People with Intellectual Disabilities, Dysphagia and Post-Covid Syndrome.

People with Intellectual Disability (ID) were more likely to contract COVID-19 infection and more likely to die from the consequences. However, there is no evidence on the long-term impact of COVID-19 infection in people with ID. Post-Covid Syndrome (PCS) is an established diagnosis that requires specialist clinical support. To date there is no data on how common PCS is in people with ID, or how symptoms present. Dysphagia is identified as a clinical marker because of the known association with PCS, and the clear objective diagnostic criteria applicable through specialist assessment. This investigation presents a cohort of people with ID, who developed dysphagia/worsening of dysphagia post diagnosis with COVID-19. Cases were identified through support from the Royal College of Speech and Language Therapists. Data was collected by electronic survey, including application of the COVID-19 Yorkshire Rehabilitation Scale-modified (C19-YRSm). The C19-YRSm is a validated assessment tool for PCS and it's impact upon functional disability. This case series identifies that symptoms consistent with PCS are present in people with ID, post-COVID-19 infection. The risk of diagnostic overshadowing or misdiagnosis is high due to the subjective nature and the quality of PCS symptoms. People with ID who develop PCS may not be readily identified by clinical services and therefore not be accessing the specialist medical support required. Furthermore, changes in behaviour secondary to PCS may lead to unnecessary increased prescribing of psychotropic medication which in itself risks worsening dysphagia. Dysphagia could be an important bellwether to identify PCS in people with ID.

Nonlinear association between body mass index and overall survival in advanced NSCLC patients treated with immune checkpoint blockade.

BACKGROUND: We investigated the association of body mass index (BMI) modeled as a continuous variable with survival outcomes in advanced non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICI). METHODS: We performed a single-institution retrospective analysis of consecutively diagnosed locally advanced or metastatic NSCLC patients treated with single-agent ICI in the first line or recurrent setting. The primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS) and objective response rate (ORR). BMI was modeled using a four-knot restricted cubic spline. Multiple Cox regression was used for survival analysis. RESULTS: Two hundred patients were included (female 54%; never smoker 12%). Adenocarcinoma was the most common histology (61%). Median age was 67 years, median BMI was 25.9 kg/m2, and 65% of patients had Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1. On multivariable analysis, only BMI and ECOG PS were independently associated with OS (p < 0.01). Mortality risk decreased as the BMI increased from 20 to 30 kg/m2 (HR 0.49, 95% CI 0.28-0.84); however, it was reversed as the BMI surpassed ~ 30 kg/m2. Compared to ECOG PS ≥ 2, patients with ECOG PS of 0-1 had a longer OS (HR 0.42, 95% CI 0.28-0.63). Similar trends were observed with PFS and ORR, but the strength of the association was weaker. CONCLUSION: We observed a nonlinear association between BMI and OS following treatment with ICI in advanced NSCLC. Risk of death increases at both extremes of BMI with a nadir that exists around 30 kg/m2.

UK paediatric speech and language therapists' perceptions on the use of telehealth in current and future clinical practice: An application of the APEASE criteria.

BACKGROUND: Telehealth for paediatric speech and language therapy became one of the most salient modes of service delivery during the COVID-19 pandemic. Evidence for speech and language therapy services via telehealth in comparison to face-to-face delivery demonstrates promising outcomes, and studies have begun to explore practitioner and client experiences. However, across the literature, many critical elements of services are overlooked, and there is a need to frame the evidence base within a theoretical model that can draw out practical implications that consider the range of factors having an impact on clinical implementation in real-world contexts. The APEASE (Acceptability, Practicability, Effectiveness, Affordability, Side-effects, and Equity) criteria offer such a model. The current study explored practising UK speech and language therapists' (SLTs) clinical experience of telehealth through the lens of the APEASE criteria and aimed to identify recommendations for future service provision from the practitioner perspective. METHODS: An online survey structured using the APEASE criteria was developed in collaboration with the UK Royal College of Speech and Language Therapists. Quantitative data were analysed using descriptive statistics and qualitative data were analysed using reflexive thematic analysis. RESULTS: Four hundred and thirty-eight qualified and practicing UK paediatric SLTs completed the survey. Telehealth was broadly acceptable and practicable to SLTs yet there remains some uncertainty about its efficacy and cost-effectiveness compared to face-to-face interventions and how equitable it is for different population groups. SLTs reported that effective implementation of telehealth services was dependent upon several contextual factors; affordability was a perceived barrier to clients having access to telehealth resources, intervention via telehealth was perceived as more acceptable than assessment, and whilst many SLTs welcomed aspects of telehealth, there were concerns about the physical and mental health consequences for practitioners. Six themes for the future development of telehealth in paediatric speech and language therapy were identified: (1) balanced and tailored services; (2) technology and equipment; (3) information and communication; (4) capacity building; (5) monitoring and evaluation; and (6) leadership and governance. CONCLUSIONS: Outcomes highlight promising, concerning and uncertain aspects of telehealth in paediatric speech and language therapy. SLTs value a flexible and tailored approach to service delivery and recommend that effective leadership, clear communication, ongoing policy and guidance development, upskilling of users and careful evaluation of impact are required to ensure optimal implementation. The APEASE criteria offer a valuable opportunity to enhance and streamline practice and research to ensure sustainable implementation of telehealth in the paediatric speech and language therapy services of tomorrow. WHAT THIS PAPER ADDS: What is already known on this subject The COVID-19 pandemic led to the increased use of telehealth as a main mode of service delivery in paediatric speech and language therapy. Pre-COVID-19, evidence for the use of telehealth in this field included small-scale experimental studies that reported on children with particular disorders and explored telehealth outcomes in comparison to face-to-face delivery. The realities of at-scale clinical practice were not well-represented, and critical elements of service such as cost-effectiveness were often overlooked in the paediatric literature. Furthermore, despite emerging global evidence for temporary telehealth responses to the crisis in speech and language therapy, the long-term and future use of telehealth remains unclear. What this paper adds to existing knowledge The current study applied the lens of the APEASE (Acceptability, Practicability, Effectiveness, Affordability, Side-effects, and Equity) criteria, which were used in this case to consider socioeconomic, ecological and cultural factors to capture an overarching understanding of the use of telehealth in paediatric speech and language therapy, and to inform the role of telehealth in future, longer-term and at-scale service development. Results indicated emerging trends in UK paediatric speech and language therapists' (SLTs') perceptions of telehealth and SLTs perceived a hybrid approach to service delivery, combining mostly face-to-face services with some telehealth, was likely to continue in the future. We identified six themes to guide the future development of telehealth in paediatric speech and language therapy services: (1) balanced and tailored services; (2) technology and equipment; (3) information and communication; (4) capacity building; (5) monitoring and evaluation; and (6) leadership and governance. What are the potential or actual clinical implications of this work? UK SLTs believe that speech and language therapy services using telehealth should be reflective, tailored and flexible to meet the requirements and circumstances of the children, young people and families served, as well as the physical and emotional needs of practitioners. SLTs recommend that this service development is clearly communicated to all stakeholders and suggested that those using telehealth should be supported through appropriate training, and ongoing effectiveness should be monitored. Telehealth is here to stay and the APEASE criteria offer a unique opportunity to ensure sustainable models of service delivery; to support co-ordinated leadership at the local, national and international levels and the development of policy and clinical guidance.

Allied health professional research engagement and impact on healthcare performance: A systematic review protocol.

BACKGROUND: Existing evidence suggests that clinician and organization engagement in research can improve healthcare processes of care and outcomes. However, current evidence has considered the relationship across all healthcare professions collectively. With the increase in allied health clinical academic and research activity, it is imperative for healthcare organizations, leaders and managers to understand engagement in research within these specific clinical fields. This systematic review aims to identify the effect of engagement in research by allied health professionals (AHPs) and organizations on healthcare performance. METHODS: This systematic review has a two-stage search strategy. The first stage will be to screen a previous systematic review examining the effectiveness of engagement in research in health and social care to identify relevant papers published pre-2012. The search strategy used in the previous review will then be rerun, but with a specific focus on allied health. This multi-database search will identify publications from 2012 to date. Only studies that assessed the effectiveness of allied health engagement in research will be included. All stages of the review will be conducted by two reviewers independently, plus documented discussions with the wider research team when discrepancies occur. This systematic review protocol follows the EQUATOR reporting guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols (PRISMA-P). DISCUSSION: The findings of this review will make a significant contribution to the evidence base around the effect of allied health engagement in research on healthcare performance. It will provide insights for clinicians and managers looking to understand the consequences of developing AHP research capability and capacity. The findings of this review will also aim to make recommendations for future evaluation approaches for engagement in research interventions. TRIAL REGISTRATION: This systematic review protocol has been registered with PROSPERO, registration number CRD42021253461. WHAT THIS PAPER ADDS: What is already known on the subject This study will provide valuable evidence for professionals and policymakers seeking to understand engagement in research in the allied health disciplines. Where supported by the data, there may be recommendations for future research regarding specific variables to be considered when planning and evaluating engagement in research in allied health practice. What this paper adds to existing knowledge A previous systematic review identified a positive association between clinician and organization engagement in research and improved processes of care and health outcomes. The reviews' findings have been used as a justification for clinicians and organizations to increase research capacity. That review evaluated literature published before 2012 and the studies that were identified predominantly reported on engagement in research by medics and nurses. An updated review is now required to include research published since 2012. This review will specifically focus on the effect of engagement in research within allied health disciplines. What are the potential or actual clinical implications of this work? Research activity among AHPs is gaining momentum. Given this growth in AHP research activity and the rise in dedicated clinical academic roles, a contemporary review to identify the specific effect of AHP engagement in research on healthcare performance is prudent. The findings will inform clinicians, clinical managers and leaders of the potential impact of research activities by AHP clinicians and organizations. This will support the planning and development of initiatives focused on research capacity, capability and culture within allied health.

Editorial Perspective: Speaking up for developmental language disorder - the top 10 priorities for research.

Developmental language disorder (DLD) is one of the most common neurodevelopmental conditions, yet is chronically underserved, with far fewer children receiving clinical services than expected from prevalence estimates, and very little research attention relative to other neurodevelopmental conditions of similar prevalence and severity. This editorial describes a research priority-setting exercise undertaken by the Royal College of Speech and Language Therapists, which aims to redress this imbalance. From consultations with researchers, practitioners and individuals with lived experience, 10 research priorities emerge. Our goal is to share these priorities with the wider research community, to raise awareness and encourage research collaboration to improve outcomes for young people with DLD.

Health-related quality-of-life impact of pembrolizumab versus best supportive care in previously systemically treated patients with advanced hepatocellular carcinoma: KEYNOTE-240.

BACKGROUND: Health-related quality of life (HRQoL) is an important outcome measure and prognostic indicator in hepatocellular carcinoma (HCC). KEYNOTE-240 (NCT02702401) assessed the efficacy and safety of pembrolizumab plus best supportive care (BSC) versus placebo plus BSC in patients with HCC who previously received sorafenib. This study presents the results of a prespecified exploratory analysis of patient-reported outcomes. METHODS: Patients completed the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) and its HCC supplement (EORTC QLQ-HCC18) electronically at baseline; at weeks 2, 3, 4, 6, 9, 12, and 18; and then every 9 weeks until 1 year or end of treatment, and at the 30-day safety follow-up visit. RESULTS: The HRQoL population included 271 and 127 patients randomly assigned to pembrolizumab and placebo, respectively. From baseline to week 12, changes in both scores were similar between pembrolizumab and placebo; global health status/QoL scores were stable. The proportions of patients who improved, remained stable, or deteriorated across all functional domain and symptom scores were generally similar between pembrolizumab and placebo. Time to deterioration was similar between the 2 arms based on the prespecified analysis of EORTC QLQ-HCC18 domains of abdominal swelling, fatigue, and pain. CONCLUSION: Pembrolizumab preserved HRQoL during treatment for advanced HCC. Combined with efficacy and safety results from KEYNOTE-240, these findings support a positive benefit/risk profile for pembrolizumab in a second-line treatment setting for patients with HCC who previously received sorafenib.

Health care providers' perceptions of use and influence of clinical decision support reminders: qualitative study following a randomized trial to improve HPV vaccination rates.

BACKGROUND: Human Papillomavirus (HPV) leads to serious health issues and remains the most common sexually transmitted infection. Despite availability of effective vaccines, HPV vaccination rates are suboptimal. Furthermore, providers recommend the HPV vaccine less than half the time for eligible patients. Prior informatics research has demonstrated the effectiveness of computer-based clinical decision support (CDS) in changing provider behavior, especially in the area of preventative services. METHODS: Following a randomized clinical trial to test the effect of a CDS intervention on HPV vaccination rates, we conducted semi-structured interviews with health care providers to understand whether they noticed the CDS reminders and why providers did or did not respond to the prompts. Eighteen providers, a mix of medical doctors and nurse practitioners, were interviewed from five publicly-funded, urban health clinics. Interview data were qualitatively analyzed by two independent researchers using inductive content analysis. RESULTS: While most providers recalled seeing the CDS reminders, few of them perceived the intervention as effective in changing their behavior. Providers stated many reasons for why they did not perceive a change in their behavior, yet the results of the trial showed HPV vaccination rates increased as a result of the intervention. CONCLUSIONS: CDS reminders may be effective at changing provider behavior even if providers perceive them to be of little use. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02551887 Registered on September 15, 2015.

Role of transcranial Doppler in cerebrovascular disease.

Transcranial Doppler (TCD) is the only noninvasive modality for the assessment of real-time cerebral blood flow. It complements various anatomic imaging modalities by providing physiological-flow related information. It is relatively cheap, easily available, and can be performed at the bedside. It has been suggested as an essential component of a comprehensive stroke centre. In addition to its importance in acute cerebrovascular ischemia, its role is expanding in the evaluation of cerebral hemodynamics in various disorders of the brain. The "established" clinical indications for the use of TCD include cerebral ischemia, sickle cell disease, detection of right-to-left shunts, subarachnoid hemorrhage, periprocedural or surgical monitoring, and brain death. We present the role of TCD in acute cerebrovascular ischemia, sonothrombolysis, and intracranial stenosis.

Sequencing of Charcot-Marie-Tooth disease genes in a toxic polyneuropathy.

OBJECTIVE: Mutations in Charcot-Marie-Tooth disease (CMT) genes are the cause of rare familial forms of polyneuropathy. Whether allelic variability in CMT genes is also associated with common forms of polyneuropathy-considered "acquired" in medical parlance-is unknown. Chemotherapy-induced peripheral neuropathy (CIPN) occurs commonly in cancer patients and is individually unpredictable. We used CIPN as a clinical model to investigate the association of non-CMT polyneuropathy with CMT genes. METHODS: A total of 269 neurologically asymptomatic cancer patients were enrolled in the clinical trial Alliance N08C1 to receive the neurotoxic drug paclitaxel, while undergoing prospective assessments for polyneuropathy. Forty-nine CMT genes were analyzed by targeted massively parallel sequencing of genomic DNA from patient blood. RESULTS: A total of 119 (of 269) patients were identified from the 2 ends of the polyneuropathy phenotype distribution: patients that were most and least susceptible to paclitaxel polyneuropathy. The CMT gene PRX was found to be deleteriously mutated in patients who were susceptible to CIPN but not in controls (p = 8 × 10(-3)). Genetic variation in another CMT gene, ARHGEF10, was highly significantly associated with CIPN (p = 5 × 10(-4)). Three nonsynonymous recurrent single nucleotide variants contributed to the ARHGEF10 signal: rs9657362, rs2294039, and rs17683288. Of these, rs9657362 had the strongest effect (odds ratio = 4.8, p = 4 × 10(-4)). INTERPRETATION: The results reveal an association of CMT gene allelic variability with susceptibility to CIPN. The findings raise the possibility that other acquired polyneuropathies may also be codetermined by genetic etiological factors, of which some may be related to genes already known to cause the phenotypically related Mendelian disorders of CMT.

Lung eQTLs to help reveal the molecular underpinnings of asthma.

Genome-wide association studies (GWAS) have identified loci reproducibly associated with pulmonary diseases; however, the molecular mechanism underlying these associations are largely unknown. The objectives of this study were to discover genetic variants affecting gene expression in human lung tissue, to refine susceptibility loci for asthma identified in GWAS studies, and to use the genetics of gene expression and network analyses to find key molecular drivers of asthma. We performed a genome-wide search for expression quantitative trait loci (eQTL) in 1,111 human lung samples. The lung eQTL dataset was then used to inform asthma genetic studies reported in the literature. The top ranked lung eQTLs were integrated with the GWAS on asthma reported by the GABRIEL consortium to generate a Bayesian gene expression network for discovery of novel molecular pathways underpinning asthma. We detected 17,178 cis- and 593 trans- lung eQTLs, which can be used to explore the functional consequences of loci associated with lung diseases and traits. Some strong eQTLs are also asthma susceptibility loci. For example, rs3859192 on chr17q21 is robustly associated with the mRNA levels of GSDMA (P = 3.55 × 10(-151)). The genetic-gene expression network identified the SOCS3 pathway as one of the key drivers of asthma. The eQTLs and gene networks identified in this study are powerful tools for elucidating the causal mechanisms underlying pulmonary disease. This data resource offers much-needed support to pinpoint the causal genes and characterize the molecular function of gene variants associated with lung diseases.

Second-generation shRNA libraries covering the mouse and human genomes.

Loss-of-function phenotypes often hold the key to understanding the connections and biological functions of biochemical pathways. We and others previously constructed libraries of short hairpin RNAs that allow systematic analysis of RNA interference-induced phenotypes in mammalian cells. Here we report the construction and validation of second-generation short hairpin RNA expression libraries designed using an increased knowledge of RNA interference biochemistry. These constructs include silencing triggers designed to mimic a natural microRNA primary transcript, and each target sequence was selected on the basis of thermodynamic criteria for optimal small RNA performance. Biochemical and phenotypic assays indicate that the new libraries are substantially improved over first-generation reagents. We generated large-scale-arrayed, sequence-verified libraries comprising more than 140,000 second-generation short hairpin RNA expression plasmids, covering a substantial fraction of all predicted genes in the human and mouse genomes. These libraries are available to the scientific community.

Estimating and Rewarding the Value of Healthcare Interventions Beyond the Healthcare Sector: A Conceptual Framework.

BACKGROUND: Evaluating healthcare interventions for their impacts beyond health outcomes may result in recognition of changes in human capital, income level, tax revenue, and government spending, which could affect economic growth and population health. In this paper, we document instances where current health technology assessment (HTA) practices fail to account for the impacts of healthcare interventions on broader society beyond the healthcare sector. METHODS: We propose a novel conceptual framework, highlighting its three components (distributional cost-effectiveness analysis [DCEA], input-output model, and voting scheme) and their contributions to capturing the economic and societal ripple effects of healthcare interventions. This manuscript also outlines a case study in which the framework is applied to the reassessment of a previously evaluated digital health therapeutic for the treatment of opioid use disorder (OUD) compared with standard of care, demonstrating its practical application. RESULTS: The DCEA health value metric indicates that digital therapeutic is more equitable, favoring socioeconomically disadvantaged groups, while standard of care exacerbates health inequality by benefiting the already advantaged. Additionally, digital therapeutic shows potential for boosting productivity, raising income, and creating jobs, supporting its consideration by employer-sponsored health plans to optimize resource allocation for treating OUD. CONCLUSION: The conceptual framework provides insights for enhancing HTAs to incorporate the broader economic and societal impacts of healthcare interventions. By integrating DCEA, extended HTA analysis with input-output modeling, and a voting scheme, decision makers can make informed choices aligned with societal priorities, although further research and validation are necessary for practical implementation across diverse healthcare contexts.

Association of antibiotic exposure with residual cancer burden in HER2-negative early stage breast cancer.

Antibiotic exposure during immunotherapy (IO) has been shown to negatively affect clinical outcomes in various cancer types. The aim of this study was to evaluate whether antibiotic exposure in patients with high-risk early-stage HER2-negative breast cancer (BC) undergoing treatment with neoadjuvant pembrolizumab impacted residual cancer burden (RCB) and pathologic complete response (pCR) in the pembrolizumab-4 arm of the ISPY-2 clinical trial. Patients received pembrolizumab for four cycles concurrently with weekly paclitaxel for 12 weeks, followed by four cycles of doxorubicin plus cyclophosphamide every 2 or 3 weeks. Patients who received at least one dose of systemic antibiotics concurrently at the time of immunotherapy (IO) were included in the antibiotic exposure group (ATB+). All other participants were included in the control group (ATB-). RCB index and PCR rates were compared between the ATB+ and ATB- groups using t-tests and Chi-squared tests, and linear and logistic regression models, respectively. Sixty-six patients were included in the analysis. 18/66 (27%) patients were in the ATB+ group. Antibiotic use during IO was associated with a higher mean RCB index (1.80 ± 1.43 versus 1.08 ± 1.41) and a lower pCR rate (27.8% versus 52.1%). The association between antibiotic use and the RCB index remained significant in multivariable linear regression analysis (RCB index-coefficient 0.86, 95% CI 0.20-1.53, P = 0.01). Our findings suggest that concurrent antibiotic exposure during neoadjuvant pembrolizumab in HER2-negative early-stage BC is associated with higher RCB. Further validation in larger cohorts is needed to confirm these findings.

The effectiveness of evidence-based healthcare educational interventions on healthcare professionals' knowledge, skills, attitudes, professional practice and healthcare outcomes: Systematic review and meta-analysis.

OBJECTIVE: The primary aim of this systematic review is to assess the effectiveness of evidence-based healthcare (EBHC) educational interventions on healthcare professionals' knowledge, skills, attitudes, behaviour of EBHC, clinical process and care outcomes. A secondary aim of the review is to assess the effects of important pedagogical moderating factors for EBHC educational interventions. METHOD: This systematic review used a forward and backward citation search strategy on the Web of Science platform (date of inception to 28 April 2023). Only randomised controlled trials (RCTs) and cluster RCTs which compared EBHC educational interventions for healthcare professionals were included. A random effects meta-analysis was undertaken for EBHC compared with an active and nonactive control for all outcomes. RESULTS: Sixty-one RCTs were identified which included a total of 5208 healthcare professionals. There was a large effect for EBHC educational interventions compared with waiting list/no treatment/sham control on knowledge (SMD, 2.69; 95% CI, 1.26-4.14, GRADE Low), skills (SMD, 0.88; 95% CI, 0.25-1.73, Very Low Certainty), attitude (SMD, 0.81; 95% CI, 0.16-1.47, Very Low Certainty) and behaviour of EBHC (SMD, 0.82; 95% CI, 0.25-1.40, Very Low Certainty). Over time the effect of EBHC educational interventions substantially decreased with no evidence of effect at 6 months for any outcome except behaviour (SMD,1.72; 95% CI, 0.74-2.71, Low Certainty). There was some evidence that blended learning, active learning and consistency in the individual delivering the intervention may be important positive moderating factors. CONCLUSION: These findings suggest that EBHC educational interventions may have a large short-term effect on improving healthcare professionals' knowledge, skills, attitude and behaviour of EBHC. These effects may be longer-lasting regarding EBHC behaviour. In terms of pedagogy, blended learning, active learning, and consistency of the individual delivering the intervention may be important positive moderating factors.

Trajectories of Health Care Contact Days for Patients With Stage IV Non-Small Cell Lung Cancer.

Importance: Patients with stage IV non-small cell lung cancer (NSCLC) experience substantial morbidity and mortality. Contact days (ie, the number of days with health care contact outside the home) measure how much of a person's life is consumed by health care, yet little is known about patterns of contact days for patients with NSCLC. Objective: To describe the trajectories of contact days in patients with stage IV NSCLC and how trajectories vary by receipt of cancer-directed treatment in routine practice. Design, Setting, and Participants: A retrospective, population-based decedent cohort study was conducted in Ontario, Canada. Participants included adults aged 20 years or older who were diagnosed with stage IV NSCLC (January 1, 2014, to December 31, 2017) and died (January 1, 2014, to December 31, 2019); there was a maximum 2-year follow-up. Data analysis was conducted from February 22 to August 16, 2023. Exposure: Systemic cancer-directed therapy (yes or no) and type of therapy (chemotherapy vs immunotherapy vs targeted therapy). Main Outcomes and Measures: Contact days (days with health care contact, outpatient or institution-based, outside the home) were identified through administrative data. The weekly percentage of contact days and fitted models with cubic splines were quantified to describe trajectories from diagnosis until death. Results: A total of 5785 decedents with stage IV NSCLC were included (median age, 70 [IQR 62-77] years; 3108 [53.7%] were male, and 1985 [34.3%] received systemic therapy). The median overall survival was 108 (IQR, 49-426) days, median contact days were 36 (IQR, 21-62), and the median percentage that were contact days was 33.3%. A median of 5 (IQR, 2-10) days were spent with specialty palliative care. Patients who did not receive systemic therapy had a median overall survival of 66 (IQR, 34-130) days and median contact days of 28 (IQR, 17-44), of which a median of 5 (IQR, 2-9) days were spent with specialty palliative care. Overall and for subgroups, normalized trajectories followed a U-shaped distribution: contact days were most frequent immediately after diagnosis and before death. Patients who received targeted therapy had the lowest contact day rate during the trough (10.6%; vs immunotherapy, 15.4%; vs chemotherapy, 17.7%). Conclusions and Relevance: In this cohort study, decedents with stage IV NSCLC had a median survival in the order of 3.5 months and spent 1 in every 3 days alive interacting with the health care system outside the home. These results highlight the need to better support patients and care partners, benchmark appropriateness, and improve care delivery.

Biomarker screen for efficacy of oncolytic virotherapy in patient-derived pancreatic cancer cultures.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a tumour entity with unmet medical need. To assess the therapeutic potential of oncolytic virotherapy (OVT) against PDAC, different oncolytic viruses (OVs) are currently investigated in clinical trials. However, systematic comparisons of these different OVs in terms of efficacy against PDAC and biomarkers predicting therapeutic response are lacking. METHODS: We screened fourteen patient-derived PDAC cultures which reflect the intra- and intertumoural heterogeneity of PDAC for their sensitivity to five clinically relevant OVs, namely serotype 5 adenovirus Ad5-hTERT, herpes virus T-VEC, measles vaccine strain MV-NIS, reovirus jin-3, and protoparvovirus H-1PV. Live cell analysis, quantification of viral genome/gene expression, cell viability as well as cytotoxicity assays and titration of viral progeny were conducted. Transcriptome profiling was employed to identify potential predictive biomarkers for response to OV treatment. FINDINGS: Patient-derived PDAC cultures showed individual response patterns to OV treatment. Twelve of fourteen cultures were responsive to at least one OV, with no single OV proving superior or inferior across all cultures. Known host factors for distinct viruses were retrieved as potential biomarkers. Compared to the classical molecular subtype, the quasi-mesenchymal or basal-like subtype of PDAC was found to be more sensitive to H-1PV, jin-3, and T-VEC. Generally, expression of viral entry receptors did not correlate with sensitivity to OV treatment, with one exception: Expression of Galectin-1 (LGALS1), a factor involved in H-1PV entry, positively correlated with H-1PV induced cell killing. Rather, cellular pathways controlling immunological, metabolic and proliferative signaling appeared to determine outcome. For instance, high baseline expression of interferon-stimulated genes (ISGs) correlated with relative resistance to oncolytic measles virus, whereas low cyclic GMP-AMP synthase (cGAS) expression was associated with exceptional response. Combination treatment of MV-NIS with a cGAS inhibitor improved tumour cell killing in several PDAC cultures and cells overexpressing cGAS were found to be less sensitive to MV oncolysis. INTERPRETATION: Considering the heterogeneity of PDAC and the complexity of biological therapies such as OVs, no single biomarker can explain the spectrum of response patterns. For selection of a particular OV, PDAC molecular subtype, ISG expression as well as activation of distinct signaling and metabolic pathways should be considered. Combination therapies can overcome resistance in specific constellations. Overall, oncolytic virotherapy is a viable treatment option for PDAC, which warrants further development. This study highlights the need for personalised treatment in OVT. By providing all primary data, this study provides a rich source and guidance for ongoing developments. FUNDING: German National Science Foundation (Deutsche Forschungsgemeinschaft, DFG), German Cancer Aid (Deutsche Krebshilfe), German National Academic Scholarship Foundation (Studienstiftung des deutschen Volkes), Survival with Pancreatic Cancer Foundation.

Retargeting of rat parvovirus H-1PV to cancer cells through genetic engineering of the viral capsid.

The rat parvovirus H-1PV is a promising anticancer agent given its oncosuppressive properties and the absence of known side effects in humans. H-1PV replicates preferentially in transformed cells, but the virus can enter both normal and cancer cells. Uptake by normal cells sequesters a significant portion of the administered viral dose away from the tumor target. Hence, targeting H-1PV entry specifically to tumor cells is important to increase the efficacy of parvovirus-based treatments. In this study, we first found that sialic acid plays a key role in H-1PV entry. We then genetically engineered the H-1PV capsid to improve its affinity for human tumor cells. By analogy with the resolved crystal structure of the closely related parvovirus minute virus of mice, we developed an in silico three-dimensional (3D) model of the H-1PV wild-type capsid. Based on this model, we identified putative amino acids involved in cell membrane recognition and virus entry at the level of the 2-fold axis of symmetry of the capsid, within the so-called dimple region. In situ mutagenesis of these residues significantly reduced the binding and entry of H-1PV into permissive cells. We then engineered an entry-deficient viral capsid and inserted a cyclic RGD-4C peptide at the level of its 3-fold axis spike. This peptide binds α(v)ß(3) and α(v)ß(5) integrins, which are overexpressed in cancer cells and growing blood vessels. The insertion of the peptide rescued viral infectivity toward cells overexpressing α(v)ß(5) integrins, resulting in the efficient killing of these cells by the reengineered virus. This work demonstrates that H-1PV can be genetically retargeted through the modification of its capsid, showing great promise for a more efficient use of this virus in cancer therapy.

Cost-Effectiveness of Aripiprazole Tablets with Sensor versus Oral Atypical Antipsychotics for the Treatment of Schizophrenia Using a Patient-Level Microsimulation Modeling Approach.

Objective: Strategies designed to track drug ingestion may improve medication adherence and clinical outcomes in adults with schizophrenia. This study aimed to estimate the cost-effectiveness of aripiprazole tablets with sensor (AS; Abilify MyCite®) versus generic oral atypical antipsychotics (AAPs) in schizophrenia from the United States payer and societal perspectives over 12 months. Methods: An individual-level microsimulation was developed to generate individual trajectories using data from a phase 3b multicenter, open-label, mirror-image trial in adults with schizophrenia treated prospectively for 6 months with AS. The patient's clinical characteristics and outcomes were computed as a function of the Positive and Negative Syndrome Scale (PANSS) scores. Direct and indirect medical cost estimates were sourced from the literature; EuroQol 5-Dimensions (EQ-5D) utilities were derived using risk equations based on patient and clinical characteristics. Scenario analyses were also conducted to assess outcomes under the assumption of treatment durability over 12 months. Results: Over 12 months, AS showed a 12.2% improvement in PANSS score. AS had an incremental cost of $2168 and incremental cost savings of $22,343 from the payer and societal perspectives, respectively, with an incremental quality-adjusted life-year (QALY) gain of 0.0298 versus oral AAPs. Further, AS resulted in a 28.2% reduction in hospitalizations over 12 months. At a willingness-to-pay of $100,000 per QALY, the net monetary benefit over 12 months was $25,323 from the payer perspective. Under the assumption of the durability of the treatment effect of AS, the findings were similar to those of the base case analyses, though with greater cost savings and QALYs gained with AS. The results from the sensitivity analyses were consistent with those of the base case analysis. Conclusion: AS may be a cost-effective strategy, with lower costs and improved quality of life among patients with schizophrenia over 12 months, from the payer and societal perspectives.

CK1δ and CK1ε Signaling Sustains Mitochondrial Metabolism and Cell Survival in Multiple Myeloma.

Multiple myeloma remains an incurable malignancy due to acquisition of intrinsic programs that drive therapy resistance. Here we report that casein kinase-1δ (CK1δ) and CK1ε are therapeutic targets in multiple myeloma that are necessary to sustain mitochondrial metabolism. Specifically, the dual CK1δ/CK1ε inhibitor SR-3029 had potent in vivo and ex vivo anti-multiple myeloma activity, including against primary multiple myeloma patient specimens. RNA sequencing (RNA-seq) and metabolic analyses revealed inhibiting CK1δ/CK1ε disables multiple myeloma metabolism by suppressing genes involved in oxidative phosphorylation (OxPhos), reducing citric acid cycle intermediates, and suppressing complexes I and IV of the electron transport chain. Finally, sensitivity of multiple myeloma patient specimens to SR-3029 correlated with elevated expression of mitochondrial genes, and RNA-seq from 687 multiple myeloma patient samples revealed that increased CSNK1D, CSNK1E, and OxPhos genes correlate with disease progression and inferior outcomes. Thus, increases in mitochondrial metabolism are a hallmark of multiple myeloma progression that can be disabled by targeting CK1δ/CK1ε. SIGNIFICANCE: CK1δ and CK1ε are attractive therapeutic targets in multiple myeloma whose expression increases with disease progression and connote poor outcomes, and that are necessary to sustain expression of genes directing OxPhos.

Interplay of Immunosuppression and Immunotherapy Among Patients With Cancer and COVID-19.

Importance: Cytokine storm due to COVID-19 can cause high morbidity and mortality and may be more common in patients with cancer treated with immunotherapy (IO) due to immune system activation. Objective: To determine the association of baseline immunosuppression and/or IO-based therapies with COVID-19 severity and cytokine storm in patients with cancer. Design, Setting, and Participants: This registry-based retrospective cohort study included 12 046 patients reported to the COVID-19 and Cancer Consortium (CCC19) registry from March 2020 to May 2022. The CCC19 registry is a centralized international multi-institutional registry of patients with COVID-19 with a current or past diagnosis of cancer. Records analyzed included patients with active or previous cancer who had a laboratory-confirmed infection with SARS-CoV-2 by polymerase chain reaction and/or serologic findings. Exposures: Immunosuppression due to therapy; systemic anticancer therapy (IO or non-IO). Main Outcomes and Measures: The primary outcome was a 5-level ordinal scale of COVID-19 severity: no complications; hospitalized without requiring oxygen; hospitalized and required oxygen; intensive care unit admission and/or mechanical ventilation; death. The secondary outcome was the occurrence of cytokine storm. Results: The median age of the entire cohort was 65 years (interquartile range [IQR], 54-74) years and 6359 patients were female (52.8%) and 6598 (54.8%) were non-Hispanic White. A total of 599 (5.0%) patients received IO, whereas 4327 (35.9%) received non-IO systemic anticancer therapies, and 7120 (59.1%) did not receive any antineoplastic regimen within 3 months prior to COVID-19 diagnosis. Although no difference in COVID-19 severity and cytokine storm was found in the IO group compared with the untreated group in the total cohort (adjusted odds ratio [aOR], 0.80; 95% CI, 0.56-1.13, and aOR, 0.89; 95% CI, 0.41-1.93, respectively), patients with baseline immunosuppression treated with IO (vs untreated) had worse COVID-19 severity and cytokine storm (aOR, 3.33; 95% CI, 1.38-8.01, and aOR, 4.41; 95% CI, 1.71-11.38, respectively). Patients with immunosuppression receiving non-IO therapies (vs untreated) also had worse COVID-19 severity (aOR, 1.79; 95% CI, 1.36-2.35) and cytokine storm (aOR, 2.32; 95% CI, 1.42-3.79). Conclusions and Relevance: This cohort study found that in patients with cancer and COVID-19, administration of systemic anticancer therapies, especially IO, in the context of baseline immunosuppression was associated with severe clinical outcomes and the development of cytokine storm. Trial Registration: ClinicalTrials.gov Identifier: NCT04354701.