University of Rochester

The increasing complexity of modern single flux quantum (SFQ) circuits has increased the importance of flux trapping and trapped magnetic fields within SFQ systems. This trapped flux reduces margins while damaging the operability of superconductive circuits. In this paper, an area efficient stripline topology is introduced to prevent flux from being trapped within striplines. The topology is composed of coupled narrow lines rather than wide striplines. The proposed topology uses a fingered narrow line configuration. The fingered narrow line topology enhances the scalability of SFQ systems while not requiring additional area. The proposed topology decreases the length of the striplines by exploiting the mutual inductance between narrow parallel lines. The topology requires less area while preventing flux from being trapped within wide superconductive striplines. Due to the configuration of the proposed stripline, residual current is eliminated in VLSI complexity SFQ circuits. The fingered narrow line topology also reduces coupling capacitance between striplines. The proposed topology is compatible with automated routing of large scale SFQ integrated circuits.

Objective: Reducing medical jargon improves patient-centered communication, which is a core objective of medical Spanish courses. We aimed to develop a reliable methodology for identifying and classifying Spanish medical jargon. Methods: Fourth-year medical students in a medical Spanish course recorded themselves explaining diagnosis, treatment, and follow-up care during ten clinical scenarios. We developed a stepwise process for identifying and classifying Spanish medical jargon in the recording transcripts. Two reviewers scored jargon, unexplained jargon, and non-Spanish (neologisms/English) word counts. We evaluated jargon metric correlations with other course performance data. Results: We identified 439 Spanish jargon words and 134 non-Spanish words across 480 transcripts. Mean Spanish jargon per minute was 6.57, and 30% was classified as unexplained. Overall inter-rater reliability was excellent (interclass correlation=0.88). Students with post-course Spanish proficiency of "very good" or higher had less unexplained jargon in follow-up care transcripts (P < 0.05); other course outcomes did not correlate with jargon findings. Conclusion: A Spanish medical jargon metric can be reliably used to evaluate student communication skills in a medical Spanish course. Next steps include engaging patient perspectives and exploring strategies to automate jargon analysis. Practice implications: Spanish medical jargon adds a previously unexplored dimension to the assessment of Spanish-language patient-centered communication.

Purpose Suicide risk is higher among violence-involved individuals. Intimate Partner Violence hotline workers are a critical source of support and can potentially be suicide prevention champions. Our primary goal was to examine the effectiveness of disseminating a free, online IPV—Suicide Prevention curriculum, via a randomized control trial, to hotline workers in ten states with the highest suicide and IPV homicide rates. Method We divided the country into five regions and, based on criterion, chose two states in each region to randomize into the two arms of the study. We examined training participation and engagement between the two approaches: (1) ‘dissemination as usual’ (control) using a National Domestic Violence Hotline email and a postcard to state/county IPV directors, versus (2) ‘enhanced dissemination’ (intervention) using a four-point touch method (postcard, phone call, email, and letter) to ‘drive’ participation. Results Participation increased in the intervention arm as approaches became more personal (i.e., email and phone calls vs. letters). Results indicate that traditional dissemination strategies such as email announcements and invitations are not as effective as varied and multiple touchpoints for IPV hotline staff. Conclusion Successful dissemination strategies to promote digital training should consider the value added by personalized connection. Future research is needed to understand how to offer effective and efficient web-based training to those providing IPV and child abuse services.

The exocrine pancreas secretes fluid and digestive enzymes in response to parasympathetic release of acetylcholine (ACh) via the vagus nerve and the gut hormone cholecystokinin (CCK). Both secretion of fluid and exocytosis of secretory granules containing enzymes and zymogens are dependent on an increase in the cytosolic [Ca2+ ] in acinar cells. It is thought that the specific spatiotemporal characteristics of the Ca2+ signals are fundamental for appropriate secretion and that these properties are disrupted in disease states in the pancreas. While extensive research has been performed to characterize Ca2+ signalling in acinar cells, this has exclusively been achieved in ex vivo preparations of exocrine cells, where it is difficult to mimic physiological conditions. Here we have developed a method to optically observe pancreatic acinar Ca2+ signals in vivo using a genetically expressed Ca2+ indicator and imaged with multi-photon microscopy in live animals. In vivo, acinar cells exhibited baseline activity in fasted animals, which was dependent on CCK1 receptors (CCK1Rs). Both stimulation of intrinsic nervous input and administration of systemic CCK induced oscillatory activity in a proportion of the cells, but the maximum frequencies were vastly different. Upon feeding, oscillatory activity was also observed, which was dependent on CCK1Rs. No evidence of a vago-vagal reflex mediating the effects of CCK was observed. Our in vivo method revealed the spatial and temporal profile of physiologically evoked Ca2+ signals, which will provide new insights into future studies of the mechanisms underlying exocrine physiology and that are disrupted in pathological conditions. KEY POINTS: In the exocrine pancreas, the spatiotemporal properties of Ca2+ signals are fundamentally important for the appropriate stimulation of secretion by the neurotransmitter acetylcholine and gut hormone cholecystokinin. These characteristics were previously defined in ex vivo studies. Here we report the spatiotemporal characteristics of Ca2+ signals in vivo in response to physiological stimulation in a mouse engineered to express a Ca2+ indicator in acinar cells. Specific Ca2+ 'signatures' probably important for stimulating secretion are evoked in vivo in fasted animals, by feeding, neural stimulation and cholecystokinin administration. The Ca2+ signals are probably the result of the direct action of ACh and CCK on acinar cells and not indirectly through a vago-vagal reflex.

Objectives To examine the effect of Nystatin oral rinse on oral Candida species and Streptococcus mutans carriage. Materials and methods Twenty healthy adults with oral candidiasis participated in the single-arm clinical trial and received Nystatin oral rinse for 7 days, 4 applications/day, and 600,000 International Units/application. Demographic-socioeconomic-oral-medical conditions were obtained. Salivary and plaque Candida species and Streptococcus mutans were assessed at baseline and 1-week and 3-month follow-ups. Twenty-four salivary cytokines were assessed. Candida albicans isolates underwent Nystatin susceptibility test. Results Half of participants (10/20) were free of salivary C. albicans after using Nystatin rinse. Salivary S. mutans was significantly reduced at 3-month follow-up (p < 0.05). Periodontal status reflected by bleeding-on-probing was significantly improved at 1-week and 3-month follow-ups (p < 0.05). Plaque accumulation was significantly reduced at 1-week follow-up (p < 0.05). Interestingly, the responses to Nystatin oral rinse were not associated with race, gender, age, oral hygiene practice, adherence to Nystatin rinse, or sweet consumption (p > 0.05). No C. albicans isolates were resistant to Nystatin. Furthermore, salivary cytokine eotaxin and fractalkine were significantly reduced at 3-month follow-up among participants who responded to Nystatin rinse (p < 0.05). Conclusions The study results indicate that oral antifungal treatment had an effect on S. mutans salivary carriage. Future clinical trials are warranted to comprehensively assess the impact of antifungal treatment on the oral flora other than S. mutans and Candida. Clinical relevance Due to the potential cariogenic role of oral Candida species, antifungal approaches shed new light on the prevention and management of dental caries from a fungal perspective.

Objective Military members and Veterans at-risk for suicide are often unlikely to seek behavioral health treatment. The primary aim of this study was to test the efficacy of brief CBT for Treatment Seeking (CBT-TS) to improve behavioral health treatment utilization among U.S. military service members and Veterans at-risk for suicide.MethodsA total of 841 participants who served in the U.S. military since 9/11 and who reported suicidality but were not in behavioral health treatment were recruited to participate in this trial. Participants were randomly assigned to either brief CBT-TS delivered by phone or an assessment-only control condition. Follow-up assessments were conducted at baseline and months 1, 3, 6, and 12 to track treatment utilization and symptoms.ResultsCBT-TS resulted in significantly greater behavioral health treatment initiation within 1 month compared to the control condition (B = .93, p < .001); and the higher treatment initiation persisted for 12 months post intervention.Conclusions This study employed a low-cost, easily implementable one-session intervention administered by phone. The study provides evidence that CBT-TS is efficacious in promoting behavioral health treatment initiation in an adult population at risk for suicidal behavior and showed enduring benefits for 6–12 months. CBT-TS provides a unique strategy for treatment engagement for at-risk adults unlikely to seek treatment.Trial RegistrationClinicaltrials.gov NCT05077514

Research suggests that unsupportive parenting practices are consistent but modest risk factors for children's behavioral and social problems, emphasizing the importance in identifying sources of variability in children's vulnerability. To address this research direction, this study examined children's callous-unemotional (CU) traits (i.e., affective indifference; lack of guilt or empathy), as a moderator of the associations among maternal and paternal unsupportive parenting and their externalizing symptoms. Participants included 240 mothers, partners, and their children (Mage = 4.6 years; 56% girls) from diverse backgrounds (48% Black; 16% Latinx) who took part in a longitudinal multi-method study with two measurement occasions spaced 2 years apart. Findings from structural equation modeling indicated the prospective association between observational assessments of unsupportive maternal (but not paternal) parenting and residualized changes in teacher reports children's externalizing problems over 2 years was significantly moderated by maternal reports of children's callous-unemotional traits (β = -.21, p < .05). Follow-up analyses of the interaction provided support for differential susceptibility. These findings highlight that children with elevated CU traits may experience diminished susceptibility to parenting, while children with lower levels of CU traits may exhibit plasticity in response to socialization environments.

Background: Thrombocytopenia is common in preterm neonates. Platelet transfusions are sometimes given to thrombocytopenic neonates with the hope of reducing the bleeding risk, however, there are little clinical data to support this practice, and platelet transfusions may increase the bleeding risk or lead to adverse complications. Our group previously reported that fetal platelets expressed lower levels of immune-related mRNA compared with adult platelets. In this study, we focused on the effects of adult versus neonatal platelets on monocyte immune functions that may have an impact on neonatal immune function and transfusion complications. Methods: Using RNA sequencing of postnatal day 7 and adult platelets, we determined age-dependent platelet gene expression. Platelets and naive bone marrow-isolated monocytes were cocultured and monocyte phenotypes determined by RNA sequencing and flow cytometry. An in vivo model of platelet transfusion in neonatal thrombocytopenic mice was used in which platelet-deficient TPOR (thrombopoietin receptor) mutant mice were transfused with adult or postnatal day 7 platelets and monocyte phenotypes and trafficking were determined. Results: Adult and neonatal platelets had differential immune molecule expression, including Selp. Monocytes incubated with adult or neonatal mouse platelets had similar inflammatory (Ly6Chi) but different trafficking phenotypes, as defined by CCR2 and CCR5 mRNA and surface expression. Blocking P-sel (P-selectin) interactions with its PSGL-1 (P-sel glycoprotein ligand-1) receptor on monocytes limited the adult platelet-induced monocyte trafficking phenotype, as well as adult platelet-induced monocyte migration in vitro. Similar results were seen in vivo, when thrombocytopenic neonatal mice were transfused with adult or postnatal day 7 platelets; adult platelets increased monocyte CCR2 and CCR5, as well as monocyte chemokine migration, whereas postnatal day 7 platelets did not. Conclusions: These data provide comparative insights into adult and neonatal platelet transfusion-regulated monocyte functions. The transfusion of adult platelets to neonatal mice was associated with an acute inflammatory and trafficking monocyte phenotype that was platelet P-sel dependent and may have an impact on complications associated with neonatal platelet transfusions.

Prior studies have observed selective neural responses in the adult human auditory cortex to music and speech that cannot be explained by the differing lower-level acoustic properties of these stimuli. Does infant cortex exhibit similarly selective responses to music and speech shortly after birth? To answer this question, we attempted to collect functional magnetic resonance imaging (fMRI) data from 45 sleeping infants (2.0- to 11.9-weeks-old) while they listened to monophonic instrumental lullabies and infant-directed speech produced by a mother. To match acoustic variation between music and speech sounds we (1) recorded music from instruments that had a similar spectral range as female infant-directed speech, (2) used a novel excitation-matching algorithm to match the cochleagrams of music and speech stimuli, and (3) synthesized "model-matched" stimuli that were matched in spectrotemporal modulation statistics to (yet perceptually distinct from) music or speech. Of the 36 infants we collected usable data from, 19 had significant activations to sounds overall compared to scanner noise. From these infants, we observed a set of voxels in non-primary auditory cortex (NPAC) but not in Heschl's Gyrus that responded significantly more to music than to each of the other three stimulus types (but not significantly more strongly than to the background scanner noise). In contrast, our planned analyses did not reveal voxels in NPAC that responded more to speech than to model-matched speech, although other unplanned analyses did. These preliminary findings suggest that music selectivity arises within the first month of life. RESEARCH HIGHLIGHTS: Responses to music, speech, and control sounds matched for the spectrotemporal modulation-statistics of each sound were measured from 2- to 11-week-old sleeping infants using fMRI. Auditory cortex was significantly activated by these stimuli in 19 out of 36 sleeping infants. Selective responses to music compared to the three other stimulus classes were found in non-primary auditory cortex but not in nearby Heschl's Gyrus. Selective responses to speech were not observed in planned analyses but were observed in unplanned, exploratory analyses.

Introduction Neuropsychiatric symptoms (NPS) in Alzheimer’s Disease (AD) are associated with negative outcomes for patients and their care partners. Agitation is one of the most common and distressing NPS, yet we lack safe and effective treatment options. While nonpharmacologic interventions are considered first line treatment, these may not be effective or appropriate for every patient. Our current approaches to the pharmacologic treatment of agitation in AD consist of the off-label use of antipsychotics, sedative/hypnotics, anxiolytics, mood-stabilizing anticonvulsants, acetylcholinesterase inhibitors, NMDA receptor antagonists, and antidepressants. Despite their prevalent use, they have questionable efficacy and significant safety concerns. Areas covered Advances in the understanding of neurobiological mechanisms of agitation have fueled recent clinical trials. This article is an update to our 2017 review. A comprehensive search of ClinicalTrials.gov was completed from January 2017 to June 2022 using the search terms “Alzheimer’s Disease” and “Agitation”. A subsequent scoping review was completed in PubMed and Google Scholar. Several agents were identified for promise in treating agitation, including: brexpiprazole, cannabinoids, dexmedetomidine, dextromethorphan, escitalopram, masupirdine, and prazosin. Expert opinion Clinical trials remain underway utilizing both novel and repurposed agents to address symptoms of agitation in AD. With increasing understanding of the neurobiological mechanisms that fuel the development of agitation in AD, the use of enhanced trial design and conduct, advanced statistical approaches, and accelerated pathways for regulatory approval, we are advancing closer to having safe and efficacious treatment options for agitation in AD.

Many questions regarding the clinical management of people experiencing pain and related health policy decision-making may best be answered by pragmatic controlled trials. To generate clinically relevant and widely applicable findings, such trials aim to reproduce elements of routine clinical care or are embedded within clinical workflows. In contrast with traditional efficacy trials, pragmatic trials are intended to address a broader set of external validity questions critical for stakeholders (clinicians, healthcare leaders, policymakers, insurers, and patients) in considering the adoption and use of evidence-based treatments in daily clinical care. This article summarizes methodological considerations for pragmatic trials, mainly concerning methods of fundamental importance to the internal validity of trials. The relationship between these methods and common pragmatic trials methods and goals is considered, recognizing that the resulting trial designs are highly dependent on the specific research question under investigation. The basis of this statement was an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) systematic review of methods and a consensus meeting. The meeting was organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership. The consensus process was informed by expert presentations, panel and consensus discussions, and a preparatory systematic review. In the context of pragmatic trials of pain treatments, we present fundamental considerations for the planning phase of pragmatic trials, including the specification of trial objectives, the selection of adequate designs, and methods to enhance internal validity while maintaining the ability to answer pragmatic research questions.

Recessive SH3TC2 variants cause Charcot-Marie-Tooth disease type 4C (CMT4C). CMT4C is typically a sensorimotor demyelinating polyneuropathy, marked by early onset spinal deformities, but its clinical characteristics and severity are quite variable. Clear relationships between pathogenic variants and the spectrum of disease manifestations are to date lacking. Gene replacement therapy has been shown to ameliorate the phenotype in a mouse model of CMT4C, emphasizing the need for natural history studies to inform clinical trial readiness. Data, including both genetic information and clinical characteristics, were compiled from the longitudinal, prospective dataset of the Inherited Neuropathy Consortium, a member of the Rare Diseases Clinical Research Network (INC-RDCRN). The Charcot Marie Tooth Neuropathy Score (CMTNS), Examination Score (CMTES) and the Rasch-weighted CMTES (CMTES-R) were used to describe symptoms, neurologic examinations, and neurophysiologic characteristics. Standardized response means were calculated at yearly intervals and a mixed model for repeated measures was used to estimate the change in CMTES and CMTES-R over time. 56 individuals (59% female), median age 27 years (range 2–67 years) with homozygous or compound heterozygous variants in SH3TC2 were identified, including 34 unique variants, 14 of which have not previously been published. 28 participants had longitudinal data available. While there was not a significant difference in the CMTES in those with protein-truncating versus non-protein-truncating variants, there were significant differences in the mean ulnar nerve compound muscle action potential amplitude, the mean radial sensory nerve action potential amplitude, and in the prevalence of scoliosis, suggesting the possibility of a milder phenotype in individuals with one or two non-protein-truncating variants. Overall, the mean value of the CMTES was 13, reflecting moderate clinical severity. There was a high rate of scoliosis (81%), scoliosis surgery (36%), and walking difficulty (94%) among study participants. The CMTES and CMTES-R appeared moderately responsive to change over extended follow-up, demonstrating a standardized response mean of 0.81 standard deviation units or 0.71 standard deviation units respectively, over 3 years. Our analysis represents the largest cross-sectional and only longitudinal study to date, of the clinical phenotype of both adults and children with CMT4C. With the promise of upcoming genetic treatments, this data will further define the natural history of the disease and inform study design in preparation for clinical trials.

Importance: The potential association of schizophrenia with distinct retinal changes is of clinical interest but has been challenging to investigate because of a lack of sufficiently large and detailed cohorts. Objective: To investigate the association between retinal biomarkers from multimodal imaging (oculomics) and schizophrenia in a large real-world population. Design, setting, and participants: This cross-sectional analysis used data from a retrospective cohort of 154 830 patients 40 years and older from the AlzEye study, which linked ophthalmic data with hospital admission data across England. Patients attended Moorfields Eye Hospital, a secondary care ophthalmic hospital with a principal central site, 4 district hubs, and 5 satellite clinics in and around London, United Kingdom, and had retinal imaging during the study period (January 2008 and April 2018). Data were analyzed from January 2022 to July 2022. Main outcomes and measures: Retinovascular and optic nerve indices were computed from color fundus photography. Macular retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (mGC-IPL) thicknesses were extracted from optical coherence tomography. Linear mixed-effects models were used to examine the association between schizophrenia and retinal biomarkers. Results: A total of 485 individuals (747 eyes) with schizophrenia (mean [SD] age, 64.9 years [12.2]; 258 [53.2%] female) and 100 931 individuals (165 400 eyes) without schizophrenia (mean age, 65.9 years [13.7]; 53 253 [52.8%] female) were included after images underwent quality control and potentially confounding conditions were excluded. Individuals with schizophrenia were more likely to have hypertension (407 [83.9%] vs 49 971 [48.0%]) and diabetes (364 [75.1%] vs 28 762 [27.6%]). The schizophrenia group had thinner mGC-IPL (-4.05 μm, 95% CI, -5.40 to -2.69; P = 5.4 × 10-9), which persisted when investigating only patients without diabetes (-3.99 μm; 95% CI, -6.67 to -1.30; P = .004) or just those 55 years and younger (-2.90 μm; 95% CI, -5.55 to -0.24; P = .03). On adjusted analysis, retinal fractal dimension among vascular variables was reduced in individuals with schizophrenia (-0.14 units; 95% CI, -0.22 to -0.05; P = .001), although this was not present when excluding patients with diabetes. Conclusions and relevance: In this study, patients with schizophrenia had measurable differences in neural and vascular integrity of the retina. Differences in retinal vasculature were mostly secondary to the higher prevalence of diabetes and hypertension in patients with schizophrenia. The role of retinal features as adjunct outcomes in patients with schizophrenia warrants further investigation.

Integrating the large, subpicosecond nonlinear optical response of epsilon-near-zero (ENZ) materials with the broad design freedoms of plasmonic metasurfaces shows potential for creating rapidly modulated optical devices with possible applications in telecommunications, sensing, and reactive beam steering. In this work, we experimentally investigate a metasurface consisting of a plasmonic gradient array on a thin layer of indium tin oxide (ITO), characterize how incident probe pulses diffract from a system as it is being dynamically modulated by a pump pulse at wavelengths near the ENZ region. Angular shifts in the diffraction orders are observed and can be principally attributed to the adiabatic wavelength conversion of the probe as it witnesses the temporal change of index induced by the pump. Of note, the asymmetric gradient metasurface, considered to be a blazed diffraction grating, shows significantly different dynamic responses for different diffraction orders. The free-space wavelength shift to +1 and −1 diffraction orders is 6 and 12 nm, resulting in steering angle changes of 0.65 and 1.5°, respectively.

A central goal of systems neuroscience is to understand how populations of sensory neurons encode and relay information to the rest of the brain. Three key quantities of interest are (i) how mean neural activity depends on the stimulus (sensitivity), (ii) how neural activity (co)varies around the mean (noise correlations), and (iii) how predictive these variations are of the subject's behavior (choice probability). Previous empirical work suggests that both choice probability and noise correlations are affected by task training, with decision-related information fed back to sensory areas and aligned to neural sensitivity on a task-by-task basis. We used Utah arrays to record activity from populations of V1 neurons from two macaque monkeys who were trained to switch between two coarse orientation-discrimination tasks. Surprisingly, we find no evidence for significant trial-by-trial changes in noise covariance between tasks, nor do we find a consistent relationship between neural sensitivity and choice probability, despite recording from well-tuned task-sensitive neurons, many of which were histologically confirmed to be in supragranular V1, and despite behavioral evidence that the monkeys switched their strategy between tasks. Thus our data at best provide weak support for the hypothesis that trial-by-trial task-switching induces changes to noise correlations and choice probabilities in V1. However, our data agrees with a recent finding of a single "choice axis" across tasks. It also raises the intriguing possibility that choice-related signals in early sensory areas are less indicative of task learning per se, and instead reflect perceptual learning that occurs in highly over-trained subjects.

During the early phases of embryonic development, the yolk sac serves as an initial placenta in many animal species. While in some, this role subsides around the end of active organogenesis, it continues to have important functions in rodents, alongside the chorio-allantoic placenta. The yolk sac is the initial site of hematopoiesis in many animal species including primates. Cells of epiblastic origin form blood islands that are the forerunners of hematopoietic cells and of the primitive endothelial cells that form the vitelline circulation. The yolk sac is also a major route of embryonic and fetal nutrition apparently as long as it functions. In mammals and especially rodents, macro and micronutrients are absorbed by active pinocytosis into the visceral yolk sac, degraded and the degradation products (i.e., amino acids) are then transferred to the embryo. Interference with the yolk sac function may directly reflect on embryonic growth and development, inducing congenital malformations or in extreme damage, causing embryonic and fetal death. In rodents, many agents were found to damage the yolk sac (i.e., anti-yolk sac antibodies or toxic substances interfering with yolk sac pinocytosis) subsequently affecting the embryo/fetus. Often, the damage to the yolk sac is transient while embryonic damage persists. In humans, decreased yolk sac diameter was associated with diabetic pregnancies and increased diameter was associated with pregnancy loss. In addition, culture of rat yolk sacs in serum obtained from pregnant diabetic women or from women with autoimmune diseases induced severe damage to the visceral yolk sac epithelium and embryonic malformations. It can be concluded that as a result of the crucial role of the yolk sac in the well-being of the early embryo, any damage to its normal function may severely and irreversibly affect further development of the embryo/fetus.

Background: Associating liver partition and portal vein ligation for staged hepatectomy for perihilar cholangiocarcinoma has been considered to be contraindicated due to the initial poor results. Given the recent reports of improved outcomes, we aimed to collect the recent experiences of different centers performing associating liver partition and portal vein ligation for staged hepatectomy for perihilar cholangiocarcinoma to analyze factors related to improved outcomes. Methods: This proof-of-concept study collected contemporary cases of associating liver partition and portal vein ligation for staged hepatectomy for perihilar cholangiocarcinoma and analyzed for morbidity, short and long-term survival, and factors associated with outcomes. Results: In total, 39 patients from 8 centers underwent associating liver partition and portal vein ligation for staged hepatectomy for perihilar cholangiocarcinoma from 2010 to 2020. The median preoperative future liver remnant volume was 323 mL (155-460 mL). The median future liver remnant increase was 58.7% (8.9% -264.5%) with a median interstage interval of 13 days (6-60 days). Post-stage 1 and post-stage 2 biliary leaks occurred in 2 (7.7%) and 4 (15%) patients. Six patients (23%) after stage 1 and 6 (23%) after stage 2 experienced grade 3 or higher complications. Two patients (7.7%) died within 90 days after stage 2. The 1-, 3-, and 5-year survival was 92%, 69%, and 55%, respectively. A subgroup analysis revealed poor survival for patients undergoing additional vascular resection and lymph node positivity. Lymph node-negative patients showed excellent survival demonstrated by 1-, 3-, and 5-year survival of 86%, 86%, and 86%. Conclusion: This study highlights that the critical attitude toward associating liver partition and portal vein ligation for staged hepatectomy for perihilar cholangiocarcinoma needs to be revised. In selected patients with perihilar cholangiocarcinoma, associating liver partition and portal vein ligation for staged hepatectomy can achieve favorable survival that compares to the outcome of established surgical treatment strategies reported in benchmark studies for perihilar cholangiocarcinoma including 1-stage hepatectomy and liver transplantation.

In the era of Industry 4.0, manufacturing enterprises are actively adopting collaborative robots (Cobots) in their productions. Current online and offline robot programming methods are difficult to use and require extensive experience or skills. On the other hand, the manufacturing industries are experiencing a labor shortage. An essential question, therefore, is: how would a new robot programming method help novice users complete complex tasks effectively, efficiently, and intuitively? To answer this question, we proposed HAR2\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$R^{2}$$\end{document}bot, a novel human-centered augmented reality programming interface with awareness of cognitive load. Using NASA’s system design theory and the cognitive load theory, a set of guidelines for designing an AR-based human-robot interaction system is obtained through a human-centered design process. Based on these guidelines, we designed and implemented a human-in-the-loop workflow with features for cognitive load management. The effectiveness and efficiency of HAR2\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$R^{2}$$\end{document}bot are verified in two complex tasks compared with existing online programming methods. We also evaluated HAR2\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$R^{2}$$\end{document}bot quantitatively and qualitatively through a user study with 16 participants. According to the user study, compared with existing methods, HAR2\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$R^{2}$$\end{document}bot has higher efficiency, a lower overall cognitive load, lower cognitive loads for each type, and higher safety.

Dr Loretta C. Ford is a true pioneer. Her work in public health launched the nurse practitioner movement. Together with Dr Henry Silver in 1965, Dr Ford co-founded the first expanded or advanced role to educate nurses to: assess, diagnose and treat common pediatric problems in primary care. Since then, there has been an increase in the number of specialty programs and an acknowledged global need for advanced practice nurses. She transformed our understanding of health and illness, the education of nurses, and the practice of humane patient care.