Processing difficulty while reading words with neighbors is not due to increased foveal load: Evidence from eye movements.

Words with high orthographic relatedness are termed "word neighbors" (angle/angel; birch/birth). Activation-based models of word recognition assume that lateral inhibition occurs between words and their activated neighbors. However, studies of eye movements during reading have not found inhibitory effects in early measures assumed to reflect lexical access (e.g., gaze duration). Instead, inhibition in eye-movement studies has been found in later measures of processing (e.g., total time, regressions in). We conducted an eye-movement boundary change study (Rayner, Cognitive Psychology, 7(1), 65-81, 1975) that manipulated the parafoveal preview of the word following the neighbor word (word N+1). In this way, we explored whether the late inhibitory effects seen with transposed letter words and words with higher-frequency neighbors result from reduced parafoveal preview due to increased foveal load and/or interference during late stages of lexical processing (the L2 stage within the E-Z Reader framework). For word N+1, while there were clear preview effects, there was not an effect of the neighborhood status of word N, nor a significant interaction. This suggests that the late inhibitory effects of earlier eye-movement studies are driven by misidentification of neighbor words rather than being due to increased foveal load.

Superficial versus deep parasternal intercostal plane blocks: cadaveric evaluation of injectate spread.

BACKGROUND: Deep and superficial parasternal intercostal plane blocks provide anterior chest wall analgesia for both breast and cardiac surgery. Our primary objective of this cadaveric study was to describe the parasternal spread of deep and superficial parasternal intercostal plane blocks. Our secondary objectives were to describe needle proximity to the internal mammary artery when performing deep parasternal intercostal plane blocks, and compare lateral injectate spread and extension into the rectus sheath. METHODS: We performed ultrasound-guided deep and superficial parasternal intercostal plane blocks 2 cm from the sternum at the T3-4 interspace in four fresh frozen cadavers as described in clinical studies. RESULTS: Parasternal spread of injectate was greater with the deep parasternal intercostal plane injection than with the superficial parasternal intercostal plane injection. The internal mammary artery was ∼3 mm away from the needle trajectory in cadaver #1 and ∼5 mm from the internal mammary artery in cadaver #2. Lateral spread extended to the midclavicular line for all deep parasternal intercostal plane blocks and beyond the midclavicular line for all superficial parasternal intercostal plane blocks. Neither block extended to the rectus sheath. CONCLUSIONS: A greater number of parasternal interspaces were covered with the deep parasternal intercostal plane block than with the superficial parasternal intercostal plane block when one injection was performed at the T3-4 interspace. However, considering proximity to the internal mammary artery, and potential devastating consequences of an arterial injury, we propose that the deep parasternal intercostal plane block be classified as an advanced block and that future studies focus on optimising superficial parasternal intercostal plane parasternal spread.

Standardizing nomenclature in regional anesthesia: an ASRA-ESRA Delphi consensus study of upper and lower limb nerve blocks.

BACKGROUND: Inconsistent nomenclature and anatomical descriptions of regional anesthetic techniques hinder scientific communication and engender confusion; this in turn has implications for research, education and clinical implementation of regional anesthesia. Having produced standardized nomenclature for abdominal wall, paraspinal and chest wall regional anesthetic techniques, we aimed to similarly do so for upper and lower limb peripheral nerve blocks. METHODS: We performed a three-round Delphi international consensus study to generate standardized names and anatomical descriptions of upper and lower limb regional anesthetic techniques. A long list of names and anatomical description of blocks of upper and lower extremities was produced by the members of the steering committee. Subsequently, two rounds of anonymized voting and commenting were followed by a third virtual round table to secure consensus for items that remained outstanding after the first and second rounds. As with previous methodology, strong consensus was defined as ≥75% agreement and weak consensus as 50%-74% agreement. RESULTS: A total of 94, 91 and 65 collaborators participated in the first, second and third rounds, respectively. We achieved strong consensus for 38 names and 33 anatomical descriptions, and weak consensus for five anatomical descriptions. We agreed on a template for naming peripheral nerve blocks based on the name of the nerve and the anatomical location of the blockade and identified several areas for future research. CONCLUSIONS: We achieved consensus on nomenclature and anatomical descriptions of regional anesthetic techniques for upper and lower limb nerve blocks, and recommend using this framework in clinical and academic practice. This should improve research, teaching and learning of regional anesthesia to eventually improve patient care.

Motor-sparing peripheral nerve blocks for hip and knee surgery.

PURPOSE OF REVIEW: To summarize the recent literature describing and comparing novel motor-sparing peripheral nerve block techniques for hip and knee surgery. This topic is relevant because the number of patients undergoing same day discharge after hip and knee surgery is increasing. Preserving lower extremity muscle function is essential to facilitate early physical therapy for these patients. RECENT FINDINGS: Distal peripheral nerve blocks may allow for preserved quadriceps motor strength and comparable analgesia to traditional techniques. However, few studies in hip and knee populations include strength or function as primary outcomes. For hip surgeries, studies have failed to show analgesic differences between regional blocks and periarticular infiltration. Similarly for knee arthroplasty in the absence of periarticular infiltration, recent evidence suggests adding combinations of blocks (ACB plus iPACK or genicular nerve blocks) may balance pain control and early ambulation. SUMMARY: The use of motor-sparing peripheral nerve block techniques enables early ambulation, adequate pain control, and avoidance of opioid-related side effects facilitating outpatient/ambulatory lower extremity surgery. Further studies of these techniques for continuous peripheral nerve block catheters are needed to assess if extended blockade continues to provide motor-sparing and opioid-sparing benefits.

Keep clam and carry on: Misperceptions of transposed-letter neighbours.

Previous research has provided evidence that readers experience processing difficulty when reading words that have a transposed-letter (TL) neighbour (e.g., TRAIL has the TL neighbour TRIAL). Here, we provide direct evidence that this interference is driven by explicit misidentifications of the word for its TL neighbour. Experiment 1 utilised an eye-tracking task in which participants read sentences aloud and reading errors were coded. Sentences had a target word that either (1) had a TL neighbour or (2) was a matched control word with no TL neighbour. In Experiment 2, participants identified words within sentences that they consciously misread and reported the interloper. In both experiments, readers explicitly misidentified many more of the TL words than control words, and most often for their TL neighbour. These findings support the idea that TL interference effects are due primarily to initial misperceptions and post-lexical checking rather than co-activation at the lexical level.

Development of VHL-recruiting STING PROTACs that suppress innate immunity.

STING acts as a cytosolic nucleotide sensor to trigger host defense upon viral or bacterial infection. While STING hyperactivation can exert anti-tumor effects by increasing T cell filtrates, in other contexts hyperactivation of STING can contribute to autoimmune and neuroinflammatory diseases. Several STING targeting agonists and a smaller subset of antagonists have been developed, yet STING targeted degraders, or PROTACs, remain largely underexplored. Here, we report a series of STING-agonist derived PROTACs that promote STING degradation in renal cell carcinoma (RCC) cells. We show that our STING PROTACs activate STING and target activated/phospho-STING for degradation. Locking STING on the endoplasmic reticulum via site-directed mutagenesis disables STING translocation to the proteasome and resultingly blocks STING degradation. We also demonstrate that PROTAC treatment blocks downstream innate immune signaling events and attenuates the anti-viral response. Interestingly, we find that VHL acts as a bona fide E3 ligase for STING in RCC; thus, VHL-recruiting STING PROTACs further promote VHL-dependent STING degradation. Our study reveals the design and biological assessment of VHL-recruiting agonist-derived STING PROTACs, as well as demonstrates an example of hijacking a physiological E3 ligase to enhance target protein degradation via distinct mechanisms.

The Relationship Between Personality Traits and the Processing of Emotion Words: Evidence from Eye-Movements in Sentence Reading.

Previous research shows that processing times on emotion words (both negative and positive) are faster than on non-emotional neutral words. In the current study, we explored how personality traits (the Big Five and the trait emotional intelligence factors) may further influence the processing of emotion versus non-emotion words by conducting two experiments where participants silently read sentences while their eye movements were recorded. The results replicated the facilitative emotion effect and showed that those with higher agreeableness scores had stronger emotion effects on positive words and those with higher extraversion scores, higher openness scores, higher agreeableness scores, lower sociability scores, and higher emotionality scores had stronger emotion effects on negative words. Furthermore, some personality traits also led to different ways that readers approach text, for example, through more risky reading strategies.

Spinal Versus General Anesthesia in Contemporary Revision Total Hip Arthroplasties.

BACKGROUND: Spinal anesthesia is increasingly used in complex patient populations including revision total hip arthroplasties (THAs). This study aimed to investigate the pain control, length of stay (LOS), and complications associated with spinal versus general anesthesia in a large institutional series of revision THAs. METHODS: We retrospectively identified 4,767 revision THAs (4,533 patients) from 2001 to 2016 using our institutional total joint registry. Of these cases, 86% had general and 14% had spinal anesthesia. Demographics between groups were similar with mean age of 66 years, 52% women, and mean body mass index of 29. Complications including all-cause rerevisions and reoperations were studied. Data were analyzed using an inverse probability of treatment weighted model based on propensity score that accounted for patient and surgical factors. The mean follow-up was 7 years. RESULTS: Patients treated with spinal anesthesia required fewer postoperative oral morphine equivalents (P < .001) and had lower numeric pain rating scale scores (P < .001). Spinal anesthesia had a decreased LOS (4.2 versus 4.8 days; P = .007), fewer cases of altered mental status (odds ratio (OR) 3.1, P = .001), fewer blood transfusions (OR 2.3, P < .001), fewer intensive care unit admissions (OR 2.3, P < .001), fewer rerevisions (OR 1.6, P = .04), and fewer reoperations (OR 1.5, P = .02). CONCLUSION: Spinal anesthesia was associated with lower oral morphine equivalent use and reduced LOS in this large cohort of revision THAs. Furthermore, spinal anesthesia was associated with fewer cases of altered mental status, transfusion, intensive care unit admission, rerevision, and reoperation after accounting for numerous patient and operative factors. LEVEL OF EVIDENCE: Level III, Retrospective Comparative Study.

Spinal Versus General Anesthesia in Contemporary Revision Total Knee Arthroplasties.

BACKGROUND: Interest in spinal anesthesia utilization in revision total knee arthroplasties (TKAs) is rising. This study investigated the pain control, length of stay (LOS), and complications associated with spinal versus general anesthesia in a single institution series of revision TKAs. METHODS: We identified 3,711 revision TKAs (3,495 patients) from 2001 to 2016 using our institutional total joint registry. There were 66% who had general anesthesia and 34% who had spinal anesthesia. Mean age, sex, and BMI were similar between groups at 67 years, 53% women, and 32, respectively. Data were analyzed using inverse probability of treatment weighted models based on propensity scores that accounted for patient and operative factors. Mean follow-up was 6 years (range, 2 to 17). RESULTS: Patients treated with spinal anesthesia required fewer postoperative oral morphine equivalents (OMEs) (P < .0001) and had lower numeric pain rating scale scores (P < .001). Spinal anesthesia was associated with shorter LOS (4.0 versus 4.6 days; P < .0001), less cases of altered mental status (AMS; Odds Ratio (OR) 2.0, P = .004), less intensive care unit (ICU) admissions (OR 1.6, P = .02), fewer re-revisions (OR 1.7, P < .001), and less reoperations (OR 1.4, P < .001). There was no difference in the incidence of VTE (P = .82), 30-day readmissions (P = .06), or 90-day readmissions (P = .18) between anesthetic techniques. CONCLUSION: We found that spinal anesthesia for revision TKAs was associated with significantly lower pain scores, reduced OME requirements, and decreased LOS. Furthermore, spinal anesthesia was associated with fewer cases of AMS, ICU admissions, and re-revisions even after accounting for numerous patient and operative factors. LEVEL OF EVIDENCE: Level III, Retrospective Comparative Study.

The Benefits of Local Anesthesia Used in Mastectomy Without Reconstruction.

BACKGROUND: The opioid epidemic has driven renewed interest in local anesthesia to reduce postoperative opioid use. Our objective was to determine if local anesthesia decreased hospital pain scores, oral morphine equivalents (OME), length of stay (LOS), and nausea/vomiting. METHODS: Single institution retrospective study of females who underwent mastectomy without reconstruction. RESULTS: Overall, 712 patients were included; 63 (8.8%) received bupivacaine (B), 512 (72%) liposomal bupivacaine (LB), and 137 (19%) no local. 95% were discharged on POD1. Liposomal bupivacaine use increased from 2014 to 2019. Additional factors associated with use of local regimen were surgeon and extent of axillary surgery. Fewer patients used postop opioids during their hospital stay if any local was used compared to none (76 vs 88%; 0.003). Compared to none, local had shorter mean PACU LOS (95 vs 87 min; P = .02), lower mean intraoperative-OME (96 vs 106; P < .001), and lower mean postoperative OME/hr (1.4 vs 1.8 P = .001). Multivariable analysis (MVA) showed lower OME/hr with LB compared to B and none (P = .002); this translates to 22 mg and 30 mg of oxycodone in a 24-hr period, respectively. MVA showed lower POD1 pain scores with LB relative to none (P = .049). Local did not impact nausea/emesis. CONCLUSION: Local anesthesia was superior to no local in several measures. However, a consistent benefit of a specific local anesthetic agent was not demonstrated (LB vs B). A prospective study is warranted to determine the optimal local regimen for this cohort and further inform clinical relevance.

A Case-Control Study of Accidental Falls During Surgical Hospitalizations.

BACKGROUND: Postoperative falls are preventable complications. The study aims were to describe the rate and circumstances surrounding postoperative falls and explore potential associations with patient and procedural characteristics with emphasis on the use of sedative medications. METHODS: Medical records of hospitalized patients undergoing non-lower extremity surgery under general anesthesia from January 1, 2010, through April 30, 2018 were reviewed for falls within 72 postoperative hours. Perioperative use of sedatives, sleep aids, gabapentinoids, and opioids were abstracted. Each fall case was matched with two controls on age, sex, and procedure type. Descriptive statistics and multivariable analysis accounting for the matched design were performed. RESULTS: There were 343 falls among 200 186 hospitalized surgical patients (incidence of 17.1 [95% CI: 15.4, 19.0] falls per 10 000 procedures) with largest proportion of falls occurring on postoperative day 2 (n = 134, 39.1%). Most falls occurred in the general hospital wards (n = 304, 88.6%) and were unwitnessed (n = 186, 55.9%). The incidence of major injuries was 1.0 (95% CI: .1 - 3.6) per 100 000 procedures. Home use of non-benzodiazepine hypnotics (odds ratio 2.68, 95% CI: 1.47, 4.88, P=.001) and blood transfusions were associated with increased fall risk. Hospital stay was longer in patients who fall (7 [4, 15] vs. 5 [3, 9] days, P < .001). CONCLUSIONS: The rate of postoperative falls in our institution was low and frequently unwitnessed. The use of non-benzodiazepine hypnotics is a modifiable risk factor associated with postoperative falls. Serious complications after falls were rare.

Spinal versus general anaesthesia in contemporary primary total knee arthroplasties.

AIMS: Spinal anaesthesia has seen increased use in contemporary primary total knee arthroplasties (TKAs). However, controversy exists about the benefits of spinal in comparison to general anaesthesia in primary TKAs. This study aimed to investigate the pain control, length of stay (LOS), and complications associated with spinal versus general anaesthesia in primary TKAs from a single, high-volume academic centre. METHODS: We retrospectively identified 17,690 primary TKAs (13,297 patients) from 2001 to 2016 using our institutional total joint registry, where 52% had general anaesthesia and 48% had spinal anaesthesia. Baseline characteristics were similar between cohorts with a mean age of 68 years (SD 10), 58% female (n = 7,669), and mean BMI of 32 kg/m2 (SD 7). Pain was evaluated using oral morphine equivalents (OMEs) and numerical pain rating scale (NPRS) data. Complications including 30- and 90-day readmissions were studied. Data were analyzed using an inverse probability of treatment weighted model based on propensity score that included many patient and surgical factors. Mean follow-up was seven years (2 to 18). RESULTS: Patients treated with spinal anaesthesia required fewer postoperative OMEs (p < 0.001) and had lower NPRS scores (p < 0.001). Spinal anaesthesia also had fewer cases of altered mental status (AMS; odds ratio (OR) 1.3; p = 0.044), as well as 30-day (OR 1.4; p < 0.001) and 90-day readmissions (OR 1.5; p < 0.001). General anaesthesia was associated with increased risk of any revision (OR 1.2; p = 0.021) and any reoperation (1.3; p < 0.001). CONCLUSION: In the largest single institutional report to date, we found that spinal anaesthesia was associated with significantly lower OME use, lower risk of AMS, and lower overall 30- and 90-day readmissions following primary TKAs. Additionally, spinal anaesthesia was associated with reduced risk of any revision and any reoperation after accounting for numerous patient and operative factors. When possible and safe, spinal anaesthesia should be considered in primary TKAs.Cite this article: Bone Joint J 2022;104-B(11):1209-1214.

Discovery of hit compounds for methyl-lysine reader proteins from a target class DNA-encoded library.

Methyl-lysine (Kme) reader domains are prevalent in chromatin regulatory proteins which bind post-translational modification sites to recruit repressive and activating factors; therefore, these proteins play crucial roles in cellular signaling and epigenetic regulation. Proteins that contain Kme domains are implicated in various diseases, including cancer, making them attractive therapeutic targets for drug and chemical probe discovery. Herein, we report on expanding the utility of a previously reported, Kme-focused DNA-encoded library (DEL), UNCDEL003, as a screening tool for hit discovery through the specific targeting of Kme reader proteins. As an efficient method for library generation, focused DELs are designed based on structural and functional features of a specific class of proteins with the intent of novel hit discovery. To broadly assess the applicability of our library, UNCDEL003 was screened against five diverse Kme reader protein domains (53BP1 TTD, KDM7B JmjC-PHD, CDYL2 CD, CBX2 CD, and LEDGF PWWP) with varying structures and functions. From these screening efforts, we identified hit compounds which contain unique chemical scaffolds distinct from previously reported ligands. The selected hit compounds were synthesized off-DNA and confirmed using primary and secondary assays and assessed for binding selectivity. Hit compounds from these efforts can serve as starting points for additional development and optimization into chemical probes to aid in further understanding the functionality of these therapeutically relevant proteins.

Features of burnout amongst pathologists: A reassessment.

There has been little rigorous assessment of burnout among pathologists and pathology trainees. Given this relative dearth of relevant literature on pathologist burnout, this report aims to raise awareness of the issue among those working in and around this specialty. Our results are based on a survey given in conjunction with the American Board of Pathology's (ABPath) biennial Continuing Certification (CC) reporting of activities required of diplomates to maintain certification. The survey was voluntary, open to all diplomates participating in CC, and conducted over two consecutive years (2019 and 2020), with alternate years comprising different sets of diplomates. The data are based on 1256 respondents (820 from 2019 to 436 from 2020). The three highest aggregate reported rates of burnout (reported as experienced nearly all of the time, most of the time, or part of the time) occurred when respondents were in their first year of residency training (41.1%) and when they were in (47.6%) and beyond (46.6%) their first three years of practice. We considered this high-low-high, or U-shaped distribution in recollected burnout over time among pathologists a notable finding and investigated its distribution among respondents. Conversely at every point in their training and practice, from half to three-quarters of respondents reported never or infrequently experiencing burnout. This study represents the largest pathologist cohort survey to date about pathologists' burnout. Importantly, especially for those considering pathology as a career, these data are on the low end of the distribution of burnout among specialties for those in practice.

Metagenomics combined with activity-based proteomics point to gut bacterial enzymes that reactivate mycophenolate.

Mycophenolate mofetil (MMF) is an important immunosuppressant prodrug prescribed to prevent organ transplant rejection and to treat autoimmune diseases. MMF usage, however, is limited by severe gastrointestinal toxicity that is observed in approximately 45% of MMF recipients. The active form of the drug, mycophenolic acid (MPA), undergoes extensive enterohepatic recirculation by bacterial ß-glucuronidase (GUS) enzymes, which reactivate MPA from mycophenolate glucuronide (MPAG) within the gastrointestinal tract. GUS enzymes demonstrate distinct substrate preferences based on their structural features, and gut microbial GUS enzymes that reactivate MPA have not been identified. Here, we compare the fecal microbiomes of transplant recipients receiving MMF to healthy individuals using shotgun metagenomic sequencing. We find that neither microbial composition nor the presence of specific structural classes of GUS genes are sufficient to explain the differences in MPA reactivation measured between fecal samples from the two cohorts. We next employed a GUS-specific activity-based chemical probe and targeted metaproteomics to identify and quantify the GUS proteins present in the human fecal samples. The identification of specific GUS enzymes was improved by using the metagenomics data collected from the fecal samples. We found that the presence of GUS enzymes that bind the flavin mononucleotide (FMN) is significantly correlated with efficient MPA reactivation. Furthermore, structural analysis identified motifs unique to these FMN-binding GUS enzymes that provide molecular support for their ability to process this drug glucuronide. These results indicate that FMN-binding GUS enzymes may be responsible for reactivation of MPA and could be a driving force behind MPA-induced GI toxicity.

Spinal Compared with General Anesthesia in Contemporary Primary Total Hip Arthroplasties.

BACKGROUND: The specific advantages of spinal anesthesia compared with general anesthesia for primary total hip arthroplasty (THA) remains unknown. Therefore, this study aimed to investigate the pain control, length of stay, and postoperative outcomes associated with spinal anesthesia compared with general anesthesia in a large cohort of primary THAs from a single, high-volume academic institution. METHODS: We retrospectively identified 13,730 primary THAs (11,319 patients) from 2001 to 2016 using our total joint registry. Of these cases, 58% had general anesthesia and 42% had spinal anesthesia. The demographic characteristics were similar between groups, with mean age of 64 years, 51% female, and mean body mass index (BMI) of 31 kg/m 2 . Data were analyzed using an inverse probability of treatment weighted model based on a propensity score that accounted for numerous patient and operative factors. The mean follow-up was 6 years. RESULTS: Patients treated with spinal anesthesia had lower Numeric Pain Rating Scale (NPRS) scores (p < 0.001) and required fewer postoperative oral morphine equivalents (OMEs) at all time points evaluated (p < 0.001). Patients treated with spinal anesthesia also had shorter hospital length of stay (p = 0.02), fewer altered mental status events (odds ratio [OR], 0.7; p = 0.02), and fewer intensive care unit (ICU) admissions (OR, 0.7; p = 0.01). There was no difference in the incidence of deep vein thrombosis (p = 0.8), pulmonary embolism (p = 0.4), 30-day readmissions (p = 0.17), 90-day readmissions (p = 0.18), all-cause revisions (p = 0.17), or all-cause reoperations (p = 0.14). CONCLUSIONS: In this large, single-institution study, we found that spinal anesthesia was associated with reduced pain scores and OME use postoperatively. Furthermore, spinal anesthesia resulted in fewer altered mental status events and ICU admissions. These data favor the use of spinal anesthesia in primary THAs. LEVEL OF EVIDENCE: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.