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Biosensors and bioassays, both of which employ proteins and nucleic acids to detect specific molecular targets, have seen significant applications in both biomedical research and clinical practice. This success is largely due to the extraordinary versatility, affinity, and specificity of biomolecular recognition. Nevertheless, these receptors suffer from an inherent limitation: single, saturable binding sites exhibit a hyperbolic relationship (the "Langmuir isotherm") between target concentration and receptor occupancy, which in turn limits the sensitivity of these technologies to small variations in target concentration. To overcome this and generate more responsive biosensors and bioassays, here we have used the sequestration mechanism to improve the steepness of the input/output curves of several bioanalytical methods. As our test bed for this we employed sensors and assays against neutrophil gelatinase-associated lipocalin (NGAL), a kidney biomarker for which enhanced sensitivity will improve the monitoring of kidney injury. Specifically, by introducing sequestration we have improved the responsiveness of an electrochemical aptamer based (EAB) biosensor, and two bioassays, a paper-based "dipstick" assay and an enzyme-linked immunosorbent assay (ELISA). Doing so we have narrowed the dynamic range of these sensors and assays several-fold, thus enhancing their ability to measure small changes in target concentration. Given that introducing sequestration requires only the addition of the appropriate concentration of a high-affinity "depletant," the mechanism appears simple and easily adaptable to tuning the binding properties of the receptors employed in a wide range of biosensors and bioassays.

Electrochemical aptamer-based (EAB) sensors, composed of an electrode-bound DNA aptamer with a redox reporter on the distal end, offer the promise of high-frequency, real-time molecular measurements in complex sample matrices and even in vivo. Here we assess the extent to which switching the aptamer terminus that is electrode-bound and the one that is redox-reporter-modified affects the performance of these sensors. Using sensors against doxorubicin, cocaine, and vancomycin as our test beds, we find that both signal gain (the relative signal change seen in the presence of a saturating target) and the frequency dependence of gain depend strongly on the attachment orientation, suggesting that this easily investigated variable is a worthwhile parameter to optimize in the design of new EAB sensors.

ObjectivesTo approximate the rate of familial myasthenia gravis and the coexistence of other autoimmune disorders in the patients and their families.DesignRetrospective cohort study.SettingClinics across North America.ParticipantsThe study included 1032 patients diagnosed with acetylcholine receptor antibody (AChR)-positive myasthenia gravis.MethodsPhenotype information of 1032 patients diagnosed with AChR-positive myasthenia gravis was obtained from clinics at 14 centres across North America between January 2010 and January 2011. A critical review of the epidemiological literature on the familial rate of myasthenia gravis was also performed.ResultsAmong 1032 patients, 58 (5.6%) reported a family history of myasthenia gravis. A history of autoimmune diseases was present in 26.6% of patients and in 28.4% of their family members.DiscussionThe familial rate of myasthenia gravis was higher than would be expected for a sporadic disease. Furthermore, a high proportion of patients had a personal or family history of autoimmune disease. Taken together, these findings suggest a genetic contribution to the pathogenesis of myasthenia gravis.

BackgroundProtein disulfide isomerase (PDI) proteins are part of the thioredoxin protein superfamily. PDIs are involved in the formation and rearrangement of disulfide bonds between cysteine residues during protein folding in the endoplasmic reticulum and are implicated in stress response pathways.MethodsEight children from four consanguineous families residing in distinct geographies within the Middle East and Central Asia were recruited for study. All probands showed structurally similar microcephaly with lissencephaly (microlissencephaly) brain malformations. DNA samples from each family underwent whole exome sequencing, assessment for repeat expansions and confirmatory segregation analysis.ResultsAn identical homozygous variant in TMX2 (c.500G>A), encoding thioredoxin-related transmembrane protein 2, segregated with disease in all four families. This variant changed the last coding base of exon 6, and impacted mRNA stability. All patients presented with microlissencephaly, global developmental delay, intellectual disability and epilepsy. While TMX2 is an activator of cellular C9ORF72 repeat expansion toxicity, patients showed no evidence of C9ORF72 repeat expansions.ConclusionThe TMX2 c.500G>A allele associates with recessive microlissencephaly, and patients show no evidence of C9ORF72 expansions. TMX2 is the first PDI implicated in a recessive disease, suggesting a protein isomerisation defect in microlissencephaly.

Coastal regions face increasing threats from rising sea levels and extreme weather events, highlighting the urgent need for accurate assessments of coastal flood risk. This study presents a novel approach to estimating global extreme sea level (ESL) exceedance probabilities using a regional frequency analysis (RFA) approach. The research combines observed and modelled hindcast data to produce a high-resolution (∼1 km) dataset of ESL exceedance probabilities, including wave setup, along the entire global coastline (excluding Antarctica). The methodology presented in this paper is an extension of the regional framework of Sweet et al. (2022), with innovations introduced to incorporate wave setup and apply the method globally. Water level records from tide gauges and a global reanalysis of tide and surge levels are integrated with a global ocean wave reanalysis. Subsequently, these data are regionalised, normalised, and aggregated and then fit with a generalised Pareto distribution. The regional distributions are downscaled to the local scale using the tidal range at every location along the global coastline obtained from a global tide model. The results show 8 cm of positive bias at the 1-in-10-year return level when compared to individual tide gauges. The RFA approach offers several advantages over traditional methods, particularly in regions with limited observational data. It overcomes the challenge of short and incomplete observational records by substituting long historical records with a collection of shorter but spatially distributed records. These spatially distributed data not only retain the volume of information but also address the issue of sparse tide gauge coverage in less populated areas and developing nations. The RFA process is illustrated using Cyclone Yasi (2011) as a case study, demonstrating how the approach can improve the characterisation of ESLs in regions prone to tropical cyclone activity. In conclusion, this study provides a valuable resource for quantifying the global coastal flood risk, offering an innovative global methodology that can contribute to preparing for – and mitigating against – coastal flooding. [ABSTRACT FROM AUTHOR]

Previous research has demonstrated that speakers changephonetic forms in response to variability in their immediatelinguistic milieu, such that they converge with an interlocutor.While much is known about the impact of social dynamics onthis process, the impact of individual variability in cognitionand perception is less well-explored. The present study seeksto examine the impact of these individual differences onphonetic convergence during a naturalistic conversation,comparing convergence in autism spectrum disorder (ASD)and typical development. Results showed a small effect oftemporal convergence within typically developing dyads,compared with evidence of divergence within ASD dyads.While preliminary, this pattern of results suggests that socialmotivation may play a more important role in phoneticconvergence than sensory accounts (such as self-monitoring).

In coastal regions, compound flooding, driven by multiple flood hazard sources, can cause greater damage than when the flood drivers occur in isolation. This study focuses on compound flooding from extreme precipitation and storm surge in China's Qiantang Estuary. We quantify the potential of compound flooding by measuring bivariate joint statistical dependence and joint return period (JRP). We find a significant positive dependence between the two flood drivers considered, as indicated by Kendall's rank correlation coefficients. Compound events occur frequently, with an average of 2.65 events per year from 1979 to 2018, highlighting the significant concern of compound flooding for this estuary. Using a copula model, we demonstrate that considering the dependence between the two flood drivers shortens the JRP of compound flooding compared to the JRP assuming total independence. For a 1-in-10-yr precipitation event and 1-in-10-yr storm surge event, the JRP is 1 in 100 years when assuming total independence. However, it decreases to 1 in 32.44 years when considering their dependence. Ignoring the dependence between flood drivers can lead to an increase in the JRP of compound events, resulting in an underestimation of the overall flood risk. Our analysis reveals a strong link between the weather patterns creating compound events and extreme storm surge only events with tropical cyclone activity. Additionally, the extreme precipitation only events were found to be connected with the frontal system of the East Asian summer monsoon. This study highlights the importance of considering the dependence between multiple flood drivers associated with certain types of the same weather systems when assessing the flood risk in coastal regions. [ABSTRACT FROM AUTHOR]

Background: The posterolateral corner (PLC) of the knee comprises important static and dynamic stabilizers, including the lateral collateral ligament, popliteus tendon, biceps femoris tendon, the popliteofibular ligament, and the posterolateral capsule. These structures are disrupted in many knee injuries, yet may be overlooked due to the complex anatomy, subjective clinical diagnostic exams, and poorly defined imaging techniques. Complete PLC lesions rarely heal with non-operative treatment, and can lead to significant instability and poor outcomes, and are therefore most successfully treated surgically. Indications: A thorough physical examination and a high index of suspicion is necessary when evaluating the knee to identify these occult injuries. Current physical exam testing for PLC injuries typically includes side to side comparisons of the varus stress test, dial test, and heel-to-table distance. However, these injuries continue to be under-diagnosed as global clinical consensus for PLC injury identification remains elusive. Technique Description: In these videos, we show the "active external rotation sign" where chronic posterior cruciate ligament-PLC deficient patients are positioned in 90° of knee flexion and are instructed to actively contract their hamstrings. Verbal cues given to the patient include "contract your hamstrings" and "dig the back of your heel into the ground." This can result in dynamic external rotation of the tibia with simultaneous posterior tibial translation on the femur. The biceps femoris pulls on the fibula and without the PLC to stabilize the knee, tibiofibular external rotation and posterior translation occurs. The biomechanics are similar to the dial test, but this detection tool utilizes active motion instead of passive motion, and presents with this abnormal and asymmetric knee motion. Results: The purpose of this presentation is to describe and demonstrate an important clinical sign that may be seen with chronic PLC injuries and that may be used as a new test for diagnosis. Discussion/Conclusion: Detection of PLC injuries with the active external rotation sign may assist in the clinical detection of incompetent PLC function, which can put cruciate reconstruction surgery at risk of failure if not simultaneously addressed. Patient Consent Disclosure Statement: The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication. [ABSTRACT FROM AUTHOR]

Background: Previous research has found that the incidence of neurovascular injury is greatest among multiligamentous knee injuries (MLKIs) with documented knee dislocation (KD). However, it is unknown whether there is a comparative difference in functional recovery based on evidence of a true dislocation. Purpose: To determine whether the knee dislocation-3 (KD3) injury pattern of MLKI with documented tibiofemoral dislocation represents a more severe injury than KD3 MLKI without documented dislocation, as manifested by poorer clinical outcomes at long-term follow-up. Study Design: Cohort study; Level of evidence, 3. Methods: A multicenter retrospective cohort study was performed of patients who underwent surgical treatment for KD3 MLKI between May 2012 and February 2021. Outcomes were assessed using the International Knee Documentation Committee (IKDC) score, Lysholm score, Tegner activity scale, and visual analog scale (VAS) for pain. Documented dislocation was defined as a radiographically confirmed tibiofemoral disarticulation, the equivalent radiology report from outside transfer, or emergency department documentation of a knee reduction maneuver. Subgroup analysis was performed comparing lateral (KD3-L) versus medial (KD3-M) injuries. Multivariable linear regression was conducted to determine whether documented dislocation was predictive of outcomes. Results: A total of 42 patients (25 male, 17 female) were assessed at a mean 6.5-year follow-up (range, 2.1-10.7 years). Twenty patients (47.6%) were found to have a documented KD; they reported significantly lower IKDC (49.9 vs 63.0; P =.043), Lysholm (59.8 vs 74.5; P =.023), and Tegner activity level (2.9 vs 4.7; P =.027) scores than the patients without documented dislocation. VAS pain was not significantly different between groups (36.4 vs 33.5; P =.269). The incidence of neurovascular injury was greater among those with documented dislocation (45.0% vs 13.6%; P =.040). Subgroup analysis found that patients with KD3-L injuries experienced a greater deficit in Tegner activity level than patients with KD3-M injuries (Δ: –3.4 vs −1.2; P =.006) and had an increased incidence of neurovascular injury (41.7% vs 11.1%; P =.042). Documented dislocation status was predictive of poorer IKDC (β = −2.15; P =.038) and Lysholm (β = −2.85; P =.007) scores. Conclusion: Patients undergoing surgical management of KD3 injuries with true, documented KD had significantly worse clinical and functional outcomes than those with nondislocated joints at a mean 6.5-year follow-up. The current MLKI classification based solely on ligament involvement may be obscuring outcome research by not accounting for true dislocation. [ABSTRACT FROM AUTHOR]

To determine if posteromedial tibial plateau (PMTP) bone bruising on pre-operative MRI is significantly associated with a ramp lesion identified during arthroscopy in patients with concomitant ACL ruptures. PubMed, CINAHL, Scopus, Web of Sciences, EMBASE, and Cochrane Library were searched systematically for studies that investigated the association between PMTP bone bruises on preoperative MRI and ramp lesions confirmed during arthroscopy. Eight studies met inclusion criteria. The Methodological Index for Nonrandomized Studies (MINORS) checklist was used to assess quality. A meta-analysis was performed to analyze odds of a ramp lesion after PMTP bone bruising identified on magnetic resonance imaging (MRI). Publication bias was assessed by funnel plot and Egger's linear regression test. There are 2.05 greater odds of medial meniscal ramp lesions in patients with an ACL rupture when PMTP bone bruising is found on preoperative MRI (95% CI, 1.29–3.25; p = 0.002). Heterogeneity of the pooled studies may be substantial (I2 = 65%; p = 0.006). Funnel plot analysis and Egger's linear regression test (p > 0.5) determined no publication bias among the studies included in the meta-analysis. Patients with acute ACL injuries and PMTP bone bruising on MRI have 2.05 times greater odds of a concomitant medial meniscal ramp lesion than those without this bone bruise pattern. [ABSTRACT FROM AUTHOR]

Coastal regions face increasing threats from rising sea levels and extreme weather events, highlighting the urgent need for accurate assessments of coastal flood risk. This study presents a novel approach to estimating global Extreme Sea Level (ESL) exceedance probabilities, using a Regional Frequency Analysis (RFA) approach. The research combines observed and modelled hindcast data to produce a high-resolution (~1 km) dataset of ESL exceedance probabilities, including wave setup, along the entire global coastline, excluding Antarctica. The RFA approach offers several advantages over traditional methods, particularly in regions with limited observational data. It overcomes the challenge of short and incomplete observational records by substituting long historical records with a collection of shorter but spatially distributed records. This spatially distributed data not only retains the volume of information but also addresses the issue of sparse tide gauge coverage in less populated areas and developing nations. The RFA process is illustrated using Cyclone Yasi (2011) as a case study, demonstrating how the approach can significantly improve the characterisation of ESLs in regions prone to tropical cyclone activity. In conclusion, this study provides a valuable resource for quantifying global coastal flood risk, offering an innovative methodology that can contribute to preparing for, and mitigating against, coastal flooding. [ABSTRACT FROM AUTHOR]

The article discusses the concept of decorative crosswalks as a creative urban design element. It is reported that these crosswalks feature colorful patterns or artistic murals, adding vibrancy to city streets and fostering a sense of community pride. It also highlights safety benefits, including reduced crash rates and increased driver awareness.