Enhancing neutrophil cytotoxicity of a panel of clinical EGFR antibodies by Fc engineering to IgA3.0.

The epidermal growth factor receptor (EGFR) plays an essential role in cellular signaling pathways that regulate cell growth, proliferation and survival, and is often found dysregulated in cancer. Several monoclonal IgG antibodies have been clinically tested over the years which exert their function via blocking the ligand binding domain (thereby inhibiting downstream signaling) and induction of Fc-related effector functions, such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). However, these IgG antibodies do not optimally recruit neutrophils, by far the most abundant white blood cell population in humans. Therefore, we reformatted six therapeutic EGFR antibodies (cetuximab, panitumumab, nimotuzumab, necitumumab, zalutumumab, and matuzumab) into the IgA3.0 format, which is an IgA2 isotype that has been adapted for clinical application. Reformatting these antibodies preserved Fab-mediated functions such as EGFR binding, growth inhibition and ligand blockade. Additionally, whole leukocyte ADCC was significantly increased when using this panel of IgA3.0 antibodies compared to their respective IgG counterparts, with no major differences between IgA3.0 antibodies. In vivo, IgA3.0 matuzumab outperformed the other antibodies, resulting in the strongest suppression of tumor outgrowth in a long intraperitoneal model. We show that neutrophils are important for the suppression of tumor outgrowth. IgA3.0 matuzumab exhibited reduced receptor internalization compared to the other antibodies, possibly accounting for its superior in vivo Fc-mediated tumor cell killing efficacy. In conclusion, reformatting EGFR antibodies into an IgA3.0 format increased Fc-mediated killing while retaining Fab-mediated functions and could therefore be a good alternative for the currently available antibody therapies.

Boarding Duration in the Emergency Department and Inpatient Delirium and Severe Agitation.

This cohort study examines the risk factors for developing delirium and/or agitation in patients in the emergency department waiting for an inpatient bed.

C16ORF70/Mytho promotes healthy ageing in C. elegans and prevents cellular senescence in mammals.

The identification of genes that confer either extension of lifespan or accelerate age-related decline was a step forward in understanding the mechanisms of ageing and revealed that it is partially controlled by genetics and transcriptional programs. Here we discovered that the human DNA sequence C16ORF70 encoded for a protein, named MYTHO (Macroautophagy and YouTH Optimizer), which controls life- and health-span. MYTHO protein is conserved from C. elegans to humans and its mRNA was upregulated in aged mice and elderly people. Deletion of the ortholog myt-1 gene in C. elegans dramatically shortened lifespan and decreased animal survival upon exposure to oxidative stress. Mechanistically, MYTHO is required for autophagy likely because it acts as a scaffold that binds WIPI2 and BCAS3 to recruit and assemble the conjugation system at the phagophore, the nascent autophagosome. We conclude that MYTHO is a transcriptionally regulated initiator of autophagy that is central in promoting stress resistance and healthy ageing.

Access to low vision rehabilitation services in Australia: practitioner perspective.

CLINICAL RELEVANCE: The burden of vision loss is both personal and economic. Having reduced vision can restrict access to education, job opportunities, and other activities, and patients can require substantial government funds for treatment and rehabilitation. An in-depth investigation of barriers and enablers is required to improve access to low vision rehabilitation services. BACKGROUND: Several clinical trials have demonstrated the effectiveness of low vision rehabilitation services, leading to improved clinical and functional abilities. However not all patients make use of these resources. METHODS: A purposive sample of primary eyecare practitioners (optometrists and orthoptists who held a variety of roles in clinical practice, academia and low vision specific organisations) were invited to participate in focus groups that were audio-recorded and transcribed verbatim. The resulting data were de-identified, cleaned, independently coded by two researchers and compared. Data were analysed using an interpretative phenomenological approach that included inductive thematic analysis. RESULTS: Of the 21 practitioners attending the five focus groups, 67% were female and 33% were male. The participants were optometrists and orthoptists with a wide range (4 to 20+ years) of clinical experience in eyecare service delivery. Four major themes emerged from the analysis: three themes focus on identifying barriers, while one theme highlighted potential enablers. These themes encompassed barriers impacting referral frequency, practitioner knowledge, patient experience, and enablers that suggest improvement options for enhancing low vision services. CONCLUSION: Miscommunication between service providers, miscommunication between patients and clinicians, late referral, cost of services and social stigma were major barriers preventing patients from receiving low vision services. Most practitioners admitted limited knowledge of the scope of services provided by low vision organisations, suggesting there is a need for enablers such as professional development, improved communication between service providers, enhanced referral guidelines and increased public awareness.

Adjuvant COX inhibition augments STING signaling and cytolytic T cell infiltration in irradiated 4T1 tumors.

Immune therapy is the new frontier of cancer treatment. Therapeutic radiation is a known inducer of immune response and can be limited by immunosuppressive mediators including cyclooxygenase-2 (COX2) that is highly expressed in aggressive triple negative breast cancer (TNBC). A clinical cohort of TNBC tumors revealed poor radiation therapeutic efficacy in tumors expressing high COX2. Herein, we show that radiation combined with adjuvant NSAID (indomethacin) treatment provides a powerful combination to reduce both primary tumor growth and lung metastasis in aggressive 4T1 TNBC tumors, which occurs in part through increased antitumor immune response. Spatial immunological changes including augmented lymphoid infiltration into the tumor epithelium and locally increased cGAS/STING1 and type I IFN gene expression were observed in radiation-indomethacin-treated 4T1 tumors. Thus, radiation and adjuvant NSAID treatment shifts "immune desert phenotypes" toward antitumor M1/TH1 immune mediators in these immunologically challenging tumors. Importantly, radiation-indomethacin combination treatment improved local control of the primary lesion, reduced metastatic burden, and increased median survival when compared with radiation treatment alone. These results show that clinically available NSAIDs can improve radiation therapeutic efficacy through increased antitumor immune response and augmented local generation of cGAS/STING1 and type I IFNs.

Sunscreen Practices and Preferences of Skin of Color Patients.

Sunscreen is an essential way to protect against photodamage from ultraviolet (UV) radiation. Despite the recognized benefits of sunscreen in preventing skin damage from UV light, its use varies across different patient groups. This cross-sectional, questionnaire-based study aims to uncover the sunscreen usage patterns, preferences, and barriers among non-Hispanic White (NHW) and skin of color (SOC) individuals. Our findings demonstrate that NHW individuals are more likely to wear sunscreen daily (31% NHW vs 25% SOC) and reapply sunscreen at least once a day (76% NHW vs 45% SOC) compared with SOC individuals. SOC individuals demonstrate a willingness to use sunscreen, but they face barriers such as cost (2% NHW vs 16% SOC), lack of knowledge in finding suitable products (22% NHW vs 41% SOC), and concerns about white cast (7% NHW vs 25% SOC). SOC individuals are less likely to know the difference between mineral and chemical sunscreen (49% NHW vs 29% SOC), less likely to learn about sunscreen from dermatologists (36% NHW vs 22% SOC), and more likely to prefer sunscreen from brands owned by people of color (13% NHW vs 47% SOC).  In addition to analyzing the broader categories of NHW and SOC, subgroup analysis was conducted on specific subgroups, including Black, Asian, and Hispanic groups. Herein, we highlight differences in motivations, sunscreen preferences, sources of information, and knowledge levels about sun protection between NHW and SOC individuals. By uncovering the unique needs and challenges faced by SOC individuals, we aim to improve culturally competent patient education and promote effective sun protection practices across diverse populations. J Drugs Dermatol. 2024;23(6):456-462.     doi:10.36849/JDD.8268.

Universal Credit receipt among working-age patients who are accessing specialist mental health services: results from a novel data linkage study.

BACKGROUND: In 2013, Universal Credit (UC) was introduced by the UK Government. Understanding of how UC provision is allocated among people with mental disorders, and its intersection with protected characteristics is limited. This study aimed to explore (1) how UC receipt, including UC conditionality regime, varied among users of specialist mental health services between 2013 and 2019 and (2) associations between sociodemographic and diagnostic patient characteristics and UC receipt. METHODS: Working-age individuals who had accessed specialist mental health services were included if they had their mental health record data successfully linked with administrative benefits data. Associations between sociodemographic, diagnostic patient characteristics and UC receipt were explored using logistic regression models. RESULTS: Of the 143 715 patients, 26.9% had received UC between 2013 and 2019. Four in five patients were allocated to the searching for work conditionality regime during their time on UC. Females were less likely to have received UC (adjusted OR (AOR) 0.87, 95% CI 0.85 to 0.89) than males, and UC receipt decreased with age. Black patients (AOR 1.39, 95% CI 1.34 to 1.44) and patients from mixed and multiple ethnic backgrounds (AOR 1.27, 95% CI 1.18 to 1.38) had a higher likelihood of UC receipt than White patients. UC receipt was lower among patients diagnosed with severe mental illness compared with other psychiatric diagnoses (AOR 0.74, 95% CI 0.71 to 0.77). CONCLUSION: One in four specialist mental health service users had received UC and a large majority were subject to conditionality. The temporality of UC conditionality and mental health service presentation needs further exploration.

Liver disease and transplantation in telomere biology disorders: An international multicenter cohort.

BACKGROUND: Patients with telomere biology disorders (TBD) develop hepatic disease, including hepatitis, cirrhosis, and hepatopulmonary syndrome. No specific treatment exists for TBD-related liver disease, and the role of liver transplantation (LT) remains controversial. Our study objectives were to describe the clinical characteristics, management, and outcomes in patients with TBD-related liver disease, and their LT outcomes. METHODS: Data from 83 patients with TBD-associated liver disease were obtained from 17 participating centers in the Clinical Care Consortium of Telomere-Associated Ailments and by self-report for our retrospective, multicenter, international cohort study. RESULTS: Group A ("Advanced") included 40 patients with advanced liver disease. Of these, 20 underwent LT (Group AT). Group M ("Mild") included 43 patients not warranting LT evaluation, none of whom were felt to be medically unfit for liver transplantation. Supplemental oxygen requirement, pulmonary arteriovenous malformation, hepatopulmonary syndrome, and higher bilirubin and international normalized ratio values were associated with Group A. Other demographics, clinical manifestations, and laboratory findings were similar between groups. Six group A patients were declined for LT; 3 died on the waitlist. Median follow-up post-LT was 2.9 years (range 0.6-13.2 y). One-year survival post-LT was 73%. Median survival post-LT has not been reached. Group AT patients had improved survival by age compared to all nontransplant patients (log-rank test p = 0.02). Of 14 patients with pretransplant hypoxemia, 8 (57%) had improved oxygenation after transplant. CONCLUSIONS: LT recipients with TBD do not exhibit excessive posttransplant mortality, and LT improved respiratory status in 57%. A TBD diagnosis should not exclude LT consideration.

Targeted Investigational Treatment Analysis of Novel Anti-androgen (TITAN) study: ultralow prostate-specific antigen decline with apalutamide plus androgen-deprivation therapy.

OBJECTIVE: To assess the association between achievement of prostate-specific antigen (PSA) levels ≤0.2 ng/mL (henceforth 'ultralow') and clinical outcomes in patients in the 'Targeted Investigational Treatment Analysis of Novel Anti-androgen' (TITAN) study (ClinicalTrials.gov Identifier NCT02489318) with metastatic castration-sensitive prostate cancer (mCSPC). PATIENTS AND METHODS: Patients in the TITAN study with mCSPC were randomised to 240 mg/day apalutamide (n = 525) or placebo (n = 527) plus androgen-deprivation therapy. This post hoc analysis assessed the achievement of a PSA level of 0.2->0.02 ng/mL ('ultralow one' [UL1]) and ≤0.02 ng/mL ('ultralow two' [UL2]) vs >0.2 ng/mL with apalutamide treatment and its association with radiographic progression-free survival (rPFS), overall survival (OS), time to castration-resistant PC (TTCRPC), and time to PSA progression (TTPP). The landmark analysis and Kaplan-Meier methods were used. RESULTS: By 3 months, more patients achieved UL1 and UL2 with apalutamide (38% and 23%) vs placebo (15% and 5%). In the apalutamide-treated patients, UL2 vs PSA >0.2 ng/mL at landmark 3 months was associated with significantly longer rPFS (hazard ratio [HR] 0.28, 95% confidence interval [CI] 0.14-0.54), OS (HR 0.24, 95% CI 0.13-0.43), TTCRPC (HR 0.2, 95% CI 0.11-0.38), and TTPP (HR 0.11, 95% CI 0.04-0.27; nominal P values all <0.001); this association was also observed but less pronounced for UL1. Similar findings were observed at 6 months. Early onset of decline to UL2 by 3 months was associated with improved survival vs PSA >0.2 ng/mL anytime (HR 0.12, 95% CI 0.06-0.22; P < 0.001) in apalutamide-treated patients. CONCLUSIONS: In this post hoc analysis of TITAN, patients with the deepest PSA decline derived the greatest benefit. These results extend our findings of apalutamide efficacy in the overall TITAN population, underscoring the clinical value of PSA kinetics as a marker for treatment efficacy. PATIENT SUMMARY: Patients with metastatic prostate cancer that is sensitive to ongoing hormonal treatment benefited significantly from the addition of apalutamide compared with placebo. Those who achieved rapid and deep PSA reduction had the greatest survival benefit.

Digital telomere measurement by long-read sequencing distinguishes healthy aging from disease.

Telomere length is an important biomarker of organismal aging and cellular replicative potential, but existing measurement methods are limited in resolution and accuracy. Here, we deploy digital telomere measurement (DTM) by nanopore sequencing to understand how distributions of human telomere length change with age and disease. We measure telomere attrition and de novo elongation with up to 30 bp resolution in genetically defined populations of human cells, in blood cells from healthy donors and in blood cells from patients with genetic defects in telomere maintenance. We find that human aging is accompanied by a progressive loss of long telomeres and an accumulation of shorter telomeres. In patients with defects in telomere maintenance, the accumulation of short telomeres is more pronounced and correlates with phenotypic severity. We apply machine learning to train a binary classification model that distinguishes healthy individuals from those with telomere biology disorders. This sequencing and bioinformatic pipeline will advance our understanding of telomere maintenance mechanisms and the use of telomere length as a clinical biomarker of aging and disease.

Outpatient inhaled corticosteroid use in bronchopulmonary dysplasia.

RATIONALE: In the outpatient setting, inhaled corticosteroids (ICS) are frequently given to children with bronchopulmonary dysplasia (BPD) for treatment of respiratory and asthma-associated symptoms. In this study we sought to determine if correlations existed between ICS use and ICS initiation and patient characteristics and outpatient respiratory outcomes. METHODS: This study included children with the diagnosis of BPD (n = 661) who were seen in outpatient pulmonary clinics at the Children's Hospital of Philadelphia between 2016 and 2021. Chart review was used to determine patient demographics, use and timing of ICS initiation, asthma diagnosis, and acute care usage following initial hospital discharge. RESULTS: At the first pulmonary visit, 9.2% of children had been prescribed an ICS at NICU discharge, 13.9% had been prescribed an ICS after NICU discharge but before their first pulmonary appointment, and 6.9% were prescribed an ICS at the completion of initial pulmonary visit. Children started on an ICS as outpatients had a higher likelihood of ER visits (adjusted odds ratio: 2.68 ± 0.7), hospitalizations (4.81 ± 1.16), and a diagnosis of asthma (3.58 ± 0.84), compared to children never on an ICS. Of those diagnosed with asthma, children prescribed an ICS in the outpatient setting received the diagnosis at an earlier age. No associations between NICU BPD severity scores and ICS use were found. CONCLUSIONS: This study identifies an outpatient BPD phenotype associated with ICS use and ICS initiation independent of NICU severity score. Additionally, outpatient ICS initiation correlates with a subsequent diagnosis of asthma and acute care usage in children with BPD.

Improved Outcomes When Home-Dose Carbidopa-Levodopa Is Continued in the Geriatric Emergency Department in Patients With Parkinson's Disease.

Parkinson's disease (PD) is a debilitating condition that affects 1.8% of people 65 years of age and older. Patients with PD often require hospitalization and are frequently admitted through the emergency department (ED). Notably, their hospital durations tend to be lengthier compared with patients without PD. The primary outcome of this research was to compare the length of stay (LOS) of patients who received carbidopa-levodopa (CL) in the ED with those who did not. Secondary outcomes included 30-day-readmission rates and administration of injectable for agitation. In addition, the percentage of patients receiving CL before and after an information management technology (IMT) alert implementation was compared in a sub-analysis. Patients that received CL during their inpatient stay were identified by a database report in this retrospective study. Patients were excluded if they were not admitted through the ED, younger than 65 years of age, or admitted to the intensive care unit after the ED. There was a total of 266 in the control group and 217 patients in the intervention group. The intervention group had a significantly shorter LOS than the control group (3.29 vs 5.37 days; P = 0.002), significantly less frequent 30-day readmissions (P = 0.032), and used fewer injectables for agitation (P = 0.035). The sub-analysis of the IMT alert revealed that prior to the alert's implementation, 28.5% of patients received CL in the ED; whereas post-alert, this percentage increased to 91.4% (P < 0.001). The results of this study found that the group of PD patients who received CL in the ED had shorter LOS, lower 30-day readmissions, and used less injectables for agitation compared with the group that did not receive CL in the ED. This improvement is possibly due to continuity of CL supply considering its short half-life and clinical importance for PD.

Comparative Effectiveness of Patient-Driven versus Standardized Diabetes Shared Medical Appointments: A Pragmatic Cluster Randomized Trial.

BACKGROUND: Diabetes self-management education and support can be effectively and efficiently delivered in primary care in the form of shared medical appointments (SMAs). Comparative effectiveness of SMA delivery features such as topic choice, multi-disciplinary care teams, and peer mentor involvement is not known. OBJECTIVE: To compare effects of standardized and patient-driven models of diabetes SMAs on patient-level diabetes outcomes. DESIGN: Pragmatic cluster randomized trial. PARTICIPANTS: A total of 1060 adults with type 2 diabetes in 22 primary care practices. INTERVENTIONS: Practice personnel delivered the 6-session Targeted Training in Illness Management (TTIM) curriculum using either standardized (set content delivered by a health educator) or patient-driven SMAs (patient-selected topic order delivered by health educators, behavioral health providers [BHPs], and peer mentors). MAIN MEASURES: Outcomes included self-reported diabetes distress and diabetes self-care behaviors from baseline and follow-up surveys (assessed at 1st and final SMA session), and HbA1c, BMI, and blood pressure from electronic health records. Analyses used descriptive statistics, linear regression, and linear mixed models. KEY RESULTS: Both standardized and patient-driven SMAs effectively improved diabetes distress, self-care behaviors, BMI (- 0.29 on average), and HbA1c (- 0.45% (mmol/mol) on average, 8.3 to 7.8%). Controlling for covariates, there was a small, significant effect of condition on overall diabetes distress in favor of standardized SMAs (F(1,841) = 4.3, p = .04), attributable to significant effects of condition on emotion and regimen distress subscales. There was a small, significant effect of condition on diastolic blood pressure in favor of standardized SMAs (F(1,5199) = 4.50, p = .03). There were no other differences between conditions. CONCLUSIONS: Both SMA models using the TTIM curriculum yielded significant improvement in diabetes distress, self-care, and HbA1c. Patient-driven diabetes SMAs involving BHPs and peer mentors and topic selection did not lead to better clinical or patient-reported outcomes than standardized diabetes SMAs facilitated by a health educator following a set topic order. NIH TRIAL REGISTRY NUMBER: NCT03590041.

Simultaneous quantification of five antiretrovirals in human tissues using ultra-high performance liquid chromatography-tandem mass spectrometry methods for therapeutic drug monitoring at the sites of action.

Although antiretroviral therapy (ART) is highly effective for the treatment of HIV-1 infection to suppress virus in the blood, HIV persists in tissues. HIV persistence in the tissues is due to numerous factors, and one of those factors are antiretroviral (ARV) concentrations. ARV concentrations in tissues must be adequate to suppress HIV at the sites of action. While therapeutic drug monitoring in the plasma is well-known, drug monitoring in the tissues provides local assessments of adequate ARV exposure to prevent localized HIV resistance formation. Towards these efforts, we validated an ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS/MS) method in human tissues (cervical, rectal, and vaginal tissues) for the simultaneous quantification of five ARVs: bictegravir, cabotegravir, dolutegravir, doravirine, and raltegravir. For this assay, protein precipitation with acetonitrile with stable, isotopically-labeled internal standards followed by supernatant pre-concentration was performed. Analyte separation was accomplished using a multistep UPLC gradient mixture of 0.1 % formic acid in water (A) and acetonitrile (B) with a Waters Cortecs T3 (2.1x100 mm) column. The assay was extensively validated as per the United States Food and Drug Administration Bioanalytical Method Validation Guidance over a clinically observed range (0.05-50 ng/mL) with superb linearity (R2 > 0.99 across all ARVs). The assay run time was 8.5 min. This analytical method achieves appropriate performance of trueness (85.5-107.4 %), repeatability, and precision (CV < 15 %). Our method will be employed for the therapeutic monitoring of guideline-recommended ARVs in human tissues for monitoring therapeutic efficacy in HIV treatment and prevention research efforts.

Impact of Airborne Exposure to PM10 Increases Susceptibility to P. aeruginosa Infection.

The effects of exposure to airborne particulate matter with a size of 10 µm or less (PM10) on C57BL/6 mouse corneas, their response to Pseudomonas aeruginosa (PA) infection, and the protective effects of SKQ1 were determined. C57BL/6 mouse corneas receiving PBS or SKQ1 were exposed to control (air) or PM10 for 2 weeks, infected, and the disease was documented by clinical score, PMN quantitation, bacterial plate count, RT-PCR and Western blot. PBS-treated, PM10-exposed corneas did not differ at 1 day postinfection (dpi), but exhibited earlier (3 dpi) corneal thinning compared to controls. By 3 dpi, PM10 significantly increased corneal mRNA levels of several pro-inflammatory cytokines, but decreased IL-10, NQO1, GR1, GPX4, and Nrf2 over control. SKQ1 reversed these effects and Western blot selectively confirmed the RT-PCR results. PM10 resulted in higher viable bacterial plate counts at 1 and 3 dpi, but SKQ1 reduced them at 3 dpi. PM10 significantly increased MPO in the cornea at 3 dpi and was reduced by SKQ1. SKQ1, used as an adjunctive treatment to moxifloxacin, was not significantly different from moxifloxacin alone. Exposure to PM10 increased the susceptibility of C57BL/6 to PA infection; SKQ1 significantly reversed these effects, but was not effective as an adjunctive treatment.

Understanding the causes of missingness in primary care: a realist review.

BACKGROUND: Although missed appointments in healthcare have been an area of concern for policy, practice and research, the primary focus has been on reducing single 'situational' missed appointments to the benefit of services. Little attention has been paid to the causes and consequences of more 'enduring' multiple missed appointments in primary care and the role this has in producing health inequalities. METHODS: We conducted a realist review of the literature on multiple missed appointments to identify the causes of 'missingness.' We searched multiple databases, carried out iterative citation-tracking on key papers on the topic of missed appointments and identified papers through searches of grey literature. We synthesised evidence from 197 papers, drawing on the theoretical frameworks of candidacy and fundamental causation. RESULTS: Missingness is caused by an overlapping set of complex factors, including patients not identifying a need for an appointment or feeling it is 'for them'; appointments as sites of poor communication, power imbalance and relational threat; patients being exposed to competing demands, priorities and urgencies; issues of travel and mobility; and an absence of choice or flexibility in when, where and with whom appointments take place. CONCLUSIONS: Interventions to address missingness at policy and practice levels should be theoretically informed, tailored to patients experiencing missingness and their identified needs and barriers; be cognisant of causal domains at multiple levels and address as many as practical; and be designed to increase safety for those seeking care.

Clinical updates and surveillance recommendations for DNA replication-repair deficiency syndromes in children and young adults.

Replication repair deficiency (RRD) is a pan-cancer mechanism characterized by abnormalities in the DNA mismatch repair (MMR) system due to pathogenic variants in the PMS2, MSH6, MSH2 or MLH1 genes, and/ or in the polymerase-proofreading genes, POLE and POLD1. RRD predisposition syndromes [constitutional MMR deficiency (CMMRD), Lynch, polymerase-proofreading associated polyposis (PPAP)] share overlapping phenotypic and biological characteristics. Moreover, cancers stemming from germline defects of one mechanism can acquire somatic defects in another, leading to complete RRD. Here we describe the recent advances in the diagnostics, surveillance, and clinical management for children with RRD syndromes. For patients with CMMRD, new data combining clinical insights and cancer genomics have revealed genotype-phenotype associations, helped in the development of novel functional assays, diagnostic guidelines, and surveillance recommendations. Recognition of non-gastrointestinal/ genitourinary malignancies, particularly aggressive brain tumors, in select children with Lynch and PPAP syndromes harbouring an RRD biology have led to new management considerations. Additionally, universal hypermutation and microsatellite instability have allowed immunotherapy to be a paradigm shift in the treatment of RRD cancers independent of their germline etiology. These advances have also stimulated a need for expert recommendations regarding genetic counselling for these patients and their families. Future collaborative work will focus on newer technologies such as quantitative measurement of circulating tumor DNA and functional genomics to tailor surveillance and clinical care, improving immune surveillance, develop prevention strategies, and deliver these novel discoveries to resource-limited settings to maximize benefits for patients globally.

Rehabilitation Services for Young-Onset Dementia: Examples from High- and Low-Middle-Income Countries.

The WHO Dementia Global Action Plan states that rehabilitation services for dementia are required to promote health, reduce disability, and maintain quality of life for those living with dementia. Current services, however, are scarce, particularly for people with young-onset dementia (YOD). This article, written by an international group of multidisciplinary dementia specialists, offers a three-part overview to promote the development of rehabilitation services for YOD. Firstly, we provide a synthesis of knowledge on current evidence-based rehabilitative therapies for early-onset Alzheimer's disease (EOAD), behavioural variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA), and posterior cortical atrophy (PCA). Secondly, we discuss the characteristics of rehabilitation services for YOD, providing examples across three continents for how these services can be embedded in existing settings and the different roles of the rehabilitation multidisciplinary team. Lastly, we conclude by highlighting the potential of telehealth in making rehabilitation services more accessible for people with YOD. Overall, with this paper, we aim to encourage clinical leads to begin introducing at least some rehabilitation into their services, leveraging existing resources and finding support in the collective expertise of the broader multidisciplinary dementia professional community.