Advancing Surveillance Strategies for Hepatocellular Carcinoma: A New Era of Efficacy and Precision.

Hepatocellular carcinoma (HCC) is one of the few cancers with a 5-year survival that has remained below 20%; however, prognosis differs by tumor stage at diagnosis. Curative treatment options among patients with early-stage HCC afford a median survival of 5-10 years. Accordingly, international society guidelines recommend semi-annual HCC surveillance in at-risk patients, including those with cirrhosis or high-risk chronic hepatitis B infection. Surveillance is associated with increased early-stage HCC detection and curative treatments, leading to reduced HCC-related mortality. Abdominal ultrasound has been the cornerstone for HCC surveillance for the past two decades, but recent data have highlighted its suboptimal sensitivity for early-stage HCC detection, particularly in patients with obesity and those with non-viral etiologies of liver disease. The combination of ultrasound plus alpha fetoprotein (AFP) has higher sensitivity for early-stage HCC detection than ultrasound alone, although the combination still misses over one-third of HCC at an early stage. Emerging imaging and blood-based biomarker strategies have promising data in biomarker phase 2 (case-control) and phase 3 (cohort) studies. Beyond ultrasound, Magnetic resonance imaging (MRI) is the best-studied imaging strategy, with superior sensitivity and specificity compared to ultrasound in a cohort study. Abbreviated MRI protocols have been proposed to address concerns about MRI radiological capacity, costs, and patient acceptance. Of biomarker strategies, GALAD (a panel including gender, age, AFP, AFP-L3, and DCP) is the best validated, with promising sensitivity for early-stage HCC detection in a national multi-center cohort study. Liquid biopsy biomarkers, including methylated DNA markers, have also shown promising accuracy in case-control studies. Abbreviated MRI and GALAD are now entering prospective trials that examine clinical outcomes such as early-stage HCC detection and screening-related harms, which are essential data to understand for adoption in clinical practice. As additional surveillance strategies become available, it will allow an era of precision surveillance in which optimal surveillance modalities are tailored to individual patient risk and expected test performance.

Hepatitis C Virus Infection and Hospital-Related Outcomes: A Systematic Review.

Background: People living with hepatitis C infection (HCV) have a significant impact on the global healthcare system, with high rates of inpatient service use. Direct-acting antivirals (DAAs) have the potential to alleviate this burden; however, the evidence on the impact of HCV infection and hospital outcomes is undetermined. This systematic review aims to assess this research gap, including how DAAs may modify the relationship between HCV infection and hospital-related outcomes. Methods: We searched five databases up to August 2022 to identify relevant studies evaluating the impact of HCV infection on hospital-related outcomes. We created an electronic database of potentially eligible articles, removed duplicates, and then independently screened titles, abstracts, and full-text articles. Results: A total of 57 studies were included. Analysis of the included studies found an association between HCV infection and increased number of hospitalizations, length of stay, and readmissions. There was less consistent evidence of a relationship between HCV and in-hospital mortality. Only four studies examined the impact of DAAs, which showed that DAAs were associated with a reduction in hospitalizations and mortality. In the 14 studies available among people living with HIV, HCV coinfection similarly increased hospitalization, but there was less evidence for the other hospital-related outcomes. Conclusions: There is good to high-quality evidence that HCV negatively impacts hospital-related outcomes, primarily through increased hospitalizations, length of stay, and readmissions. Given the paucity of studies on the effect of DAAs on hospital outcomes, future research is needed to understand their impact on hospital-related outcomes.

The cervical branch-first technique in complex resternotomy.

Background: Branch-first total aortic arch repair is a paradigm shift in the technical approach for uninterrupted neuroprotection during open aortic surgery. This technique is further modified to instigate hazardous sternal reentry in patients with hostile mediastinal anatomy at risk of aortic injury. Methods: Intraoperative preparation and the illustrated operative technique of the cervical branch-first technique are described. The accompanying case series narrates the experiences and outcomes of 4 patients who underwent successful complex reoperative aortic surgery utilizing this technique. Results: The indications for resternotomy included a sixth reoperation for recurrent mycotic aortic pseudoaneurysm, a third reoperation for extensive infective endocarditis, a reoperation for complete Bentall graft dehiscence with contained aortic rupture, and a third reoperation for residual type A dissection. All patients survived their proposed surgery. Two patients were operated on in an emergency setting. Two patients separated from cardiopulmonary bypass with extracorporeal support. None experienced permanent neurological sequelae, gut ischemia, peripheral arterial complications, or in-hospital mortality. One mortality due to decompensated heart failure was reported at 6 months postoperatively. Conclusions: The cervical branch-first technique offers unparalleled advantage in neuroprotection from an early stage of complex reoperative aortic surgery. It provides an independent circuit for complete antegrade cerebral perfusion, irrespective of suspension to circulatory flows to the rest of the body during complex reentry into hostile chests. Our experience to date has demonstrated promising outcomes and further refinements will guide patient selection best suited for this technique.

Genomic structures and regulation patterns at HPV integration sites in cervical cancer.

Human papillomavirus (HPV) integration has been implicated in transforming HPV infection into cancer, but its genomic consequences have been difficult to study using short-read technologies. To resolve the dysregulation associated with HPV integration, we performed long-read sequencing on 63 cervical cancer genomes. We identified six categories of integration events based on HPV-human genomic structures. Of all HPV integrants, defined as two HPV-human breakpoints bridged by an HPV sequence, 24% contained variable copies of HPV between the breakpoints, a phenomenon we termed heterologous integration. Analysis of DNA methylation within and in proximity to the HPV genome at individual integration events revealed relationships between methylation status of the integrant and its orientation and structure. Dysregulation of the human epigenome and neighboring gene expression in cis with the HPV-integrated allele was observed over megabase-ranges of the genome. By elucidating the structural, epigenetic, and allele-specific impacts of HPV integration, we provide insight into the role of integrated HPV in cervical cancer.

A longitudinal single-cell atlas of treatment response in pediatric AML.

Pediatric acute myeloid leukemia (pAML) is characterized by heterogeneous cellular composition, driver alterations and prognosis. Characterization of this heterogeneity and how it affects treatment response remains understudied in pediatric patients. We used single-cell RNA sequencing and single-cell ATAC sequencing to profile 28 patients representing different pAML subtypes at diagnosis, remission and relapse. At diagnosis, cellular composition differed between genetic subgroups. Upon relapse, cellular hierarchies transitioned toward a more primitive state regardless of subtype. Primitive cells in the relapsed tumor were distinct compared to cells at diagnosis, with under-representation of myeloid transcriptional programs and over-representation of other lineage programs. In some patients, this was accompanied by the appearance of a B-lymphoid-like hierarchy. Our data thus reveal the emergence of apparent subtype-specific plasticity upon treatment and inform on potentially targetable processes.

Automated Classification of Quality Defect Issues Relating to Substandard Medicines Using a Hybrid Machine Learning and Rule-Based Approach.

BACKGROUND AND OBJECTIVE: Substandard medicines can lead to serious safety issues affecting public health; however, the nature of such issues can be widely heterogeneous. Health product regulators seek to prioritise critical product quality defects for review to ensure that prompt risk mitigation measures are taken. This study aims to classify the nature of issues for substandard medicines using machine learning to augment a risk-based and timely review of cases. METHODS: A combined machine learning algorithm with a keyword-based model was developed to classify quality issues using text relating to substandard medicines (CISTERM). The nature of issues for product defect cases were classified based on Medical Dictionary for Regulatory Activities-Health Sciences Authority (MedDRA-HSA) lowest-level terms. RESULTS: Product defect cases received from January 2010 to December 2021 were used for training (n = 11,082) and for testing (n = 2771). The machine learning model achieved a good recall (precision) of 92% (96%) for 'Product adulterated and/or contains prohibited substance', 86% (90%) for 'Out of specification or out of trend test result' and 90% (91%) for 'Manufacturing non-compliance'. CONCLUSION: Post-market surveillance of substandard medicines remains a key activity for drug regulatory authorities. A combined machine learning algorithm with keyword-based model can help to prioritise the review of product quality defect issues in a timely manner.

Myeloid leukemia vulnerabilities embedded in long noncoding RNA locus MYNRL15.

The noncoding genome presents a largely untapped source of new biological insights, including thousands of long noncoding RNA (lncRNA) loci. While lncRNA dysregulation has been reported in myeloid malignancies, their functional relevance remains to be systematically interrogated. We performed CRISPRi screens of lncRNA signatures from normal and malignant hematopoietic cells and identified MYNRL15 as a myeloid leukemia dependency. Functional dissection suggests an RNA-independent mechanism mediated by two regulatory elements embedded in the locus. Genetic perturbation of these elements triggered a long-range chromatin interaction and downregulation of leukemia dependency genes near the gained interaction sites, as well as overall suppression of cancer dependency pathways. Thus, this study describes a new noncoding myeloid leukemia vulnerability and mechanistic concept for myeloid leukemia. Importantly, MYNRL15 perturbation caused strong and selective impairment of leukemia cells of various genetic backgrounds over normal hematopoietic stem and progenitor cells in vitro, and depletion of patient-derived xenografts in vivo.

Prevalence of subclinical lung cancer detected at autopsy: a systematic review.

BACKGROUND: Lung cancer screening in high-risk populations with low-dose computed tomography is supported by international associations and recommendations. Overdiagnosis is considered a risk of screening with associated harms. The aim of this paper is to determine the prevalence of subclinical lung cancer diagnosed post-mortem to better understand the reservoir of subclinical lung cancer. METHODS: We searched EMBASE, PubMed, and MEDLINE databases from inception until March 2022 with no language restrictions. We considered all studies with ≥100 autopsies in adults. Two reviewers independently assessed eligibility of studies, extracted data, and assessed risk of bias of included studies. We performed a meta-analysis using a random-effects model for prevalence of subclinical lung cancer diagnosed post-mortem with sensitivity and subgroup analyses. RESULTS: A total of 13 studies with 16 730 autopsies were included. Pooled prevalence was 0.4% (95% CI 0.20 to 0.82%, I2 = 84%, tau2 = 1.19, low certainty evidence,16 730 autopsies). We performed a sensitivity analysis excluding studies which did not specify exclusion of children in their cohort, with a pooled prevalence of subclinical lung cancer of 0.87% (95% CI 0.48 to 1.57%, I2 = 71%, tau2 = 0.38, 6998 autopsies, 8 studies). CONCLUSIONS: This is the first published systematic review to evaluate the prevalence of post-mortem subclinical lung cancer. Compared to autopsy systematic reviews in breast, prostate and thyroid cancers, the pooled prevalence is lower in lung cancer for subclinical cancer. This result should be interpreted with caution due to the included studies risk of bias and heterogeneity, with further high-quality studies required in target screening populations.

GDF15 enhances body weight and adiposity reduction in obese mice by leveraging the leptin pathway.

GDF15 regulates its anorexic effects through the hindbrain area postrema (AP) and nucleus of the solitary tract (NTS) neurons where its receptor, glial-derived neurotrophic factor receptor alpha-like (GFRAL), is expressed. The actions of GDF15 may interact with other appetite regulators elevated in obesity, such as leptin. Here, we report that in mice with high-fat-diet-induced obesity (HFD), the combined infusion of GDF15 and leptin causes significantly greater weight and adiposity loss than either treatment alone, indicating potentiation between GDF15 and leptin. Furthermore, obese, leptin-deficient ob/ob mice are less responsive to GDF15, as are normal mice treated with a competitive leptin antagonist. GDF15 and leptin induce more hindbrain neuronal activation in HFD mice than either treatment alone does. We report extensive connections between GFRAL- and LepR-expressing neurons and find LepR knockdown in the NTS to reduce the GDF15-mediated activation of AP neurons. Overall, these findings suggest that leptin signaling pathways in the hindbrain increase GDF15's metabolic actions.

PBRM1-deficient PBAF complexes target aberrant genomic loci to activate the NF-κB pathway in clear cell renal cell carcinoma.

PBRM1 encodes an accessory subunit of the PBAF SWI/SNF chromatin remodeller, and the inactivation of PBRM1 is a frequent event in kidney cancer. However, the impact of PBRM1 loss on chromatin remodelling is not well examined. Here we show that, in VHL-deficient renal tumours, PBRM1 deficiency results in ectopic PBAF complexes that localize to de novo genomic loci, activating the pro-tumourigenic NF-κB pathway. PBRM1-deficient PBAF complexes retain the association between SMARCA4 and ARID2, but have loosely tethered BRD7. The PBAF complexes redistribute from promoter proximal regions to distal enhancers containing NF-κB motifs, heightening NF-κB activity in PBRM1-deficient models and clinical samples. The ATPase function of SMARCA4 maintains chromatin occupancy of pre-existing and newly acquired RELA specific to PBRM1 loss, activating downstream target gene expression. Proteasome inhibitor bortezomib abrogates RELA occupancy, suppresses NF-κB activation and delays growth of PBRM1-deficient tumours. In conclusion, PBRM1 safeguards the chromatin by repressing aberrant liberation of pro-tumourigenic NF-κB target genes by residual PBRM1-deficient PBAF complexes.

Antiplasmodial activity, structure-activity relationship and studies on the action of novel benzimidazole derivatives.

Malaria cases and deaths keep being excessively high every year. Some inroads gained in the last two decades have been eroded especially due to the surge of resistance to most antimalarials. The search for new molecules that can replace the ones currently in use cannot stop. In this report, the synthesis of benzimidazole derivatives guided by structure-activity parameters is presented. Thirty-six molecules obtained are analyzed according to their activity against P. falciparum HB3 strain based on the type of substituent on rings A and B, their electron donor/withdrawing, as well as their dimension/spatial properties. There is a preference for electron donating groups on ring A, such as Me in position 5, or better, 5, 6-diMe. Ring B must be of the pyridine type such as picolinamide, other modifications are generally not favorable. Two molecules, 1 and 33 displayed antiplasmodial activity in the high nanomolar range against the chloroquine sensitive strain, with selectivity indexes above 10. Activity results of 1, 12 and 16 on a chloroquine resistance strain indicated an activity close to chloroquine for compound 1. Analysis of some of their effect on the parasites seem to suggest that 1 and 33 affect only the parasite and use a route other than interference with hemozoin biocrystallization, the route used by chloroquine and most antimalarials.

RUNX1 isoform disequilibrium promotes the development of trisomy 21-associated myeloid leukemia.

Gain of chromosome 21 (Hsa21) is among the most frequent aneuploidies in leukemia. However, it remains unclear how partial or complete amplifications of Hsa21 promote leukemogenesis and why children with Down syndrome (DS) (ie, trisomy 21) are particularly at risk of leukemia development. Here, we propose that RUNX1 isoform disequilibrium with RUNX1A bias is key to DS-associated myeloid leukemia (ML-DS). Starting with Hsa21-focused CRISPR-CRISPR-associated protein 9 screens, we uncovered a strong and specific RUNX1 dependency in ML-DS cells. Expression of the RUNX1A isoform is elevated in patients with ML-DS, and mechanistic studies using murine ML-DS models and patient-derived xenografts revealed that excess RUNX1A synergizes with the pathognomonic Gata1s mutation during leukemogenesis by displacing RUNX1C from its endogenous binding sites and inducing oncogenic programs in complex with the MYC cofactor MAX. These effects were reversed by restoring the RUNX1A:RUNX1C equilibrium in patient-derived xenografts in vitro and in vivo. Moreover, pharmacological interference with MYC:MAX dimerization using MYCi361 exerted strong antileukemic effects. Thus, our study highlights the importance of alternative splicing in leukemogenesis, even on a background of aneuploidy, and paves the way for the development of specific and targeted therapies for ML-DS, as well as for other leukemias with Hsa21 aneuploidy or RUNX1 isoform disequilibrium.

Psychiatric healthcare resource utilization following initiation of aripiprazole once-monthly: a retrospective real-world study.

OBJECTIVES: This observational retrospective real-world study examined changes in healthcare resource utilization (HCRU) pre- and post-initiation of aripiprazole once-monthly (AOM 400) in patients with schizophrenia or bipolar I disorder. METHODS: Electronic health record-derived, de-identified data from the NeuroBlu Database (2013-2020) were used to identify patients ≥18 years with schizophrenia (n = 222) or bipolar I disorder (n = 129) who were prescribed AOM 400, and had visit data within 3, 6, 9, or 12 months pre- and post-initial AOM 400 prescription. Rates of inpatient hospitalization, emergency department visits, inpatient readmissions, and average length of stay were examined and compared over 3, 6, 9, and 12 months pre-/post-AOM 400 using a McNemar test. RESULTS: Statistically significant differences were seen in both schizophrenia and bipolar I disorder patient cohorts pre- and post-AOM 400 in inpatient hospitalization rates (p < .001 all time points, both cohorts) and 30-day readmission per patient rates (p < .001 all time points, both cohorts). Statistically significant improvement in mean length of stay was observed in both cohorts at all time points, except for at six months in patients with schizophrenia. Emergency department visit rates were significantly lower after AOM 400 initiation for both cohorts at all time points (p < .001). CONCLUSIONS: A reduction in the rate of hospitalizations, emergency department visits, 30-day readmissions, and average length-of-stay was observed for patients diagnosed with either schizophrenia or bipolar I disorder, which suggests a positive effect of AOM 400 treatment on HCRU outcomes and is supportive of earlier analyses from different data sources.

Anti-Trypanosomal Bufadienolides from the Oocytes of the Toad Rhinella alata (Anura, Bufonidae).

Amphibians are widely known as a prolific source of bioactive metabolites. In this work, we isolated and characterized compounds with antiparasitic activity from the oocytes of the toad Rhinella alata collected in Panama. Bio-guided isolation and structural elucidation were carried out using chromatographic and spectroscopic techniques, respectively. The organic extract was subjected to solid phase extraction followed by HPLC purification of the fraction with in vitro activity against Trypanosoma cruzi trypomastigotes. Seven steroids (1-7) of the bufadienolide family were isolated, and their structures were determined using NMR and MS analyses; of these 19-formyl-dyscinobufotalin, (3) is reported as a new natural product. Compounds 1 and 3-7 resulted in a good anti-trypanosomal activity profile. Among these, 16ß-hydroxyl-hellebrigenin (1) and bufalin (7) showed significant selectivity values of >5 and 2.69, respectively, while the positive control benznidazole showed a selectivity of 18.81. Furthermore, molecular docking analysis showed compounds 1, 3 and 7 interact through H-bonds with the amino acid residues GLN-19, ASP-158, HIS-159 and TRP-177 from cruzipain at the catalytic site. Given the lack of therapeutic options to treat American trypanosomiasis, this work can serve as the basis for further studies that aim for the development of bufadienolides or their derivatives as drugs against Chagas disease.

Unusual Cortical Phenotype After Hematopoietic Stem Cell Transplantation in a Patient With Osteopetrosis.

The osteopetroses are a group of rare genetic diseases caused by osteoclast dysfunction or absence. The hallmark of osteopetrosis is generalized increased bone mineral density (BMD). However, the bone is fragile and fractures are common. Autosomal recessive osteopetrosis is usually a severe disorder and often life-threatening in childhood. We present male siblings with autosomal recessive osteopetrosis due to biallelic variants in TCIRG1 who survived childhood and underwent hematopoietic stem cell transplant (HSCT) in adulthood. One sibling died of posttransplant complications. After transplant, the other sibling had improvement of multiple clinical parameters, including some decline in BMD Z-scores by dual-energy X-ray absorptiometry (DXA) and cessation of fractures. However, spine quantitative computed tomography 11 years after transplant demonstrated an anvil pattern of sclerosis with BMD Z-score of +18.3. High-resolution peripheral quantitative computed tomography (HR-pQCT) of the tibia demonstrated near complete obliteration of the marrow space combined with an unusual cortical phenotype, suggesting extensive cortical porosity at the distal tibia. This case highlights that despite successful transplantation and subsequent improvement in clinical parameters, this patient continued to have significantly elevated bone density and decreased marrow space. Transplant-associated increased cortical porosity is multifactorial and occurs in two-thirds of non-osteopetrotic patients undergoing HSCT. This finding after transplant in osteopetrosis may suggest particular sensitivity of the cortical bone to resorptive activity of transplanted osteoclasts. The case also suggests HR-pQCT may be a useful modality for imaging and assessing the therapeutic effects on bone in individuals with osteopetrosis. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Chromatin Rewiring by Mismatch Repair Protein MSH2 Alters Cell Adhesion Pathways and Sensitivity to BET Inhibition in Gastric Cancer.

Mutations in the DNA mismatch repair gene MSH2 are causative of microsatellite instability (MSI) in multiple cancers. Here, we discovered that besides its well-established role in DNA repair, MSH2 exerts a novel epigenomic function in gastric cancer. Unbiased CRISPR-based mass spectrometry combined with genome-wide CRISPR functional screening revealed that in early-stage gastric cancer MSH2 genomic binding is not randomly distributed but rather is associated specifically with tumor-associated super-enhancers controlling the expression of cell adhesion genes. At these loci, MSH2 genomic binding was required for chromatin rewiring, de novo enhancer-promoter interactions, maintenance of histone acetylation levels, and regulation of cell adhesion pathway expression. The chromatin function of MSH2 was independent of its DNA repair catalytic activity but required MSH6, another DNA repair gene, and recruitment to gene loci by the SWI/SNF chromatin remodeler SMARCA4/BRG1. Loss of MSH2 in advanced gastric cancers was accompanied by deficient cell adhesion pathway expression, epithelial-mesenchymal transition, and enhanced tumorigenesis in vitro and in vivo. However, MSH2-deficient gastric cancers also displayed addiction to BAZ1B, a bromodomain-containing family member, and consequent synthetic lethality to bromodomain and extraterminal motif (BET) inhibition. Our results reveal a role for MSH2 in gastric cancer epigenomic regulation and identify BET inhibition as a potential therapy in MSH2-deficient gastric malignancies. SIGNIFICANCE: DNA repair protein MSH2 binds and regulates cell adhesion genes by enabling enhancer-promoter interactions, and loss of MSH2 causes deficient cell adhesion and bromodomain and extraterminal motif inhibitor synthetic lethality in gastric cancer.

Long noncoding RNAs as regulators of pediatric acute myeloid leukemia.

Long noncoding RNAs (lncRNAs) are increasingly emerging as regulators across human development and disease, and many have been described in the context of hematopoiesis and leukemogenesis. These studies have yielded new molecular insights into the contribution of lncRNAs to AML development and revealed connections between lncRNA expression and clinical parameters in AML patients. In this mini review, we illustrate the versatile functions of lncRNAs in AML, with a focus on pediatric AML, and present examples that may serve as future therapeutic targets or predictive factors.

A mobile health intervention to encourage physical activity in children: a randomised controlled trial.

BACKGROUND: Despite immense benefits of physical activity on health and developmental outcomes, few children achieve recommended daily levels of physical activity. Given more than half of families with children own a dog, we investigated the effect of a mobile health (mHealth) intervention to encourage dog-facilitated physical activity through increased family dog walking and children's active play with their dog. METHODS: The PLAYCE PAWS study was a three-armed randomised pilot trial conducted in Perth, Western Australia. Children aged 5-10 years with a family dog were randomised to 4 weeks of either 1) SMS-only intervention, 2) 'SMS + pedometer' intervention or 3) 'usual care' control. The mHealth intervention involved SMS messages to parents; the 'SMS + pedometer' group also received a dog pedometer and personalised dog steps diary. Parent-reported measures were collected at baseline, 1- and 3-months post intervention. The primary outcome was weekly frequency of family dog walking and dog play; secondary outcomes were child attachment to the dog and feasibility of the intervention. RESULTS: A total of 150 children were randomised in staggered blocks to SMS-only (n = 50), 'SMS + pedometer' (n = 50) or usual care (n = 50). No differences were observed in family dog walking and dog play at 1-month. SMS-only children (OR 2.6, 95% CI 1.17, 5.83, P = 0.019) and all intervention children (OR 1.97, 95% CI 1.01, 3.86, P = 0.048) were more likely to increase total dog-facilitated physical activity (sum of family dog walking and dog play responses) at 3-months. The positive associations with total dog-facilitated physical activity disappeared (all P > 0.05) after adjusting for socio-demographic factors. CONCLUSIONS: The PLAYCE PAWS mHealth intervention did not significantly affect dog-facilitated physical activity in children. Given high levels of dog ownership in the community, SMS prompts could be a low-cost intervention to encourage more physical activity in children. Further research is needed to understand how increased interaction with the family dog impacts on children's overall physical activity and other health and development outcomes. TRIAL REGISTRATION: ANZCTR, ACTRN12620000288921 , retrospectively registered on 4/3/2020.

A risk classification model for prioritising the management of quality issues relating to substandard medicines in Singapore.

BACKGROUND: Monitoring for substandard medicines by regulatory agencies is a key post-market surveillance activity. It is important to prioritise critical product defects for review to ensure that prompt risk mitigation actions are taken. METHODS: A regulatory risk impact prioritisation model for product defects (RISMED) with 11 factors considering the seriousness and extent of impact of a defect was developed. The model generated an overall score that categorised cases into high, medium or low impact. The model was further developed into a statistical risk scoring model (stat-RISMED) using multivariate logistic regression that classified cases into high and non-high impact. Both models were evaluated against an expert-derived gold standard annotation corpus and tested on an independent dataset. RESULTS: Product defect cases received from January 2011 to June 2020 (n = 660) were used to train stat-RISMED and cases from July 2020 to June 2021 (n = 220) for validation. The stat-RISMED identified four factors associated with high impact cases, namely defect classification based on MedDRA-HSA terms, therapeutic indication of product, detectability of defect and whether any overseas regulatory actions were performed. Compared to RISMED, stat-RISMED achieved an improved sensitivity (94% vs 42%) and positive predictive value (47% vs 43%) for the identification of high impact cases, against the gold standard labels. CONCLUSIONS: This study reported characteristics that predicts cases with high impact, and the use of a statistical model to identify such cases. The model may potentially be applied to prioritise product defect issues and strengthen overall surveillance efforts of substandard medicines.