External validation of models for predicting risk of colorectal cancer using the China Kadoorie Biobank.

BACKGROUND: In China, colorectal cancer (CRC) incidence and mortality have been steadily increasing over the last decades. Risk models to predict incident CRC have been developed in various populations, but they have not been systematically externally validated in a Chinese population.  This study aimed to assess the performance of risk scores in predicting CRC using the China Kadoorie Biobank (CKB), one of the largest and geographically diverse prospective cohort studies in China. METHODS: Nine models were externally validated in 512,415 participants in CKB and included 2976 cases of CRC. Model discrimination was assessed, overall and by sex, age, site, and geographic location, using the area under the receiver operating characteristic curve (AUC). Model discrimination of these nine models was compared to a model using age alone. Calibration was assessed for five models, and they were re-calibrated in CKB. RESULTS: The three models with the highest discrimination (Ma (Cox model) AUC 0.70 [95% CI 0.69-0.71]; Aleksandrova 0.70 [0.69-0.71]; Hong 0.69 [0.67-0.71]) included the variables age, smoking, and alcohol. These models performed significantly better than using a model based on age alone (AUC of 0.65 [95% CI 0.64-0.66]). Model discrimination was generally higher in younger participants, males, urban environments, and for colon cancer. The two models (Guo and Chen) developed in Chinese populations did not perform better than the others. Among the 10% of participants with the highest risk, the three best performing models identified 24-26% of participants that went on to develop CRC. CONCLUSIONS: Several risk models based on easily obtainable demographic and modifiable lifestyle factor have good discrimination in a Chinese population. The three best performing models have a higher discrimination than using a model based on age alone.

Foetal thymus size in pregnancies after assisted reproductive technologies.

PURPOSE: The aim of our study was to compare thymus sizes in foetuses conceived using assisted reproductive technologies (ART) to those conceived naturally (control group). METHODS: Sonographic foetal thymus size was assessed retrospectively in 162 pregnancies conceived using ART and in 774 pregnancies conceived naturally. The anteroposterior thymic and the intrathoracic mediastinal diameter were measured to calculate the thymic-thoracic ratio (TT-ratio). The ART cases were subdivided into two groups: (1) intracytoplasmic sperm injection (ICSI; n = 109) and (2) in vitro fertilisation (IVF; n = 53). RESULTS: The TT-ratio was smaller in pregnancies conceived using ART (p < 0.001). In both ART subgroups (ICSI and IVF), the TT-ratio was lower compared to the control group (p < 0.001). However, no difference between the two subgroups could be detected (p = 0.203). CONCLUSIONS: Our data show reduced thymus size in foetuses conceived using ART compared to controls. These findings indicate that the use of ART may lead to certain deviations in organogenesis.

An In Vitro Study of the Role of Implant Positioning on Ulnohumeral Articular Contact in Distal Humeral Hemiarthroplasty.

PURPOSE: To investigate the effect of implant positioning on ulnohumeral contact using patient-specific distal humeral (DH) implants. METHODS: Seven reverse-engineered DH implants were manufactured based on computed tomography scans of their osseous geometry. Native ulnae were paired with corresponding native humeri and custom DH implants in a loading apparatus. The ulna was set at 90° of flexion and the humeral component (either native bone or reverse-engineered implant) was positioned from 5° varus to 5° valgus in 2.5° increments under a 100-N compressive load. Contact with the ulna was measured with both the native distal humerus and the reverse-engineered DH implant at all varus-valgus (VV) angles, using a joint casting method. Contact patches were digitized and analyzed in 4 ulnar quadrants. Output variables were contact area and contact pattern. RESULTS: Mean contact area of the native articulation was significantly greater than with the distal humeral hemiarthroplasty (DHH) implants across all VV positions. Within the native condition, contact area did not significantly change owing to VV angulation. Within the DHH condition, contact area also did not significantly change owing to VV angulation. Conversely, in the DHH condition, contact pattern did significantly change. Medial ulnar contact pattern was significantly affected by VV angulation. Lateral ulnar contact was variably affected, but generally decreased as well. CONCLUSIONS: Ulnar contact patterns were changed as a result of VV implant positioning using reverse-engineered DH implants, most notably on the medial aspect of the joint. Implant positioning plays a crucial role in producing contact patterns more like those observed in the native joint. CLINICAL RELEVANCE: Recent clinical evidence reports nonsymmetrical ulnar wear after DHH. This work suggests that implant positioning is likely a contributing factor and that more exact implant positioning may lead to better clinical outcomes.

A Hybrid Electrospun-Extruded Polydioxanone Suture for Tendon Tissue Regeneration.

Many surgical tendon repairs fail despite advances in surgical materials and techniques. Tendon repair failure can be partially attributed to the tendon's poor intrinsic healing capacity and the repurposing of sutures from other clinical applications. Electrospun materials show promise as a biological scaffold to support endogenous tendon repair, but their relatively low tensile strength has limited their clinical translation. It is hypothesized that combining electrospun fibers with a material with increased tensile strength may improve the suture's mechanical properties while retaining biophysical cues necessary to encourage cell-mediated repair. This article describes the production of a hybrid electrospun-extruded suture with a sheath of submicron electrospun fibers and a core of melt-extruded fibers. The porosity and tensile strength of this hybrid suture is compared with an electrospun-only braided suture and clinically used sutures Vicryl and polydioxanone (PDS). Bioactivity is assessed by measuring the adsorbed serum proteins on electrospun and melt-extruded filaments using mass spectrometry. Human hamstring tendon fibroblast attachment and proliferation were quantified and compared between the hybrid and control sutures. Combining an electrospun sheath with melt-extruded cores created a hybrid braid with increased tensile strength (70.1 ± 0.3N) compared with an electrospun only suture (12.9 ± 1 N, p < 0.0001). The hybrid suture had a similar force at break to clinical sutures, but lower stiffness and stress. The Young's modulus was 772.6 ± 32 MPa for the hybrid suture, 1693.0 ± 69 MPa for PDS, and 3838.0 ± 132 MPa for Vicryl, p < 0.0001. Hybrid sutures had lower overall porosity than electrospun-only sutures (40 ± 4% and 60 ± 7%, respectively, p = 0.0018) but had a significantly larger overall porosity and average pore diameter compared with surgical sutures. There were similar clusters of adsorbed proteins on electrospun and melt-extruded filaments, which were distinct from PDS. Tendon fibroblast attachment and cell proliferation on hybrid and electrospun sutures were significantly higher than on clinical sutures. This study demonstrated that a bioactive suture with increased tensile strength and lower stiffness could be produced by adding a core of 10 µm melt-extruded fibers to a sheath of electrospun fibers. In contrast to currently used sutures, the hybrid sutures promoted a bioactive response: serum proteins adsorbed, and fibroblasts attached, survived, grew along the sutures, and adopted appropriate morphologies.

Estimating the effect of COVID-19 on trial design characteristics: a registered report.

There have been reports of poor-quality research during the COVID-19 pandemic. This registered report assessed design characteristics of registered clinical trials for COVID-19 compared to non-COVID-19 trials to empirically explore the design of clinical research during a pandemic and how it compares to research conducted in non-pandemic times. We did a retrospective cohort study with a 1 : 1 ratio of interventional COVID-19 registrations to non-COVID-19 registrations, with four trial design outcomes: use of control arm, randomization, blinding and prospective registration. Logistic regression was used to estimate the odds ratio of investigating COVID-19 versus not COVID-19 and estimate direct and total effects of investigating COVID-19 for each outcome. The primary analysis showed a positive direct and total effect of COVID-19 on the use of control arms and randomization. It showed a negative direct effect of COVID-19 on blinding but no evidence of a total effect. There was no evidence of an effect on prospective registration. Taken together with secondary and sensitivity analyses, our findings are inconclusive but point towards a higher prevalence of key design characteristics in COVID-19 trials versus controls. The findings do not support much existing COVID-19 research quality literature, which generally suggests that COVID-19 led to a reduction in quality. Limitations included some data quality issues, minor deviations from the pre-registered plan and the fact that trial registrations were analysed which may not accurately reflect study design and conduct. Following in-principle acceptance, the approved stage 1 version of this manuscript was pre-registered on the Open Science Framework at https://doi.org/10.17605/OSF.IO/5YAEB. This pre-registration was performed prior to data analysis.

A systematic review of economic evaluations of interventions targeting childhood overweight and obesity.

This systematic review critically appraised and synthesized evidence from economic evaluations of interventions targeting childhood excess weight. We conducted systematic searches in 11 databases from inception to April 19, 2023. Studies were eligible if they evaluated interventions targeting children up to 18 years and the study intervention(s) targeted childhood excess weight or sought to improve diet or physical activity, regardless of the type of economic evaluation or the underpinning study design. We synthesized evidence using narrative synthesis methods. One-hundred fifty-one studies met the eligibility criteria and were classified into three groups based on the intervention approach: prevention-only (13 studies), prevention and treatment (100 studies), and treatment-only (38 studies). The predominant setting and study design differed considerably between the three groups of studies. However, compared with usual care, most interventions were deemed cost-effective. The study participants' ages, sex, and socioeconomic status were crucial to intervention cost-effectiveness. Interventions whose effects were projected beyond childhood, such as bariatric surgery, lower protein infant formula, and home-based general practitioner consultations, tended to be cost-effective. However, cost-effectiveness was sensitive to the assumptions underlying the persistence and intensity of such effects. Our findings can inform future recommendations on the conduct of economic evaluations of interventions targeting childhood overweight and obesity, as well as practice and policy recommendations.

Host-biomaterial interactions in mesh complications after pelvic floor reconstructive surgery.

Polypropylene (PPL) mesh is widely used in pelvic floor reconstructive surgery for prolapse and stress urinary incontinence. However, some women, particularly those treated using transvaginal PPL mesh placement for prolapse, experience intractable pain and mesh exposure or extrusion. Explanted tissue from patients with complications following transvaginal implantation of mesh is typified by a dense fibrous capsule with an immune cell-rich infiltrate, suggesting that the host immune response has a role in transvaginal PPL mesh complications through the separate contributions of the host (patient), the biological niche within which the material is implanted and biomaterial properties of the mesh. This immune response might be strongly influenced by both the baseline inflammatory status of the patient, surgical technique and experience, and the unique hormonal, immune and microbial tissue niche of the vagina. Mesh porosity, surface area and stiffness also might have an effect on the immune and tissue response to transvaginal mesh placement. Thus, a regulatory pathway is needed for mesh development that recognizes the roles of host and biological factors in driving the immune response to mesh, as well as mandatory mesh registries and the longitudinal surveillance of patients.

In vitro evaluation of the response of human tendon-derived stromal cells to a novel electrospun suture for tendon repair.

Recurrent tears after surgical tendon repair remain common. Repair failures can be partly attributed to the use of sutures not designed for the tendon cellular niche nor for the promotion of repair processes. Synthetic electrospun materials can mechanically support the tendon whilst providing topographical cues that regulate cell behaviour. Here, a novel electrospun suture made from twisted polydioxanone (PDO) polymer filaments is compared to PDS II, a clinically-used PDO suture currently utilised in tendon repair. We evaluated the ability of these sutures to support the attachment and proliferation of human tendon-derived stromal cells using PrestoBlue and Scanning Electron Microscopy. Suture surface chemistry was analysed using X-ray Photoelectron Spectroscopy. Bulk RNA-Seq interrogated the transcriptional response of primary tendon-derived stromal cells to sutures after 14 days. Electrospun suture showed increased initial cell attachment and a stronger transcriptional response compared to PDS II, with relative enrichment of pathways including mTorc1 signalling and depletion of epithelial mesenchymal transition. Neither suture induced transcriptional upregulation of inflammatory pathways compared to baseline. Twisted electrospun sutures therefore show promise in improving outcomes in surgical tendon repair by allowing increased cell attachment whilst maintaining an appropriate tissue response.

Early development of a polycaprolactone electrospun augment for anterior cruciate ligament reconstruction.

Despite the clinical success of Anterior Cruciate Ligament reconstruction (ACLR) in some patients, unsatisfactory clinical outcomes secondary to graft failure are seen, indicating the need to develop new regeneration strategies. The use of degradable and bioactive textiles has the potential to improve the biological repair of soft tissue. Electrospun (ES) filaments are particularly promising as they have the ability to mimic the structure of natural tissues and influence endogenous cell behaviour. In this study, we produced continuous polycaprolactone (PCL) ES filaments using a previously described electrospinning collection method. These filaments were stretched, twisted, and assembled into woven structures. The morphological, tensile, and biological properties of the woven fabric were then assessed. Scanning electron microscopy (SEM) images highlighted the aligned and ACL-like microfibre structure found in the stretched filaments. The tensile properties indicated that the ES fabric reached suitable strengths for a use as an ACLR augmentation device. Human ACL-derived cell cultured on the fabric showed approximately a 3-fold increase in cell number over 2 weeks and this was equivalent to a collagen coated synthetic suture commonly used in ACLR. Cells generally adopted a more elongated cell morphology on the ES fabric compared to the control suture, aligning themselves in the direction of the microfibres. A NRU assay confirmed that the ES fabric was non-cytotoxic according to regulatory standards. Overall, this study supports the development of ES textiles as augmentation devices for ACLR.

Industry ties and evidence in public comments on the FDA framework for modifications to artificial intelligence/machine learning-based medical devices: a cross sectional study.

OBJECTIVES: To determine the extent and disclosure of financial ties to industry and use of scientific evidence in comments on a US Food and Drug Administration (FDA) regulatory framework for modifications to artificial intelligence/machine learning (AI/ML)-based software as a medical device (SaMD). DESIGN: Cross-sectional study. SETTING: We searched all publicly available comments on the FDA 'Proposed Regulatory Framework for Modifications to Artificial Intelligence/Machine Learning (AI/ML)-Based Software as a Medical Device (SaMD)-Discussion Paper and Request for Feedback' from 2 April 2019 to 8 August 2019. MAIN OUTCOME MEASURES: The proportion of articles submitted by parties with financial ties to industry, disclosing those ties, citing scientific articles, citing systematic reviews and meta-analyses, and using a systematic process to identify relevant literature. RESULTS: We analysed 125 comments submitted on the proposed framework. 79 (63%) comments came from parties with financial ties; for 36 (29%) comments, it was not clear and the absence of financial ties could only be confirmed for 10 (8%) comments. No financial ties were disclosed in any of the comments that were not from industry submitters. The vast majority of submitted comments (86%) did not cite any scientific literature, just 4% cited a systematic review or meta-analysis and no comments indicated that a systematic process was used to identify relevant literature. CONCLUSIONS: Financial ties to industry were common and undisclosed, and scientific evidence, including systematic reviews and meta-analyses, were rarely cited. To ensure regulatory frameworks best serve patient interests, the FDA should mandate disclosure of potential conflicts of interest (including financial ties) in comments, encourage the use of scientific evidence, and encourage engagement from non-conflicted parties.

Effect of annealing on the mechanical properties and the degradation of electrospun polydioxanone filaments.

Annealing, or heat treatment, has traditionally been used as a treatment to improve the strength and stiffness of electrospun materials. Understanding the extent to which annealing can improve the mechanical properties and alter the degradation rate of electrospun polydioxanone filaments could influence the range of its potential clinical applications. In this study, we investigated the effect of annealing electrospun polydioxanone filaments at varying times and temperatures and subsequently subjecting them to in vitro degradation in phosphate buffer saline for up to 6 weeks. Fibre alignment, tensile strength and thermal properties were assessed. It was determined that annealing at 65°C for 3h only marginally improved the tensile strength (9±2%) but had a significant effect on reducing strain and rate of degradation, as well as maintaining fibre alignment within the filament. The filament retained significantly more of its force at failure after 4 weeks (82±15%, compared to 61±20% for non annealed filaments) and after 6 weeks of degradation (81±9%, compared to 55±13% for non annealed filaments). Conversely, annealing filaments at 75°C improved the initial tensile strength of the filament (17±6%), but over 6 weeks, both samples annealed at 75°C and 85°C otherwise performed similarly or mechanically worse than those not annealed. These findings suggest that annealing at low temperatures is more useful as a method to tailor degradation rate than to improve mechanical properties. The ability to modulate the degradation profile with annealing may become useful to tailor the properties of electrospun materials without altering the chemistry of the polymer used. This might better match the degradation of the implant and gradual loss of mechanical properties with the new matrix deposition within the structure, enabling multiple regenerative strategies within a single biomaterial system.

Synthetic sutures: Clinical evaluation and future developments.

Today's sutures are the result of a 4000-year innovation process with regard to their materials and manufacturing techniques, yet little has been done to enhance the therapeutic value of the suture itself. In this review, we explore the historical development, regulatory database and clinical literature of sutures to gain a fuller picture of suture advances to date. First, we examine historical shifts in suture manufacturing companies and review suture regulatory databases to understand the forces driving suture development. Second, we gather the existing clinical evidence of suture efficacy from reviewing the clinical literature and the Food and Drug Administration database in order to identify to what extent sutures have been clinically evaluated and the key clinical areas that would benefit from improved suture materials. Finally, we apply tissue engineering and regenerative medicine design hypotheses to suture materials to identify routes by which bioactive sutures can be designed and passed through regulatory hurdles, to improve surgical outcomes. Our review of the clinical literature revealed that many of the sutures currently in use have been available for decades, yet have never been clinically evaluated. Since suture design and development is industry driven, incremental modifications have allowed for a steady outflow of products while maintaining a safe regulatory position and limiting costs. Until recently, there has been little academic interest in suture development, however the rise of regenerative medicine strategies is shifting the suture paradigm from an inert material, which mechanically approximates tissue, to a bioactive material, which also actively promotes cell-directed repair and a positive healing response. These materials hold significant therapeutic potential, but could be associated with an increased regulatory burden, cost, and clinical evaluation compared with current devices.