Genotype correlates with clinical course and outcome of children with tight junction protein 2 (TJP2) deficiency-related cholestasis.

BACKGROUND AND AIMS: The study aimed to describe the clinical course and outcomes, and analyze the genotype-phenotype correlation in patients with tight junction protein 2 (TJP2) deficiency. APPROACH AND RESULTS: Data from all children with chronic cholestasis and either homozygous or compound heterozygous mutations in TJP2 were extracted and analyzed. The patients were categorized into 3 genotypes: TJP2-A (missense mutations on both alleles), TJP2-B (missense mutation on one allele and a predicted protein-truncating mutation [PPTM] on the other), and TJP2-C (PPTMs on both alleles). A total of 278 cases of genetic intrahepatic cholestasis were studied, with TJP2 deficiency accounting for 44 cases (15.8%). Of these, 29 were homozygous and 15 were compound heterozygous variants of TJP2 . TJP2-A genotype was identified in 21 (47.7%), TJP2-B in 7 cases (15.9%), and TJP2-C in 16 cases (36.4%), respectively. Patients with the TJP2-C genotype were more likely to experience early infantile cholestasis (87.5% vs. 53.5%, p =0.033), less likely to clear jaundice (12.5% vs. 52.2%, p =0.037), more likely to develop ascites, and had higher serum bile acids. Patients with the TJP2-C genotype were more likely to die or require liver transplantation (native liver survival: 12.5% vs. 78.6%, p <0.001), with a median age at death/liver transplantation of 2.5 years. Cox regression analysis revealed that TJP2-C mutations ( p =0.003) and failure to resolve jaundice ( p =0.049) were independent predictors of poor outcomes. CONCLUSIONS: Patients with the TJP2-C genotype carrying PPTMs in both alleles had a rapidly progressive course, leading to early decompensation and death if they did not receive timely liver transplantation.

Direct benefit transfer for nutritional support of patients with TB in India-analysis of national TB program data of 3.7 million patients, 2018-2022.

BACKGROUND: Patients with TB have additional nutritional requirements and thus additional costs to the household. Ni-kshay Poshan Yojana(NPY) is a Direct Benefit Transfer (DBT) scheme under the National Tuberculosis Elimination Programme(NTEP) in India which offers INR 500 monthly to all notified patients with TB for nutritional support during the period of anti-TB treatment. Five years after its implementation, we conducted the first nationwide evaluation of NPY. METHODS: In our retrospective cohort study using programmatic data of patients notified with TB in nine randomly selected Indian states between 2018 and 2022, we estimated the proportion of patients who received at least one NPY instalment and the median time to receive the first instalment. We determined the factors associated (i) with non-receipt of NPY using a generalised linear model with Poisson family and log link and (ii) with time taken to receive first NPY benefit in 2022 using quantile regression at 50th percentile. RESULTS: Overall, 3,712,551 patients were notified between 2018 and 2022. During this period, the proportion who received at least one NPY instalment had increased from 56.9% to 76.1%. Non-receipt was significantly higher among patients notified by private sector (aRR 2.10;2.08,2.12), reactive for HIV (aRR 1.69;1.64,1.74) and with missing/undetermined diabetic status (aRR 2.02;1.98,2.05). The median(IQR) time to receive the first instalment had reduced from 200(109,331) days in 2018 to 91(51,149) days in 2022. Patients from private sector(106.9;106.3,107.4days), those with HIV-reactive (103.7;101.8,105.7days), DRTB(104.6;102.6,106.7days) and missing/undetermined diabetic status (115.3;114,116.6days) experienced longer delays. CONCLUSIONS: The coverage of NPY among patients with TB had increased and the time to receipt of benefit had halved in the past five years. Three-fourths of the patients received at least one NPY instalment, more than half of whom had waited over three months to receive the first instalment. NTEP has to focus on timely transfer of benefits to enable patients to meet their additional nutritional demands, experience treatment success and avoid catastrophic expenditure.

Congenital Bile Acid Synthesis Defect Type 3 With Severe Neonatal Cholestasis.

Congenital bile acid synthesis defect type 3 is a rare metabolic liver disease with only eight patients reported in literature. We describe clinical, pathological and molecular features for a ninth patient. A 4-month-old infant presented to us with conjugated hyperbilirubinemia. His liver biopsy revealed giant cell change, steatosis, and activity with diffuse fibrosis. Immunostaining with bile salt export pump showed preserved canalicular pattern and γ-glutamyl transferase 1 staining showed unusual complete membranous pattern. Genetic workup revealed homozygous single base pair duplication in exon 3 of the CYP7B1 gene. He succumbed to liver disease at 7 months of age.

Compound Heterozygous Myosin 5B (Myo5b) Mutation with Early Onset Progressive Cholestasis and No Intestinal Failure.

Background: Exome sequencing studies have recently identified novel genes implicated in normal or low GGT pediatric cholestasis including myosin 5B (MYO5B). Case report: We identified novel compound heterozygote mutations in exon 14 and exon 19 of the MYO5B gene in an 18-month-old Indian child with history of fluctuating jaundice and severe pruritus. His liver biopsy showed portal and perivenular fibrosis with focal bridging septa and mild activity. He is currently on UDCA, cholestyramine and vitamin supplements. There is no history of diarrhea. His asymptomatic mother showed heterozygous mutation in exon 19 of the MYO5B gene and his asymptomatic father showed heterozygous mutation in exon 14 of the MYO5B gene. Conclusion: Our report confirms that patients with compound heterozygote mutations in MYO5B develop progressive cholestasis with no intestinal disease.

Rapid HIV-1 Capsid Interaction Screening Using Fluorescence Fluctuation Spectroscopy.

The HIV capsid is a multifunctional protein capsule that mediates the delivery of the viral genetic material into the nucleus of the target cell. Host cell proteins bind to a number of repeating binding sites on the capsid to regulate steps in the replication cycle. Here, we develop a fluorescence fluctuation spectroscopy method using self-assembled capsid particles as the bait to screen for fluorescence-labeled capsid-binding analytes ("prey" molecules) in solution. The assay capitalizes on the property of the HIV capsid as a multivalent interaction platform, facilitating high sensitivity detection of multiple prey molecules that have accumulated onto capsids as spikes in fluorescence intensity traces. By using a scanning stage, we reduced the measurement time to 10 s without compromising on sensitivity, providing a rapid binding assay for screening libraries of potential capsid interactors. The assay can also identify interfaces for host molecule binding by using capsids with defects in known interaction interfaces. Two-color coincidence detection using the fluorescent capsid as the bait further allows the quantification of binding levels and determination of binding affinities. Overall, the assay provides new tools for the discovery and characterization of molecules used by the HIV capsid to orchestrate infection. The measurement principle can be extended for the development of sensitive interaction assays, utilizing natural or synthetic multivalent scaffolds as analyte-binding platforms.

Self-Assembly of Fluorescent HIV Capsid Spheres for Detection of Capsid Binders.

The human immunodeficiency virus (HIV) capsid is a cone-shaped capsule formed from the viral capsid protein (CA), which is arranged into a lattice of hexamers and pentamers. The capsid comprises multiple binding interfaces for the recruitment of host proteins and macromolecules used by the virus to establish infection. Here, we coassembled CA proteins engineered for pentamer cross-linking and fluorescence labeling, into spherical particles. The CA spheres, which resemble the pentamer-rich structure of the end caps of the native HIV capsid, were immobilized onto surfaces as biorecognition elements for fluorescence microscopy-based quantification of host protein binding. The capsid-binding host protein cyclophilin A (CypA) is bound to CA spheres with the same affinity as CA tubes but at a higher CypA/CA stoichiometry, suggesting that the level of recruitment of CypA to the HIV capsid is dependent on curvature.

Knowledge and attitude of HIV/AIDS among women in Nigeria: a cross-sectional study.

Background: The Human Immunodeficiency Virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS) epidemic is one of the world's most serious public health and social problems. Promoting knowledge and attitude towards HIV/AIDS is a key strategy to control the prevalence of this growing epidemic. This study aimed to measure knowledge and attitude about HIV/AIDS along with the factors of association Nigerian women. Methods: This is a cross-sectional study based on data from the 2013 Demographic Health Survey (DHS) conducted among community dwelling women in Nigeria. A set of 13 questions was identified relevant to knowledge and attitude about HIV/AIDS. Each correct answer was scored as 1 and wrong answer as '0'. Normality of the variables was examined using Shapiro-Wilks tests. The socioeconomic and community factors associated with HIV/AIDS knowledge and attitude were examined by linear regression with dummy variables model. Results: Means score (SD) on knowledge of transmission was 6.4 (2.0) and that for attitude was 2.1 (1.2). In the regression models, knowledge and attitude of HIV/AIDS were positively associated with survey years and respondents' age; geographical region was significantly associated with HIV/AIDS knowledge and attitude; rural respondents had significant reduction in knowledge [Exp(B)=0.86; 95% confidence interval (CI)=0.83-0.89] and positive attitude to HIV/AIDS [Exp(B)=0.91; 95% CI=0.89-0.93] compared with the urban counterpart, respectively. Conclusion: Findings of the present study suggested that women's knowledge and attitude about HIV/AIDS in Nigeria needs more attention to attain the global target to end its epidemics and other communicable diseases by 2030.

Road Anomalies Detection System Evaluation.

Anomalies on road pavement cause discomfort to drivers and passengers, and may cause mechanical failure or even accidents. Governments spend millions of Euros every year on road maintenance, often causing traffic jams and congestion on urban roads on a daily basis. This paper analyses the difference between the deployment of a road anomalies detection and identification system in a “conditioned” and a real world setup, where the system performed worse compared to the “conditioned” setup. It also presents a system performance analysis based on the analysis of the training data sets; on the analysis of the attributes complexity, through the application of PCA techniques; and on the analysis of the attributes in the context of each anomaly type, using acceleration standard deviation attributes to observe how different anomalies classes are distributed in the Cartesian coordinates system. Overall, in this paper, we describe the main insights on road anomalies detection challenges to support the design and deployment of a new iteration of our system towards the deployment of a road anomaly detection service to provide information about roads condition to drivers and government entities.

Urban-rural difference in satisfaction with primary healthcare services in Ghana.

BACKGROUND: Understanding regional variation in patient satisfaction about healthcare systems (PHCs) on the quality of services provided is instrumental to improving quality and developing a patient-centered healthcare system by making it more responsive especially to the cultural aspects of health demands of a population. Reaching to the innovative National Health Insurance Scheme (NHIS) in Ghana, surpassing several reforms in healthcare financing has been a milestone. However, the focus of NHIS is on the demand side of healthcare delivery. Studies focusing on the supply side of healthcare delivery, particularly the quality of service as perceived by the consumers are required. A growing number of studies have focused on regional differences of patient satisfaction in developed countries, however little research has been conducted concerning patient satisfaction in resource-poor settings like in Ghana. This study was therefore dedicated to examining the variation in satisfaction across rural and urban women in Ghana. METHODS: Data for the present study were obtained from the latest demographic and health survey in Ghana (GDHS 2014). Participants were 3576 women aged between 15 and 49 years living in non-institutional settings in Ghana. Summary statistics in percentages was used to present respondents' demographic, socioeconomic characteristics. Chi-square test was used to find association between urban-rural differentials with socio-economic variables. Multiple logistic regression was performed to measure the association of being satisfied with primary healthcare services with study variables. Model fitness was tested by pseudo R 2. Statistical significance was set at p < 0.05. RESULTS: The findings in this study revealed that about 57.1% were satisfied with primary health care services. The urban and rural areas reported 57.6 and 56.6% respectively which showed no statistically significant difference (z = 0.64; p = 0.523; 95%CI: -0.022, 0.043). Bivariate analysis showed that region, highest level of education, wealth index and type of facility were significantly associated with location of residence (urban-rural areas). After adjusting for confounding variables using logistic regression, geographical location became a key factor of satisfaction with primary healthcare services by location of residence. In urban areas, respondents from Greater Accra had 64% increase in the level of satisfaction when compared to those in Western region (OR = 1.64; 95CI: 1.09-2.47), Upper East had 75% increase in satisfaction compared to Western region (OR = 1.75; 95%CI: 1.08-2.84), Northern had an estimated 44% reduction in satisfaction when compared to Western region (OR = 0.56; 95%CI: 0.34-0.92). However, rural areas in Central, Volta, Eastern, Ashanti, Brong Aghafo, Northern and Upper West region had 51, 81, 69, 46, 62, 75 and 61% reduction respectively in the level of satisfaction when compared to Western region. CONCLUSIONS: Patient satisfaction is an important indicator of health outcomes. Quality of care and measuring level of patient satisfaction has been found to be the most useful tool to predict utilization and compliance. In fact, satisfied patients are more likely than unsatisfied ones to continue using health care services. Our results suggest that policymakers need to better understand the determinants of satisfaction with the health system and how different socio-demographic groups perceive satisfaction with healthcare services so as to address health inequalities between urban and rural areas within the same country.

Compensatory substitutions in the HIV-1 capsid reduce the fitness cost associated with resistance to a capsid-targeting small-molecule inhibitor.

UNLABELLED: The HIV-1 capsid plays multiple roles in infection and is an emerging therapeutic target. The small-molecule HIV-1 inhibitor PF-3450074 (PF74) blocks HIV-1 at an early postentry stage by binding the viral capsid and interfering with its function. Selection for resistance resulted in accumulation of five amino acid changes in the viral CA protein, which collectively reduced binding of the compound to HIV-1 particles. In the present study, we dissected the individual and combinatorial contributions of each of the five substitutions Q67H, K70R, H87P, T107N, and L111I to PF74 resistance, PF74 binding, and HIV-1 infectivity. Q67H, K70R, and T107N each conferred low-level resistance to PF74 and collectively conferred strong resistance. The substitutions K70R and L111I impaired HIV-1 infectivity, which was partially restored by the other substitutions at positions 67 and 107. PF74 binding to HIV-1 particles was reduced by the Q67H, K70R, and T107N substitutions, consistent with the location of these positions in the inhibitor-binding pocket. Replication of the 5Mut virus was markedly impaired in cultured macrophages, reminiscent of the previously reported N74D CA mutant. 5Mut substitutions also reduced the binding of the host protein CPSF6 to assembled CA complexes in vitro and permitted infection of cells expressing the inhibitory protein CPSF6-358. Our results demonstrate that strong resistance to PF74 requires accumulation of multiple substitutions in CA to inhibit PF74 binding and compensate for fitness impairments associated with some of the sequence changes. IMPORTANCE: The HIV-1 capsid is an emerging drug target, and several small-molecule compounds have been reported to inhibit HIV-1 infection by targeting the capsid. Here we show that resistance to the capsid-targeting inhibitor PF74 requires multiple amino acid substitutions in the binding pocket of the CA protein. Three changes in CA were necessary to inhibit binding of PF74 while maintaining viral infectivity. Replication of the PF74-resistant HIV-1 mutant was impaired in macrophages, likely owing to altered interactions with host cell factors. Our results suggest that HIV-1 resistance to capsid-targeting inhibitors will be limited by functional constraints on the viral capsid protein. Therefore, this work enhances the attractiveness of the HIV-1 capsid as a therapeutic target.

Trends and determinants of HIV/AIDS knowledge among women in Bangladesh.

BACKGROUND: Globally, women share an indiscriminate burden of the HIV epidemic and the associated socioeconomic consequences. Previous studies have demonstrated a positive correlation between levels of HIV knowledge with its prevalence. However, for Bangladesh such evidence is non-existent. In this study, we aimed to explore the extent of HIV knowledge in relation to the socio-demographic variables such as age, region, area of residence i.e., urban or rural, wealth index and education, and investigate the factors influencing the level of HIV knowledge among Bangladeshi women. METHODS: We used data from the Bangladesh Demographic and Health Survey (BDHS) survey conducted in 2011. In total 12,512 women ageing between 15 and 49 ever hearing about HIV regardless of HIV status were selected for this study. HIV knowledge level was estimated by analyzing respondents' answers to a set of 11 basic questions indicative of general awareness and mode of transmission. Descriptive statistics, cross-tabulation and multinominal logistic regression were performed for data analysis. RESULTS: Little over half the respondents had good knowledge regarding HIV transmission risks. The mean HIV knowledge score was -0.001 (SD 0.914). Average correct response rate about mode of transmission was higher than for general awareness. Educational level of women and sex of household head were found to be significantly associated with HIV knowledge in the high score group. Those with no education, primary education or secondary education were less likely to be in the high score group for HIV knowledge when compared with those with higher than secondary level of education. Similarly those with male as household head were less likely to be in the higher score group for HIV knowledge. CONCLUSIONS: Level of HIV knowledge among Bangladeshi women is quite low, and the limiting factors are rooted in various demographic and household characteristics. Education and sex of the household head have been found to be significantly correlated with the level of HIV knowledge and propound sound grounds for their incorporation in the future HIV prevention strategies. Education of women may also have wider ramifications allowing reduction in gender inequality, which in turn favors higher knowledge about HIV.

The host proteins transportin SR2/TNPO3 and cyclophilin A exert opposing effects on HIV-1 uncoating.

Following entry of the HIV-1 core into target cells, productive infection depends on the proper disassembly of the viral capsid (uncoating). Although much is known regarding HIV-1 entry, the actions of host cell proteins that HIV-1 utilizes during early postentry steps are poorly understood. One such factor, transportin SR2 (TRN-SR2)/transportin 3 (TNPO3), promotes infection by HIV-1 and some other lentiviruses, and recent studies have genetically linked TNPO3 dependence of infection to the viral capsid protein (CA). Here we report that purified recombinant TNPO3 stimulates the uncoating of HIV-1 cores in vitro. The stimulatory effect was reduced by RanGTP, a known ligand for transportin family members. Depletion of TNPO3 in target cells rendered HIV-1 less susceptible to inhibition by PF74, a small-molecule HIV-1 inhibitor that induces premature uncoating. In contrast to the case for TNPO3, addition of the CA-binding host protein cyclophilin A (CypA) inhibited HIV-1 uncoating and reduced the stimulatory effect of TNPO3 on uncoating in vitro. In cells in which TNPO3 was depleted, HIV-1 infection was enhanced 4-fold by addition of cyclosporine, indicating that the requirement for TNPO3 in HIV-1 infection is modulated by CypA-CA interactions. Although TNPO3 was localized primarily to the cytoplasm, depletion of TNPO3 from target cells inhibited HIV-1 infection without reducing the accumulation of nuclear proviral DNA, suggesting that TNPO3 facilitates a stage of the virus life cycle subsequent to nuclear entry. Our results suggest that TNPO3 and cyclophilin A facilitate HIV-1 infection by coordinating proper uncoating of the core in target cells.

The NACOB multi-surface walking dataset.

Walking is a fundamental aspect of human movement, and understanding how irregular surfaces impact gait is crucial. Existing gait research often relies on laboratory settings with ideal surfaces, limiting the applicability of findings to real-world scenarios. While some irregular surface datasets exist, they are often small or lack biomechanical gait data. In this paper, we introduce a new irregular surface dataset with 134 participants walking on surfaces of varying irregularity, equipped with inertial measurement unit (IMU) sensors on the trunk and lower right limb (foot, shank, and thigh). Collected during the North American Congress on Biomechanics conference in 2022, the dataset aims to provide a valuable resource for studying biomechanical adaptations to irregular surfaces. We provide the detailed experimental protocol, as well as a technical validation in which we developed a machine learning model to predict the walking surface. The resulting model achieved an accuracy score of 95.8%, demonstrating the discriminating biomechanical characteristics of the dataset's irregular surface gait data.

Real-world evaluation of RetCAD deep-learning system for the detection of referable diabetic retinopathy and age-related macular degeneration.

CLINICAL RELEVANCE: The challenges of establishing retinal screening programs in rural settings may be mitigated by the emergence of deep-learning systems for early disease detection. BACKGROUND: Deep-learning systems have demonstrated promising results in retinal disease detection and may be particularly useful in rural settings where accessibility remains a barrier to equitable service provision. This study aims to evaluate the real-world performance of Thirona RetCAD for the detection of referable diabetic retinopathy and age-related macular degeneration in a rural Australian population. METHODS: Colour fundus images from participants with known diabetic retinopathy or age-related macular degeneration were randomly selected from ophthalmology clinics in four rural Australian centres. Grading was confirmed retrospectively by two retinal specialists. RetCAD produced a quantitative measure (0-100) for DR and AMD severity. The area under the ROC curve (AUC) was calculated. Sensitivity, specificity, and positive and negative predictive values were calculated at a pre-defined cut-point of ≥50. RESULTS: A total of 150 images from 82 participants were included. The mean age (SD) was 64.0 (12.8) years. Seventy-nine (52.7%) eyes had evidence of referable DR, while 54 (36.0%) had evidence of referable AMD. The AUC for referable DR detection was 0.971 (95% CI 0.950-0.936) with a sensitivity of 86.1% (76.8%-92.0%) and a specificity of 91.6% (82.8%-96.1%) at the pre-defined cut-point. Using the Youden Index method, the optimal cut-point was 41.2 (sensitivity 93.7%, specificity 90.1%). The AUC for the detection of referable AMD was 0.880 (0.824-0.936). At the pre-defined cut-point sensitivity was 88.9% (77.8%-94.8%) and specificity was 66.7% (56.8%-75.3%). The optimal cut-point was 52.6 (sensitivity 87.0%, specificity 75.0%). CONCLUSION: RetCAD is comparable with but does not outperform equivalent deep-learning systems for retinal disease detection. RetCAD may be suitable as an automated screening tool in a rural Australian setting.

Virtual and augmented reality in cardiovascular care in low and middle income country.

The global health sector has witnessed an escalating integration of Virtual Reality (VR) and Augmented Reality (AR) technologies, particularly in high-income countries. The application of these cutting-edge technologies is gradually extending to Low- and Middle-Income Countries (LMICs), notably in the domain of cardiovascular care. AR and VR technologies are revolutionizing cardiovascular care by offering solutions for diagnosis, medical training, and surgical planning. AR and VR provide detailed and immersive visualizations of cardiac structures, aiding in diagnosis and intervention planning. In cardiovascular care, VR reduces patient-reported pain, eases anxiety, and accelerates post-procedural recovery. AR and VR are also valuable for life support training, creating immersive and controlled learning environments. AR and VR have the potential to significantly impact healthcare in low- and middle-income countries with enhanced accessibility and affordability. This review outlines the existing spectrum of VR and AR adoption and its burgeoning utility in the cardiovascular domain within LMICs.

Cardiovascular Outcomes of Transcatheter Aortic Valve Implantation in Patients With Chronic Kidney Disease in Octogenarian Population.

Limited data are available regarding in-hospital outcomes of transcatheter aortic valve implantation (TAVI) in the octogenarian population with chronic kidney disease (CKD). We sought to study the cardiovascular outcomes of TAVI in CKD hospitalization with different stages at the national cohort registry. We used the National Inpatient Sample database to compare TAVI CKD low-grade (LG) (stage I to IIIa, b) versus TAVI CKD high-grade (HG) (stage IV to V) in octogenarians. Outcomes such as inpatient mortality, cardiogenic shock, new permanent pacemaker implantation, acute kidney injury), sudden cardiac arrest, mechanical circulatory support, major bleeding, transfusion, and resource utilization were compared between the 2 cohorts. A total of 74,766 octogenarian patients (TAVI CKD-HG n = 12,220; TAVI CKD-LG n = 62,545) were included in our study. On matched analysis, TAVI CKD-HG had higher odds of in-hospital mortality (adjusted odds ratio [aOR] 2.18, 95% confidence interval [CI] 1.0-2.5, p <0.0001), cardiogenic shock (aOR 1.22, 95% CI 1.07 to 1.39, p = 0.0019), permanent pacemaker implantation (aOR 1.14, 95% CI 1.06 to 1.23, p = 0.0006), acute kidney injury (aOR 1.19, 95% CI 1.13 to 1.27, p <0.0001), sudden cardiac arrest (aOR 1.32, 95% CI 1.09 to 1.61, p = 0.004), major bleeding (aOR 1.1, 95% CI 1.006 to 1.22, p <0.0368) and higher rates of blood transfusion (aOR 1.62, 95% CI 1.5 to 1.75, p <0.0001) when compared with the TAVI CKD-LG cohort. However, there was no statistically significant difference in the odds of cerebrovascular accident and mechanical circulatory support use between the 2 groups.

Pharmacologic hyperstabilisation of the HIV-1 capsid lattice induces capsid failure.

The HIV-1 capsid has emerged as a tractable target for antiretroviral therapy. Lenacapavir, developed by Gilead Sciences, is the first capsid-targeting drug approved for medical use. Here, we investigate the effect of lenacapavir on HIV capsid stability and uncoating. We employ a single particle approach that simultaneously measures capsid content release and lattice persistence. We demonstrate that lenacapavir's potent antiviral activity is predominantly due to lethal hyperstabilisation of the capsid lattice and resultant loss of compartmentalisation. This study highlights that disrupting capsid metastability is a powerful strategy for the development of novel antivirals.