a radioimmunotherapy experiment. Escalating single doses (3.7, 11, or 37 MBq) and saline control were administered to 22Rv1-PSCA tumor bearing mice and anti-tumor effects (tumor volume) and toxicity (body weight) were monitored. RESULTS: Minibodies radiolabeled with therapeutic beta emitters [131I]I-A11 Mb and [177Lu]Lu-DTPA-A11 Mb exhibited comparable tumor cell growth inhibition in vitro. In vivo surrogate immunoPET imaging using [89Zr]Zr-DFO-A11 Mb showed activity retention in liver and kidney up to 72 h, while [124I]I-A11 Mb cleared from liver, kidney, and blood by 48 h. Based on full biodistribution and dosimetry calculations, administering 37 MBq [131I]I-A11 Mb was predicted to deliver a favorable dose to the tumor (35 Gy), with a therapeutic index of 22 (tumor:bone marrow). For [177Lu]Lu-DTPA-A11 Mb, the kidneys would be dose-limiting, and the maximum tolerated activity (7.4 MBq) was not predicted to deliver an effective radiation dose to tumor. Radioimmunotherapy with a single dose of [131I]I-A11 Mb showed dose-dependent tumor inhibition with minimal off-target toxicity and improved median survival (19 and 24 days, P < 0.001) compared with untreated mice (12 days). CONCLUSIONS: These findings show the potential of the anti-PSCA minibody for targeted radioimmunotherapy with minimal toxicity, and the application of immunoPET and dosimetry for personalized treatment.

Immediate and long-term effects of BCI-based rehabilitation of the upper extremity after stroke: a systematic review and meta-analysis.

BACKGROUND: A substantial number of clinical studies have demonstrated the functional recovery induced by the use of brain-computer interface (BCI) technology in patients after stroke. The objective of this review is to evaluate the effect sizes of clinical studies investigating the use of BCIs in restoring upper extremity function after stroke and the potentiating effect of transcranial direct current stimulation (tDCS) on BCI training for motor recovery. METHODS: The databases (PubMed, Medline, EMBASE, CINAHL, CENTRAL, PsycINFO, and PEDro) were systematically searched for eligible single-group or clinical controlled studies regarding the effects of BCIs in hemiparetic upper extremity recovery after stroke. Single-group studies were qualitatively described, but only controlled-trial studies were included in the meta-analysis. The PEDro scale was used to assess the methodological quality of the controlled studies. A meta-analysis of upper extremity function was performed by pooling the standardized mean difference (SMD). Subgroup meta-analyses regarding the use of external devices in combination with the application of BCIs were also carried out. We summarized the neural mechanism of the use of BCIs on stroke. RESULTS: A total of 1015 records were screened. Eighteen single-group studies and 15 controlled studies were included. The studies showed that BCIs seem to be safe for patients with stroke. The single-group studies consistently showed a trend that suggested BCIs were effective in improving upper extremity function. The meta-analysis (of 12 studies) showed a medium effect size favoring BCIs for improving upper extremity function after intervention (SMD = 0.42; 95% CI = 0.18-0.66; I2 = 48%; P < 0.001; fixed-effects model), while the long-term effect (five studies) was not significant (SMD = 0.12; 95% CI = - 0.28 - 0.52; I2 = 0%; P = 0.540; fixed-effects model). A subgroup meta-analysis indicated that using functional electrical stimulation as the external device in BCI training was more effective than using other devices (P = 0.010). Using movement attempts as the trigger task in BCI training appears to be more effective than using motor imagery (P = 0.070). The use of tDCS (two studies) could not further facilitate the effects of BCI training to restore upper extremity motor function (SMD = - 0.30; 95% CI = - 0.96 - 0.36; I2 = 0%; P = 0.370; fixed-effects model). CONCLUSION: The use of BCIs has significant immediate effects on the improvement of hemiparetic upper extremity function in patients after stroke, but the limited number of studies does not support its long-term effects. BCIs combined with functional electrical stimulation may be a better combination for functional recovery than other kinds of neural feedback. The mechanism for functional recovery may be attributed to the activation of the ipsilesional premotor and sensorimotor cortical network.

Healthcare Professionals Risk Assessments for Alert Overrides in High-Risk IV Infusions Using Simulated Scenarios.

This study aimed to use healthcare professionals' assessments to calculate expected risk of intravenous (IV) infusion harm for simulated high-risk medications that exceed soft limits and to investigate the impact of relevant risk factors. We designed 30 infusion scenarios for four high-risk medications, propofol, morphine, insulin, and heparin, infused in adult intensive care unit (AICU) and adult medical and surgical care unit (AMSU). A total of 20 pharmacists and 5 nurses provided their assessed expected risk of harm in each scenario. Descriptive statistics, analysis of variance with least square mean, and post hoc test were conducted to test the effects of field limit type, soft (SoftMax), and hard maximum drug limit types (HardMax), and care area-medication combination on risk of harm. The results showed that overdosing scenarios with continuous and bolus dose limit types were assessed with significantly higher risks than those of bolus dose rate type. An overdose infusion in AICU over a large SoftMax was assessed to be of higher risk than over a small one, but not in AMSU. For overdose infusions with three levels of drug amount, greater drug amount in AICU and AMSU was assessed to have higher risk, except insignificant risk difference between the infusions with higher and moderate drug amount in AMSU. This study obtained expected risk for simulated high-risk IV infusions and found that different field limit and SoftMax types can affect expected risk based on healthcare professionals' perspectives. The findings will be regarded as benchmarks for validating risk quantification models in future research.

Tri-functional platform for construction of modular antibody fragments for in vivo 18F-PET or NIRF molecular imaging.

Positron emission tomography (PET) molecular imaging is a powerful tool for interrogating physiological and biochemical processes to understand the biology of disease and advance therapeutic developments. Near-infrared fluorescence (NIRF) optical imaging has become increasingly popular for intraoperative staging to enable cellular resolution imaging of tumor margins during surgical resection. In addition, engineered antibody fragments have emerged as promising molecular imaging agents given their exquisite target selectivity, rapid systemic clearance and site-selective chemical modification. We report a tri-functional platform for construction of a modular antibody fragment that can rapidly be labeled with radionuclides or fluorophores for PET or NIRF molecular imaging of prostate stem cell antigen (PSCA).

[89Zr]A2cDb Immuno-PET of Prostate Cancer in a Human Prostate Stem Cell Antigen Knock-in (hPSCA KI) Syngeneic Model.

PURPOSE: A great challenge in the diagnosis and treatment of prostate cancer is distinguishing between indolent or local disease and aggressive or metastatic disease. Antibody-based positron emission tomography (immuno-PET) as a cancer-specific imaging modality could improve diagnosis of primary disease, aid the detection of metastases to regional lymph nodes as well as to distant sites (e.g., bone), and monitor response to therapy. PROCEDURE: In search for a more physiologically relevant disease model, a human prostate stem cell antigen knock-in (hPSCA KI) mouse model was generated. The use of a syngeneic prostate cancer cell line transduced to express human PSCA (RM-9-hPSCA) enabled the evaluation of anti-PSCA immuno-PET in immunocompetent mice and in the context of normal tissue expression of PSCA. Two PSCA-specific humanized antibody fragments, A11 minibody and A2 cys-diabody, were radiolabeled with positron emitters iodine-124 and zirconium-89, respectively ([124I]A11 Mb and [89Zr]A2cDb), and used for immuno-PET in wild-type, hPSCA KI and tumor-bearing mice. RESULTS: The hPSCA KI mice express PSCA at low levels in the normal prostate, bladder and stomach, reproducing the expression pattern seen in humans. [124I]A11 Mb immuno-PET detected increased levels of PSCA expression in the stomach, and because I-124 is non-residualizing, very little activity was seen in organs of clearance (liver, kidney, spleen). However, due to the longer half-life of the 80 kDa protein, blood activity (and thus urine activity) at 20 h postinjection remains high. The smaller 50 kDa [89Zr]A2cDb cleared faster, resulting in lower blood and background activity, despite the use of a residualizing radiometal. Importantly, [89Zr]A2cDb immuno-PET showed antigen-specific targeting of PSCA-expressing tumors and minimal nonspecific uptake in PSCA-negative controls. CONCLUSION: Tracer biodistribution was not significantly impacted by normal tissue expression of PSCA. [89Zr]A2cDb immuno-PET yielded high tumor-to-blood ratio at early time points. Rapid renal clearance of the 50 kDa tracer resulted in an unobstructed view of the pelvic region at 20 h postinjection that would allow the detection of cancer in the prostate.