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.

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.

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.

Effect 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) (1) enhanced the convergent validity of the ShortMAC-F with performance-based mobility measures (ii) affected mean scale score, structural validity, reliability, and interpretability. DESIGN: Secondary analysis of randomized clinical trial data. SETTING: A tertiary teaching hospital. 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, whereas the modified "level walking" item enquired about difficulty in walking 400 m. Before and 12 weeks after TKA, patients completed the WOMAC-F questionnaire, modified ShortMAC-F questionnaire, knee pain scale questionnaire, sit-to-stand test, fast gait speed test, and stair climb test. Interpretability was evaluated by calculating anchor-based substantial clinical benefit 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's α, 0.75-0.83), correlation with pain intensity (correlation values, 0.48-0.52), and substantial clinical benefit 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.

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.

jYCaMP: an optimized calcium indicator for two-photon imaging at fiber laser wavelengths.

Femtosecond lasers at fixed wavelengths above 1,000 nm are powerful, stable and inexpensive, making them promising sources for two-photon microscopy. Biosensors optimized for these wavelengths are needed for both next-generation microscopes and affordable turn-key systems. Here we report jYCaMP1, a yellow variant of the calcium indicator jGCaMP7 that outperforms its parent in mice and flies at excitation wavelengths above 1,000 nm and enables improved two-color calcium imaging with red fluorescent protein-based indicators.

Evaluation of factors associated with limb thrombus formation after endovascular aortic aneurysm repair.

BACKGROUND: Limb thrombus formation is a complication that can occur after endovascular aortic repair (EVAR), and its clinical significance has continued to be debated. Our objective was to report the incidence of limb thrombus after EVAR and determine the association of specific demographic, anatomic, and/or graft variables. METHODS: A retrospective analysis of EVAR patients at a single tertiary center between January 2010 and December 2018 was performed to determine the limb thrombus rate. Demographic, graft, and anatomic variables were analyzed for an association with limb thrombus. RESULTS: A total of 301 patients were included. The average follow-up was 27.6 ± 4.9 months. The mean age was 76.5 ± 0.5 years, and 85% were men. Limb thrombus occurred in 22 patients (7.3%). Of these 22 patients, 11 (50.0%) had had occlusive limb thrombus, 14 (63.6%) were symptomatic, and 17 (77.3%) had required intervention. The patients with limb thrombus were younger (69.8 ± 1.3 years vs 77.1 ± 0.5 years; P < .0001) and more likely to be smokers (10.2% vs 5.2%; P = .10). The incidence of limb thrombus with the Alpha graft (10.7%; Cook Medical Inc, Bloomington, IN) was compared with that with non-Cook grafts (4.0%; P = .07). The average common iliac artery diameter for patients with and without limb thrombus was 14.1 mm and 16.1 mm, respectively (P < .01). Right-sided limb thrombus was more likely in smaller right iliac arteries (14.7 ± 0.9 cm vs 17.0 ± 0.6 cm; P < .05), with a similar finding on the left (13.6 ± 0.9 cm vs 15.2 ± 0.4 cm; P = .13). Unilateral limb thrombus was almost twice as likely on the main body side than on the contralateral side (11 vs 6). Limb thrombus was not associated with aortoiliac disease (odds ratio [OR], 1.31; 95% confidence interval [CI], 0.37-4.62), limb extension (OR, 0.47; 95% CI, 0.06-3.62), or nonmatching limb heights (OR, 1.36; 95% CI, 0.54-3.43). Limb thrombus was also not associated with increased 30-day mortality (P > .05). CONCLUSIONS: Limb thrombus formation is a complication that can occur after EVAR (7.3%). In our study, limb thrombus was seen more frequently in younger patients and those who smoked. Cook Alpha grafts had a thrombus formation rate of 10.7%, which was not significantly higher than that with other brands. Limb thrombus was more likely in smaller iliac arteries and on the main body side.

Acute Hyperglycemia and In-Hospital Mortality in Spontaneous Intracerebral Hemorrhage.

Hyperglycemia is reported to predict worse outcome in patients with stroke, including intracerebral hemorrhage (ICH). In 83 consecutive cases of ICH at a tertiary stroke center, hyperglycemia (serum glucose >7 mmol/L) compared to normoglycemia at presentation was associated with higher rates of in-hospital mortality (51.2% vs. 26.2%, OR 2.3, CI 1.2-7.6, p = 0.02). The association with in-hospital mortality withstood adjustment for age, ICH volume, intraventricular hemorrhage, and infratentorial ICH location, but not baseline Glasgow Coma Scale. Acute hyperglycemia is associated with in-hospital mortality in spontaneous ICH patients, though this may be an indirect, rather than a causal relationship.

Aseptic revision total knee arthroplasty outcomes were equivalent to patients' own pre-failure state but inferior to patients without revision.

PURPOSE: The purpose of this study was to (1) longitudinally compare the patient-reported outcome measures (PROMs) of the same patients who underwent primary TKA and revision TKA, and (2) compared the results of these revision TKA with a matched cohort of well-functioning primary TKA. The hypothesis was revision TKA could result in equivalent outcomes to patients' own primary TKA or the primary TKA of patients who did not require revision. METHODS: Prospectively collected data of 123 patients who underwent primary TKA and subsequently aseptic revision TKA ("revised group"), were matched using nearest-neighbor method to 123 well-functioning primary TKA that did not require revision ("control group"). Preoperative (prior to primary TKA), at time of failure (prior to revision TKA), postoperative 6-month and 2-year PROMs included Knee Society scores (KSS), Oxford Knee Score (OKS) and Short Form-36 (SF-36). Minimal clinically important difference (MCID) attainment was analyzed. Wilcoxon and McNemar's tests were used to compare outcomes within the revised group (primary vs revision), Mann-Whitney U test and Chi-Square test for the revised and control groups. RESULTS: The revised group had poorer KSS objective (p = 0.045), KSS functional (p < 0.001), OKS (p = 0.011) and SF-36 PCS (p < 0.001) at time of failure (prior to revision TKA), compared to their preoperative PROMs (prior to primary TKA). Revision TKA resulted in restoration of KSS objective, OKS and SF-36 PCS (NS) that were equivalent to their primary TKA, but poorer KSS functional (p < 0.050). Patients in the revised group had a lower proportion of MCID attainment in KSS objective (p = 0.014) and OKS (p < 0.001) at 2-year after primary TKA when compared to the control group. Revision TKA also led to poorer KSS objective, KSS functional and SF-36 PCS (p < 0.050) when compared to primary TKA of the control group. CONCLUSION: Outcomes following aseptic revision were equivalent to patients' own pre-failure state but inferior to patients with non-revised implants. An individualized approach toward goal setting and assessing adequacy of aseptic revision TKA can be adopted based on patients' pre-failure outcomes. LEVEL OF EVIDENCE: III.

The patient acceptable symptom state for the knee society score, oxford knee score and short form-36 following unicompartmental knee arthroplasty.

PURPOSE: The patient acceptable symptom state (PASS) is a target value on a patient-reported outcome measures (PROM) scale beyond which patients deem themselves to have attained an acceptable outcome. This study aimed to define the PASS thresholds for generic and knee-specific PROMs at 2 years after unicompartmental knee arthroplasty (UKA). METHODS: Prospectively collected data of 955 patients who underwent UKA for medial osteoarthritis at a single institution was reviewed. Patients were assessed preoperatively and 2 years postoperatively using the Knee Society Knee Score (KSKS), Function Score (KSFS), Oxford Knee Score (OKS), SF-36 Physical Component Score (PCS) and Mental Component Score (MCS). Responses to an anchor question assessing patients' overall rating of treatment results were dichotomized and used to determine if PASS was achieved. PASS thresholds for each PROM were selected based on the Youden index on a receiver operating characteristics (ROC) curve. Sensitivity analyses were performed for different subgroups (by age, gender, BMI), baseline score tertiles and an alternate definition of PASS. RESULTS: In total, 92.7% reported their current state as acceptable. The areas under the curve (AUC) for ROCs were 0.72-0.83, except for the SF-36 PCS (AUC 0.64), indicating good discriminative accuracy of the other PROMs. PASS thresholds were 85.5 for KSKS, 77.5 for KSFS, 41.5 for OKS, 49.9 for SF-36 PCS and 54.6 for SF-36 MCS. Sensitivity analyses revealed that the thresholds were robust. Patients who attained a PASS were at least 4-5 times more likely to be satisfied and have expectations fulfilled. CONCLUSION: PASS thresholds can be used to define treatment success in future outcome studies. At the individual level, they provide clinically relevant benchmarks for surgeons when assessing postoperative recovery. LEVEL OF EVIDENCE: III.

Clinical Frailty Scale is a better predictor for adverse post-operative complications and functional outcomes than Modified Frailty Index and Charlson Comorbidity Index after total knee arthroplasty.

PURPOSE: Studies have demonstrated correlations between frailty and comorbidity scores with adverse outcomes in total knee replacement (TKR). However, there is a lack of consensus on the most suitable pre-operative assessment tool. This study aims to compare Clinical Frailty Scale (CFS), Modified Frailty Index (MFI), and Charlson Comorbidity Index (CCI) in predicting adverse post-operative complications and functional outcomes following a unilateral TKR. METHODS: In total, 811 unilateral TKR patients from a tertiary hospital were identified. Pre-operative variables were age, gender, body mass index (BMI), American Society of Anesthesiologists (ASA) class, CFS, MFI, and CCI. Binary logistic regression analysis was performed to ascertain odd ratios of pre-operative variables on adverse post-operative complications (length of stay < LOS >, complications, ICU/HD admission, discharge location, 30-day readmission, 2-year reoperation). Multiple linear regression analyses were used to estimate the standardized effects of pre-operative variables on the Knee Society Functional Score (KSFS), Knee Society Knee Score (KSKS), Oxford Knee Score (OKS), and 36-Item Short Form Survey (SF-36). RESULTS: CFS is a strong predictor for LOS (OR 1.876, p < 0.001), complications (OR 1.83-4.97, p < 0.05), discharge location (OR 1.84, p < 0.001), and 2-year reoperation rate (OR 1.98, p < .001). ASA and MFI were predictors for ICU/HD admission (OR:4.04, p = 0.002; OR 1.58, p = 0.022, respectively). None of the scores was predictive for 30-day readmission. A higher CFS was associated with a worse outcome for 6-month KSS, 2-year KSS, 6-month OKS, 2-year OKS, and 6-month SF-36. CONCLUSION: CFS is a superior predictor for post-operative complications and functional outcomes than MFI and CCI in unilateral TKR patients. This suggests the importance of assessing pre-operative functional status when planning for TKR. LEVEL OF EVIDENCE: Diagnostic, II.

Cost-Effectiveness of Robot-Assisted Total Knee Arthroplasty: A Markov Decision Analysis.

BACKGROUND: Robot-assisted total knee arthroplasty (rTKA) may improve clinical outcomes for patients who have end-stage osteoarthritis of the knee. However, the costs of rTKA are high, and there is a paucity of data evaluating the cost-effectiveness of rTKA. We aimed to analyze the cost per quality-adjusted life-year (QALY) of rTKA relative to manual TKA. METHODS: A Markov decision analysis was performed using known parameters for costs, outcomes, implant survivorships, and mortalities. The cost-effectiveness of rTKA relative to manual TKA was assessed for end-stage knee osteoarthritis patients who had a mean age of 65 years (range, 27 to 94 years). The rTKA costs were calculated for a pay-per-use contract robot. RESULTS: Using the Markov Model with an annual case volume of 500 patients and a mean age of 65 years, the overall health gain per patient was 13.34 QALYs after rTKA and 13.31 QALYs after manual TKA. This resulted in an overall gain in QALYs of 0.03 for each patient undergoing an rTKA compared with manual TKA and an incremental cost of $128,526 Singapore Dollars per QALY. CONCLUSION: Robotic TKA is not a cost-effective alternative to conventional TKA using a pay-per-use contract robot.

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.

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.

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.

The effect of topical tranexamic acid on functional outcomes and quality of life in patients undergoing unicompartmental knee arthroplasty.

INTRODUCTION: Tranexamic acid (TXA) is being increasingly utilized to reduce blood loss after knee joint arthroplasty. However, there is a lack of studies on the effect of topical TXA on the functional outcomes and quality of life after Unicompartmental Knee Arthroplasty (UKA). The aim of this study was to determine the effect of topical TXA on functional outcomes and quality of life scores in patients undergoing UKA. MATERIALS AND METHODS: We retrospectively analysed patients undergoing unilateral UKA at a single tertiary hospital from 2005 to 2017. Patients were divided into 2 groups: (1) The control group which did not receive TXA (n = 742); (2) The TXA group which received topical TXA (n = 331). Functional outcomes were assessed using the Knee Society Function Score (KSFS), Knee Society Knee Score (KSKS) and Oxford Knee Score (OKS), while quality of life was evaluated with the Physical Component Score (PCS) and Mental Component Score (MCS) of Short-Form 36 (SF-36) preoperatively and at 6 months and 2 years follow-up. RESULTS: At 6 months and 2 years post-surgery, there were no significant differences in the functional scores between the groups. The number of patients who attained minimum clinically important difference (MCID) for each of the functional scores was also comparable between the groups. CONCLUSIONS: In patients undergoing UKA, functional outcomes and quality of life scores were comparable between those who received topical TXA and those who did not. There was no significant improvement or impairment in knee function associated with topical TXA administration in UKA up to 2 years follow-up.

A conserved acetylation switch enables pharmacological control of tubby-like protein stability.

Tubby-like proteins (TULPs) are characterized by a conserved C-terminal domain that binds phosphoinositides. Collectively, mammalian TULP1-4 proteins play essential roles in intracellular transport, cell differentiation, signaling, and motility. Yet, little is known about how the function of these proteins is regulated in cells. Here, we present the protein-protein interaction network of TULP3, a protein that is responsible for the trafficking of G-protein-coupled receptors to cilia and whose aberrant expression is associated with severe developmental disorders and polycystic kidney disease. We identify several protein interaction nodes linked to TULP3 that include enzymes involved in acetylation and ubiquitination. We show that acetylation of two key lysine residues on TULP3 by p300 increases TULP3 protein abundance and that deacetylation of these sites by HDAC1 decreases protein levels. Furthermore, we show that one of these sites is ubiquitinated in the absence of acetylation and that acetylation inversely correlates with ubiquitination of TULP3. This mechanism is evidently conserved across species and is active in zebrafish during development. Finally, we identify this same regulatory module in TULP1, TULP2, and TULP4 and demonstrate that the stability of these proteins is similarly modulated by an acetylation switch. This study unveils a signaling pathway that links nuclear enzymes to ciliary membrane receptors via TULP3, describes a dynamic mechanism for the regulation of all tubby-like proteins, and explores how to exploit it pharmacologically using drugs.

Perceptions of and barriers to cancer screening by the sexual and gender minority community: a glimpse into the health care disparity.

PURPOSE: A disparity exists in cancer screening rates for the Sexual and Gender Minority (SGM) community. We sought to understand the perceptions and baseline knowledge of cancer screening among SGM community members. METHODS: Survey administered via social media from June 2018 to October 2018. We asked 31 questions focused on cancer screening, human papillomavirus, emotional distress, and experience with the health care system. Those included were 18 years or older. Cancer screening attitudes and knowledge, as well as perceptions of the health care system were investigated. RESULTS: There were 422 respondents analyzed: 24.6% identified as female, 25.5% as male, 40.1% transgender, and 9.6% as other. 65.4% of the SGM community is not certain what cancer screening to do for themselves. Only 27.3% and 55.7% knew that HPV was a risk factor associated with head and neck cancer and anal cancer, respectively. Half stated their emotional distress prevents them from getting cancer screening. It was identified that process changes in making appointments, comforts during the visit, and formal training for physicians and nurses could increase cancer screening compliance for this community. The transgender population had a trend in more gaps in knowledge of appropriate cancer screening and significant excess emotional distress. CONCLUSION: Gaps in cancer screening knowledge and emotional and financial distress may be responsible for the disparity of lower cancer screening rates for the SGM population and the transgender population may be most at risk. Appreciating the cancer screening concerns of the SGM population can help shape future clinical and institutional approaches to improve health care delivery.

No differences in 10-year clinical outcomes and quality of life between patients with different mediolateral femoral component positions in fixed-bearing medial unicompartmental knee arthroplasty.

PURPOSE: There has been a paucity of literature evaluating the role of mediolateral femoral component position (FCP) in medial unicompartmental arthroplasty (UKA). Hence, the aim of this study is to evaluate whether the mediolateral FCP in UKA will affect the 10-year clinical outcomes and quality of life of patients who underwent medial UKA. METHODS: Data of 262 patients who underwent medial UKA were analyzed. All patients were assessed at 6 months, 2 years and 10 years using the Knee Society Function Score, Knee Society Knee Score, Oxford Knee Score, Short-Form 36 Physical/Mental Component Scores and postoperative satisfaction. The mediolateral FCP on postoperative radiographs was measured by independent assessors using the Picture Archiving and Communication Systems. 144 patients were distributed into group C (center), 98 into group M (medial) and 20 into group L (lateral) according to FCP, and one-way ANOVA was used to compare the functional outcomes of the three groups. RESULTS: No statistical differences were found between the three groups in terms of 10-year clinical outcomes, quality of life, satisfaction rates and revision rates. CONCLUSION: Differences in mediolateral FCP did not result in significant difference in 10-year postoperative clinical outcomes for patients who underwent fixed-bearing medial UKAs. LEVEL OF EVIDENCE: Retrospective study, Level III.

Defining the minimal clinically important difference for the knee society score following revision total knee arthroplasty.

BACKGROUND: No previous study has evaluated the MCID for revision total knee arthroplasty (TKA). This study aimed to identify the MCID for the Knee Society Score (KSS), for revision TKA. METHODS: Prospectively collected data from 270 patients who underwent revision TKA at a single institution was analysed. Clinical assessment was performed preoperatively, at 6 months and 2 years using Knee Society Function Score (KSFS) and Knee (KSKS) Scores, and Oxford Knee Score (OKS). MCID was evaluated with a three-pronged methodology, using (1) anchor-based method with linear regression, (2) anchor-based method with receiver operating characteristic (ROC) and area under curve (AUC), (3) distribution-based method with standard deviation (SD). The anchors used were improvement in OKS ≥ 5, patient satisfaction, and implant survivorship following revision TKA. RESULTS: The cohort comprised 70% females, with mean age of 69.0 years, that underwent unilateral revision TKA. The MCID determined by anchor-based linear regression method using OKS was 6.3 for KSFS, and 6.6 for KSKS. The MCID determined by anchor-based ROC was between 15 and 20 for KSFS (AUC: satisfaction = 71.8%, survivorship = 61.4%) and between 33 and 34 for KSKS (AUC: satisfaction = 76.3%, survivorship = 67.1%). The MCID determined by distribution-based method of 0.5 SD was 11.7 for KSFS and 11.9 for KSKS. CONCLUSION: The MCID of 6.3 points for KSFS, and 6.6 points for KSKS, is a useful benchmark for future studies looking to compare revision against primary TKA outcomes. Clinically, the MCID between 15 and 20 for KSFS and between 33 and 34 for KSKS is a powerful tool for discriminating patients with successful outcomes after revision TKA. Implant survivorship is an objective and naturally dichotomous outcome measure that complements the subjective measure of patient satisfaction, which future MCID studies could consider utilizing as anchors in ROC. LEVEL OF EVIDENCE: II.