A direct saphenous nerve block in TKA: A surgeon friendly technique! Cadaveric study.

Introduction: Effective management of postoperative pain in total knee arthroplasty (TKA) poses a significant challenge for surgeons. Achieving rapid recovery without pain and promoting early ambulation in immediate and early postoperative periods are essential for patient satisfaction. There are many pain management protocols including nerve blocks. Nerve blocks procedures were done using USG and anaesthetist dependent. This cadaveric study aimed to define the VMO (Vastus medialis obliquus) triangle to target the 'safe zone' of the saphenous nerve during TKA: A surgeon's friendly technique. Methods: 12 formalin-fixed embalmed cadaveric lower limbs were dissected to explore anatomy, trajectory, the relation of saphenous nerve and measured the distances from the nearby palpable bony landmarks. Results: The average distance to target the saphenous nerve i.e target point from midpoint of superior pole of the patella was 10.6cm, the average angle to target the saphenous nerve is the angle between the line joining the medial epicondyle to the midpoint of the superior pole of the patella is found to be 64.2°. The average distance from midpoint of superior pole patella to medial epicondyle is found to be 8.1cm. Therefore, triangle so formed using these three points (1. Medial epicondyle, 2. The midpoint of superior pole of the patella, 3. Target point of the saphenous nerve) is called a VMO triangle. Conclusions: The saphenous nerve course, relations, and the distances from intraoperative bony landmarks for the VMO triangle during TKA which is a reproducible triangle so may be useful for arthroplasty surgeons to achieve successful saphenous nerve block and to avoid related complications during total knee arthroplasty (TKA).

Screen use in transgender and gender-questioning adolescents: Findings from the Adolescent Brain Cognitive Development (ABCD) Study.

OBJECTIVE: To assess the association between transgender or gender-questioning identity and screen use (recreational screen time and problematic screen use) in a demographically diverse national sample of early adolescents in the U.S. METHODS: We analyzed cross-sectional data from Year 3 of the Adolescent Brain Cognitive DevelopmentSM Study (ABCD Study®, N = 9859, 2019-2021, mostly 12-13-years-old). Multiple linear regression analyses estimated the associations between transgender or questioning gender identity and screen time, as well as problematic use of video games, social media, and mobile phones, adjusting for confounders. RESULTS: In a sample of 9859 adolescents (48.8% female, 47.6% racial/ethnic minority, 1.0% transgender, 1.1% gender-questioning), transgender adolescents reported 4.51 (95% CI 1.17-7.85) more hours of total daily recreational screen time including more time on television/movies, video games, texting, social media, and the internet, compared to cisgender adolescents. Gender-questioning adolescents reported 3.41 (95% CI 1.16-5.67) more hours of total daily recreational screen time compared to cisgender adolescents. Transgender identification and questioning one's gender identity was associated with higher problematic social media, video game, and mobile phone use, compared to cisgender identification. CONCLUSIONS: Transgender and gender-questioning adolescents spend a disproportionate amount of time engaging in screen-based activities and have more problematic use across social media, video game, and mobile phone platforms.

Tail length and E525K dilated cardiomyopathy mutant alter human ß-cardiac myosin super-relaxed state.

Dilated cardiomyopathy (DCM) is a condition characterized by impaired cardiac function, due to myocardial hypo-contractility, and is associated with point mutations in ß-cardiac myosin, the molecular motor that powers cardiac contraction. Myocardial function can be modulated through sequestration of myosin motors into an auto-inhibited "super-relaxed" state (SRX), which may be further stabilized by a structural state known as the "interacting heads motif" (IHM). Here, we sought to determine whether hypo-contractility of DCM myocardium results from reduced function of individual myosin molecules or from decreased myosin availability to interact with actin due to increased IHM/SRX stabilization. We used an established DCM myosin mutation, E525K, and characterized the biochemical and mechanical activity of wild-type and mutant human ß-cardiac myosin constructs that differed in the length of their coiled-coil tail, which dictates their ability to form the IHM/SRX state. We found that short-tailed myosin constructs exhibited low IHM/SRX content, elevated actin-activated ATPase activity, and fast velocities in unloaded motility assays. Conversely, longer-tailed constructs exhibited higher IHM/SRX content and reduced actomyosin ATPase and velocity. Our modeling suggests that reduced velocities may be attributed to IHM/SRX-dependent sequestration of myosin heads. Interestingly, longer-tailed E525K mutants showed no apparent impact on velocity or actomyosin ATPase at low ionic strength but stabilized IHM/SRX state at higher ionic strength. Therefore, the hypo-contractility observed in DCM may be attributable to reduced myosin head availability caused by enhanced IHM/SRX stability in E525K mutants.

Focal adhesion kinase-YAP signaling axis drives drug-tolerant persister cells and residual disease in lung cancer.

Targeted therapy is effective in many tumor types including lung cancer, the leading cause of cancer mortality. Paradigm defining examples are targeted therapies directed against non-small cell lung cancer (NSCLC) subtypes with oncogenic alterations in EGFR, ALK and KRAS. The success of targeted therapy is limited by drug-tolerant persister cells (DTPs) which withstand and adapt to treatment and comprise the residual disease state that is typical during treatment with clinical targeted therapies. Here, we integrate studies in patient-derived and immunocompetent lung cancer models and clinical specimens obtained from patients on targeted therapy to uncover a focal adhesion kinase (FAK)-YAP signaling axis that promotes residual disease during oncogenic EGFR-, ALK-, and KRAS-targeted therapies. FAK-YAP signaling inhibition combined with the primary targeted therapy suppressed residual drug-tolerant cells and enhanced tumor responses. This study unveils a FAK-YAP signaling module that promotes residual disease in lung cancer and mechanism-based therapeutic strategies to improve tumor response.

Association of body mass index with progression from binge-eating behavior into binge-eating disorder among adolescents in the United States: a prospective analysis of pooled data.

The association between body mass index (BMI) and binge-eating disorder (BED) is well-established. However, data on the extent to which BMI is associated with progression from binge-eating behavior into BED among adolescents are limited, which was the aim of this investigation. Participants were 9,964 U.S. adolescents from the Adolescent Brain Cognitive Development (ABCD) Study, aged 9-13 at the time of study enrollment. A computerized parent-reported assessment was used to establish adolescents' binge-eating behaviors and BED. Cox proportional hazards models adjusting for sociodemographic covariates were used to examine prospective associations between BMI and likelihood of BED onset among a) adolescents with binge-eating behavior, and b) adolescents with no binge-eating behavior. Of 975 adolescents who met study criteria for binge-eating behavior, 89 (9.1%) subsequently met study criteria for BED. Of 8,989 adolescents with no binge-eating behavior, 82 (0.9%) subsequently met study criteria for BED. BMI percentile was significantly associated with the likelihood of BED onset in participants with [ adjusted HR =1.03 (1.00, 1.06)] and participants without [adjusted HR =1.05 (1.03, 1.07)] binge-eating behavior. Results were also significant when examining BMI as a dichotomous predictor (above and below 85th percentile) among those with [adjusted HR =2.60 (1.00, 6.68) and those without [adjusted HR =6.01 (3.90, 11.10)] binge-eating behavior. Overall, results indicate that elevated BMI is prospectively associated with a greater risk for BED onset among U.S. adolescents with or without binge-eating behavior. Adolescents with a higher BMI may benefit from screening for binge eating, and prevention/early intervention strategies to mitigate the risk for developing BED.

Genome-wide interaction study of dietary intake of fibre, fruits, and vegetables with risk of colorectal cancer.

BACKGROUND: Consumption of fibre, fruits and vegetables have been linked with lower colorectal cancer (CRC) risk. A genome-wide gene-environment (G × E) analysis was performed to test whether genetic variants modify these associations. METHODS: A pooled sample of 45 studies including up to 69,734 participants (cases: 29,896; controls: 39,838) of European ancestry were included. To identify G × E interactions, we used the traditional 1--degree-of-freedom (DF) G × E test and to improve power a 2-step procedure and a 3DF joint test that investigates the association between a genetic variant and dietary exposure, CRC risk and G × E interaction simultaneously. FINDINGS: The 3-DF joint test revealed two significant loci with p-value <5 × 10-8. Rs4730274 close to the SLC26A3 gene showed an association with fibre (p-value: 2.4 × 10-3) and G × fibre interaction with CRC (OR per quartile of fibre increase = 0.87, 0.80, and 0.75 for CC, TC, and TT genotype, respectively; G × E p-value: 1.8 × 10-7). Rs1620977 in the NEGR1 gene showed an association with fruit intake (p-value: 1.0 × 10-8) and G × fruit interaction with CRC (OR per quartile of fruit increase = 0.75, 0.65, and 0.56 for AA, AG, and GG genotype, respectively; G × E -p-value: 0.029). INTERPRETATION: We identified 2 loci associated with fibre and fruit intake that also modify the association of these dietary factors with CRC risk. Potential mechanisms include chronic inflammatory intestinal disorders, and gut function. However, further studies are needed for mechanistic validation and replication of findings. FUNDING: National Institutes of Health, National Cancer Institute. Full funding details for the individual consortia are provided in acknowledgments.

More Harm Than Good: It is Time to Reconsider Prophylactic Fasciotomy in Lower-Extremity Vascular Injury.

INTRODUCTION: Four-compartment calf fasciotomy (CF) can be limb-saving. Prophylactic fasciotomy (PP) is advised in high-risk situations to prevent limb loss. Calf fasciotomy can cause significant morbidity, particularly if performed unnecessarily. We hypothesized that selective use of fasciotomies (SF) after lower-extremity vascular injury would lead to a lower rate of overall fasciotomies without an increase in limb complications than prophylactic fasciotomies (PFs). METHODS: Trauma patients who sustained lower-extremity vascular injury that required operative repair at a high-volume trauma center were retrospectively reviewed and grouped by SF or PF (2016-2022). SF were individuals who were observed and underwent CF only if signs of compartment syndrome developed, whereas PF were individuals who underwent CF without signs of compartment syndrome. The primary outcome was amputation rate. Secondary outcomes were fasciotomy rate, need for reoperative vascular surgery, and clinical characteristics predisposing use of PF. RESULTS: Of 101 overall patients, 30 patients (29.4%) had PF. Of the remaining 71 (SF group), 43.7% (n = 31) were spared CF. The median time from injury to vascular repair in both groups was the same (7 hours, P = .15). There was no difference in rate of vascular reoperation per group (PF = 26.7% vs SF = 23.9%, P = .77). The only clinical characteristic associated with PF was need for arterial shunt (OR 4.2, P = .028). CONCLUSIONS: In trauma patients with lower-extremity vascular injury undergoing vascular repair, selective use of fasciotomy can spare almost half of patients the need for fasciotomy without an increase in limb complications.

Functional outcomes in single stage bilateral ACL reconstruction with a maximum follow up of 10 years.

Background: Bilateral ACL injuries are a rarity and there is no particular consensus on whether this rare problem has to be tackled in stages or in a single stage. There are a few studies and case reports in the literature about the outcomes in single staged bilateral Anterior cruciate ligament reconstruction (ACLR). This study is focused on functional outcomes after a single staged bilateral ACLR, as well as impact of simultaneity of the injury, meniscal tears, notch stenosis and hyperlaxity. Materials and methods: A retrospective study was conducted from 2013 to 2021. Patients with bilateral ACL injury either simultaneous or non simultaneous, with or without meniscal tears were included in this study. Pre operative diagnosis was made both clinically and by MR imaging. All patients underwent a single staged bilateral ACL reconstruction. Pre operative functional scores (IKDC and Lysholm) were taken at admission and patients were examined at regular follow ups. Final functional scores were collected in a phone interview. Results: 33 patients underwent bilateral ACLR in a single stage during the study period but one patient had revision ACLR in one knee and so was excluded. Of the 32 patients, 25 (78%) had non simultaneous injury and 7 (22%) had a simultaneous injury, meniscus tear was noted in 27 (84.4%), notch stenosis in 19 (59.3%) and hyperlaxity in 12 (37.5%). IKDC and Lysholm scores have improved postoperatively. No statistically significant difference was found with or without simultaneous injury or meniscus tears. Conclusion: Single stage bilateral ACL reconstruction is a safe, reproducible approach to bilateral ACL injuries whether they were simultaneous or non simultaneous or with or without meniscal tears.

Hierarchical joint analysis of marginal summary statistics-Part I: Multipopulation fine mapping and credible set construction.

Recent advancement in genome-wide association studies (GWAS) comes from not only increasingly larger sample sizes but also the shift in focus towards underrepresented populations. Multipopulation GWAS increase power to detect novel risk variants and improve fine-mapping resolution by leveraging evidence and differences in linkage disequilibrium (LD) from diverse populations. Here, we expand upon our previous approach for single-population fine-mapping through Joint Analysis of Marginal SNP Effects (JAM) to a multipopulation analysis (mJAM). Under the assumption that true causal variants are common across studies, we implement a hierarchical model framework that conditions on multiple SNPs while explicitly incorporating the different LD structures across populations. The mJAM framework can be used to first select index variants using the mJAM likelihood with different feature selection approaches. In addition, we present a novel approach leveraging the ideas of mediation to construct credible sets for these index variants. Construction of such credible sets can be performed given any existing index variants. We illustrate the implementation of the mJAM likelihood through two implementations: mJAM-SuSiE (a Bayesian approach) and mJAM-Forward selection. Through simulation studies based on realistic effect sizes and levels of LD, we demonstrated that mJAM performs well for constructing concise credible sets that include the underlying causal variants. In real data examples taken from the most recent multipopulation prostate cancer GWAS, we showed several practical advantages of mJAM over other existing multipopulation methods.

A Wavelet-Based Approach for Motion Artifact Reduction in Ambulatory Seismocardiography.

Wearable sensing has become a vital approach to cardiac health monitoring, and seismocardiography (SCG) is emerging as a promising technology in this field. However, the applicability of SCG is hindered by motion artifacts, including those encountered in practice of which the strongest source is walking. This holds back the translation of SCG to clinical settings. We therefore investigated techniques to enhance the quality of SCG signals in the presence of motion artifacts. To simulate ambulant recordings, we corrupted a clean SCG dataset with real-walking-vibrational noise. We decomposed the signal using several empirical-mode-decomposition methods and the maximum overlap discrete wavelet transform (MODWT). By combining MODWT, time-frequency masking, and nonnegative matrix factorization, we developed a novel algorithm which leveraged the vertical axis accelerometer to reduce walking vibrations in dorsoventral SCG. The accuracy and applicability of our method was verified using heart rate estimation. We used an interactive selection approach to improve estimation accuracy. The best decomposition method for reduction of motion artifact noise was the MODWT. Our algorithm improved heart rate estimation from 0.1 to 0.8 r-squared at -15 dB signal-to-noise ratio (SNR). Our method reduces motion artifacts in SCG signals up to a SNR of -19 dB without requiring any external assistance from electrocardiography (ECG). Such a standalone solution is directly applicable to the usage of SCG in daily life, as a content-rich replacement for other wearables in clinical settings, and other continuous monitoring scenarios. In applications with higher noise levels, ECG may be incorporated to further enhance SCG and extend its usable range. This work addresses the challenges posed by motion artifacts, enabling SCG to offer reliable cardiovascular insights in more difficult scenarios, and thereby facilitating wearable monitoring in daily life and the clinic.

Influence of trophic overlaps and trophic niche amplitude on microplastic intake of fish species in shallow areas of a neotropical coastal lagoon.

Plastic pollution is a global challenge that affects all marine ecosystems, and reflects all types of uses and activities of human society in these environments. In marine ecosystems, microplastics and mesoplastics interact with invertebrates and become available to higher predators, such as fish, which can ingest these contaminants. This study aimed to analyze how ecological food interactions (diet overlap and trophic niche amplitude) among fish species contribute to the ingestion of plastic particles. The gastrointestinal contents of six fish species (Atherinella brasiliensis, Eucinostomus melanopterus, Eucinostomus argenteus, Genidens genidens, Coptodon rendalli, and Geophagus brasiliensis) were analyzed to identify prey items and plastic ingestion. Based on the ontogenetic classification, A. brasiliensis, E. melanopterus, and G. genidens were divided into juveniles and adults, and the six fish species analyzed were divided into nine predator groups. Most of the plastics ingested by the fish species were blue microplastic (MP) fibers (< 0.05 mm) classified as polyester terephthalate, polyethylene, and polybutadiene. Considering all the analyzed predators, the average number and weight of plastics ingested per individual were 2.01 and 0.0005 g, respectively. We observed that predators with a high trophic overlap could present a relationship with the intake of MP fibers owing to predation on the same resources. In addition, we observed the general pattern that when a species expands its trophic diversity and niche, it can become more susceptible to plastic ingestion. For example, the species with the highest Levin niche amplitude, E. argenteus juveniles, had the highest mean number (2.9) of ingested MP fibers. Understanding the feeding ecology and interactions among species, considering how each predator uses habitats and food resources, can provide a better understanding of how plastic particle contamination occurs and which habitats are contaminated with these polluting substances.

Genetic risk impacts the association of menopausal hormone therapy with colorectal cancer risk.

BACKGROUND: Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk. METHODS: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated. RESULTS: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10-8). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%-4.0%) vs 6.1% (5.7%-6.5%) (difference 2.4%, P-value = 1.83 × 10-14); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%-1.8%) vs 2.2% (1.9%-2.4%) (difference 0.6%, P-value = 1.01 × 10-3), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk. CONCLUSIONS: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use.

Dynamic light-responsive RhoA activity regulates mechanosensitive stem cell fate decision in 3D matrices.

The behavior of stem cells is regulated by mechanical cues in their niche that continuously vary due to extracellular matrix (ECM) remodeling, pulsated mechanical stress exerted by blood flow, and/or cell migration. However, it is still unclear how dynamics of mechanical cues influence stem cell lineage commitment, especially in a 3D microenvironment where mechanosensing differs from that in a 2D microenvironment. In the present study, we investigated how temporally varying mechanical signaling regulates expression of the early growth response 1 gene (Egr1), which we recently discovered to be a 3D matrix-specific mediator of mechanosensitive neural stem cell (NSC) lineage commitment. Specifically, we temporally controlled the activity of Ras homolog family member A (RhoA), which is known to have a central role in mechanotransduction, using our previously developed Arabidopsis thaliana cryptochrome-2-based optoactivation system. Interestingly, pulsed RhoA activation induced Egr1 upregulation in stiff 3D gels only, whereas static light stimulation induced an increase in Egr1 expression across a wide range of 3D gel stiffnesses. Actin assembly inhibition limited Egr1 upregulation upon RhoA activation, implying that RhoA signaling requires an actin-involved process to upregulate Egr1. Consistently, static-light RhoA activation rather than pulsed-light activation restricted neurogenesis in soft gels. Our findings indicate that the dynamics of RhoA activation influence Egr1-mediated stem cell fate within 3D matrices in a matrix stiffness-dependent manner.

Quantifying Bone and Skin Movement in the Residual Limb-Socket Interface of Individuals With Transtibial Limb Loss Using Dynamic Stereo X-Ray: Protocol for a Lower Limb Loss Cadaver and Clinical Study.

BACKGROUND: Relative motion between the residual limb and socket in individuals with transtibial limb loss can lead to substantial consequences that limit mobility. Although assessments of the relative motion between the residual limb and socket have been performed, there remains a substantial gap in understanding the complex mechanics of the residual limb-socket interface during dynamic activities that limits the ability to improve socket design. However, dynamic stereo x-ray (DSX) is an advanced imaging technology that can quantify 3D bone movement and skin deformation inside a socket during dynamic activities. OBJECTIVE: This study aims to develop analytical tools using DSX to quantify the dynamic, in vivo kinematics between the residual limb and socket and the mechanism of residual tissue deformation. METHODS: A lower limb cadaver study will first be performed to optimize the placement of an array of radiopaque beads and markers on the socket, liner, and skin to simultaneously assess dynamic tibial movement and residual tissue and liner deformation. Five cadaver limbs will be used in an iterative process to develop an optimal marker setup. Stance phase gait will be simulated during each session to induce bone movement and skin and liner deformation. The number, shape, size, and placement of each marker will be evaluated after each session to refine the marker set. Once an optimal marker setup is identified, 21 participants with transtibial limb loss will be fitted with a socket capable of being suspended via both elevated vacuum and traditional suction. Participants will undergo a 4-week acclimation period and then be tested in the DSX system to track tibial, skin, and liner motion under both suspension techniques during 3 activities: treadmill walking at a self-selected speed, at a walking speed 10% faster, and during a step-down movement. The performance of the 2 suspension techniques will be evaluated by quantifying the 3D bone movement of the residual tibia with respect to the socket and quantifying liner and skin deformation at the socket-residuum interface. RESULTS: This study was funded in October 2021. Cadaver testing began in January 2023. Enrollment began in February 2024. Data collection is expected to conclude in December 2025. The initial dissemination of results is expected in November 2026. CONCLUSIONS: The successful completion of this study will help develop analytical methods for the accurate assessment of residual limb-socket motion. The results will significantly advance the understanding of the complex biomechanical interactions between the residual limb and the socket, which can aid in evidence-based clinical practice and socket prescription guidelines. This critical foundational information can aid in the development of future socket technology that has the potential to reduce secondary comorbidities that result from complications of poor prosthesis load transmission. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/57329.

Changes in plasma concentrations of per- and Polyfluoroalkyl substances after bariatric surgery in adolescents from the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study.

Exposure to per- and poly-fluoroalkyl substances (PFAS) is ubiquitous due to their persistence in the environment and in humans. Extreme weight loss has been shown to influence concentrations of circulating persistent organic pollutants (POPs). Using data from the multi-center perspective Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) cohort, we investigated changes in plasma-PFAS in adolescents after bariatric surgery. Adolescents (Mean age = 17.1 years, SD = 1.5 years) undergoing bariatric surgery were enrolled in the Teen-LABS study. Plasma-PFAS were measured at the time of surgery and then 6-, 12-, and 36 months post-surgery. Linear mixed effect models were used to evaluate longitudinal changes in plasma-PFAS after the time of bariatric surgery. This study included 214 adolescents with severe obesity who had available longitudinal measures of plasma-PFAS and underwent bariatric surgery between 2007 and 2012. Underlying effects related to undergoing bariatric surgery were found to be associated with an initial increase or plateau in concentrations of circulating PFAS up to 6 months after surgery followed by a persistent decline in concentrations of 36 months (p < 0.001 for all plasma-PFAS). Bariatric surgery in adolescents was associated with a decline in circulating PFAS concentrations. Initially following bariatric surgery (0-6 months) concentrations were static followed by decline from 6 to 36 months following surgery. This may have large public health implications as PFAS are known to be associated with numerous metabolic related diseases and the significant reduction in circulating PFAS in individuals who have undergone bariatric surgery may be related to the improvement of such metabolic related diseases following bariatric surgery.

Recalibration of a Non-Laboratory-Based Risk Model to Estimate Pre-Diabetes/Diabetes Mellitus Risk in Primary Care in Hong Kong.

INTRODUCTION/OBJECTIVES: A non-laboratory-based pre-diabetes/diabetes mellitus (pre-DM/DM) risk prediction model developed from the Hong Kong Chinese population showed good external discrimination in a primary care (PC) population, but the estimated risk level was significantly lower than the observed incidence, indicating poor calibration. This study explored whether recalibrating/updating methods could improve the model's accuracy in estimating individuals' risks in PC. METHODS: We performed a secondary analysis on the model's predictors and blood test results of 919 Chinese adults with no prior DM diagnosis recruited from PC clinics from April 2021 to January 2022 in HK. The dataset was randomly split in half into a training set and a test set. The model was recalibrated/updated based on a seven-step methodology, including model recalibrating, revising and extending methods. The primary outcome was the calibration of the recalibrated/updated models, indicated by calibration plots. The models' discrimination, indicated by the area under the receiver operating characteristic curves (AUC-ROC), was also evaluated. RESULTS: Recalibrating the model's regression constant, with no change to the predictors' coefficients, improved the model's accuracy (calibration plot intercept: -0.01, slope: 0.69). More extensive methods could not improve any further. All recalibrated/updated models had similar AUC-ROCs to the original model. CONCLUSION: The simple recalibration method can adapt the HK Chinese pre-DM/DM model to PC populations with different pre-test probabilities. The recalibrated model can be used as a first-step screening tool and as a measure to monitor changes in pre-DM/DM risks over time or after interventions.

Can the introduction of a 12-lead ECG help reduce mortality in those presenting with foot ulceration to multidisciplinary diabetic foot clinics? An observational evaluation of a real-world implementation pilot in England.

AIMS/HYPOTHESIS: The risk of dying within 2 years of presentation with diabetic foot ulceration is over six times the risk of amputation, with CVD the major contributor. Using an observational evaluation of a real-world implementation pilot, we aimed to assess whether for those presenting with diabetic foot ulceration in England, introducing a 12-lead ECG into routine care followed by appropriate clinical action was associated with reduced mortality. METHODS: Between July 2014 and December 2017, ten multidisciplinary diabetic foot services in England participated in a pilot project introducing 12-lead ECGs for new attendees with foot ulceration. Inception coincided with launch of the National Diabetes Footcare Audit (NDFA), whereby all diabetic footcare services in England were invited to enter data on new attendees with foot ulceration. Poisson regression models assessed the mortality RR at 2 and 5 years following first assessment of those receiving care in a participating pilot unit vs those receiving care in any other unit in England, adjusting for age, sex, ethnicity, deprivation, type and duration of diabetes, ulcer severity, and morbidity in the year prior to first assessment. RESULTS: Of the 3110 people recorded in the NDFA at a participating unit during the pilot, 33% (1015) were recorded as having received an ECG. A further 25,195 people recorded in the NDFA had attended another English footcare service. Unadjusted mortality in the pilot units was 16.3% (165) at 2 years and 37.4% (380) at 5 years for those who received an ECG, and 20.5% (430) and 45.2% (950), respectively, for those who did not receive an ECG. For people included in the NDFA at other units, unadjusted mortality was 20.1% (5075) and 42.6% (10,745), respectively. In the fully adjusted model, mortality was not significantly lower for those attending participating units at 2 (RR 0.93 [95% CI 0.85, 1.01]) or 5 years (RR 0.95 [95% CI 0.90, 1.01]). At participating units, mortality in those who received an ECG vs those who did not was lower at 5 years (RR 0.86 [95% CI 0.76, 0.97]), but not at 2 years (RR 0.87 [95% CI 0.72, 1.04]). Comparing just those that received an ECG with attendees at all other centres in England, mortality was lower at 5 years (RR 0.87 [95% CI 0.78, 0.96]), but not at 2 years (RR 0.86 [95% CI 0.74, 1.01]). CONCLUSIONS/INTERPRETATION: The evaluation confirms the high mortality seen in those presenting with diabetic foot ulceration. Overall mortality at the participating units was not significantly reduced at 2 or 5 years, with confidence intervals just crossing parity. Implementation of the 12-lead ECG into the routine care pathway proved challenging for clinical teams-overall a third of attendees had one, although some units delivered the intervention to over 60% of attendees-and the evaluation was therefore underpowered. Nonetheless, the signals of potential mortality benefit among those who had an ECG suggest that units in a position to operationalise implementation may wish to consider this. DATA AVAILABILITY: Data from the National Diabetes Audit can be requested through the National Health Service Digital Data Access Request Service process at: https://digital.nhs.uk/services/data-access-request-service-dars/dars-products-and-services/data-set-catalogue/national-diabetes-audit-nda.

Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes.

Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.

Computationally guided AAV engineering for enhanced gene delivery.

Gene delivery vehicles based on adeno-associated viruses (AAVs) are enabling increasing success in human clinical trials, and they offer the promise of treating a broad spectrum of both genetic and non-genetic disorders. However, delivery efficiency and targeting must be improved to enable safe and effective therapies. In recent years, considerable effort has been invested in creating AAV variants with improved delivery, and computational approaches have been increasingly harnessed for AAV engineering. In this review, we discuss how computationally designed AAV libraries are enabling directed evolution. Specifically, we highlight approaches that harness sequences outputted by next-generation sequencing (NGS) coupled with machine learning (ML) to generate new functional AAV capsids and related regulatory elements, pushing the frontier of what vector engineering and gene therapy may achieve.