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Category: Orthopedic Radiology Introduction/Purpose: Radiographs are one of the most common and widely available diagnostic imaging techniques that are used to evaluate orthopedic conditions. However, incidental findings on imaging may be observed as well, some of which may be very serious and have significant heath as well as legal ramifications if missed. This study evaluates the number of clinically relevant incidental findings reported for orthopaedic radiographs ordered in an academic orthopedic multispecialty group over one year. Methods: A retrospective review was conducted of 13,948 eligible radiographs recorded at our institution over a 12-month period. Reports were categorized based on exam type. Incidental findings were first categorized as either concern for malignancy or non-malignancy. The possibly malignant findings were further subdivided into malignancies in Bone or Lung tissues. The non- malignant findings were categorized into the following groups: Benign Bone Disease, Gastrointestinal Pathology, Gynecologic Pathology, Incidental Fracture, Infection, Inflammation, Respiratory Pathology, Soft Tissue Mass, Urologic Pathology, Vascular Pathology or Other. Results: Of the 13,948 radiographs, 286 radiographs reported at least one incidental finding totaling to 287 (2.06%) incidental findings. The 3 studies with the highest rates of incidental findings were Leg Length Alignment films (3.94%), Spine (3.88%), and Pelvis & Hip (2.76%). The three categories with the lowest rates of incidental findings were Hand & Wrist (0.56%), Tibia/Fibula Foot & Ankle (0.84%), and Forearm & Elbow (1.13%). Over one-third of incidental findings concerned malignancy or metastases with 87 (30.1%) and 18 (6.23%) identified in bone tissue and lung tissue, respectively. Benign Bone Disease (24.9%), Gastrointestinal Pathology (6.57%), and Gynecologic Pathology (5.88%) were categories with the highest rates of non-malignant incidental findings. Follow-up was recommended for 122 (42.5%) incidental findings. Conclusion: This study describes the rates of incidental findings on orthopedic radiographs. Radiographs of midline structures are more likely to report an incidental finding as opposed to radiographs of distal extremities. The exception is leg alignment films because these image the entirety of the lower extremity and the pelvis and thus a far larger volume of the body. Over one-third of incidental findings concerned possible malignancy or metastases and therefore follow-up with focused imaging should be recommended if suspicious. This information will be particularly useful for orthopaedic surgeons who read their own radiographs without a radiologist formally reviewing the films.

Category: Trauma Introduction/Purpose: Fractures of the talus are rare, but serious injuries to the hindfoot associated with high-energy mechanisms in often polytraumatized patients. The collective knowledge regarding talus injuries is lacking in many regards. Limited effort has been previously made to identify and characterize associated injuries ordinarily occurring in conjunction with fractures of the talus. The purpose of the current study was to [1] determine what associated injuries occur in high incidence in patients presenting with major fractures of the talus, and to [2] identify clinical injury patterns that warrant special attention in patients presenting with talus fractures. Methods: A retrospective review was conducted for patients with talar body or neck fractures at three level-1 academic trauma centers in Boston, MA between June 1, 2004 and June 30, 2018. Patient charts were reviewed for demographic details, injury mechanism, open versus closed injury status, and all associated orthopaedic and non-orthopaedic injuries identified during the initial patient encounter and hospitalization. Results: 253 patients met criteria for inclusion. The final study population included 158 (61%) talar neck fractures, 82 (32%) body fractures, and 18 (7%) head fractures. Falls from height, MVC/MCC, low energy falls and sports injuries were the most common mechanisms of injury in declining order. 64% of patients presenting with a talus fracture had at least one other concomitant injury. The table demonstrates the breakdown of associated injuries rates by body area. Conclusion: Talus fractures are commonly associated with injuries to different anatomic sites and systems. Trauma to the ipsilateral foot is most common necessitating complete imaging of the foot and ankle in all patients presenting with talus fractures. Trauma to the chest, abdomen, and pelvis occurred most commonly following motor vehicle trauma. Talar fractures and lumbar spine injuries was also observed frequently and underscores the importance of lumbar spine evaluation in patients presenting with major talus fractures, particularly those occurring after falls from height. This study presents valuable information to surgeons when evaluating and assessing injured patients to optimize care for patients.

Category: Trauma Introduction/Purpose: A shortened fibula may be caused by several conditions like tumors, premature closure of the growth plate and most frequently, malunion. Biomechanically a shortened fibula causes a lateral shift of the talus, widening of the ankle mortise, decreased tibiotalar contact area and eventually could lead to osteoarthritis. Even in a posttraumatic scenario, with moderate or severe osteoarthritis, fibular lengthening has shown to be beneficial in terms of pain reduction and improved function.Several osteotomies have been described with their advantages and disadvantages in terms of technical difficulty, need for bone graft and the ability to correct length and rotation.We present an easy and reproducible surgical technique on a case, that allow restoring length and rotation independently and it does not require complex distractor devices. Methods: Case report: A 34 year old female patient who presented 8 months status post initial open reduction internal fixation (ORIF). She developed a fibular nonunion, broken distal fixation with a shortened fibula and non-anatomic mortise and presented for revision surgery.Surgical technique: The fibula is exposed in standard fashion. A fully-threaded cortical screw is placed across the tibia, distal to the fibula fracture and parallel to the plafond. Next, a second screw is placed into the fibula bicortically from anterior to posterior and approximately 12 mm distal to the tibial screw. A toothed laminar spreader is then placed in-between the screws and distracted resulting in a lengthening of the fibula. A 2 mm Kirschner wire is placed to hold reduction once fibular length is restored and ORIF continues in standard fashion. Results: The technique we present has several advantages. The technique is straightforward, easy to reproduce, and cost effective. Since the anchoring points used for distraction are not both in the fibula, rotation is not implicitly locked in as in the case when both anchoring points are in the fibula, allowing for independent and progressive adjustment of both length and rotation. There is also less risk of proximal migration of the fibular head as no force is applied directly to the proximal fibula. There is also less risk of proximal migration of the fibular head as no force is applied directly to the proximal fibula. Conclusion: Fibular lengthening can achieve improved function, pain relief and decrease the risk of osteoarthritis in selected patients. Several techniques with different degrees of difficulty have been described to treat this condition, but most are not versatile enough in correcting the length and rotation independently. The technique that we present has the advantage of correcting the length and rotation as needed, without requiring complex devices.

Objective: To investigate in vitro antioxidant and anti-inflammatory activities of Korean blueberry (Vaccinium corymbosum L.). Methods: Total phenolic and flavonoid contents of the Korean blueberry water and ethanol extracts were determined before determining the potential of the extracts as antioxidant. Antioxidant activity of the extracts was determined by following some well established methods for free radical scavenging such as 2,2-diphenyl-picrylhydrazyl hydrate, 1,2,2-azinobis-(3-ethylbenzothiazoline-6-sulfonicacid), free radical induced DNA damage, superoxide dismutase-like and catalase assay etc. Furthermore, 1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan and nitric oxide assay were performed to determine the anti-inflammatory activity of the extracts. Results: Total phenolic contents were found (115.0±3.0) and (4.2±3.0) mg GAE/100 g fresh mass for both extracts, respectively and flavonoid contents were (1 942.8±7.0) and (1 292.1±6.0) mg CE/100g fresh mass for water and ethonal extracts, respectively. Both the extracts displayed significant scavenging activity of some radicals such as 2,2-diphenyl-picrylhydrazyl hydrate (IC50 at 1.8 mg/mL and 2.05 mg/mL, respectively), 1,2,2-azinobis-(3-ethylbenzothiazoline-6-sulfonicacid) (IC50 at 1.5 mg/mL and 1.6 mg/mL, respectively) and nitrite (IC50 at 1.7 mg/mL and 1.5 mg/mL, respectively) etc. The extracts were found to prevent inflammation as well by reducing nitric oxide production and cytotoxicity in cell. Conclusions: The findings suggest that the fresh Korean blueberry could be used as a source of natural antioxidants and anti-inflammatory agents.

Nuclear inclusion a (NIa) of turnip mosaic virus is a cytosolic protease that cleaves amyloid β (Aβ) when heterologously overexpressed. Lentivirus-mediated expression of NIa in the brains of APP(sw)/PS1 mice significantly reduces cerebral Aβ levels and plaque depositions, and improves behavioral deficits. Here, the effects of NIa and neprilysin (NEP), a well-known Aβ-cleaving protease, on oligomeric Aβ-induced cell death were evaluated. NIa cleaved monomeric and oligomeric Aβ at a similar rate, whereas NEP only cleaved monomeric Aβ. Oligomeric Aβ-induced cytotoxicity and mitochondrial dysfunction were significantly ameliorated by NIa, but not by NEP. Endocytosed fluorescently-labeled Aβ localized to mitochondria, and this was significantly reduced by NIa, but not by NEP. These data suggest that NIa may exerts its protective roles by degrading Aβ and thus preventing mitochondrial deposition of Aβ.

Complement is both evolutionary and scientifically old. It predates the adaptive immunity by some 600 million years and was first described in 1905 by Jules Bordet and Paul Ehrlich. For the most of its, the existence complement system has been ignored by most scientists and clinicians due to the perception of it being complicated and its relevance for the pathogenesis of human disease being unclear. With the recent US Food and Drug Administration (FDA) approvals of pegcetacoplan for both paroxysmal nocturnal haemoglobinuria (PNH) and geographic atrophy (GA), avacincaptad pegol for GA and iptacopan and danicopan for PNH, we are at a crucial juncture for complement-targeting therapies. A number of companies and academic institutions are developing next-generation complement therapies, which is resulting in an increasingly competitive landscape. If one looks at the serum complement cascade, all 3 pathways now have biotechnology or pharmaceutical industry players with 1 or multiple clinical-stage inhibitors that are expected to be FDA approved within the next few years. Furthermore, with the limited number of clinically validated targets in complement-mediated disease, the competition in this space is set to further intensify in the coming years. In this review, we will discuss the timeline of the academic discoveries that led to the development of the current crop of FDA-approved complement therapeutics. We follow with a discussion of an increasingly crowded complement therapy space and of the scientific advances that have emerged in recent two decades underpinning future innovation, including advances in our understanding of complement biology, such as local and intracellular complement, emerging complement targets, combinational approaches of complement and non-complement therapeutics to unlock new disease indications and new technologies such as gene therapy. We will also give a comprehensive overview of the gene therapy landscape and how it can be utilized to target complement dysregulation.

Abstract Introduction Emergency department clinicians, and particularly nurses in triage, frequently perform routine blood tests on patients whose allocated triage category is not time critical (triage categories 3, 4 and 5 of the Australasian Triage Scale). Some observers have questioned the utility of routine blood testing in these acute healthcare settings given the cost and workload implications. Methods A quantitative method using retrospective observational design was utilised guided by STROBE checklist. Electronic medical records of patient data collected at a quaternary Australian metropolitan hospital emergency department were reviewed. Results and discussion A total of 74,878 adult patients attended the emergency department between 1st January and 31st December 2021 and a sample of 383 were randomly allocated for this study. Of the 383 patients included, 51% were female, age ranges were 18–99 years (mean 51.6). The majority were Australasian Triage scale (ATS) triage category 3 (55%) and 62% had blood tests performed. Blood test performance was found to be associated with advancing age (p

Abstract Introduction Advance Care Planning (ACP) refers to a process that includes Advance Care Directives (ACD) and Goals of Care (GOC), a practice widely used for over three decades. Following the findings of an audit and a cross-sectional study in 2019 and 2021 respectively, we implemented several educational and other interventional strategies aimed at enhancing staff awareness and emphasizing the importance of recognizing and documenting of ACD/GOC. The aim of this study was to evaluate the acknowledgement and use of ACD and GOC by Emergency Department (ED) staff following these interventions. Method We used a mixed methods approach, incorporating both observational and cross-sectional designs with reflexive thematic analysis. Data extraction for the observational study took place between 1st April and 30th June 2023 focusing on a target population of randomly sampled adults aged ≥ 65 years. Demographics and other ACD and GOC related patients’ clinical data were collected. Data collection for the cross-sectional study occurred between 19th July and 13th September 2023 targeting all ED staff. Information gathered included demographics, awareness about ACD and GOC, including storage location and implementation, as well as knowledge of Medical Treatment decision Makers (MTDM), a jurisdictional term identifying a person legally appointed to make healthcare decisions on behalf of someone who lacks decision-making capacity and other Victorian State legislative requirements were collected. Results In the observational period, 22,335 patients attended the ED and 19% (n = 6546) qualified for inclusion from which a sample of 308 patients were randomly extracted. We found ACD documents were noted in the medical records of 6.5% of the sample, fewer than 8% identified in our previous study. There was no correlation between ACD record availability and age (p = 0.054; CI ranging from − 0.065 to 7.768). The response rate for the cross-sectional survey was 12% (n = 340) in contrast to earlier study with 28% (n = 476) respondents. Staff knowledge and familiarity with ACD was 25% and GOC 45%. Conclusion After implementing interventions in staff education and ACP awareness, we found that ACD documentation did not improve. However, GOC documentation increased in the context of heightened institutional awareness and integration into the Electronic Medical Records (EMR).

ObjectiveTo establish lactate and glucose differences between affected and non-affected limbs in cats with feline arterial thromboembolism (FATE). To evaluate the correlation between these values and survival to discharge as well as congestive heart failure (CHF).MethodsBlood glucose and lactate concentrations were prospectively obtained on admission from client-owned FATE cats and client-owned cats presented for other conditions. The glucose and lactate concentrations of the front limbs (or non-affected) and the hind limbs (or affected) were measured. Lactate (Δlactate) and glucose (Δglucose) differences between the two limbs were calculated.ResultsThe FATE group and control groups included 18 and 41 cats, respectively. The median age of the cats within the FATE group and control groups was 9.5 years and 5 years, respectively. The median Δlactate was significantly higher in the FATE group than in the control group (7.2 mmol/L versus 0.1 mmol/L, respectively; p ≤ 0.01). The median Δglucose was significantly higher in the FATE group than in the control group (155 mg/dL versus 3 mg/dL, respectively; p ≤ 0.01). A diagnosis of FATE was made using a ∆lactate cutoff of 2.2 mmol/L (100% sensitivity and 95% specificity) or a ∆glucose cutoff of 41 mg/dL (100% sensitivity and specificity). There was no correlation between Δlactate and Δglucose and survival to discharge. A higher ∆glucose was significantly associated with concurrent CHF (p = 0.01).ConclusionBoth Δlactate and Δglucose were accurate diagnostic tools for cats with FATE. Neither were correlated with survival to discharge. Higher Δglucose values were significantly associated with the presence of CHF.

IntroductionLacticaseibacillus rhamnosus GG (LGG) is a well-studied probiotic with a history of safe use.MethodsIn this double-blind, prospective study, growth and tolerance were evaluated in healthy term infants randomized to: marketed, routine intact cow's milk protein-based formula (Control, n = 172) or a similar investigational formula with added LGG (INV-LGG, n = 179; 106 CFU LGG®/g powder) from 14 to 120 days of age. Anthropometrics, stool characteristics, fussiness, and gassiness were evaluated through Day 120. Medically confirmed adverse events were recorded throughout the study period. The primary outcome was rate of weight gain from Day 14–120.ResultsOf 351 infants enrolled, 275 completed (Control, n = 131; INV-LGG, n = 144). No significant group differences in rate of weight gain from Day 14–120 were detected. Study formula acceptance and tolerance was good with no significant differences in study discontinuation due to study formula or parent-reported gassiness, stool frequency, or stool consistency; however mean fussiness relative to normal was significantly lower for INV-LGG vs Control at Days 60 and 90.DiscussionIn healthy term infants, a routine intact cow's milk protein-based formula with added LGG supported adequate growth and was well tolerated. Further studies are needed to evaluate potential benefits for fussiness and efficacy outcomes. Clinical Trial RegistrationClinicaltrials.gov, identifier (NCT01897922).

Abstract Background and Objectives We determined normalization rates for hemoglobin, lactate dehydrogenase (LDH), and fatigue in patients with paroxysmal nocturnal hemoglobinuria (PNH) treated with pegcetacoplan (PEG) in the PEGASUS (NCT03500549) and PRINCE (NCT04085601) phase III trials. Methods Enrolled patients had PNH and hemoglobin

PurposeOver the past decades, video games have become a substantial part of the entertainment industry. While ubiquitous, video game participation remains low among people with disabilities amid potential negative effects. This article analyzes the risks and benefits that video games may present to individuals with disabilities.MethodologyIn this conceptual article, we explored the literature pertaining to video games and disability. To better understand the impact of video games on individuals with disabilities, we focused on the unique features of video games through the lens of the Self-Determination Theory.FindingsOur findings show that individuals with disabilities are most at risk from excessive video game use, leading to increased aggression, sedentary behavior, and negative impact on academic performance. Identified benefits include promoting physical rehabilitation and psychological well-being, improving cognitive abilities and emotional regulation, and utility in promoting exercises, and managing chronic pain.OriginalityThis article presents a number of strategies and resources to help guide individuals with disabilities, educators, practitioners, and researchers in maximizing the benefits of video games while controlling the risks.

Strategies to advance T cell based immune therapies are mostly focusing on the improvement of CD8 T cell effector functions, such as cytotoxicity or recruitment to the tumor. Here authors show that by combining in situ vaccination with oncolytic Newcastle Disease Virus and Flt3L-driven dendritic cell expansion, the anti-tumor T cell response is amplified via increased antigen cross-presentation.

Discussion forums are a key component of online learning platforms, allowing learners to ask for help, provide help to others, and connect with others in the learning community. Analyzing patterns of forum usage and their association with course outcomes can provide valuable insight into how learners actually use discussion forums, and suggest strategies for shaping forum dynamics to improve learner experiences and outcomes. However, the fine-grained coding of forum posts required for this kind of analysis is a manually intensive process that can be challenging for large datasets, e.g., those that result from popular MOOCs. To address this issue, we propose an AI-assisted labeling process that uses advanced natural language processing techniques to train machine learning models capable of labeling a large dataset while minimizing human annotation effort. We fine-tune pretrained transformer-based deep learning models on category, structure, and emotion classification tasks. The transformer-based models outperform a more traditional baseline that uses support vector machines and a bag-of-words input representation. The transformer-based models also perform better when we augment the input features for an individual post with additional context from the post's thread (e.g., the thread title). We validate model quality through a combination of internal performance metrics, human auditing, and common-sense checks. For our Python MOOC dataset, we find that annotating approximately 1% of the forum posts achieves performance levels that are reliable for downstream analysis. Using labels from the validated AI models, we investigate the association of learner and course attributes with thread resolution and various forms of forum participation. We find significant differences in how learners of different age groups, gender, and course outcome status ask for help, provide help, and make posts with emotional (positive or negative) sentiment.

Background Cancer immunotherapies are generally effective in patients whose tumors contain a priori primed T-cells reactive to tumor antigens (TA). One approach to prime TA-reactive T-cells is to administer immunostimulatory molecules, cells, or pathogens directly to the tumor site, that is, in situ vaccination (ISV). We recently described an ISV using Flt3L to expand and recruit dendritic cells (DC), radiotherapy to load DC with TA, and pattern recognition receptor agonists (PRRa) to activate TA-loaded DC. While ISV trials using synthetic PRRa have yielded systemic tumor regressions, the optimal method to activate DCs is unknown.Methods To discover optimal DC activators and increase access to clinical grade reagents, we assessed whether viral or bacterial components found in common pathogen vaccines are an effective source of natural PRRa (naPRRa). Using deep profiling (155-metric) of naPRRa immunomodulatory effects and gene editing of specific PRR, we defined specific signatures and molecular mechanisms by which naPRRa potentiate T-cell priming.Results We observed that vaccine naPRRa can be even more potent in activating Flt3L-expanded murine and human DCs than synthetic PRRa, promoting cross-priming of TA-reactive T-cells. We developed a mechanistically diverse naPRRa combination (BCG, PedvaxHIB, Rabies) and noted more potent T-cell cross-priming than with any single naPRRa. The naPRRa triplet—as part of Flt3L-primed ISV—induced greater intratumoral CD8 T-cell infiltration, T-cells reactive to a newly defined tumorous neoantigen, durable tumor regressions.Conclusions This work provides rationale for the translation of pathogen vaccines as FDA-approved clinical-grade DC activators which could be exploited as immune-stimulants for early phase trials.

Galactic-scale outflows of molecular gas from star-forming galaxies constitute the most direct evidence for the regulation of star formation. In the early Universe ( z > 4), such outflows have recently been inferred from gravitationally lensed dusty star-forming galaxies (DSFGs) based on ubiquitous detections of OH absorption extending to more blueshifted velocities than [C ii ] or CO emission in spatially integrated spectra. Because these lines are redshifted to submillimeter wavelengths, such measurements require careful corrections for atmospheric absorption lines, and a proper accounting of sometimes large variations in measurement uncertainties over these lines. Taking these factors into consideration, we reanalyze OH and [C ii ] data taken with the Atacama Large Millimeter/submillimeter Array for five sources where such data are available, of which four were categorised as exhibiting outflows. Based on their spatially integrated spectra alone, we find statistically significant (≥3 σ ) OH absorption more blueshifted than [C ii ] emission in only one source. By contrast, searching channel maps for signals diluted below the detection threshold in spatially integrated spectra, we find evidence for a separate kinematic component in OH absorption in all five sources in the form of (i) more blueshifted OH absorption than [C ii ] emission and/or (ii) a component in OH absorption exhibiting a different spatio-kinematic pattern than in [C ii ] emission, the latter presumably tracing gas in a rotating disk. Providing a more complete and accurate assessment of molecular outflows in gravitationally lensed DSFGs, we suggest methods to assess the precision of corrections for atmospheric absorption better and to measure the source continuum in future observations more accurately.

Abstract Background Maternal mortality has a significant global impact, especially in low-resource settings. Little prior research has been conducted on the potential effects of poor maternal outcomes on the personal and professional well-being of healthcare providers. This study explores the in-depth experiences and perspectives of obstetric providers in Ghana who work in a setting with frequent maternal mortalities. Methods This is a qualitative study of semi-structured interviews conducted at the Komfo Anokye Teaching Hospital in Ghana. Participants were obstetric healthcare providers, defined as midwives, house officers currently rotating on the obstetrics/gynecology service, and obstetrician/gynecologists at any training or practice level (residents, fellows, and specialists). Interviews were audio-recorded, transcribed verbatim, and uploaded into NVivo for qualitative analysis. Using the Attride-Stirling qualitative model, an incremental and iterative process was used to code interviews with keyword phrases and develop a framework of organizing and global themes. Results Interviews were conducted with 27 participants—15 midwives and 12 physicians (three obstetrician/gynecologist residents, six obstetrician/gynecologist specialists, and three house officers), with sample size determined by data saturation. Obstetric providers’ experiences in a setting with frequent maternal mortalities were dependent on their level of preparedness to manage maternal mortalities and the workplace environment. Providers’ level of preparedness was dependent on both the training they had received on the medical management of obstetric emergencies, as well as a lack of training on the mental health aspects of coping with maternal mortality. The impact of the workplace environment was dependent on systems failures and limited resources, blame from colleagues and supervisors, and a lack of support in the workplace. In turn, obstetric providers’ experiences managing frequent maternal mortalities impacted their clinical care performance and mental health. Conclusions Maternal deaths have profound personal and professional impacts on the healthcare providers who manage them. A large need exists for additional institutional training and support for obstetric providers who manage maternal mortality, especially in low-resource settings like Ghana.

Abstract Objectives We systematically reviewed the current literature evaluating the ability of fully-automated deep learning (DL) and semi-automated traditional machine learning (TML) MRI-based artificial intelligence (AI) methods to differentiate clinically significant prostate cancer (csPCa) from indolent PCa (iPCa) and benign conditions. Methods We performed a computerised bibliographic search of studies indexed in MEDLINE/PubMed, arXiv, medRxiv, and bioRxiv between 1 January 2016 and 31 July 2021. Two reviewers performed the title/abstract and full-text screening. The remaining papers were screened by four reviewers using the Checklist for Artificial Intelligence in Medical Imaging (CLAIM) for DL studies and Radiomics Quality Score (RQS) for TML studies. Papers that fulfilled the pre-defined screening requirements underwent full CLAIM/RQS evaluation alongside the risk of bias assessment using QUADAS-2, both conducted by the same four reviewers. Standard measures of discrimination were extracted for the developed predictive models. Results 17/28 papers (five DL and twelve TML) passed the quality screening and were subject to a full CLAIM/RQS/QUADAS-2 assessment, which revealed a substantial study heterogeneity that precluded us from performing quantitative analysis as part of this review. The mean RQS of TML papers was 11/36, and a total of five papers had a high risk of bias. AUCs of DL and TML papers with low risk of bias ranged between 0.80–0.89 and 0.75–0.88, respectively. Conclusion We observed comparable performance of the two classes of AI methods and identified a number of common methodological limitations and biases that future studies will need to address to ensure the generalisability of the developed models.