A year-round satellite sea-ice thickness record from CryoSat-2.

Arctic sea ice is diminishing with climate warming1 at a rate unmatched for at least 1,000 years2. As the receding ice pack raises commercial interest in the Arctic3, it has become more variable and mobile4, which increases safety risks to maritime users5. Satellite observations of sea-ice thickness are currently unavailable during the crucial melt period from May to September, when they would be most valuable for applications such as seasonal forecasting6, owing to major challenges in the processing of altimetry data7. Here we use deep learning and numerical simulations of the CryoSat-2 radar altimeter response to overcome these challenges and generate a pan-Arctic sea-ice thickness dataset for the Arctic melt period. CryoSat-2 observations capture the spatial and the temporal patterns of ice melting rates recorded by independent sensors and match the time series of sea-ice volume modelled by the Pan-Arctic Ice Ocean Modelling and Assimilation System reanalysis8. Between 2011 and 2020, Arctic sea-ice thickness was 1.87 ± 0.10 m at the start of the melting season in May and 0.82 ± 0.11 m by the end of the melting season in August. Our year-round sea-ice thickness record unlocks opportunities for understanding Arctic climate feedbacks on different timescales. For instance, sea-ice volume observations from the early summer may extend the lead time of skilful August-October sea-ice forecasts by several months, at the peak of the Arctic shipping season.

The AKT inhibitor AZD5363 elicits synthetic lethality in ARID1A-deficient gastric cancer cells via induction of pyroptosis.

BACKGROUND: Gastric cancer (GC) is a deadly disease with poor overall survival and limited therapeutic options. Genetic alterations such as mutations and/or deletions in chromatin remodeling gene AT-rich interactive domain 1 A (ARID1A) occur frequently in GC. Although ARID1A mutations/deletions are not a druggable target for conventional treatments, novel therapeutic strategies based on a synthetic lethal approach may be effective for the treatment of ARID1A-deficient cancers. METHODS: A kinase inhibitor library containing 551 compounds was screened in ARID1A isogenic GC cells for the ability to induce synthetic lethality effect. Selected hits' activity was validated, and the mechanism of the most potent candidate drug, AKT inhibitor AD5363 (capivasertib), on induction of the synthetic lethality with ARID1A deficiency was investigated. RESULTS: After robust vulnerability screening of 551 diverse protein kinase inhibitors, we identified the AKT inhibitor AZD5363 as being the most potent lead compound in inhibiting viability of ARID1A-/- cells. A synthetic lethality between loss of ARID1A expression and AKT inhibition by AZD5363 was validated in both GC cell model system and xenograft model. Mechanistically, AZD5363 treatment induced pyroptotic cell death in ARID1A-deficient GC cells through activation of the Caspase-3/GSDME pathway. Furthermore, ARID1A occupied the AKT gene promoter and regulated its transcription negatively, thus the GC cells deficient in ARID1A showed increased expression and phosphorylation of AKT. CONCLUSIONS: Our study demonstrates a novel synthetic lethality interaction and unique mechanism between ARID1A loss and AKT inhibition, which may provide a therapeutic and mechanistic rationale for targeted therapy on patients with ARID1A-defective GC who are most likely to be beneficial to AZD5363 treatment.

Public Health Informatics and the Perioperative Physician: Looking to the Future.

The role of informatics in public health has increased over the past few decades, and the coronavirus disease 2019 (COVID-19) pandemic has underscored the critical importance of aggregated, multicenter, high-quality, near-real-time data to inform decision-making by physicians, hospital systems, and governments. Given the impact of the pandemic on perioperative and critical care services (eg, elective procedure delays; information sharing related to interventions in critically ill patients; regional bed-management under crisis conditions), anesthesiologists must recognize and advocate for improved informatic frameworks in their local environments. Most anesthesiologists receive little formal training in public health informatics (PHI) during clinical residency or through continuing medical education. The COVID-19 pandemic demonstrated that this knowledge gap represents a missed opportunity for our specialty to participate in informatics-related, public health-oriented clinical care and policy decision-making. This article briefly outlines the background of PHI, its relevance to perioperative care, and conceives intersections with PHI that could evolve over the next quarter century.

Risk of tibial baseplate loosening is low in patients following unrestricted kinematic alignment total knee arthroplasty using a cruciate-retaining medial conforming insert: A study using radiostereometric analysis at 2 years.

PURPOSE: Assessing the risk of tibial baseplate loosening in patients after unrestricted kinematically aligned (unKA) total knee arthroplasty (TKA) using a medially conforming insert is important because baseplates generally are aligned in varus which has been linked to an increased incidence of aseptic loosening following mechanically aligned TKA. Two limits that indicate long-term stability in patients are a change in maximum total point motion between 1 and 2 years (ΔMTPM) < 0.2 mm and anterior tilt at 2 years < 0.8°. The purposes were to determine: (1) the number of patients with ΔMTPM > 0.2 mm, (2) the number of patients with anterior tilt > 0.8° and (3) whether increased varus baseplate and limb alignment were associated with increased migration. METHODS: Thirty-five patients underwent cemented, caliper-verified, unKA TKA using a medially conforming tibial insert with posterior cruciate ligament (PCL) retention. Biplanar radiographs acquired on the day of surgery and at 1.5, 3, 6, 12 and 24 months were processed with model-based radiostereometric analysis (RSA) software to determine migration and the number of patients with migration above the two stability limits. Medial proximal tibial angle (MPTA), hip-knee-ankle angle (HKAA) and posterior slope angle (PSA) were analyzed for an association with migration in six degrees of freedom and in MTPM. RESULTS: Thirty-two of 35 patients were available for analysis at 2 years. One patient exhibited ΔMTPM > 0.2 mm. The same patient exhibited anterior tilt > 0.8°. Varus rotation (p = 0.048, r ≤ 0.34) and medial translation (p = 0.0273, r ≤ 0.29) increased with increased varus baseplate alignment. CONCLUSION: The results indicate low risk of long-term baseplate loosening in patients. Although varus rotation and medial translation increased with increased varus baseplate alignment, the magnitudes of the migrations were minimal and did not increase ΔMTPM and anterior tilt. LEVEL OF EVIDENCE: Level II, therapeutic prospective cohort study.

Reoperation, Implant Survival, and Clinical Outcome After Kinematically Aligned Total Knee Arthroplasty: A Concise Clinical Follow-Up at 16 Years.

BACKGROUND: The preceding study reported a 10-year follow-up of 222 kinematically aligned total knee arthroplasties (TKA) performed in 217 patients in 2007. As 35% of tibial components and 8% of limbs were in >3° varus, the present study assessed whether this adversely affected reoperation, implant survival, and function at 16 years. METHODS: We retrospectively reviewed a single surgeon's private practice database to determine the patients who underwent reoperation as well as Forgotten Joint Score and Oxford Knee Score. RESULTS: There were 7 patients who had a major reoperation (revision of a loose tibial component [n = 2], and revision of well-fixed component due to stiffness [n = 1], patella instability [n = 1], pain [n = 1], and infection [n = 2]). There were 5 who had a minor reoperation that retained the components, and 91 patients (94 TKAs) died. Implant survivorship was 93% using reoperation for any reason as the endpoint. The median (interquartile range) Forgotten Joint and Oxford Knee scores were 88 (57 to 100) and 45 (39 to 48) points, respectively. CONCLUSION: The kinematically aligned TKA had a 7% reoperation rate at 16 years follow-up, comparable to or lower than reports of mechanically aligned TKA, which supports the concept of the unrestricted version of kinematic alignment in which the patient's prearthritic alignment is fully restored regardless of deformity.

Exploiting the Receptor-Binding Domains of R-Spondin 1 to Target Leucine-Rich Repeat-Containin G-Coupled Protein Receptor 5-Expressing Stem Cells in Ovarian Cancer.

Leucine-rich repeat-containing G-protein-coupled receptor (LGR5) and LGR6 mark epithelial stem cells in normal tissues and tumors. They are expressed by stem cells in the ovarian surface and fallopian tube epithelia from which ovarian cancer arises. High-grade serous ovarian cancer is unique in expressing unusually high levels of LGR5 and LGR6 mRNA. R-spondins are the natural ligands for LGR5 and LGR6 to which they bind with nanomolar affinity. To target stem cells in ovarian cancer, we used the sortase reaction to site-specifically conjugate the potent cytotoxin monomethyl auristatin E (MMAE) via a protease sensitive linker to the two furin-like domains of RSPO1 (Fu1-Fu2) that mediate its binding to LGR5 and LGR6 and their co-receptors Zinc And Ring Finger 3 and Ring Finger Protein 43 via a protease-cleavable linker. An immunoglobulin Fc domain added to the N-terminal end served to dimerize the receptor-binding domains so that each molecule carries two MMAE. The resulting molecule, FcF2-MMAE, demonstrated: 1) selective LGR5-dependent low nanomolar cytotoxicity against ovarian cancer cells in vitro; 2) selectivity that was dependent on binding to both the LGR receptors and ubiquitin ligase co-receptors; 3) favorable stability and plasma pharmacokinetic properties when administered intravenously with an elimination half-life of 29.7 hours; 4) selective inhibition of LGR5-rich as opposed to isogenic LGR5-poor tumors in vivo; and, 5) therapeutic efficacy in three aggressive wild-type human ovarian cancer xenograft models. These results demonstrate the successful use of the Fu1-Fu2 domain of RSPO1 as a drug carrier and the ability of FcF2-MMAE to target cells in tumors that express stem cell markers. SIGNIFICANCE STATEMENT: FcF2-MMAE is a novel cancer therapeutic that exploits the high-affinity binding domains of RSPO1 to target monomethyl auristatin E to tumor stem cells that express LGR5. FcF2-MMAE has low nanomolar LGR5-dependent cytotoxicity in vitro, favorable pharmacokinetics, and differential efficacy in an isogenic LGR5-poor versus LGR5-rich ovarian cancer xenograft model when given on a weekly schedule.

The Transcription Factor bZIP60 Links the Unfolded Protein Response to the Heat Stress Response in Maize.

The unfolded protein response (UPR) and the heat shock response (HSR) are two evolutionarily conserved systems that protect plants from heat stress. The UPR and HSR occur in different cellular compartments and both responses are elicited by misfolded proteins that accumulate under adverse environmental conditions such as heat stress. While the UPR and HSR appear to operate independently, we have found a link between them in maize (Zea mays) involving the production of the BASIC LEUCINE ZIPPER60 (bZIP60) transcription factor, a pivotal response of the UPR to heat stress. Surprisingly, a mutant (bzip60-2) knocking down bZIP60 expression blunted the HSR at elevated temperatures and prevented the normal upregulation of a group of heat shock protein genes in response to elevated temperature. The expression of a key HEAT SHOCK FACTOR TRANSCRIPTION FACTOR13 (HSFTF13, a HEAT SHOCK FACTOR A6B [HSFA6B] family member) was compromised in bzip60-2, and the HSFTF13 promoter was shown to be a target of bZIP60 in maize protoplasts. In addition, the upregulation by heat of genes involved in chlorophyll catabolism and chloroplast protein turnover were subdued in bzip60-2, and these genes were also found to be targets of bZIP60. Thus, the UPR, an endoplasmic-reticulum-associated response, quite unexpectedly contributes to the nuclear/cytoplasmic HSR in maize.

Caliper-Verified Kinematically Aligned Total Knee Arthroplasty: Rationale, Targets, Accuracy, Balancing, Implant Survival, and Outcomes.

Peer-reviewed studies published up to May 2022 are used to provide a comprehensive understanding of unrestricted kinematically aligned total knee arthroplasty. The intent is to cultivate the curiosity of those interested in this method of personalized alignment. The rationale of unrestricted kinematic alignment is to set the femoral and tibial components coincident with the patient's prearthritic joint lines, restore the femoral and tibial phenotypes, and coalign the three kinematic axes of the components with those of the knee. The surgical technique, learning curve, and accuracy of performing kinematically aligned total knee arthroplasty with a caliper and company manufactured manual instrumentation should be explored and compared with robotic instrumentation. Kinematic alignment restores the native knee's medial and lateral tibial compartment forces, which mechanically aligned total knee arthroplasty cannot do even after ligament release. In addition, insert conformity plays a role in restoring native tibiofemoral kinematics. A literature review of clinical outcomes, long-term durability, and the risk of varus tibial component failure and patellofemoral instability shows unrestricted kinematic alignment has comparable if not superior results when compared with mechanical alignment.

More passive internal tibial rotation with posterior cruciate ligament retention than with excision in a medial pivot TKA implanted with unrestricted caliper verified kinematic alignment.

PURPOSE: Excision of the posterior cruciate ligament (PCL) is recommended when implanting a medial pivot (MP) total knee arthroplasty (TKA) to reduce the risk of limiting flexion by over-tensioning the flexion space. The present study determined whether PCL retention (1) limits internal tibial rotation and (2) causes anterior lift-off of the insert in 90° flexion after implantation of an MP design with unrestricted caliper verified kinematic alignment (KA). METHODS: Four surgeons implanted an MP TKA design with medial ball-in-socket and lateral flat tibial insert in ten fresh-frozen cadaveric knees. Before and after PCL excision, trial inserts with medial goniometric markings measured the angular I-E tibial orientation relative to the trial femoral component's medial condyle in extension and at 90° flexion, and the surgeon recorded the occurrence of anterior lift-off of the insert at 90° flexion. RESULTS: PCL retention resulted in greater internal tibial rotation than PCL excision, with mean values of 15° vs 7° degrees from maximum extension to 90° flexion, respectively (p < 0.0007). At 90° flexion, no TKAs with PCL retention and one TKA with PCL excision had anterior lift-off of the insert (N.S.). CONCLUSIONS: This preliminary study of ten cadaveric knees showed that PCL retention restored more passive internal tibial rotation than PCL excision with a negligible risk of anterior lift-off. However, in vivo analysis from multiple authors with a larger sample size is required to recommend PCL retention with an MP TKA design implanted with unrestricted caliper verified KA.

Posterior rim loading of a low-conforming tibial insert in unrestricted kinematic alignment is caused by rotational alignment of an asymmetric baseplate designed for mechanical alignment.

PURPOSE: Because different targets are used for internal-external rotation, an asymmetric baseplate designed for mechanical alignment may lead to under-coverage and concomitant posterior rim loading in the lateral compartment following unrestricted kinematic alignment (KA) TKA. Recognizing that such loading can lead to premature wear and/or subsidence, our aim was to determine the cause(s) so that occurrence could be remedied. Our hypothesis was that baseplate design features such as asymmetric shape when aligned in KA would consistently contribute to posterior rim loading in the lateral compartment. METHODS: Based on analysis of fluoroscopic images of 50 patients performing dynamic, weight bearing deep knee bend and step up and of postoperative CT images, five possible causes were investigated. Causes included internal rotation of the baseplate when positioned in KA; posterior position of the lateral femoral condyle at extension; internal tibial rotation with flexion; internal rotational deviation of the baseplate from the KA rotation target; and posterior slope. RESULTS: The incidence of posterior rim loading was 18% (9 of 50 patients). When positioned in KA, the asymmetric baseplate left 15% versus 10% of the AP depth of the lateral compartment uncovered posteriorly for posterior rim loading and non-posterior rim loading groups, respectively (p = 0.009). The lateral femoral condyle at extension was more posterior by 4 mm for the posterior rim loading group (p = 0.003). CONCLUSIONS: Posterior rim loading in the lateral compartment was caused in part by the asymmetric design of the tibial baseplate designed for mechanical alignment which was internally rotated when positioned in KA thus under-covering a substantial percentage of the posterior lateral tibia. This highlights the need for new, asymmetric baseplates designed to maximize coverage when used in KA. LEVEL OF EVIDENCE: III.

The posterolateral upslope of a low-conforming insert blocks the medial pivot during a deep knee bend in TKA: a comparative analysis of two implants with different insert conformities.

PURPOSE: Tibial insert conformity in total knee arthroplasty (TKA) is of interest due to the potential effect on tibiofemoral kinematics. This study determined differences in anterior-posterior movements of the femoral condyles, pivot locations, and internal tibial rotation in different arcs of flexion for two implants with different insert conformities in kinematically aligned TKA. METHODS: Twenty-five patients treated with a medial and lateral low-conforming, posterior cruciate ligament (PCL) retaining (LC CR) implant followed by a medial ball-in-socket and flat, lateral PCL sacrificing (B-in-S CS) implant in the contralateral knee underwent single-plane fluoroscopy during a deep knee bend. Analysis following 3D-to-2D image registration determined tibiofemoral kinematics and patients completed validated outcome scores for both knees. RESULTS: The mean follow-up of 1.6 ± 0.4 years for the knee with the B-in-S CS implant was shorter than the 2.7 ± 1.2 years for the LC CR implant. From 0º to 30º of flexion, a medial pivot occurred with the tibia rotating internally approximately 5º with both implants. From 30º to 90º, the pivot remained medial and internal rotation increased to 10º with the B-in-S CS implant. In contrast, neither femoral condyle moved more than 1 mm with the LC CR implant from 30º to 60º, but from 60º to 90º degrees, a lateral pivot occurred and internal rotation increased. Internal rotation of the tibia on the femur from 0° to maximum flexion occurred about a medial pivot similar to the native knee for the B-in-S CS implant and was 4.5° greater than that of the LC CR implant (10.4° vs 5.9°). There was no difference in the median patient-reported outcome scores between implant designs. CONCLUSIONS: Tibial insert conformity is a primary determinant of a medial or lateral pivot during a deep knee bend. One explanation for the transition from a medial to lateral pivot between 30º and 60º with the LC CR implant is the chock-block effect of the insert's posterolateral upslope which impedes posterior movement of the lateral femoral condyle. Because there is no posterolateral upslope in the insert of the B-in-S CS implant, the tibia pivots medially throughout flexion similar to the native knee. LEVEL OF EVIDENCE: Level III.

Low tibial baseplate migration 1 year after unrestricted kinematically aligned total knee arthroplasty using a medial conforming implant design.

PURPOSE: Varus alignment of the tibial baseplate and limb > 3° might adversely affect baseplate fixation after total knee arthroplasty (TKA), especially for unrestricted kinematically aligned (KA) TKA which aligns a majority of baseplates in varus. The purposes of this study were to determine whether baseplate migration at 1 year (1) was significantly less than a stability limit of 0.5 mm, (2) increased over time, and (3) was related to varus alignment of the baseplate and limb after unrestricted KA TKA. METHODS: Thirty-five patients underwent unrestricted KA TKA using a fixed-bearing, cemented, medial conforming tibial insert with posterior cruciate ligament retention. Using model-based radiostereometric analysis, maximum total point motion (MTPM) (i.e., largest displacement on the baseplate) was computed at 6 weeks, 3 months, 6 months, and 1 year postoperatively relative to the day of surgery. Baseplate and limb alignment were measured postoperatively on long-leg CT scanograms. RESULTS: At 1 year, mean MTPM of 0.35 mm was significantly less than the 0.5 mm stability limit (p = 0.0002). Mean MTPM did not increase from 6 weeks to 1 year (p = 0.3047). Notably, 89% (31/35) of tibial baseplates and 46% (16/35) of limbs were > 3° varus. Baseplate and limb alignment had no relationship to MTPM at 1 year (|r|≤ 0.173, p ≥ 0.3276). CONCLUSION: Low and non-progressive tibial baseplate migration 1 year after unrestricted KA TKA with a medial conforming design should allay any concern that unrestricted KA TKA increases risk of baseplate loosening due to varus alignment of the baseplate and limb. LEVEL OF EVIDENCE: Level II, therapeutic prospective cohort study.

Better forgotten joint scores when the angle of the prosthetic trochlea is lateral to the quadriceps vector in kinematically aligned total knee arthroplasty.

PURPOSE: The primary aim was to analyze unrestricted kinematic alignment (unKA) total knee arthroplasty (TKA) and determine the frequency of medial deviation of the prosthetic trochlear angle (PTA) of the femoral component relative to the quadriceps vector (QV) that terminates at the anterior inferior iliac spine (AIIS), and whether patients with medial deviation had a worse Forgotten Joint Score (FJS) and Oxford Knee Score (OKS) relative to those with lateral deviation. The secondary aim was to determine the frequency of medial deviation for mechanical alignment (MA) TKA simulations. METHODS: From a database of a single surgeon, the study extracted de-identified data on 147 patients with a CT scanogram showing the pelvis and AIIS, a limb with an unKA TKA, and a native (i.e., healthy) opposite limb. On the scanogram, an examiner, blinded to the PROMs, measured the PTA-QV angle on the unKA TKA and on the opposite limb simulated MA TKA by drawing the PTA at 6° valgus relative to the femoral mechanical axis and measuring the PTA-QV angle. RESULTS: Medial deviation of the PTA occurred in 86% of patients with unKA TKA, and the 126 with medial deviation had a 17/1 point worse median FJS/OKS than the 21 with lateral deviation at a mean follow-up of 47 ± 8 months, respectively (p < 0.0001, p = 0.0053). In addition, 21%, 17%, and 8% of MA TKA had medial deviation after radiographic simulation using reported surgical errors for manual, patient-specific, and robotic instrumentation, respectively. CONCLUSION: In most patients with unKA TKA and a smaller proportion with MA TKA, a PTA of 6° valgus was medial to the QV, which, by excluding the patient's Q-angle, might alter patellofemoral kinematics like an incorrectly oriented trochleoplasty. The 17-point worse FJS in the patients with an unKA TKA and medial deviation of the PTA suggests the surgical target should be to orient the PTA lateral to the QV. LEVEL OF EVIDENCE: IV.

A Torn or Reconstructed Anterior Cruciate Ligament Does Not Adversely Affect Clinical Outcome Scores and the Incidence of Reoperation After Unrestricted Kinematically Aligned Total Knee Arthroplasty.

BACKGROUND: There are no reports as to whether the condition of the anterior cruciate ligament (ACL) adversely affects the 2 to 3 year function and reoperation risk of a kinematically aligned (KA) total knee arthroplasty (TKA) performed with posterior cruciate ligament (PCL) retention and an intermediate medial conforming (MC) insert. METHODS: A single surgeon's prospective database query identified 418 consecutive primary TKAs performed between January 2019 and December 2019. The surgeon recorded the ACL condition in the operative note. Patients filled out the Forgotten Joint Score (FJS), Oxford knee score (OKS), and Knee Injury and Osteoarthritis Outcome Scores for Joint Replacement at the final follow-up. There were 299 patients with an intact ACL, 99 with a torn ACL, and 20 with a reconstructed ACL. The mean follow-up was 31 months (range, 20 to 45). RESULTS: The median FJS, OKS, and Knee Injury and Osteoarthritis Outcome Score (KOOS) of the reconstructed/torn/intact KA TKAs were 90/79/67, 47/44/43, and 92/88/80 points, respectively. The median OKS and KOOS of the reconstructed ACL cohort were 4 and 11 points higher than in the intact ACL cohort (P = .003, .04). One patient who had a reconstructed ACL underwent manipulation under anesthesia (MUA) for stiffness. The 5 reoperations in the intact ACL cohort were for instability (n = 2), revision after failed MUA for stiffness (n = 2), and infection (n = 1). CONCLUSION: These results suggest that patients who have a torn and reconstructed ACL can expect high function and a low risk of reoperation comparable to patients who have an intact ACL when treated with unrestricted, caliper-verified KA, PCL retention, and an intermediate MC insert.

Ball-in-socket medial conformity with posterior cruciate ligament retention neither limits internal tibial rotation and knee flexion nor lowers clinical outcome scores after unrestricted kinematically aligned total knee arthroplasty.

PURPOSE: For a new tibial insert design with ball-in-socket (B-in-S) medial conformity (MC), posterior cruciate ligament (PCL) retention, and flat lateral articular surface (B-in-S MC + PCL), this study determined whether internal tibial rotation and knee flexion were limited and clinical outcome scores were lower during weight-bearing activities relative to an insert with intermediate (I) (i.e., less than ball-in-socket) medial conformity (I MC + PCL). METHODS: Twenty-five patients were treated with bilateral unrestricted, caliper-verified kinematic alignment (KA) total knee arthroplasty (TKA) with an I MC + PCL insert and B-in-S MC + PCL insert in opposite knees. Each patient performed weight-bearing deep knee bend, step up, and chair rise under single-plane fluoroscopy. Analysis following 3D model-to-2D image registration determined internal tibial rotation. For each TKA, knee flexion was measured and patients completed clinical outcome scoring questionnaires. RESULTS: Internal tibial rotation did not differ between conformities during chair rise and step up (p = 0.3419 and 0.1030, respectively). During deep knee bend, internal tibial rotation between 90° and maximum flexion was 3° greater in the B-in-S MC + PCL group (18° vs 15°) (p = 0.0290). Mean knee flexion (p = 0.3115) and median Forgotten Joint Score (FJS), Oxford Knee Score (OKS), and Western Ontario and McMasters Universities Arthritis Index (WOMAC) scores (p = 0.2100, 0.2154, and 0.4542, respectively) did not differ between conformities. CONCLUSION: An insert with ball-in-socket medial conformity, which maximizes anteroposterior (AP) stability, did not limit internal tibial rotation and knee flexion and did not lower patient-reported outcomes when implanted with unrestricted caliper-verified KA and PCL retention. The high AP stability provided by the medial ball-in-socket might interest those surgeons exploring the treatment of the active patient with a desire to return to high-level and athletic activities.

Robotic Assay for Drought (RoAD): an automated phenotyping system for brassinosteroid and drought responses.

Brassinosteroids (BRs) are a group of plant steroid hormones involved in regulating growth, development, and stress responses. Many components of the BR pathway have previously been identified and characterized. However, BR phenotyping experiments are typically performed in a low-throughput manner, such as on Petri plates. Additionally, the BR pathway affects drought responses, but drought experiments are time consuming and difficult to control. To mitigate these issues and increase throughput, we developed the Robotic Assay for Drought (RoAD) system to perform BR and drought response experiments in soil-grown Arabidopsis plants. RoAD is equipped with a robotic arm, a rover, a bench scale, a precisely controlled watering system, an RGB camera, and a laser profilometer. It performs daily weighing, watering, and imaging tasks and is capable of administering BR response assays by watering plants with Propiconazole (PCZ), a BR biosynthesis inhibitor. We developed image processing algorithms for both plant segmentation and phenotypic trait extraction to accurately measure traits including plant area, plant volume, leaf length, and leaf width. We then applied machine learning algorithms that utilize the extracted phenotypic parameters to identify image-derived traits that can distinguish control, drought-treated, and PCZ-treated plants. We carried out PCZ and drought experiments on a set of BR mutants and Arabidopsis accessions with altered BR responses. Finally, we extended the RoAD assays to perform BR response assays using PCZ in Zea mays (maize) plants. This study establishes an automated and non-invasive robotic imaging system as a tool to accurately measure morphological and growth-related traits of Arabidopsis and maize plants in 3D, providing insights into the BR-mediated control of plant growth and stress responses.

The SANAD II study of the effectiveness and cost-effectiveness of levetiracetam, zonisamide, or lamotrigine for newly diagnosed focal epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial.

BACKGROUND: Levetiracetam and zonisamide are licensed as monotherapy for patients with focal epilepsy, but there is uncertainty as to whether they should be recommended as first-line treatments because of insufficient evidence of clinical effectiveness and cost-effectiveness. We aimed to assess the long-term clinical effectiveness and cost-effectiveness of levetiracetam and zonisamide compared with lamotrigine in people with newly diagnosed focal epilepsy. METHODS: This randomised, open-label, controlled trial compared levetiracetam and zonisamide with lamotrigine as first-line treatment for patients with newly diagnosed focal epilepsy. Adult and paediatric neurology services across the UK recruited participants aged 5 years or older (with no upper age limit) with two or more unprovoked focal seizures. Participants were randomly allocated (1:1:1) using a minimisation programme with a random element utilising factor to receive lamotrigine, levetiracetam, or zonisamide. Participants and investigators were not masked and were aware of treatment allocation. SANAD II was designed to assess non-inferiority of both levetiracetam and zonisamide to lamotrigine for the primary outcome of time to 12-month remission. Anti-seizure medications were taken orally and for participants aged 12 years or older the initial advised maintenance doses were lamotrigine 50 mg (morning) and 100 mg (evening), levetiracetam 500 mg twice per day, and zonisamide 100 mg twice per day. For children aged between 5 and 12 years the initial daily maintenance doses advised were lamotrigine 1·5 mg/kg twice per day, levetiracetam 20 mg/kg twice per day, and zonisamide 2·5 mg/kg twice per day. All participants were included in the intention-to-treat (ITT) analysis. The per-protocol (PP) analysis excluded participants with major protocol deviations and those who were subsequently diagnosed as not having epilepsy. Safety analysis included all participants who received one dose of any study drug. The non-inferiority limit was a hazard ratio (HR) of 1·329, which equates to an absolute difference of 10%. A HR greater than 1 indicated that an event was more likely on lamotrigine. The trial is registered with the ISRCTN registry, 30294119 (EudraCt number: 2012-001884-64). FINDINGS: 990 participants were recruited between May 2, 2013, and June 20, 2017, and followed up for a further 2 years. Patients were randomly assigned to receive lamotrigine (n=330), levetiracetam (n=332), or zonisamide (n=328). The ITT analysis included all participants and the PP analysis included 324 participants randomly assigned to lamotrigine, 320 participants randomly assigned to levetiracetam, and 315 participants randomly assigned to zonisamide. Levetiracetam did not meet the criteria for non-inferiority in the ITT analysis of time to 12-month remission versus lamotrigine (HR 1·18; 97·5% CI 0·95-1·47) but zonisamide did meet the criteria for non-inferiority in the ITT analysis versus lamotrigine (1·03; 0·83-1·28). The PP analysis showed that 12-month remission was superior with lamotrigine than both levetiracetam (HR 1·32 [97·5% CI 1·05 to 1·66]) and zonisamide (HR 1·37 [1·08-1·73]). There were 37 deaths during the trial. Adverse reactions were reported by 108 (33%) participants who started lamotrigine, 144 (44%) participants who started levetiracetam, and 146 (45%) participants who started zonisamide. Lamotrigine was superior in the cost-utility analysis, with a higher net health benefit of 1·403 QALYs (97·5% central range 1·319-1·458) compared with 1·222 (1·110-1·283) for levetiracetam and 1·232 (1·112, 1·307) for zonisamide at a cost-effectiveness threshold of £20 000 per QALY. Cost-effectiveness was based on differences between treatment groups in costs and QALYs. INTERPRETATION: These findings do not support the use of levetiracetam or zonisamide as first-line treatments for patients with focal epilepsy. Lamotrigine should remain a first-line treatment for patients with focal epilepsy and should be the standard treatment in future trials. FUNDING: National Institute for Health Research Health Technology Assessment programme.

The SANAD II study of the effectiveness and cost-effectiveness of valproate versus levetiracetam for newly diagnosed generalised and unclassifiable epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial.

BACKGROUND: Valproate is a first-line treatment for patients with newly diagnosed idiopathic generalised or difficult to classify epilepsy, but not for women of child-bearing potential because of teratogenicity. Levetiracetam is increasingly prescribed for these patient populations despite scarcity of evidence of clinical effectiveness or cost-effectiveness. We aimed to compare the long-term clinical effectiveness and cost-effectiveness of levetiracetam compared with valproate in participants with newly diagnosed generalised or unclassifiable epilepsy. METHODS: We did an open-label, randomised controlled trial to compare levetiracetam with valproate as first-line treatment for patients with generalised or unclassified epilepsy. Adult and paediatric neurology services (69 centres overall) across the UK recruited participants aged 5 years or older (with no upper age limit) with two or more unprovoked generalised or unclassifiable seizures. Participants were randomly allocated (1:1) to receive either levetiracetam or valproate, using a minimisation programme with a random element utilising factors. Participants and investigators were aware of treatment allocation. For participants aged 12 years or older, the initial advised maintenance doses were 500 mg twice per day for levetiracetam and valproate, and for children aged 5-12 years, the initial daily maintenance doses advised were 25 mg/kg for valproate and 40 mg/kg for levetiracetam. All drugs were administered orally. SANAD II was designed to assess the non-inferiority of levetiracetam compared with valproate for the primary outcome time to 12-month remission. The non-inferiority limit was a hazard ratio (HR) of 1·314, which equates to an absolute difference of 10%. A HR greater than 1 indicated that an event was more likely on valproate. All participants were included in the intention-to-treat (ITT) analysis. Per-protocol (PP) analyses excluded participants with major protocol deviations and those who were subsequently diagnosed as not having epilepsy. Safety analyses included all participants who received one dose of any study drug. This trial is registered with the ISRCTN registry, 30294119 (EudraCt number: 2012-001884-64). FINDINGS: 520 participants were recruited between April 30, 2013, and Aug 2, 2016, and followed up for a further 2 years. 260 participants were randomly allocated to receive levetiracetam and 260 participants to receive valproate. The ITT analysis included all participants and the PP analysis included 255 participants randomly allocated to valproate and 254 randomly allocated to levetiracetam. Median age of participants was 13·9 years (range 5·0-94·4), 65% were male and 35% were female, 397 participants had generalised epilepsy, and 123 unclassified epilepsy. Levetiracetam did not meet the criteria for non-inferiority in the ITT analysis of time to 12-month remission (HR 1·19 [95% CI 0·96-1·47]); non-inferiority margin 1·314. The PP analysis showed that the 12-month remission was superior with valproate than with levetiracetam. There were two deaths, one in each group, that were unrelated to trial treatments. Adverse reactions were reported by 96 (37%) participants randomly assigned to valproate and 107 (42%) participants randomly assigned to levetiracetam. Levetiracetam was dominated by valproate in the cost-utility analysis, with a negative incremental net health benefit of -0·040 (95% central range -0·175 to 0·037) and a probability of 0·17 of being cost-effectiveness at a threshold of £20 000 per quality-adjusted life-year. Cost-effectiveness was based on differences between treatment groups in costs and quality-adjusted life-years. INTERPRETATION: Compared with valproate, levetiracetam was found to be neither clinically effective nor cost-effective. For girls and women of child-bearing potential, these results inform discussions about benefit and harm of avoiding valproate. FUNDING: National Institute for Health Research Health Technology Assessment Programme.

Daily temperature cycles promote alternative splicing of RNAs encoding SR45a, a splicing regulator in maize.

Elevated temperatures enhance alternative RNA splicing in maize (Zea mays) with the potential to expand the repertoire of plant responses to heat stress. Alternative RNA splicing generates multiple RNA isoforms for many maize genes, and here we observed changes in the pattern of RNA isoforms with temperature changes. Increases in maximum daily temperature elevated the frequency of the major modes of alternative splices (AS), in particular retained introns and skipped exons. The genes most frequently targeted by increased AS with temperature encode factors involved in RNA processing and plant development. Genes encoding regulators of alternative RNA splicing were themselves among the principal AS targets in maize. Under controlled environmental conditions, daily changes in temperature comparable to field conditions altered the abundance of different RNA isoforms, including the RNAs encoding the splicing regulator SR45a, a member of the SR45 gene family. We established an "in protoplast" RNA splicing assay to show that during the afternoon on simulated hot summer days, SR45a RNA isoforms were produced with the potential to encode proteins efficient in splicing model substrates. With the RNA splicing assay, we also defined the exonic splicing enhancers that the splicing-efficient SR45a forms utilize to aid in the splicing of model substrates. Hence, with rising temperatures on hot summer days, SR45a RNA isoforms in maize are produced with the capability to encode proteins with greater RNA splicing potential.

Negligible effect of surgeon experience on the accuracy and time to perform unrestricted caliper verified kinematically aligned TKA with manual instruments.

PURPOSE: Surgeons performing total knee arthroplasty (TKA) are interested in the accuracy and time it takes to make the four femoral resections that determine the setting of the femoral component. A method for quantifying the error of each resection is the thickness, measured by a caliper, minus the femoral target. The present study tested the hypothesis that the mean deviation of the resection from the femoral target, the percentage of resections with a deviation of ± 0.5, 1.0, 1.5, and 2.0 mm, and the time to complete the femoral cuts were not different between experienced (E) and less-experienced (LE) surgeons performing unrestricted caliper verified kinematically aligned (KA) TKA with manual instruments. METHODS: This study analyzed intraoperative verification worksheets from 203 patients treated by ten E surgeons and 58 patients treated by four LE surgeons. The worksheet recorded (1) the thickness of the femoral target for the distal medial (DM), distal lateral (DL), posterior medial (PM), and posterior lateral (PL) resections and the caliper thickness of the resections with a resolution of 0.5 mm, and (2) the time to complete them. The most accurate resection has a mean difference ± standard deviation of 0 ± 0.0 mm. RESULTS: The accuracy of the 1044 initial resections (261 patients) was significantly closer to the femoral target for E vs. the LE surgeons: 0.0 ± 0.4 vs. - 0.3 ± 0.5 for the DM, 0.0 ± 0.5 vs. - 0.4 ± 0.6 for the DL, - 0.1 ± 0.5 vs. - 0.2 ± 0.5 PM, and - 0.1 ± 0.5 vs. - 0.4 ± 0.6 for the PL resections (p ≤ 0.0248). E surgeons completed the femoral resections in 12 min; 5 min faster than LE surgeons (p < 0.0001). CONCLUSIONS: Because the mean difference in femoral resections with manual instruments for E vs. LE surgeons was < 0.5 mm which is within the caliper's resolution, differences in accuracy were not clinically relevant. Surgeons exploring other alignment options and robotic, navigation, and patient-specific instrumentation might find these values helpful when deciding to change. LEVEL OF EVIDENCE: III; case-control study.