TULIPs decorate the three-dimensional genome of PFA ependymoma.

Posterior fossa group A (PFA) ependymoma is a lethal brain cancer diagnosed in infants and young children. The lack of driver events in the PFA linear genome led us to search its 3D genome for characteristic features. Here, we reconstructed 3D genomes from diverse childhood tumor types and uncovered a global topology in PFA that is highly reminiscent of stem and progenitor cells in a variety of human tissues. A remarkable feature exclusively present in PFA are type B ultra long-range interactions in PFAs (TULIPs), regions separated by great distances along the linear genome that interact with each other in the 3D nuclear space with surprising strength. TULIPs occur in all PFA samples and recur at predictable genomic coordinates, and their formation is induced by expression of EZHIP. The universality of TULIPs across PFA samples suggests a conservation of molecular principles that could be exploited therapeutically.

The feasibility and usability of mixed reality teaching in a hospital setting based on self-reported perceptions of medical students.

BACKGROUND: Clinical teaching during encounters with real patients lies at the heart of medical education. Mixed reality (MR) using a Microsoft HoloLens 2 (HL2) offers the potential to address several challenges: including enabling remote learning; decreasing infection control risks; facilitating greater access to medical specialties; and enhancing learning by vertical integration of basic principles to clinical application. We aimed to assess the feasibility and usability of MR using the HL2 for teaching in a busy, tertiary referral university hospital. METHODS: This prospective observational study examined the use of the HL2 to facilitate a live two-way broadcast of a clinician-patient encounter, to remotely situated third and fourth year medical students. System Usability Scale (SUS) Scores were elicited from participating medical students, clinician, and technician. Feedback was also elicited from participating patients. A modified Evaluation of Technology-Enhanced Learning Materials: Learner Perceptions Questionnaire (mETELM) was completed by medical students and patients. RESULTS: This was a mixed methods prospective, observational study, undertaken in the Day of Surgery Assessment Unit. Forty-seven medical students participated. The mean SUS score for medical students was 71.4 (SD 15.4), clinician (SUS = 75) and technician (SUS = 70) indicating good usability. The mETELM Questionnaire using a 7-point Likert Scale demonstrated MR was perceived to be more beneficial than a PowerPoint presentation (Median = 7, Range 6-7). Opinion amongst the student cohort was divided as to whether the MR tutorial was as beneficial for learning as a live patient encounter would have been (Median = 5, Range 3-6). Students were positive about the prospect of incorporating of MR in future tutorials (Median = 7, Range 5-7). The patients' mETELM results indicate the HL2 did not affect communication with the clinician (Median = 7, Range 7-7). The MR tutorial was preferred to a format based on small group teaching at the bedside (Median = 6, Range 4-7). CONCLUSIONS: Our study findings indicate that MR teaching using the HL2 demonstrates good usability characteristics for providing education to medical students at least in a clinical setting and under conditions similar to those of our study. Also, it is feasible to deliver to remotely located students, although certain practical constraints apply including Wi-Fi and audio quality.

Bandgap-universal passivation enables stable perovskite solar cells with low photovoltage loss.

The efficiency and longevity of metal-halide perovskite solar cells are typically dictated by nonradiative defect-mediated charge recombination. In this work, we demonstrate a vapor-based amino-silane passivation that reduces photovoltage deficits to around 100 millivolts (>90% of the thermodynamic limit) in perovskite solar cells of bandgaps between 1.6 and 1.8 electron volts, which is crucial for tandem applications. A primary-, secondary-, or tertiary-amino-silane alone negatively or barely affected perovskite crystallinity and charge transport, but amino-silanes that incorporate primary and secondary amines yield up to a 60-fold increase in photoluminescence quantum yield and preserve long-range conduction. Amino-silane-treated devices retained 95% power conversion efficiency for more than 1500 hours under full-spectrum sunlight at 85°C and open-circuit conditions in ambient air with a relative humidity of 50 to 60%.

Sex differences in muscle morphology between male and female sprinters.

There is a marked difference between males and females in sprint running performance, yet a comprehensive investigation of sex differences in the muscle morphology of sprinters, which could explain the performance differences, remains to be completed. This study compared muscle volumes of 23 individual leg muscles and 5 functional muscle groups, assessed with 3 T magnetic resonance imaging, between male (n = 31) and female (n = 22) sprinters, as well as subgroups of elite males (EM, n = 5), elite females (EF, n = 5), and performance-matched (to elite females) males (PMMEF, n = 6). Differences in muscle volume distribution between EM, EF, and unathletic male (UM) controls were also assessed. For the full cohorts, male sprinters were more muscular than their female counterparts, but the differences were nonuniform and anatomically variable, with the largest differences in the hip extensors and flexors. However, among elite sprinters the sex differences in the volume of the functional muscle groups were almost uniform (absolute volume +47-53%), and the muscle volume distribution of EM was more similar to EF than to UM (P < 0.039). For PMMEF, relative hip extensor volume, but not stature or percent body fat, differentiated for performance (PMMEF and EF < EM) rather than sex. In conclusion, although the full cohorts of sprinters showed a marked sex difference in the amount and distribution of muscle mass, elite sprinters appeared to be selected for a common muscle distribution phenotype that for these elite subgroups was a stronger effect than that of sex. Relative hip extensor muscle volume, rather than stature, percent body fat, or total relative muscle volume, appeared to be the primary determinant of the sex difference in performance.NEW & NOTEWORTHY We present novel evidence suggesting muscle volume, specifically relative hip extensor volume, may be a primary deterministic variable for the sex difference in sprint performance, such that with matched sprint times, male and female sprinters may be expected to have equivalent muscle morphology. We highlight striking similarities in distribution of leg muscle mass between elite male and female sprinters and provide evidence for the existence of a muscular distribution phenotype specific to elite sprinters, irrespective of sex.

Topological "Shape" in Micellar Dynamics.

For micelles, "shape" is prominent in rheological computations of fluid flow, but this "shape" is often expressed too informally to be useful for rigorous analyses. We formalize topological "shape equivalence" of micelles, both globally and locally, to enable visualization of computational fluid dynamics. Although topological methods in visualization provide significant insights into fluid flows, this opportunity has been limited by the known difficulties in creating representative geometry. We present an agile geometric algorithm to represent the micellar shape for input into fluid flow visualizations. We show that worm-like and cylindrical micelles have formally equivalent shapes, but that visualization accentuates unexplored differences. This global-local paradigm is extensible beyond micelles.

15-year survivorship of a unique dual-modular femoral stem in primary hip arthroplasty.

BACKGROUND: Hip offset, version, and length are interdependent femoral variables which determine stability and leg length. Balancing these competing variables remains a core challenge in hip arthroplasty. The potential benefits of modular femoral stems have been overshadowed by higher rates of failure. The objective of this study was to assess the survivorship of a unique dual-modular femoral stem at an average 15-year follow-up period. METHODS: The records of all patients with osteoarthritis who underwent primary total hip arthroplasty with this device between 2004-2009 were reviewed. There were no exclusions for BMI or other factors. We examined the data with Kaplan-Meier survival analysis. The primary endpoint for survival was mechanical failure of the modular neck-body junction. RESULTS: The survivorship of this device in 172 subjects was 100% with none experiencing mechanical failure of the modular junction at an average of 15 years. 60 patients died of causes unrelated to their THA and 9 patients were lost to follow-up. There were three early (≤ 12 months) dislocations (1.7%), and seven total dislocations (4.1%). 16 patients underwent reoperations during the follow-up period, none for any complication of the modular junction. Radiographic results showed well-fixed femoral stems in all cases. There were no leg length discrepancies of greater than 10 mm, and 85% were within 5 mm. CONCLUSION: There were no mechanical failures of the modular junction in any of the subjects over the average 15-year period, demonstrating that this dual-modular design is not associated with increased failure rates. We achieved a 1.7% early dislocation rate and a 4.1% total dislocation rate without any clinically significant leg length discrepancies.

Evaluation of the Safety of Uninterrupted Warfarin Anticoagulation With Tranexamic Acid in Total Joint Arthroplasty.

BACKGROUND: The continuation of long-term warfarin therapy is gaining acceptance in minor surgeries but maintaining therapeutic international normalized ratio (INR) values among patients during major orthopedic procedures raises concern. While bridging therapy with low-molecular-weight heparin is currently recommended for patients receiving anticoagulation, few studies have evaluated the safety of continuing warfarin during total joint arthroplasty. This study evaluated the safety and efficacy of continuous warfarin anticoagulation through total joint arthroplasty with and without prophylactic tranexamic acid (TXA). MATERIALS AND METHODS: We conducted a retrospective, matched-pair analysis of two experimental groups of patients who underwent primary total hip arthroplasty or total knee arthroplasty performed by a single surgeon. Our first experimental group, warfarin plus TXA (warfarin+TXA), consisted of 21 patients who underwent arthroplasty while receiving therapeutic anticoagulation with warfarin (INR, 2.0-3.0) and who received prophylactic TXA. Our second experimental group, warfarin without TXA (warfarin-TXA), consisted of 40 patients who underwent arthroplasty while receiving therapeutic anticoagulation with warfarin (INR, 2.0-3.0) without prophylactic TXA. RESULTS: The percent change in hemoglobin value after surgery, red blood cells transfused, surgical site infections, bleeding complications, and thrombotic complications were similar between both experimental and control groups. When comparing the historical group with the warfarin+TXA group, the addition of TXA resulted in a statistical decrease in mean red blood cells transfused and estimated blood loss, with no statistically significant increase in complications. CONCLUSION: Many factors must be considered when choosing perioperative thromboembolic prophylaxis for arthroplasty candidates with medical comorbidities requiring long-term anticoagulation. This study presents data indicating that it could be safe and effective to continue therapeutic warfarin while using prophylactic TXA. [Orthopedics. 202x;4x(x):xx-xx.].

Prophylactic negative pressure wound therapy to improve wound healing rates following ileostomy closure: a randomized controlled trial.

BACKGROUND: Reversal of ileostomy is associated with morbidity including wound infection and prolonged wound healing. Negative pressure wound therapy (NPWT) has been shown to reduce time to wound healing by secondary intention. The aim of this study was to determine whether NPWT improved wound healing rates, compared with simple wound dressings, in patients undergoing reversal of ileostomy where the skin wound is closed with a purse-string suture. METHODS: This was a dual-centre, open-label, randomized controlled trial with two parallel intervention arms. Patients undergoing elective loop ileostomy reversal were randomized 1:1 to receive NPWT or simple wound dressings. The primary endpoint of the study was assessment of complete wound healing at day 42 post reversal of ileostomy and the secondary endpoints were patient-reported wound cosmesis using a visual analogue scale and rates of surgical site infection (SSI). RESULTS: The study was conducted from June 2018 to December 2021. The trial was approved by the local ethics committee. We enrolled 40 patients, 20 in each arm. One patient in each arm was lost to follow up. Nine patients (9/19, 47.36%) in the simple dressing group had wound healing vs. 13 patients (13/19, 68.42%) in the NPWT group (P = 0.188). There was no significant difference in patient- reported wound cosmesis or SSI. CONCLUSION: There was no difference in wound healing rates when comparing NPWT to simple wound dressings at early and late time points post reversal of ileostomy, where the skin wound was closed with a purse-string suture.

Update for surgeons on novel induction treatments for acute severe inflammatory bowel disease associated colitis.

BACKGROUND: The landscape of biologic agents for the treatment of inflammatory bowel disease (IBD) associated colitis is rapidly evolving, requiring surgeons to be up-to-date as part of multi-disciplinary, evidence-based care. An update on novel therapies used to induce remission in IBD-associated colitis is presented. METHODS: A systematic search through Ovid MEDLINE and CENTRAL using a combination of MeSH terms and Boolean operators was conducted. RESULTS: One thousand and twenty articles from which 38 articles were selected for inclusion in this review. Novel agents were trialled as 4th or 5th line treatment following conventional treatment failure. Rates of serious adverse effects were low. Janus kinase (JAK) inhibitors (upadacitinib and tofacitinib) were efficacious in inducing remission in ulcerative colitis, and IL-23p19 inhibitors (mirikizumab, guselkumab, and risankizumab) in Crohn's colitis. Evidence was limited for other drug classes. CONCLUSION: JAK-inhibitors and IL-23p19 inhibitors were found to be the most effective agents for inducting remission following failure of standard of care treatment. A significant proportion of patients did not respond, highlighting the inherent challenge in optimizing treatment for moderate to severe IBD-associated colitis. More robust study designs and comparator trials are required.

The impact of COVID-19 on general surgical trainees' surgical exposure in Australia.

BACKGROUND: The COVID-19 pandemic disrupted the provision of surgical services in Australia. To prepare for a surge of COVID-19 patients, elective surgery was mandatorily reduced or ceased at multiple timepoints in Australian states between 2020 and 2022. Operative exposure is a critical component of surgical training in general surgery, and readiness for practice is an ongoing priority. However, the impact of COVID-19 on operative exposure in Australian General Surgical Trainees (AGST) has not been quantified. METHODS: This study was a retrospective longitudinal cohort study using de-identified operative logbook data for Australian General surgical Trainees (AGST) from the Royal Australasian College of Surgeons (RACS) Morbidity and Audit Logbook Tool (MALT) system between February 2019 and July 2021. Bivariate analysis was used to determine the impact of COVID-19 on general surgical trainees' exposure to operative surgery and trainees' operative autonomy. RESULTS: Data from 1896 unique 6-month training terms and 543 285 surgical cases was included over the data collection period. There was no statistically significant impact of the COVID-19 pandemic on AGST operative exposure to major, minor operations, endoscopies, or operative autonomy. CONCLUSIONS: The impact of COVID-19 on surgical trainees globally has been significant. Although this study does not assess all aspects of surgical training, this data demonstrates that there has not been a significant impact of the pandemic on operative exposure or autonomy of AGST.

Direct and integrating sampling in terahertz receivers from wafer-scalable InAs nanowires.

Terahertz (THz) radiation will play a pivotal role in wireless communications, sensing, spectroscopy and imaging technologies in the decades to come. THz emitters and receivers should thus be simplified in their design and miniaturized to become a commodity. In this work we demonstrate scalable photoconductive THz receivers based on horizontally-grown InAs nanowires (NWs) embedded in a bow-tie antenna that work at room temperature. The NWs provide a short photoconductivity lifetime while conserving high electron mobility. The large surface-to-volume ratio also ensures low dark current and thus low thermal noise, compared to narrow-bandgap bulk devices. By engineering the NW morphology, the NWs exhibit greatly different photoconductivity lifetimes, enabling the receivers to detect THz photons via both direct and integrating sampling modes. The broadband NW receivers are compatible with gating lasers across the entire range of telecom wavelengths (1.2-1.6 µm) and thus are ideal for inexpensive all-optical fibre-based THz time-domain spectroscopy and imaging systems. The devices are deterministically positioned by lithography and thus scalable to the wafer scale, opening the path for a new generation of commercial THz receivers.

Genetic Ablation of C/EBPα-p300 Pathway Blocks Development of Obese Pregnancy Associated Liver Disorders in Offspring.

BACKGROUND & AIMS: The obesity-associated nonalcoholic fatty liver disease represents a common cause of pediatric liver diseases, including the pediatric liver cancer hepatoblastoma. The mechanisms behind the development of fatty liver in children are not yet known. We examined the role of the C/EBPα-p300 pathway in the development of maternal obesity-associated fatty liver phenotype in offspring. METHODS: Because the ability of C/EBPα to promote fatty liver phenotype is enhanced by CDK4-mediated phosphorylation of C/EBPα at Ser193 and subsequent formation of C/EBPα-p300 complexes, we used wild-type (WT) and C/EBPα-S193D and C/EBPα-S193A mutant mice to study the effects of maternal high-fat diet (HFD) on the liver health of offspring. The females of these mouse lines were fed an HFD before mating, and the pups were further subjected to either an HFD or a normal diet for 12 weeks. RESULTS: WT female mice on the HFD before and during pregnancy and their subsequent offspring on the HFD had severe fatty liver, fibrosis, and an increased rate of liver proliferation. However, the HFD in C/EBPα-S193A mice did not cause development of these disorders. In HFD-HFD treated WT mice, C/EBPα is phosphorylated at Ser193 and forms complexes with p300, which activate expression of genes involved in development of fatty liver, fibrosis, and proliferation. However, S193A-C/EBPα mice do not have complexes of C/EBPα-S193A with p300, leading to a lack of activation of genes of fatty liver, fibrosis, and proliferation. The mutant C/EBPα-S193D mice have accelerated cdk4-dependent pathway and have developed steatosis at early stages. CONCLUSIONS: These studies identified the epigenetic cause of obese pregnancy-associated liver diseases and suggest a potential therapy based on inhibition of cdk4-ph-S193-C/EBPα-p300 pathway.

H3K27me3 spreading organizes canonical PRC1 chromatin architecture to regulate developmental programs.

Polycomb Repressive Complex 2 (PRC2)-mediated histone H3K27 tri-methylation (H3K27me3) recruits canonical PRC1 (cPRC1) to maintain heterochromatin. In early development, polycomb-regulated genes are connected through long-range 3D interactions which resolve upon differentiation. Here, we report that polycomb looping is controlled by H3K27me3 spreading and regulates target gene silencing and cell fate specification. Using glioma-derived H3 Lys-27-Met (H3K27M) mutations as tools to restrict H3K27me3 deposition, we show that H3K27me3 confinement concentrates the chromatin pool of cPRC1, resulting in heightened 3D interactions mirroring chromatin architecture of pluripotency, and stringent gene repression that maintains cells in progenitor states to facilitate tumor development. Conversely, H3K27me3 spread in pluripotent stem cells, following neural differentiation or loss of the H3K36 methyltransferase NSD1, dilutes cPRC1 concentration and dissolves polycomb loops. These results identify the regulatory principles and disease implications of polycomb looping and nominate histone modification-guided distribution of reader complexes as an important mechanism for nuclear compartment organization. Highlights: The confinement of H3K27me3 at PRC2 nucleation sites without its spreading correlates with increased 3D chromatin interactions.The H3K27M oncohistone concentrates canonical PRC1 that anchors chromatin loop interactions in gliomas, silencing developmental programs.Stem and progenitor cells require factors promoting H3K27me3 confinement, including H3K36me2, to maintain cPRC1 loop architecture.The cPRC1-H3K27me3 interaction is a targetable driver of aberrant self-renewal in tumor cells.

Correction to "A Templating Approach to Controlling the Growth of Coevaporated Halide Perovskites".

[This corrects the article DOI: 10.1021/acsenergylett.3c01368.].

The Joint Awareness Score: A Shortened, Simplified, Improved Alternative to the Forgotten Joint Score.

Background: The Forgotten Joint Score (FJS) is a 12-question patient-reported outcomes measure created to measure a patient's awareness of their artificial joint. The FJS has attained wide usage, though it is not without weaknesses. Our patients report that the semantics of the English translation are flawed and that the 5 answer options for each question are poorly differentiated. Additionally, the FJS will result in no score if 3 or more questions are unanswered. This prompted the development of an alternative patient-reported outcomes measure, the Joint Awareness Score (JAS), that builds upon the core concept of joint awareness underlying the FJS, but that is easier to understand and shorter to complete. We completed an exploratory, pilot study to evaluate this outcomes instrument. Our hypothesis is that the JAS will correlate strongly with the FJS and could be used as a substitute. Methods: Knee arthroplasty patients in a prospective registry were administered the FJS and the JAS. Internal consistency and correlation were calculated with Cronbach's alpha and Pearson's correlation coefficient, respectively. Results: This study included 174 patients. Cronbach's alpha for FJS was 0.97 for 6 months and 0.97 for 12 months, whereas JAS was 0.89 at 6 months and 0.85 at 12 months. Pearson correlation comparing FJS and JAS at 6 months was 0.88 (95% confidence interval: 0.83, 0.92) and 0.86 (95% confidence interval: 0.78, 0.92) at 12 months. Conclusions: The Joint Awareness Score is a new patient-reported outcomes measure that is a substitute for the FJS, with half the number of questions, improved semantics, and simplified answers.

Strategies for the production of isotopically labelled Fab fragments of therapeutic antibodies in Komagataella phaffii (Pichia pastoris) and Escherichia coli for NMR studies.

The importance and fast growth of therapeutic monoclonal antibodies, both innovator and biosimilar products, have triggered the need for the development of characterization methods at high resolution such as nuclear magnetic resonance (NMR) spectroscopy. However, the full power of NMR spectroscopy cannot be unleashed without labelling the mAb of interest with NMR-active isotopes. Here, we present strategies using either Komagataella phaffii (Pichia pastoris) or Escherichia coli that can be widely applied for the production of the antigen-binding fragment (Fab) of therapeutic antibodies of immunoglobulin G1 kappa isotype. The E. coli approach consists of expressing Fab fragments as a single polypeptide chain with a cleavable linker between the heavy and light chain in inclusion bodies, while K. phaffii secretes a properly folded fragment in the culture media. After optimization, the protocol yielded 10-45 mg of single chain adalimumab-Fab, trastuzumab-Fab, rituximab-Fab, and NISTmAb-Fab per liter of culture. Comparison of the 2D-1H-15N-HSQC spectra of each Fab fragment, without their polyhistidine tag and linker, with the corresponding Fab from the innovator product showed that all four fragments have folded into the correct conformation. Production of 2H-13C-15N-adalimumab-scFab and 2H-13C-15N-trastuzumab-scFab (>98% enrichment for all three isotopes) yielded NMR samples where all amide deuterons have completely exchanged back to proton during the refolding procedure.

The Expression Kinetics and Immunogenicity of Lipid Nanoparticles Delivering Plasmid DNA and mRNA in Mice.

In recent years, lipid nanoparticles (LNPs) have emerged as a revolutionary technology for vaccine delivery. LNPs serve as an integral component of mRNA vaccines by protecting and transporting the mRNA payload into host cells. Despite their prominence in mRNA vaccines, there remains a notable gap in our understanding of the potential application of LNPs for the delivery of DNA vaccines. In this study, we sought to investigate the suitability of leading LNP formulations for the delivery of plasmid DNA (pDNA). In addition, we aimed to explore key differences in the properties of popular LNP formulations when delivering either mRNA or DNA. To address these questions, we compared three leading LNP formulations encapsulating mRNA- or pDNA-encoding firefly luciferase based on potency, expression kinetics, biodistribution, and immunogenicity. Following intramuscular injection in mice, we determined that RNA-LNPs formulated with either SM-102 or ALC-0315 lipids were the most potent (all p-values < 0.01) and immunogenic (all p-values < 0.05), while DNA-LNPs formulated with SM-102 or ALC-0315 demonstrated the longest duration of signal. Additionally, all LNP formulations were found to induce expression in the liver that was proportional to the signal at the injection site (SM102: r = 0.8787, p < 0.0001; ALC0315: r = 0.9012, p < 0.0001; KC2: r = 0.9343, p < 0.0001). Overall, this study provides important insights into the differences between leading LNP formulations and their applicability to DNA- and RNA-based vaccinations.

A Templating Approach to Controlling the Growth of Coevaporated Halide Perovskites.

Metal halide perovskite semiconductors have shown significant potential for use in photovoltaic (PV) devices. While fabrication of perovskite thin films can be achieved through a variety of techniques, thermal vapor deposition is particularly promising, allowing for high-throughput fabrication. However, the ability to control the nucleation and growth of these materials, particularly at the charge-transport layer/perovskite interface, is critical to unlocking the full potential of vapor-deposited perovskite PV. In this study, we explore the use of a templating layer to control the growth of coevaporated perovskite films and find that such templating leads to highly oriented films with identical morphology, crystal structure, and optoelectronic properties independent of the underlying layers. Solar cells incorporating templated FA0.9Cs0.1PbI3-xClx show marked improvements with steady-state power conversion efficiency over 19.8%. Our findings provide a straightforward and reproducible method of controlling the charge-transport layer/coevaporated perovskite interface, further clearing the path toward large-scale fabrication of efficient PV devices.

Cation-Disorder Engineering Promotes Efficient Charge-Carrier Transport in AgBiS2 Nanocrystal Films.

Efficient charge-carrier transport is critical to the success of emergent semiconductors in photovoltaic applications. So far, disorder has been considered detrimental for charge-carrier transport, lowering mobilities, and causing fast recombination. This work demonstrates that, when properly engineered, cation disorder in a multinary chalcogenide semiconductor can considerably enhance the charge-carrier mobility and extend the charge-carrier lifetime. Here, the properties of AgBiS2 nanocrystals (NCs) are explored as a function of Ag and Bi cation-ordering, which can be modified via thermal-annealing. Local Ag-rich and Bi-rich domains formed during hot-injection synthesis are transformed to induce homogeneous disorder (random Ag-Bi distribution). Such cation-disorder engineering results in a sixfold increase in the charge-carrier mobility, reaching ≈2.7 cm2 V-1 s-1 in AgBiS2 NC thin films. It is further demonstrated that homogeneous cation disorder reduces charge-carrier localization, a hallmark of charge-carrier transport recently observed in silver-bismuth semiconductors. This work proposes that cation-disorder engineering flattens the disordered electronic landscape, removing tail states that would otherwise exacerbate Anderson localization of small polaronic states. Together, these findings unravel how cation-disorder engineering in multinary semiconductors can enhance the efficiency of renewable energy applications.