3-Hydroxykynurenine targets kainate receptors to promote defense against infection.

Bacterial infection involves a complex interaction between the pathogen and host where the outcome of infection is not solely determined by pathogen eradication. To identify small molecules that promote host survival by altering the host-pathogen dynamic, we conducted an in vivo chemical screen using zebrafish embryos and found that treatment with 3-hydroxykynurenine (3-HK) protects from lethal bacterial infection. 3-HK, a metabolite produced through host tryptophan metabolism, has no direct antibacterial activity but enhances host survival by restricting bacterial expansion in macrophages through a systemic mechanism that targets kainate-sensitive glutamate receptors. These findings reveal a new pathway by which tryptophan metabolism and kainate-sensitive glutamate receptors function and interact to modulate immunity, with important implications for the coordination between the immune and nervous systems in pathological conditions.

Participant Assessment of an Alternative Flexible Congregate Nutrition Meal Program for Older Adults.

Congregate Nutrition Services have long been a pillar of public health assistance, championing the independence and community engagement of older Americans. The advent of COVID-19, however, restricted access to these services due to the closure of physical locations. In response, Lanakila Meals on Wheels initiated a virtual congregate meal program, Kupuna U, in collaboration with community partners in Honolulu County. The program combined grab-and-go or home-delivered meals with virtual and in-person classes to improve both nutrition and socialization for older adults. This study aimed to capture participant feedback to assess and enhance the Kupuna U program, developing it as a flexible and scalable congregate meal solution applicable nationwide. Five focus group discussions were conducted with program participants (n = 34). The majority of participants were female (74%), Asian (73%), and living alone (56%). Participants found the program beneficial, enhancing their nutrition, social engagement, and learning experiences on various topics tailored for older adults. Supportive staff played a crucial role in motivating participants to stay engaged. Participants also identified potential enhancements to the program, including more activities and courses, expanded hours, additional in-person options at various locations, and culturally tailored meals.

Diagnostic accuracy of non-invasive tests to screen for at-risk MASH-An individual participant data meta-analysis.

BACKGROUND & AIMS: There is a need to reduce the screen failure rate (SFR) in metabolic dysfunction-associated steatohepatitis (MASH) clinical trials (MASH+F2-3; MASH+F4) and identify people with high-risk MASH (MASH+F2-4) in clinical practice. We aimed to evaluate non-invasive tests (NITs) screening approaches for these target conditions. METHODS: This was an individual participant data meta-analysis for the performance of NITs against liver biopsy for MASH+F2-4, MASH+F2-3 and MASH+F4. Index tests were the FibroScan-AST (FAST) score, liver stiffness measured using vibration-controlled transient elastography (LSM-VCTE), the fibrosis-4 score (FIB-4) and the NAFLD fibrosis score (NFS). Area under the receiver operating characteristics curve (AUROC) and thresholds including those that achieved 34% SFR were reported. RESULTS: We included 2281 unique cases. The prevalence of MASH+F2-4, MASH+F2-3 and MASH+F4 was 31%, 24% and 7%, respectively. Area under the receiver operating characteristics curves for MASH+F2-4 were .78, .75, .68 and .57 for FAST, LSM-VCTE, FIB-4 and NFS. Area under the receiver operating characteristics curves for MASH+F2-3 were .73, .67, .60, .58 for FAST, LSM-VCTE, FIB-4 and NFS. Area under the receiver operating characteristics curves for MASH+F4 were .79, .84, .81, .76 for FAST, LSM-VCTE, FIB-4 and NFS. The sequential combination of FIB-4 and LSM-VCTE for the detection of MASH+F2-3 with threshold of .7 and 3.48, and 5.9 and 20 kPa achieved SFR of 67% and sensitivity of 60%, detecting 15 true positive cases from a theoretical group of 100 participants at the prevalence of 24%. CONCLUSIONS: Sequential combinations of NITs do not compromise diagnostic performance and may reduce resource utilisation through the need of fewer LSM-VCTE examinations.

Quality and Accessibility of Home Assessment mHealth Apps for Community Living: Systematic Review.

BACKGROUND: Home assessment is a critical component of successful home modifications, enabling individuals with functional limitations to age in place comfortably. A high-quality home assessment tool should facilitate a valid and reliable assessment involving health care and housing professionals, while also engaging and empowering consumers and their caregivers who may be dealing with multiple functional limitations. Unlike traditional paper-and-pencil assessments, which require extensive training and expert knowledge and can be alienating to consumers, mobile health (mHealth) apps have the potential to engage all parties involved, empowering and activating consumers to take action. However, little is known about which apps contain all the necessary functionality, quality appraisal, and accessibility. OBJECTIVE: This study aimed to assess the functionality, overall quality, and accessibility of mHealth home assessment apps. METHODS: mHealth apps enabling home assessment for aging in place were identified through a comprehensive search of scholarly articles, the Apple (iOS) and Google Play (Android) stores in the United States, and fnd.io. The search was conducted between November 2022 and January 2023 following a method adapted from PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). Reviewers performed a content analysis of the mobile app features to evaluate their functionality, overall quality, and accessibility. The functionality assessment used a home assessment component matrix specifically developed for this study. For overall quality, the Mobile Application Rating Scale (MARS) was used to determine the apps' effectiveness in engaging and activating consumers and their caregivers. Accessibility was assessed using the Web Content Accessibility Guidelines (WCAG) 2.1 (A and AA levels). These 3 assessments were synthesized and visualized to provide a comprehensive evaluation. RESULTS: A total of 698 apps were initially identified. After further screening, only 6 apps remained. Our review revealed that none of the apps used thoroughly tested assessment tools, offered all the functionality required for reliable home assessment, achieved the "good" quality threshold as measured by the MARS, or met the accessibility criteria when evaluated against WCAG 2.1. However, DIYModify received the highest scores in both the overall quality and accessibility assessments. The MapIt apps also showed significant potential due to their ability to measure the 3D environment and the inclusion of a desktop version that extends the app's functionality. CONCLUSIONS: Our review revealed that there are very few apps available within the United States that possess the necessary functionality, engaging qualities, and accessibility to effectively activate consumers and their caregivers for successful home modification. Future app development should prioritize the integration of reliable and thoroughly tested assessment tools as the foundation of the development process. Furthermore, efforts should be made to enhance the overall quality and accessibility of these apps to better engage and empower consumers to take necessary actions to age in place.

RNAi mediated silencing of STAT3/PD-L1 in tumor-associated immune cells induces robust anti-tumor effects in immunotherapy resistant tumors.

Malignant tumors are often associated with an immunosuppressive tumor microenvironment (TME), rendering most of them resistant to standard-of-care immune checkpoint inhibitors (CPIs). Signal transducer and activator of transcription 3 (STAT3), a ubiquitously expressed transcription factor, has well-defined immunosuppressive functions in several leukocyte populations within the TME. Since the STAT3 protein has been challenging to target using conventional pharmaceutical modalities, we investigated the feasibility of applying systemically delivered RNA interference (RNAi) agents to silence its mRNA directly in tumor-associated immune cells. In preclinical rodent tumor models, chemically stabilized acylated small interfering RNAs (siRNAs) selectively silenced Stat3 mRNA in multiple relevant cell types, reduced STAT3 protein levels, and increased cytotoxic T cell infiltration. In a murine model of CPI-resistant pancreatic cancer, RNAi-mediated Stat3 silencing resulted in tumor growth inhibition, which was further enhanced in combination with CPIs. To further exemplify the utility of RNAi for cancer immunotherapy, this technology was used to silence Cd274, the gene encoding the immune checkpoint protein programmed death-ligand 1 (PD-L1). Interestingly, silencing of Cd274 was effective in tumor models that are resistant to PD-L1 antibody therapy. These data represent the first demonstration of systemic delivery of RNAi agents to the TME and suggest applying this technology for immuno-oncology applications.

First-line chemoimmunotherapy and immunotherapy in patients with non-small cell lung cancer and brain metastases: a registry study.

Introduction: Brain metastases commonly occur in patients with non-small cell lung cancer (NSCLC). Standard first-line treatment for NSCLC, without an EGFR, ALK or ROS1 mutation, is either chemoimmunotherapy or anti-PD-1 monotherapy. Traditionally, patients with symptomatic or untreated brain metastases were excluded from the pivotal clinical trials that established first-line treatment recommendations. The intracranial effectiveness of these treatment protocols has only recently been elucidated in small-scale prospective trials. Methods: Patients with NSCLC and brain metastases, treated with first-line chemoimmunotherapy or anti-PD-1 monotherapy were selected from the Australian Registry and biObank of thoracic cancers (AURORA) clinical database covering seven institutions. The primary outcome was a composite time-to-event (TTE) outcome, including extracranial and intracranial progression, death, or need for local intracranial therapy, which served as a surrogate for disease progression. The secondary outcome included overall survival (OS), intracranial objective response rate (iORR) and objective response rate (ORR). Results: 116 patients were included. 63% received combination chemoimmunotherapy and 37% received anti-PD-1 monotherapy. 69% of patients received upfront local therapy either with surgery, radiotherapy or both. The median TTE was 7.1 months (95% CI 5 - 9) with extracranial progression being the most common progression event. Neither type of systemic therapy or upfront local therapy were predictive of TTE in a multivariate analysis. The median OS was 17 months (95% CI 13-27). Treatment with chemoimmunotherapy was predictive of longer OS in multivariate analysis (HR 0.35; 95% CI 0.14 - 0.86; p=0.01). The iORR was 46.6%. The iORR was higher in patients treated with chemoimmunotherapy compared to immunotherapy (58% versus 31%, p=0.01). The use of chemoimmunotherapy being predictive of iORR in a multivariate analysis (OR 2.88; 95% CI 1.68 - 9.98; p=0.04). Conclusion: The results of this study of real-world data demonstrate the promising intracranial efficacy of chemoimmunotherapy in the first-line setting, potentially surpassing that of immunotherapy alone. No demonstrable difference in survival or TTE was seen between receipt of upfront local therapy. Prospective studies are required to assist clinical decision making regarding optimal sequencing of local and systemic therapies.

Prognostic and predictive biomarkers in head and neck cancer: something old, something new, something borrowed, something blue and a sixpence in your shoe.

A biomarker is a measurable indicator of biological or pathological processes or the response to an exposure or intervention and is used to guide management decisions. In head and neck pathology, biomarkers are assessed by histological criteria and immunohistochemical and molecular studies. Surgical resection remains the mainstay of management of many head and neck malignancies. Adjuvant radiotherapy and/or systemic therapy may be administered depending on the presence of adverse prognostic factors identified on histopathological or immunohistochemical examination. In this review, we outline the clinically relevant prognostic and predictive factors in head and neck malignancies including conventionally recognised factors such as tumour size, depth of invasion, lymphovascular and perineural invasion and margin status as well as novel evolving factors such as recurrent genetic rearrangements and assessment of immune checkpoints. Practical issues are discussed to assist with recognising and reporting of these factors. A summary of useful tools such as structured pathology report formats is also included to assist with comprehensive reporting of all clinically relevant parameters, minimise risk and improve workflow efficiencies.

Immune checkpoint inhibitor therapy for advanced cutaneous squamous cell carcinoma in Australia: a retrospective real world cohort study.

OBJECTIVES: To review the outcomes of immune checkpoint inhibitor (ICI) treatment of advanced cutaneous squamous cell carcinoma (CSCC) outside clinical trials. STUDY DESIGN: Retrospective observational study; review of patient records in fifteen Australian institutions. SETTING, PARTICIPANTS: All Australian adults with locally advanced or metastatic CSCC not amenable to curative surgery or radiotherapy treated with ICIs, 5 May 2017 - 23 May 2022, through a cemiplimab compassionate access scheme (Therapeutic Goods Administration Special Access Scheme) or who personally covered the cost of pembrolizumab prior to the start of the access scheme. MAIN OUTCOME MEASURES: Best overall response rate (ORR) according to standardised assessment criteria using the hierarchy: Response Evaluation Criteria in Solid Tumors (RECIST 1.1), the modified World Health Organization clinical response criteria, and the Positron Emission Tomography Response Criteria (PERCIST 1.0); overall and progression-free survival. RESULTS: A total of 286 people with advanced CSCC received ICI therapy during May 2017 - May 2022 (cemiplimab, 270; pembrolizumab, 16). Their median age was 75.2 years (range, 39.3-97.5 years) and 232 were men (81%); median follow-up time was 12.2 months (interquartile range, 5.5-20.5 months). Eighty-eight people (31%) were immunocompromised, 27 had autoimmune disease, and 59 of 277 (21%) had ECOG performance scores of 2 or 3. The ORR was 60% (166 of 278 evaluable patients): complete responses were recorded for 74 (27%) and partial responses for 92 patients (33%). Twelve-month overall survival was 78% (95% confidence interval [CI], 72-83%); progression-free survival was 65% (95% CI, 58-70%). Poorer ECOG performance status was associated with poorer overall survival (per unit: adjusted hazard ratio [aHR], 3.0; 95% CI, 2.0-4.3) and progression-free survival (aHR, 2.4; 95% CI, 1.8-3.3), as was being immunocompromised (overall: aHR, 1.8; 95% CI, 1.1-3.0; progression-free: aHR, 1.8; 95% CI, 1.2-2.7). Fifty-five people (19%) reported immune-related adverse events of grade 2 or higher; there were no treatment-related deaths. CONCLUSION: In our retrospective study, the effectiveness and toxicity of ICI therapy were similar to those determined in clinical trials. Our findings suggest that ICIs could be effective and well tolerated by people with advanced CSCC who are ineligible for clinical trials.

Real world efficacy and toxicity of consolidation durvalumab following chemoradiotherapy in older Australian patients with unresectable stage III non-small cell lung cancer.

INTRODUCTION: Consolidation durvalumab following platinum-based chemoradiotherapy (CRT) significantly improved overall survival for patients with unresectable stage III non-small cell lung cancer (NSCLC) in the PACIFIC trial. However, older patients were underrepresented in PACIFIC, and subsequent analyses suggested trends toward poorer survival and increased toxicity in patients aged ≥70 years old. We assessed the effectiveness and safety of consolidation durvalumab following CRT in older Australian patients with unresectable stage III NSCLC. MATERIALS AND METHODS: This retrospective observational study was conducted across seven sites in Sydney, Australia between January 2018 and September 2021. All adult patients with unresectable stage III NSCLC who received platinum-based chemoradiotherapy followed by at least one cycle of consolidation durvalumab were included. Older patients were defined as being ≥70 years old. RESULTS: Of 152 patients included in the analysis, 42.8% (n = 67) patients were 70 years or older. Median follow-up was 26.1 months. The two-year overall survival and median PFS was similar between older and younger patients. At two years, 74.8% (95% confidence interval [CI]: 65.4-84.2%) of patients <70 years old and 65.2% (95% CI: 53.4-77.0%) of older patients were alive (p = 0.07; hazard ratio [HR] 1.64, 95% CI: 0.95-2.81). Median progression-free survival (PFS) in patients <70 years was 30.3 months (95% CI: 22.2-38.4 months) compared with 26.7 months (95% CI: 12.8-40.6 months) in older patients (p = 0.22; HR 1.46, 95% CI: 0.80-2.65). Toxicity was also similar, with 11.5% of patients <70 years old and 18.5% of older patients experiencing grade 3-4 adverse events (AEs; p = 0.23); 16.1% and 24.6% of the patients, respectively, discontinued treatment due to toxicity (p = 0.19). Grade 3-4 AEs and treatment discontinuation were associated with Charlson Comorbidity Index >5 (p = 0.011) and chronic obstructive pulmonary disease diagnosis at presentation (p = 0.002), respectively. DISCUSSION: Older Australian patients receiving consolidation durvalumab following CRT experienced comparable outcomes to their younger peers. Comorbidity burden may be more important determinants of treatment tolerance than chronological age.

The Effect of Diet Composition on the Post-operative Outcomes of Roux-en-Y Gastric Bypass in Mice.

PURPOSE: Roux-en-Y gastric bypass (RYGB) leads to the improvement of many obesity-associated conditions. The degree to which post-operative macronutrient composition contributes to metabolic improvement after RYGB is understudied. METHODS: A mouse model of RYGB was used to examine the effects of diet on the post-operative outcomes of RYGB. Obese mice underwent either Sham or RYGB surgery and were administered either chow or HFD and then monitored for an additional 8 weeks. RESULTS: After RYGB, reductions to body weight, fat mass, and lean mass were similar regardless of diet. RYGB and HFD were independently detrimental to bone mineral density and plasma vitamin D levels. Independent of surgery, HFD accelerated hematopoietic stem and progenitor cell proliferation and differentiation and exhibited greater myeloid lineage commitment. Independent of diet, systemic iron deficiency was present after RYGB. In both Sham and RYGB groups, HFD increased energy expenditure. RYGB increased fecal energy loss, and HFD after RYGB increased fecal lipid content. RYGB lowered fasting glucose and liver glycogen levels but HFD had an opposing effect. Indices of insulin sensitivity improved independent of diet. HFD impaired improvements to dyslipidemia, NAFLD, and fibrosis. CONCLUSION: Post-operative diet plays a significant role in determining the degree to which RYGB reverses obesity-induced metabolic abnormalities such as hyperglycemia, dyslipidemia, and NAFLD. Diet composition may be targeted in order to assist in the treatment of post-RYGB bone mineral density loss and vitamin D deficiency as well as to reverse myeloid lineage commitment. HFD after RYGB continues to pose a significant multidimensional health risk.

Late-Onset COL4A1 Mutation with Recurrent Ischemic and Hemorrhagic Strokes.

INTRODUCTION: Mutations in type IV collagen gene COL4A1 are identified as a cause of autosomal dominant cerebrovascular disease. We report an unusual late-onset presentation. CASE REPORT: A 64-year-old male was found to have an ischemic stroke and diffuse white matter changes. Genetic testing revealed COL4A1 gene mutation of heterozygous Alu insertion at intron 16. Alu elements are known as "jumping genes," and Alu insertion is not previously reported in COL4A1 genetic syndromes. Our case has attributes consistent with a heritable leukoencephalopathy: (1) late-onset presentation, (2) intracerebral hemorrhages and microbleeds, (3) bilateral symmetrical leukoencephalopathy, (4) recurrence over a short period of time, (5) bilateral retinopathy, and (6) family history notable for brain aneurysm, kidney diseases, and early-onset stroke. CONCLUSIONS: Although the majority of COL4A1 genetic syndromes featuring cerebral small vessel disease are in children, this case highlights a late-onset patient with key features of COL4A1 syndromes associated with a heterozygous Alu intronic insertion.

Resident Experiences in Pathways to Health for Cleveland Refugees: A Pilot Study.

Refugee families often report discomfort with navigating the United States health care system, while medical trainees feel unprepared to meet the needs of refugee families. Pediatric residents partnered with a local refugee resettlement organization to create and deliver a user-friendly health care navigation curriculum to newly arrived refugee families. Pediatric residents completed pre-intervention and post-intervention surveys to assess their comfort and interest in working with refugee populations. Residents reported high interest in working with refugees despite little direct experience working with this population. There was a significant increase in residents' reported understanding of refugee health as a result of this intervention. Future research is needed to assess the efficacy of such curricula for both refugee families and pediatric residents.

The impact of substance use on posttraumatic stress disorder symptoms and treatment discontinuation.

This study examined the impact of ongoing substance use during posttraumatic stress disorder (PTSD) and substance use disorder (SUD) treatment on PTSD symptoms and treatment discontinuation. The study represents a secondary analysis of U.S. military veterans (N = 183) who participated in a randomized clinical trial for the treatment of both PTSD and SUD. Veterans mostly identified as Black (53.8%) or White (41.9%) and male (92.4%). Substance use, PTSD symptoms, and treatment discontinuation were measured at 4-week intervals throughout treatment. Predictors were the percentage of days with alcohol, cannabis, and other substance use (primarily cocaine and opioids) and the average number of alcoholic drinks per drinking day. Outcomes were PTSD symptoms and treatment discontinuation at concurrent and prospective assessments. Multilevel models accounted for the nested structure of the longitudinal data. Alcohol, cannabis, and other substance use did not predict PTSD symptoms or treatment discontinuation prospectively. Concurrently, we observed that as a participant's percentage of drinking days increased by 34.7% (i.e., 1 standard deviation), PTSD symptoms during the same period were 0.07 standard deviations higher (i.e., 1 point on the PCL), B = 0.03, p = .033. No other substances were related to PTSD symptoms concurrently. The findings demonstrate that PTSD symptoms improved regardless of substance use during exposure-based PTSD and SUD treatment, and treatment discontinuation was not associated with substance use. This study suggests that substance use during treatment cannot directly explain the poorer treatment outcomes observed in the literature on comorbid PTSD/SUD compared to PTSD-only populations.

Ex vivo tissue modelling informs drug selection for rare cancers.

The identification and therapeutic targeting of actionable gene mutations across many cancer types has resulted in improved response rates in a minority of patients. The identification of actionable mutations is usually not sufficient to ensure complete nor durable responses, and in rare cancers, where no therapeutic standard of care exists, precision medicine indications are often based on pan-cancer data. The inclusion of functional data, however, can provide evidence of oncogene dependence and guide treatment selection based on tumour genetic data. We applied an ex vivo cancer explant modelling approach, that can be embedded in routine clinical care and allows for pathological review within 10 days of tissue collection. We now report that ex vivo tissue modelling provided accurate longitudinal response data in a patient with BRAFV600E -mutant papillary thyroid tumour with squamous differentiation. The ex vivo model guided treatment selection for this patient and confirmed treatment resistance when the patient's disease progressed after 8 months of treatment.

Black Emerging Adults With Uncontrolled Asthma: A Qualitative Study.

RATIONALE: Asthma morbidity and mortality are disproportionately high in the Black population, especially among Black emerging adults (BEAs) (age 18-30 years). Few studies have been done to identify unique challenges to asthma care in BEAs. OBJECTIVE: To assess the challenges and barriers to asthma care BEAs experience. METHODS: We conducted virtual focus groups consisting of BEAs (n = 16) with a physician diagnosis of asthma. Discussion questions regarding asthma triggers, management, and challenges were used. Focus group discussions were recorded and transcribed verbatim. The transcripts were then coded by 3 coders using a thematic saturation approach. RESULTS: Seven major domains were identified: heightened anxiety around asthma management; asthma symptoms interfering with school and/or work; asthma in social group setting; transitioning to adulthood leading to increased autonomy and financial independence; use of technology in asthma management; concerns regarding coronavirus disease 2019; and perceived discrimination and biases. These domains create complex barriers to optimal asthma management and overlapping elements were identified. Technology was described as a potential method to address these challenges. CONCLUSIONS: BEAs with asthma have unique challenges due to age and race. Physicians should address these challenges through innovative means such as technology-based interventions.

Influence of EGFR mutation status and PD-L1 expression in stage III unresectable non-small cell lung cancer treated with chemoradiation and consolidation durvalumab.

BACKGROUND: Consolidation durvalumab after concurrent chemoradiation is the standard of care for unresectable stage III non-small cell lung cancer (NSCLC) based on the PACIFIC trial. However, there have been reports in the literature suggesting the efficacy of the treatment differs in patients whose tumors harbor epidermal growth factor receptor (EGFR) mutations and in those with low programed death ligand-1 (PD-L1) expression. This study describes the survival outcomes for patients with unresectable stage III NSCLC treated with chemoradiation followed by durvalumab with a specific focus on EGFR mutation status and PD-L1 expression. METHODS: This retrospective observational study was conducted across six sites in Greater Sydney, Australia. It included all patients diagnosed with unresectable stage III NSCLC treated with chemoradiation and who received at least one cycle of durvalumab between January 2018 and September 2021. Patients were stratified according to EGFR mutation status and PD-L1 tumor proportion score (TPS) of 1%. RESULTS: Of the 145 patients included in the analysis, 15/145 (10%) patients harbored an EGFR mutation and 61/145 (42%) patients had PD-L1 TPS of <1%. At a median follow-up of 15.1 months from the start of durvalumab, median progression-free survival (PFS) in EGFR mutant versus wild-type patients was 7.5 and 33.9 months, respectively (hazard ratio [HR]: 2.7; 95% confidence intervals [95% CI] 1.2-5.7; p = .01). Overall survival (OS) was not different between EGFR mutant and wild-type patients. There was no statistically significant difference in PFS (HR .7, 95% CI .4-1.7, p = .43) or OS (HR .5, 95% CI .4-4.7, p = .16) between patients with PD-L1 TPS of <1% versus PD-L1 TPS of ≥1%. CONCLUSIONS: Our data adds to the growing evidence that suggests consolidation durvalumab after definitive chemoradiation may not be as efficacious in patients with EGFR-mutant tumors compared with EGFR wild-type NSCLC.

The impact of brain lesions on tDCS-induced electric fields.

Transcranial direct current stimulation (tDCS) can enhance motor and language rehabilitation after stroke. Though brain lesions distort tDCS-induced electric field (E-field), systematic accounts remain limited. Using electric field modelling, we investigated the effect of 630 synthetic lesions on E-field magnitude in the region of interest (ROI). Models were conducted for two tDCS montages targeting either primary motor cortex (M1) or Broca's area (BA44). Absolute E-field magnitude in the ROI differed by up to 42% compared to the non-lesioned brain depending on lesion size, lesion-ROI distance, and lesion conductivity value. Lesion location determined the sign of this difference: lesions in-line with the predominant direction of current increased E-field magnitude in the ROI, whereas lesions located in the opposite direction decreased E-field magnitude. We further explored how individualised tDCS can control lesion-induced effects on E-field. Lesions affected the individualised electrode configuration needed to maximise E-field magnitude in the ROI, but this effect was negligible when prioritising the maximisation of radial inward current. Lesions distorting tDCS-induced E-field, is likely to exacerbate inter-individual variability in E-field magnitude. Individualising electrode configuration and stimulator output can minimise lesion-induced variability but requires improved estimates of lesion conductivity. Individualised tDCS is critical to overcome E-field variability in lesioned brains.