Impact of context specificity on response to the shortened WOMAC function scale in patients undergoing total knee arthroplasty.

OBJECTIVE: To determine, in patients undergoing total knee arthroplasty (TKA), whether increasing context specificity of selected items of the shortened version of the Western Ontario and McMaster Universities Osteoarthritis Index function (WOMAC-F) scale (ShortMAC-F) (i) enhanced the convergent validity of the ShortMAC-F with performance-based mobility measures and (ii) impacted on mean scale score, structural validity, reliability, and interpretability. DESIGN: Secondary analysis of randomized clinical trial data. SETTING AND PARTICIPANTS: Patients undergoing TKA (n=114). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The ShortMAC-F was modified by specifying the "ascending stairs" and "rising from sitting" items to enquire about difficulty in performing the tasks without reliance on compensatory strategies, while the modified "level walking" item enquired about difficulty in walking 400 meters. Before and 12 weeks after TKA, patients completed the WOMAC-F, modified ShortMAC-F, knee pain scale, sit-to-stand test, fast gait speed test, and stair-climb test. Interpretability was evaluated by calculating anchor-based substantial clinical benefit (SCB) estimates. RESULTS: The modified ShortMAC-F correlated significantly more strongly than ShortMAC-F or WOMAC-F with pooled performance measures (differences in correlation values, 0.12-0.14). Increasing item context specificity of the ShortMAC-F did not influence its psychometric properties of unidimensionality (comparative fit and Tucker-Lewis indices >0.95; root mean square error of approximation, 0.05-0.08), reliability (Cronbach alpha, 0.75-0.83), correlation with pain intensity (correlation values, 0.48-0.52), and SCB estimates (16 percentage points); however, it resulted in lower mean score (4.5-4.8 points lower). CONCLUSIONS: The modified ShortMAC-F showed sufficient measurement properties for clinical application, and it seemed more adept than WOMAC-F at correlating with performance-based measures in TKA.

Unicompartmental knee arthroplasty in obese patients, poorer survivorship at 15 years.

Introduction: The preclusion of obese patients from unicompartmental knee arthroplasty (UKA) has increasingly been challenged. This study aimed to evaluate the impact of Body Mass Index (BMI) on UKA at 15-year follow-up. Materials and methods: 169 unilateral UKA patients from 2003 to 2007 were followed-up prospectively for at least 15 years. 70 patients were left for analysis after accounting for patient demise, revision surgery and loss to follow-up. 48 of these patients (69%) were in the Control group (BMI <30 kg/m2) and 22 (31%) were in the Obese group (BMI ≥30 kg/m2). Patients were assessed before and after operation using the Knee Society Function Score (KSFS), Knee Society Knee Score (KSKS), Oxford Knee Score (OKS), and Physical (PCS) and Mental (MCS) component of the Short Form 12. Survivorship analysis was also performed. Results: Obese patients went through UKA at an earlier age than the non-obese patients (54.7 ± 4.7 years compared to 59.9 ± 7.8 years, p = 0.005). At 2, 10, and 15-year follow-up, both groups achieved clinically significant improvements in outcomes. There was no significant association found between obesity and outcome using multiple linear regression. While propensity matching found PCS improvement at 2 years to be greater in obese patients, no significant association between obesity and 15-year outcome was found. All 13 patients who required revision, underwent total knee arthroplasty (TKA). The overall 15-year survivorship was 74.2% within the obese group and 92.4% within the control group. Conclusion: Compared to non-obese patients, obese patients had poorer 15-year survivorship with greater odds of requiring revision surgery. However, assuming implant survival, obese patients can expect a non-inferior outcome relative to their non-obese counterparts in all patient reported outcome measures 15 years after surgery.

Postponement of total knee arthroplasties due to pandemic causes significant deterioration on patients' preoperative knee and quality of life scores.

Introduction: Elective surgeries were postponed during the COVID-19 pandemic to alleviate healthcare strains, affecting majority of elective orthopaedic surgeries such as total knee arthroplasties (TKAs). The aim of this study is to evaluate the impact on knee function and quality of life of patients who had their planned TKA postponed due to the pandemic. Methods: This is a retrospective analysis of data collected in a tertiary hospital. Patients included were diagnosed with primary knee osteoarthritis and they were initially scheduled for primary TKA between January to April 2020 but surgery was postponed by at least 6 months from the initial operative date. 160 patients were included in this study (53 males and 107 females, mean age 68.0 ± 8.1). Patients were assessed prior to initial surgery date and assessed again, prior to the postponed surgery date. Clinical scores included Knee Society Function Score (KSFS), Knee Society Knee Score (KSKS), Oxford Knee scores (OKS) and Short-Form 36 Physical and Mental Component Scores. (SF36 PCS and MCS). Paired T-test was performed for parametric data whereas Wilcoxon signed-rank analysis was performed for non-parametric data. Results: Comparing initial preoperative versus postponement preoperative scores, the cohort had significantly poorer KSKS (38.4 ± 15.4 and 36.5 ± 15.4, p = 0.034), SF36 PCS (34.3 ± 9.2 and 32.7 ± 8.6, p = 0.02) and OKS (34.9 ± 0.77 and 35.8 ± 8.6, p = 0.02) scores respectively. Conclusion: The postponement of elective TKAs has resulted in a significant deterioration of knee scores and physical quality of live scores of patients in a short span of 6 months. Further studies can evaluate if there are repercussions on long term TKAs outcomes. Level of evidence: Retrospective study, Level III.

Severe genu varus deformity does not affect enhanced recovery after surgery total knee arthroplasty outcomes.

INTRODUCTION: Enhanced recovery after surgery (ERAS) has been increasingly adopted in orthopaedic surgery. Although not an exclusion criterion, patients undergoing total knee arthroplasty (TKA) with preoperative severe varus deformity may be less likely to be enrolled for ERAS. This study aimed to compare the success of ERAS TKA between patients with severe preoperative varus deformities (≥ 15° varus) and the control group (< 15° varus to 14° valgus). Our secondary aim was to compare postoperative complications and functional outcomes between the two groups. MATERIALS & METHODS: 310 TKAs performed from August 2019 to February 2021 were analyzed with a follow-up of 6 months postoperatively. The primary outcome, ERAS TKA success, was defined as length of hospital stay of < 24 h. Other parameters included 30-day postoperative complications and clinical outcomes such as the original Oxford Knee Score (OKS), the Knee Society Knee (KSKS) and Function Score (KSFS), Visual Analog Scale for Pain (VAS-P), 36-Item Short-Form Health Survey (SF-36) Physical Component Summary (PCS) and SF-36 Mental Component Summary (MCS). RESULTS: There were 119 patients in the severe deformity group and 191 patients in the control group. There were no significant differences in ERAS success between the severe deformity group and control group, with both groups achieving similarly high rates (> 90%) of ERAS success. There were also no differences in 30-day postoperative complications and 6-month postoperative clinical outcomes. CONCLUSION: Patients with severe preoperative varus deformity undergoing ERAS TKA achieved high ERAS success rates (> 90%). Genu varum is not a contraindication for ERAS TKA.

The Emotional Impact and Coping Mechanisms Following Adverse Patient Events Among Canadian Vascular Surgeons and Trainees.

BACKGROUND: This study's objective is to evaluate the emotional experiences, coping mechanisms, and support resources for Canadian vascular surgeons and trainees following an adverse patient event or near miss. METHODS: This is a cross-sectional survey study of all Canadian Society for Vascular Surgery (CSVS) members from October to November 2021. We collected data on participant experiences with adverse events, their emotional responses, the coping mechanisms used, and their perceptions on available support resources. RESULTS: The survey was sent to 233 CSVS members yielding 66 responses. The majority (77%) of respondents had experiences with adverse event causing serious patient harm. The most common negative experience following an adverse event included feelings of negativity towards oneself, general distress, and anxiety about potential for future errors. The most common coping mechanism was seeking advice from a mentor or close colleague. Peers (82%) and senior colleagues (59%) were the most preferred sources of support. Most of the respondents would reach out to a mentor if they had 1, but 30% reported no mentor or close colleague for support. CONCLUSION: Adverse patient events and near misses have serious negative impact on the lives of Canadian vascular surgeons and trainees. Peers and senior colleagues are the most desired source for support, but this is not universally available. Organized efforts are needed to bring awareness in our vascular surgery community on the ubiquitous nature and detrimental effects of adverse events.

Enhanced recovery after surgery (ERAS) protocol reduces need for patient selection for day surgery total knee arthroplasty.

Introduction: This study explored the safety and efficacy of Enhanced Recovery After Surgery (ERAS) together with a Day-surgery protocol on some commonly used selection criteria for expedited discharge after Total Knee Arthroplasty (TKA). Methods: ERAS Day surgery TKA performed between Aug 2020 to July 2021 were included in this study. Discharge within 24 h was considered passing protocol. Complications such as infection, re-admission, and re-operation within 30-days were recorded. Patient demographics, medical comorbidities, and outcome measures at 6-month post-operatively were analysed between those who were successfully discharged within 24 h and those with prolong admission. Results: A total of 342 patients were included in the study. 315 patients (92.1 %) were discharged within 24 h s. Inadequately controlled pain was the most common reason for delayed discharge (17.9 %). No statistically significant difference in gender, age, Charlson Comorbidity Index (CCI), Body Mass Index (BMI), and American Society of Anaesthesiologist Classification (ASA) were noted between patients who failed protocol and those who passed. Readmission rate within 30days was 2.6 %. Infection occurred in 5 cases, including 2 prosthetic joint infection (PJI) requiring debridement, antibiotics, and implant retention (DAIR), 2 surgical site infection treated with antibiotics, and 1 pneumonia. No 30-days complication occurred in patients who initially failed ERAS Day-surgery protocol. Binary logistic regression was statistically insignificant on effect of gender, age, CCI, BMI, and ASA on passing protocol or 30-days complications. Propensity score matching of patients with prolong stay of more than 24 h did not demonstrate any difference in 6-month outcome. Conclusion: Patient characteristics such as gender, age, CCI, BMI, and ASA did not influence successful completion of ERAS Day-surgery protocol. Even if patients were initially enrolled in ERAS Day-surgery protocol but failed to be discharged within 24 h, this did not predispose them to increased 30-days complication or poorer 6-month outcome. Level of evidence: III.

Touch-screen automatisms in the digital age.

OBJECTIVE: To describe a novel set of gestural automatisms related to the use of digital screens on smartphones and tablets in patients with epilepsy. METHODS: Representative patients were selected from among those admitted to the Epilepsy Monitoring Unit at the Toronto Western Hospital between April 2016 and January 2020, and included if they exhibited automatisms clearly related to or mimicking digital device use. RESULTS: In total 5 patients were included, 4 female. All had temporal lobe epilepsy: 2 had left mesial temporal sclerosis and 3 had normal imaging. Nearly equal numbers of seizures began with right (5/9) and left (4/9) temporal onsets, with most automatisms occurring after seizure propagation to bilateral temporal involvement (6/9). Left-handed automatisms were most common (8/9). The majority of the automatisms (7/9) were perseverative on device usage prior to the seizure. CONCLUSION: Gestural automatisms appear related to the contemporary lived experience, culture, and habitual behaviour of patients with epilepsy. In the modern era, the use of smartphones and tablets are both common and habitual for many, and this case series shows that touch-screen automatisms may be added to the semiological panoply of temporal lobe seizures.

Patient Acceptable Symptom State Thresholds for the Knee Society Score, Oxford Knee Score, and 36-Item Short Form Survey Ten Years Following Unicompartmental Knee Arthroplasty.

BACKGROUND: The patient acceptable symptom state (PASS) refers to a cutoff value on any patient-reported outcome measures (PROMs) scale, beyond which patients consider themselves as having achieved an acceptable outcome. This study aimed to identify PASS thresholds for knee-specific and generic PROMs at 10 years post-unicompartmental knee arthroplasty (UKA). METHODS: There were 269 patients who underwent UKA for medial osteoarthritis from 2004 to 2007 at a single institution and were surveyed preoperatively and 10 years postoperatively using the Knee Society Function Score (KSFS), Knee Society Knee Score (KSKS), Oxford Knee Score (OKS), 36-Item Short Form Survey (SF-36) Mental Component Score (MCS), and SF-36 Physical Component Score (PCS). Treatment outcomes and expectations were assessed using an anchor question, and PASS attainment was determined using the Youden index on a receiver operating characteristic (ROC) curve. Also, a similar study that identified 2-year long-term PROM PASS thresholds for UKA was referenced and compared. RESULTS: Overall, 91.1% reported acceptable outcomes. The area under the curve for ROCs of KSKS, OKS, and PCS were 0.80, 0.75, and 0.71, respectively. The area under the curve for ROCs of KSFS and MCS were both 0.64. The PASS thresholds were 67.5 for KSFS, 70.5 for KSKS, 39.5 for OKS, 44.6 for PCS, and 43.8 for MCS. Patients who achieved a PASS were at least 3 times more likely to have satisfactory outcomes. CONCLUSIONS: To our knowledge, this is the first study that identified 10-year long-term PROM PASS thresholds for UKA. Accounting for our finding that a decade-long follow-up yielded lower PASS thresholds, time-specific UKA PROM PASS thresholds should be considered. LEVEL OF EVIDENCE: III.

Evaluation of hydrophilic polymer embolization from endovascular sheath devices in an in vitro perfusion system.

Objective: Case reports, tissue pathology, and autopsies have suggested that the hydrophilic polymer coating designed to improve endovascular deliverability and minimize vessel trauma can embolize and be associated with adverse outcomes such as ischemia, infarction, and death. This study sought to determine whether hydrophilic polymers shed off commercially available sheaths in a controlled in vitro environment, with the hypothesis that significant differences between coated and uncoated (control) sheaths would be found. Methods: Six sheaths from each manufacturer, including Zenith Alpha abdominal endovascular stent grafts (Cook Medical), DrySeal sheaths (W.L. Gore & Associates), and Sentrant Introducer sheaths (Medtronic), were tested in an in vitro environment. Noncoated Check-Flo performer introducer sheaths (Cook Medical) were used as controls. Each test circuit ran for 150 minutes at an output of 3 L/min, the circuit was then drained and the fluid collected. Quantitative analysis included weighing the dried filter paper and using particle size light scattering to quantify the particle size and count. Attenuated total reflectance spectroscopy was also used. Results: Each of the three coated sheaths had significantly greater shedding compared with the control sheaths. The Cook Zenith alpha sheath had significantly more residue weight (2.87 ± 0.52 mg/L) than the Gore DrySeal (1.07 ± 0.06 mg/L) and Medtronic Sentrant introducer (0.98 ± 0.14 mg/L) sheaths. The average particle size was not significantly different between the coated and uncoated (control) sheaths. Attenuated total reflectance spectroscopy identified sheath particulate in the Cook Zenith Alpha and Medtronic Sentrant samples. Conclusions: Polymer embolization was present and significantly greater in all three commercially available hydrophilic sheaths compared with the control group. Further investigation is needed into the clinical significance of these findings.

Reversible and irreversible inhibitors of coronavirus Nsp15 endoribonuclease.

The emergence of severe acute respiratory syndrome coronavirus 2, the causative agent of coronavirus disease 2019, has resulted in the largest pandemic in recent history. Current therapeutic strategies to mitigate this disease have focused on the development of vaccines and on drugs that inhibit the viral 3CL protease or RNA-dependent RNA polymerase enzymes. A less-explored and potentially complementary drug target is Nsp15, a uracil-specific RNA endonuclease that shields coronaviruses and other nidoviruses from mammalian innate immune defenses. Here, we perform a high-throughput screen of over 100,000 small molecules to identify Nsp15 inhibitors. We characterize the potency, mechanism, selectivity, and predicted binding mode of five lead compounds. We show that one of these, IPA-3, is an irreversible inhibitor that might act via covalent modification of Cys residues within Nsp15. Moreover, we demonstrate that three of these inhibitors (hexachlorophene, IPA-3, and CID5675221) block severe acute respiratory syndrome coronavirus 2 replication in cells at subtoxic doses. This study provides a pipeline for the identification of Nsp15 inhibitors and pinpoints lead compounds for further development against coronavirus disease 2019 and related coronavirus infections.

Autocrine Factors Produced by Mesenchymal Stem Cells in Response to Cell-Cell Contact Inhibition Have Anti-Tumor Properties.

Recently, mesenchymal stem cell (MSC) therapies have been questioned as MSCs are capable of both promoting and inhibiting tumorigenesis. Both MSCs and tumor cells replicate to increase their population size; however, MSCs, but not tumor cells, stop dividing when they reach confluence due to cell-cell contact inhibition and then differentiate. We hypothesized that contact inhibition results in the production of effector molecules by confluent MSCs and these effectors are capable of suppressing tumor cell growth. To test this hypothesis, we co-cultured breast cancer cells (MDA-MB-231) with either confluent or sub-confluent bone-marrow-derived MSCs (BM-MSCs); in addition, we treated various tumor cells with conditioned media (CM) obtained from either confluent or sub-confluent BM-MSCs. The results showed that the growth of tumor cells co-cultured with confluent BM-MSCs or treated with CM obtained from confluent BM-MSCs was inhibited, and this effect was significantly stronger than that seen with tumor cells co-cultured with sub-confluent BM-MSCs or CM obtained from sub-confluent BM-MSCs. Subcutaneous tumor formation was completely prevented by the inoculation of tumor cells mixed with CM. In the future, soluble anti-tumor effectors, produced by confluent MSCs, may be used as cell-free therapeutics; this approach provides a solution to current concerns associated with cell-based therapies.

Enhanced recovery after day surgery total knee arthroplasty, the new standard of care: An Asian perspective.

BACKGROUND: This study describes the implementation of Enhanced Recovery After Surgery (ERAS) total knee arthroplasty (TKA) with day-surgery protocol to assess the outcome of ERAS day surgery TKA compared with traditional ERAS inpatient TKA in terms of length of stay (LOS), 30-day readmission, complications, and patient-reported outcome measures (PROMs). METHODS: Patients who underwent unilateral primary TKA from August 2020 to July 2021 were followed up. All TKAs were performed with the ERAS protocol. Patients who fulfilled the following inclusion criteria were offered day-surgery protocol: (1) ASA ≤ 3; (2) agreeable for discharge home. In addition, this day-surgery protocol comprised the following: (i) on-call physiotherapy review; (ii) home visit by physiotherapist at 1 week postoperative; (iii) home visit by nurse at 2 weeks postoperative. Day surgery was defined as discharge within 24 h. Patients were followed up for 6 months and PROMs, postoperative complications, and re-admissions recorded. RESULTS: A total of 738 patients were included (342 ERAS day surgery, 396 ERAS inpatient). 92.4% of patients in the day-surgery group were successfully discharged within 24 h, leading to a shorter mean LOS of 1.13 days compared with 4.12 days in the inpatient group (P < 0.005). Both groups achieved significant and comparable improvement in Knee Society Score, Oxford Knee Score, and Physical and Mental component of Short Form-36. Both groups had similar rate of 30-day readmission and complications. CONCLUSION: Patients who underwent ERAS day surgery TKA achieved similar functional and quality of life improvement compared with ERAS inpatient TKA with no increased complication rate. ERAS day surgery TKA is safe and cost effective, and its use should be promoted.

Novel morphogenic knee implant delivers comparable mid-term outcomes as compared to conventional non-morphogenic implants.

INTRODUCTION: Conventional total knee arthroplasty (C-TKA) implants have well-established mid- and long-term outcomes. The novel TKA (N-TKA) implants provide morphogenic implant components with smaller size increments to facilitate anatomical replication. The aim of the study is to evaluate if these advantages provides better clinical outcomes. MATERIALS AND METHODS: Registry data prospectively collected within a single institution from 2014 to 2018 was reviewed and propensity score matching was performed to match C-TKA to N-TKA. 70 pairs of cruciate retaining (CR) TKA and 116 pairs of posterior stabilized (PS) TKA were identified. Range of motion, SF-36, Knee Society Knee Score (KSKS), Knee Society Function Score (KSFS) and Oxford Knee Score (OKS) were assessed preoperatively, 6 and 24 months postoperatively. Satisfaction was assessed 6 and 24 months postoperatively. Independent T test was performed for parametric data, whereas Wilcoxon rank-sum analysis was performed for non-parametric data. RESULTS: Both C-TKA and N-TKA cohorts demonstrated statistically significant improvement for KSKS, KSFS, OKS and SF-36 at 6 and 24 months postoperatively. C-TKA CR patients had better flexion at 6 months as compared to N-TKA CR (108.7° versus 98.3°, respectively, p = 0.046). At 24 months, there was no difference between C-TKA and N-TKA for range of motion, KSKS, KSFS, OKS and SF-36 PCS, regardless of insert type (p > 0.05). CONCLUSIONS: Both models showed great postoperative improvements in KSFS, KSKS, OKS and SF-36 and have comparable early and mid-term outcomes, suggesting that N-TKAs are suitable substitutes for C-TKA. Longer follow-up studies are required to evaluate the long-term outcomes of N-TKAs. LEVEL OF EVIDENCE: lll.

Evolving microbial patterns of acute mastoiditis in pediatric patients undergoing mastoidectomy.

OBJECTIVE: To investigate the microbial patterns and clinical outcomes of pediatric patients undergoing mastoidectomy for acute coalescent mastoiditis and to identify factors associated with poor outcomes and/or prolonged treatment. STUDY DESIGN: Monocentric retrospective cohort study. SETTING: Tertiary referral pediatric hospital in Indiana. METHODS: By cross-referencing database data from the Pediatric Health Information System (PHIS) querying for all inpatient stays (patients younger than eighteen) with a diagnostic code of mastoiditis between January 1st, 2010 and August 31, 2019, and the electronic health record (Cerner) for Riley Hospital for Children, 46 patients with mastoidectomy were included. A two-tailed T-test was used to evaluate continuous parametric data. Statistical significance was determined as P < 0.05. For continuous variables, data was analyzed using continuous logistic regression. A criteria of p > 0.1 was used for inclusion in the multivariate regression. RESULTS: Inclusion criteria was met by 46 patients. From 2010 to 2019, S. pyogenes and S. pneumoniae were the most common bacteria, each isolated in 11 of 42 bacterial isolates (26.2%). There was no growth in 35.4% (17/48) of intra-operative wound cultures. On univariate analysis, patients with negative cultures had longer length of hospital stay (LOS) (7.7 days [6.5] vs. 4.3 [2.8]; p = 0.018) as well as higher rates of PICC (peripherally inserted central catheter) placement (53.3% vs. 19.4%; p = 0.021). There was a statistically significant difference in terms of gender (p = 0.021), with 15 males and 16 females in the positive culture cohort and 13 males and 2 females in the negative culture cohort. On multivariate analysis, which included gender, PICC placement, both intracranial and extracranial complications, duration of antibiotics, and LOS, female gender was the only significant predictor of positive culture status (p = 0.039). CONCLUSION: S. pyogenes and S. pneumoniae were the predominant etiologic agents in acute coalescent mastoiditis between 2010 and 2019, and negative wound cultures were associated with worse clinical outcomes.

Resting-State Connectivity Changes After Goal-Oriented Attentional Self-Regulation Training in Veterans With Mild Traumatic Brain Injury: Preliminary Findings from a Randomized Controlled Trial.

Mild traumatic brain injury (mTBI) can have lasting consequences on cognitive functioning and well-being. Goal-Oriented Attentional Self-Regulation (GOALS) training has been shown to improve attention and executive functioning, as well as emotional functioning, in veterans with chronic TBI. An ongoing clinical trial (NCT02920788) is further evaluating GOALS training, including underlying neural mechanisms of change. The present study aimed to examine training-induced neuroplasticity by resting-state functional connectivity (rsFC) changes in GOALS versus active control. Veterans with a history of mTBI ≥6 months post-injury (N = 33) were randomly assigned to GOALS (n = 19) or an intensity-matched active control group (Brain Health Education [BHE] training; n = 14). GOALS consists of attention regulation and problem solving applied to individually defined, relevant goals through a combination of group, individual, and home practice sessions. Participants underwent multi-band resting-state functional magnetic resonance imaging at baseline and post-intervention. Exploratory 2 × 2 mixed analyses of variance identified pre-to-post changes in seed-based connectivity for GOALS versus BHE in five significant clusters. GOALS versus BHE demonstrated a significant increase in right lateral pre-frontal cortex connectivity with the right frontal pole and right middle temporal gyrus, as well as increased posterior cingulate connectivity with the pre-central gyrus. Rostral pre-frontal cortex connectivity with the right precuneus and the right frontal pole decreased in GOALS versus BHE. These GOALS-related changes in rsFC point to potential neural mechanisms underlying the intervention. This training-induced neuroplasticity may play a role in improved cognitive and emotional functioning post-GOALS.

NL-201 Upregulates MHC-I Expression and Intratumoral T-cell Receptor Diversity, and Demonstrates Robust Antitumor Activity as Monotherapy and in Combination with PD-1 Blockade.

Cytokine engineering has shown promise as a means to create novel immunomodulatory agents or to improve upon the therapeutic potential of natural cytokines. NL-201, a de novo, hyperstable, IL2 receptor alpha (IL2Rα)-independent agonist of the receptors for IL2 and IL15, elicits robust preclinical activity in syngeneic murine cancer models, including those resistant to immune checkpoint inhibitors (ICI). Here, we report that NL-201 monotherapy converts 'cold' tumor microenvironments (TME) to immunologically 'hot' states by driving pro-inflammatory gene expression, enhancing IFNγ-dependent MHC-I expression, and expanding both T-cell number and clonal diversity. In addition, the combination of NL-201 and anti-PD-1 resulted in complementary antitumor activity in the immunologically 'cold' and ICI resistant B16F10, EMT6, and Renca syngeneic models. In the B16F10 model, treatment with NL-201 plus anti-PD-1 increased the abundance of CD4+ and CD8+ effector T cells in the TME. These findings reveal an important mechanistic basis for the antitumor activity of NL-201 both as a monotherapy and in combination with PD-1 antagonists, and provide further context for the role of IL2Rα-based signaling in ICI-resistant tumors.

The Application of a Self-Made Integrated Three-in-One Microsensor and Commercially Available Wind Speed Sensor to the Cold Air Pipe of the Heating, Ventilation, and Air Conditioning in a Factory for Real-Time Wireless Measurement.

In this study, the integrated three-in-one (temperature, humidity, and wind speed) microsensor was made through the technology of the Micro-electro-mechanical Systems (MEMS) to measure three important physical quantities of the internal environment of the cold air pipe of the Heating, Ventilation and Air Conditioning (HVAC) in the factory, plan the installation positions of the integrated three-in-one microsensor and commercially available wind speed sensor required by the internal environment of the cold air pipe, and conduct the actual 310-h long term test and comparison. In the experiment, it was also observed that the self-made micro wind speed sensor had higher stability compared to the commercially available wind speed sensor (FS7.0.1L.195). The self-made micro wind speed sensor has a variation range of ±200 mm/s, while the commercially available wind speed sensor a variation range of ±1000 mm/s. The commercially available wind speed sensor (FS7.0.1L.195) can only measure the wind speed; however, the self-made integrated three-in-one microsensor can conduct real-time measurements of temperature and humidity according to the environment at that time, and use different calibration curves to know the wind speed. As a result, it is more accurate and less costly than commercially available wind speed sensors. The material cost of self-made integrated three-in-one microsensor includes chemicals, equipment usage fees, and wires. In the future, factories may install a large number of self-made integrated three-in-one microsensors in place of commercially available wind speed sensors. Through real-time wireless measurements, the self-made integrated three-in-one microsensors can achieve the control optimization of the HVAC cold air pipe's internal environment to improve the quality of manufactured materials.

High-speed low-light in vivo two-photon voltage imaging of large neuronal populations.

Monitoring spiking activity across large neuronal populations at behaviorally relevant timescales is critical for understanding neural circuit function. Unlike calcium imaging, voltage imaging requires kilohertz sampling rates that reduce fluorescence detection to near shot-noise levels. High-photon flux excitation can overcome photon-limited shot noise, but photobleaching and photodamage restrict the number and duration of simultaneously imaged neurons. We investigated an alternative approach aimed at low two-photon flux, which is voltage imaging below the shot-noise limit. This framework involved developing positive-going voltage indicators with improved spike detection (SpikeyGi and SpikeyGi2); a two-photon microscope ('SMURF') for kilohertz frame rate imaging across a 0.4 mm × 0.4 mm field of view; and a self-supervised denoising algorithm (DeepVID) for inferring fluorescence from shot-noise-limited signals. Through these combined advances, we achieved simultaneous high-speed deep-tissue imaging of more than 100 densely labeled neurons over 1 hour in awake behaving mice. This demonstrates a scalable approach for voltage imaging across increasing neuronal populations.

PERIRHINAL CORTEX LEARNS A PREDICTIVE MAP (INTERNAL MODEL) OF THE TASK ENVIRONMENT.

Goal-directed tasks involve acquiring an internal model, known as a predictive map, of relevant stimuli and associated outcomes to guide behavior. Here, we identified neural signatures of a predictive map of task behavior in perirhinal cortex (Prh). Mice learned to perform a tactile working memory task by classifying sequential whisker stimuli over multiple training stages. Chemogenetic inactivation demonstrated that Prh is involved in task learning. Chronic two-photon calcium imaging, population analysis, and computational modeling revealed that Prh encodes stimulus features as sensory prediction errors. Prh forms stable stimulus-outcome associations that expand in a retrospective manner and generalize as animals learn new contingencies. Stimulus-outcome associations are linked to prospective network activity encoding possible expected outcomes. This link is mediated by cholinergic signaling to guide task performance, demonstrated by acetylcholine imaging and perturbation. We propose that Prh combines error-driven and map-like properties to acquire a predictive map of learned task behavior.