Collecting patient-reported outcomes (PROs) can improve symptom control and quality of life, enhance doctor-patient communication, and reduce acute care needs for patients with cancer. Digital solutions facilitate PRO collection, but without robust electronic health record (EHR) integration, effective deployment can be hampered by low patient and clinician engagement and high development and deployment costs. The important components of digital PRO platforms have been defined, but procedures for implementing integrated solutions are not readily available.As part of the NCI's IMPACT consortium, six health care systems partnered with Epic to develop an EHR-integrated, PRO-based electronic symptom management program (eSyM) to optimize postoperative recovery and well-being during chemotherapy. The agile development process incorporated user-centered design principles that required engagement from patients, clinicians, and health care systems. Whenever possible, the system used validated content from the public domain and took advantage of existing EHR capabilities to automate processes.eSyM includes symptom surveys on the basis of the PRO-Common Terminology Criteria for Adverse Events (PRO-CTCAE) plus two global wellness questions; reminders and symptom self-management tip sheets for patients; alerts and symptom reports for clinicians; and population management dashboards. EHR dependencies include a secure Health Insurance Portability and Accountability Act-compliant patient portal; diagnosis, procedure and chemotherapy treatment plan data; registries that identify and track target populations; and the ability to create reminders, alerts, reports, dashboards, and charting shortcuts.eSyM incorporates validated content and leverages existing EHR capabilities. Build challenges include the innate technical limitations of the EHR, the constrained availability of site technical resources, and sites' heterogenous EHR configurations and policies. Integration of PRO-based symptom management programs into the EHR could help overcome adoption barriers, consolidate clinical workflows, and foster scalability and sustainability. We intend to make eSyM available to all Epic users. This effort benefited from existing EHR capabilities , but it has faced technical challenges  and operational hurdles .RelevanceA symptom management program that is designed to optimize postoperative recovery and well-being during chemotherapy, uses validated content, and is embedded within an existing EHR could help overcome adoption barriers, consolidate clinical workflows, and foster scalability and sustainability.12 Severe symptoms often receive attention only after causing distress and requiring costly interventions; and mild-moderate symptoms can be left unattended even when early interventions could improve quality of life and prevent the development of severe symptoms. Recent studies suggest that patient-reported outcomes (PROs) help address these shortcomings by enhancing symptom detection and improving symptom control.13 Studies have found that using telehealth and web-based services to collect electronic PROs (ePROs) from patients with cancer is feasible14 and deemed useful by patients and clinicians.15 Moreover, collecting ePROs has helped decrease symptom burden, improve quality of life, reduce acute care utilization,16 and prolong survival.17Historically, the cancer care delivery system has used a reactive symptom management strategy making it ill-equipped to anticipate, monitor, and address symptoms before they escalate.21 not every-day practice. First, prior efforts were conducted at large, well-resourced cancer centers.13 Can these tools have an impact across community and rural settings? Second, prior efforts targeted a limited number of cancer types and symptoms.22 Can a common solution be applied across a broader range of cancers, symptoms, and treatments? Finally, prior efforts typically relied on free-standing ePRO applications that may be costly, complicated to deploy, and lack electronic health record (EHR) integration.23 Can EHR-integrated solutions offer practical advantages while retaining the same impact on outcomes as free-standing applications?Efforts to deploy PRO-based symptom management solutions, although limited, have shown promise. However, important questions regarding PRO use in the routine cancer care setting remain since past work has focused on the collection and interpretability of PROs in clinical trials,24 IMPACT funded three research projects to address gaps in symptom management, including the Symptom Management Implementation of Patient-Reported Outcomes in Oncology (SIMPRO) Consortium. The SIMPRO consortium sought to develop, implement, and evaluate the impact of a multicomponent electronic symptom management system (eSyM) for patients recovering from surgery or receiving chemotherapy  Cancer Moonshot Initiative sponsored the IMPACT (Improving the Management of symPtoms during And following Cancer Treatment) Consortium to improve symptom control for patients with cancer. IMPACT research sites engage patients in systematic symptom reporting and guideline-based clinical management, as well as evaluate the effects on patient-centered outcomes.rapy Fig . To crea26 Collaboration between the cancer centers and Epic was crucial, since the primary goal was to develop an EHR-integrated system with the potential to reach the broader oncology community.The SIMPRO consortium is composed of six US cancer centers (Data Supplement) that were chosen because they had minimal pre-existing ePRO experience; were Epic  EHR users; and provided care to diverse patient populations including rural, elderly, and vulnerable groups who might benefit from an ePRO solution. The SIMPRO consortium also includes Epic as a key partner. Epic builds and maintains health record software for 250 million people worldwide, including 73% of the NCI's Designated Cancer Centers.The SIMPRO team (Data Supplement) included three representatives from each SIMPRO site: a principal investigator physician, an Epic support technical lead, and a project manager. Epic was represented by staff from the Beacon (oncology), Healthy Planet (registry and reporting), and MyChart  teams. Subject matter experts in questionnaire design, cancer care delivery, and implementation science were engaged as needed.27 It incorporated user-centered design principles that required robust engagement from patients, clinicians, and health system administrators. The build team met weekly to review design components, troubleshoot technical issues, and develop the prototype system; site investigators and technical leads met monthly to review build requests and progress; and content experts and patients participated as needed. Design and configuration decisions, which were primarily the responsibility of the build team, were guided by three principles—create a system that could reduce hospitalizations and ED visits, was easy to use, and could be implemented at any Epic-based health care institution. The consensus-based decision-making process required input and approval from all sites to ensure the final solution was practically robust and widely supported.The development process was agile and collaborative.The program implementation schedule followed a randomized stepped-wedge design with six go-live waves, each lasting 6 months. During each go-live wave, one site introduced medical oncology eSyM and another site introduced surgery eSyM. The medical oncology and surgery go-lives for each site were staggered to occur during different waves to permit a rigorous evaluation of eSyM's impact. Technical preparation, build, and testing typically require approximately 3 months of work before launch; program validation and optimization require approximately 1 month after launch; and the effort required has been relatively consistent across sites. Postlaunch eSyM updates have been made if they foster the system's primary goal and are endorsed by all SIMPRO sites. This manuscript describes eSyM features that are common to all six sites and identifies aspects that required site-specific configuration.We created two independent programs—one for medical oncology and one for surgery—that could function in concert. Although eSyM functionality could vary on the basis of whether a patient had surgery or was receiving chemotherapy, it would not vary on the basis of cancer type, chemotherapy type, or surgery type, because it would be easier for health systems to deploy a standardized versus a customized system.The initial phase of the project focuses on patients undergoing surgery or receiving chemotherapy for gynecologic, thoracic, and GI malignancies. This eased the burden of deployment and allowed for comparison to patient populations for which eSyM was not launched. Also, eSyM was created for English-speaking adults; future iterations will address other cancer types, languages, and ages.29 Pictogram questions for overall well-being and functional status were added to contextualize symptom responses.eSyM focuses on detecting and managing symptoms between clinic visits using the extensively validated Patient-Reported Outcome-Common Terminology Criteria for Adverse Events (PRO-CTCAE) instrument.All content, including questionnaires and patient self-management tip sheets, is available from or shared with the public domain. eSyM relies on existing Epic software capabilities, with a priority placed on automating processes whenever possible, to reduce barriers to adoption.Several program requirements were established a priori, on the basis of findings from previously published studies, the team's prior experiences, and the overarching program goal:The eSyM program was designed to help patients, clinicians, and staff work together to reduce hospitalizations and ED visits during chemotherapy and following surgery Fig . eSyM haTwo patient registries automatically identify eligible patients. The medical oncology registry identifies patients who have a new treatment plan in the Beacon oncology module scheduled to begin in the next 30 days, a relevant International Classification of Diseases-10 cancer diagnosis code, and an encounter at a participating site. The surgery registry identifies patients who have a relevant current procedural terminology code in the OpTime module, a surgery date in the next 30 days, and a recent encounter with a participating surgical department or surgeon. The surgery registry focuses on cancer-directed procedures, excluding diagnostic interventions , but does not require a cancer diagnosis, because this information may not be available until the pathology report is finalized several weeks after surgery. Groupers define relevant cancer diagnoses or surgeries. They can be updated as the program evolves or customized by sites if they decide to modify the program.31 This tool asks about a symptom's frequency, severity, and/or interference; and uses an algorithm to translate responses into a four-item score .29 Pictogram questions assess overall well-being and physical function to help contextualize symptom responses (Data Supplement).33Two eSyM questionnaires were developed—one for medical oncology and one for surgery Fig . Nine syThe medical oncology questionnaire series becomes active  the day after the first treatment is completed. A questionnaire can be completed up to twice/week until 180 days after the treatment plan is initiated or the series is discontinued, whichever comes first. The surgery questionnaire series becomes active the day after a patient is discharged from the hospitalization during which the index procedure was performed. A questionnaire can be completed up to three times/week for weeks 1-2, up to twice/week for weeks 3-4, and up to once/week for weeks 5-8. The schedules were chosen to focus on times when patients are most likely to experience severe symptoms. Questionnaires take < 5 minutes. Responses file automatically to the patient's medical record.To avoid confusion and streamline workflows, patients are only asked to complete one questionnaire series at a time. If an active eSyM patient begins a new chemotherapy plan or has another surgery, then the old questionnaire series ends and a new series starts. There is no limit to the number of times a questionnaire series can be applied. For patients who opt out of eSyM, program staff can manually discontinue questionnaire series.Patients access all eSyM tools through the MyChart portal Fig . An eSyMThe eSyM program generates three context-dependent patient messages: (1) for new patients, a welcome message with program instructions; (2) for patients with unanswered questionnaires, a reminder message to complete the questionnaire with a direct link; and (3) for patients who report severe  symptoms, a message encouraging the patient to contact the care team. All patient messages are delivered via MyChart. If permitted by the health care system, patients can choose to have reminders delivered via e-mail or text.Multiple tools are available to support clinicians caring for eSyM patients. InBasket messages alert the care team when patients submit questionnaires with severe symptoms (Data Supplement). Alerts are monitored during business hours only; follow-up calls are conducted as needed on the basis of clinical judgment. Reported symptoms and symptom scores, including trends, appear in the EHR in multiple locations (Data Supplement). Clinicians use ‘smart phrases’ to add symptom scores to notes to aid documentation. Flags can indicate which patients on a clinic schedule are part of the eSyM program.A dashboard and four workbench reports are used to manage the active eSyM cohort Fig A. The meFour of six planned go-live waves have been completed on schedule. As of August 2021, two sites are live with eSyM medical oncology, two sites are live with eSyM surgery, and two sites are live with both. After the last two go-live waves, all six sites will be live with both surgery and medical oncology (estimated Spring 2022).Since September 2019, 3,352 unique patients have submitted 26,268 symptom questionnaires. Across all sites, two third of patients with patient portal access completed at least one eSyM questionnaire and one third completed eSyM multiple questionnaires. Patient feedback has been positive; reasons for not using the program include (1) limited access to internet-enabled devices, (2) limited technology confidence, (3) no symptoms to report, and (4) no encouragement from the care team to submit symptom reports. In response to this feedback, additional training materials outlining the importance of PRO collection have been created, and alternative ePRO collection methods, including iPads in clinic and proxy reporting at home, have been offered. A process-flow diagram  across sites, achieving high levels of patient participation in eSyM has required direct encouragement from the care team. On the administrative side, dedicated support from a program coordinator at each site has been crucial to enable program trainings, patient outreach, and system validation. Some sites, however, have faced difficulties integrating this new coordinator role into their pre-existing workflows. These challenges, which have been highlighted by others,36 have presented learning opportunities that have helped prepare for subsequent go-lives. They also represent ongoing barriers to scaling eSyM across diverse, real-world health care systems.Developing and deploying eSyM presented technical and operational challenges Fig . RelyingCreation of an ePRO-based symptom management program that is fully integrated into the EHR represents a milestone in the evolution of PROs as a tool to support routine cancer care delivery. As evidence demonstrating the utility and effectiveness of ePRO-based solutions grow, health systems may wonder if they should deploy free-standing versus EHR-integrated solutions. Compared with freestanding, an integrated solution provides efficiencies for patients, clinicians, operations, and technical staff, but it also imposes constraints and limitations (Data Supplement). Considering that health care systems sometimes lack the time and resources needed to support multiple clinician- and/or patient-facing applications, an option that can be disseminated via a major EHR vendor may offer distinct advantages.Future work will include measuring the impact of eSyM on patients' symptom burden and need for acute care, optimizing eSyM functionality and usability, and extending eSyM to other sites and populations (Data Supplement). Quantitative and qualitative data are being collected from patients and key stakeholders to understand facilitators and barriers to eSyM adoption and utilization. Preliminary findings from SIMPRO suggest that limited internet access and low computer literacy remain as significant barriers to the routine use of ePRO-based symptom management solutions in rural and resource-poor areas. These barriers need to be overcome to prevent this new technology from exacerbating existing disparities.


Editorial on the Research TopicTranslational research in neuropathic pain: Current status and future directions by Karri J, Nagpal A and Li S. (2022) Front. Pain Res. 3: 1024013. doi: 10.3389/fpain.2022.1024013The pathophysiology of neuropathic pain and the neuromodulation of underlying mechanisms by various interventions  has yet to be clearly elucidated –3. ConseWhile translational research has been long simplified as the implementation of basic science findings into the clinical setting, it has been increasingly recognized that such linear and unidirectional approaches may be limited given the vast differences in pain physiology, perception, and modulation that exist between animal models and human patients –8. RatheThe need for objective and reproducible pain assessments has been a long-heralded goal for scientists and clinicians alike , 7. As aWith the era of personalized medicine, there has been an emerging interest for delivering patient-specific, targeted treatments . PatientThe scope of this editorial serves to frame the context of these studies and allows readers to recognize both their potential when applied to humans, and possible barriers in translating findings to the clinical space.Karri et al (2022): Recent advances from SCI-specific animal studies and translational models have furthered our understanding of neuronal excitability, glial dysregulation, and chronic inflammation processes that mediate neuropathic pain. These developments have subsequently facilitated exploration of spinal neuromodulation as a treatment modality. In this narrative review, we provide a comprehensive review of the pathogenesis of neuropathic pain following SCI, intrathecal drug delivery as a treatment, and novel pharmacologics across impactful animal and clinical studies.Kwilasz et al (2022): Previously, it has been shown that toll-like receptor 4 (TLR4) antagonists, such as (+)-naltrexone [(+)-NTX], block neuropathic pain and associated spinal inflammation in rats. In this study, Kwilasz et al. utilize a novel rat model of EAE to extend these findings to demonstrate that (+)-NTX blocks TLR2 in addition to TLR4, as well as completely prevented the EAE-induced memory impairments and robustly attenuated the associated proinflammatory effects.Shillo et al (2021): Via robust immunobiological studies of gathered skin biopsies from patients with type 2 diabetes and healthy volunteers, Shillo et al. found that diabetics with painful neuropathy had increased dermal vasculature and decreased sub-epidermal nerve fiber density relative to diabetics with painless neuropathy. They thus conclude that this hypoxia-induced increase of vasculature may expose associated nociceptor fibers to a relative excess of algogens, thus leading to painful-DPN.Andressa de Souza et al (2021): Neuromodulation by tDCS as an adjunct therapy operates by facilitating cortical plasticity to enhance the effectiveness of therapies. It's being a non-invasive intervention also makes it an attractive option for treating various pain syndromes, including post-stroke shoulder pain as studied here. However, the authors demonstrated that physical therapy combined with active tDCS did not yield any additive analgesic benefits compared to physical therapy alone, likely due to a ceiling effect of the physical therapy.Nagpal et al (2021): The abuse liability associated with opioid medications may possibly be diminished with use of adjunct atypical antipsychotics, which could block dopamine reward associated with opioids. In this pilot, Nagpal et al. found that the antipsychotic-opioid combination did not alter analgesic responses to thermal stimuli or increase the incidence of adverse effects. Such findings are critical for future development of analgesic drug combinations and facilitate future study of abuse potential in drug users.Joksimovic et al (2022): In this review, the current mechanistic understandings of painful diabetic neuropathy are summarized, with a focus on nociceptive ion channels. These nociceptive ion channels are of particular interest as novel pharmacologic targets given long established successes in neuromodulating these targets in animal models.


While survival rates for many cancers have improved dramatically over the last 20 years, patients with pancreatic cancer have persistently poor outcomes. The majority of patients with pancreatic cancer are not suitable for potentially curative surgery due to locally advanced or metastatic disease stage at diagnosis. Therefore, early detection would potentially improve survival of pancreatic cancer patients through earlier intervention. Here, we present clinical challenges in the early detection of pancreatic cancer, characterise high risk groups for pancreatic cancer and current screening programs in high-risk individuals. The aim of this scoping review is to investigate the role of both established and novel imaging modalities for early detection of pancreatic cancer. Furthermore, we investigate innovative imaging techniques for early detection of pancreatic cancer, but its widespread application requires further investigation and potentially a combination with other non-invasive biomarkers.Pancreatic cancer, one of the most lethal malignancies, is increasing in incidence. While survival rates for many cancers have improved dramatically over the last 20 years, people with pancreatic cancer have persistently poor outcomes. Potential cure for pancreatic cancer involves surgical resection and adjuvant therapy. However, approximately 85% of patients diagnosed with pancreatic cancer are not suitable for potentially curative therapy due to locally advanced or metastatic disease stage. Because of this stark survival contrast, any improvement in early detection would likely significantly improve survival of patients with pancreatic cancer through earlier intervention. This comprehensive scoping review describes the current evidence on groups at high risk for developing pancreatic cancer, including individuals with inherited predisposition, pancreatic cystic lesions, diabetes, and pancreatitis. We review the current roles of imaging modalities focusing on early detection of pancreatic cancer. Additionally, we propose the use of advanced imaging modalities to identify early, potentially curable pancreatic cancer in high-risk cohorts. We discuss innovative imaging techniques for early detection of pancreatic cancer, but its widespread application requires further investigation and potentially a combination with other non-invasive biomarkers. Pancreatic ductal adenocarcinoma (PDAC) is estimated to be the second leading cause of cancer-related deaths by 2030 . The higFor this narrative review, our search strategy consisted of a general search of diagnostic and therapeutic images in pancreatic cancer, followed by a search of specific imaging modalities and, finally, reviewing the papers for leads to other—not yet included—imaging techniques.Patients with cystic lesions are at increased risk for developing PDAC . There ap < 0.01), but lower in individuals who had two first-degree relatives with PDAC  or with one affected first-degree relative  .,18.17,18Pancreatic cystic lesions can be divided into three main types: inflammatory, serous and mucinous, as well as other rare cyst types. For the scope of this review, mucinous cystic lesions are described as precursor lesions, harbouring a greater potential for malignancy. It is now well-known that most PDAC originate from microscopic pancreatic intraepithelial neoplasia (PanIN) and macroscopic precursor lesions. PanIN refers to microscopic, intraductal neoplasms (by definition <5 mm) lined by gastric–foveolar epithelia of varying degrees of architectural and cytologic atypia. These cannot be detected by current imaging modalities. While PanINs contribute to most of PDACs, a significant proportion of PDACs arise from macroscopic mucinous neoplasms, such as intraductal papillary mucinous neoplasms (IPMN) and mucinous cystic neoplasms (MCN) . These cIPMNs are macroscopic (>1 cm by definition) cystic tumours characterised by intraductal growth of papillary lesions with typically copious and thick mucin production. IPMNs commonly originate from the main pancreatic duct, its contributing branches, or possible mixed origin. They are more common in elderly men (>65 years). Most patients with IPMNs are asymptomatic; some patients may have nonspecific symptoms of abdominal pain, jaundice, as well as symptoms due to exocrine and/or endocrine pancreatic insufficiency. The pathologic nomenclature of IPMNs is complex and evolving. The incidence and type of invasive malignancy developing in IPMNs differ from one histologic type to another. Pancreatic ductal communication is the key feature differentiating these from other cystic neoplasms. Main duct IPMN is characterized by cystic dilatation of the main duct, variable ductal wall thickening, and thick, abundant mucin that distends and obstructs the duct . Main duMucinous cystic neoplasms, the least common macroscopic precursor lesion, differ from IPMNs in that they do not communicate with the ductal system, and they are almost always solitary. In addition, 98% of mucinous cystic neoplasms occur in perimenopausal women with a distinct proclivity to involve the distal pancreas (>90% occur in the tail region) and histologically characterised by a pathognomonic spindle cell ovarian-type stroma. Surgical resection is recommended in mucinous cystic neoplasms of greater than 4 cm, symptomatic tumours, and enhancing mural nodules. European evidence-based guidelines suggest that asymptomatic or smaller mucinous cystic neoplasms without suspicious features need long-term surveillance  as long as they do not have surgical contraindications . The risAlthough the association between diabetes mellitus and PDAC has been known since 1800s, the intricate relationship between the two conditions has yet to be fully understood. Diabetes appears to have a multidirectional association with PDAC. The onset of diabetes has been shown to precede occurrence of PDAC by a few years and resolve after the resection . The mecAcute pancreatitis can be the initial clinical presentation of PDAC and can precede the diagnosis of PDAC by several weeks or months . Few stuTo date, there is no evidence that screening for PDAC or treatment of screen detected PDAC improve disease-specific morbidity or mortality . HoweverThe International Cancer of the Pancreas Screening (CAPS) Consortium met in 2020 to update the consensus recommendations for the management of individuals with increased risk of PDAC based on family history or germline mutation status . An inteThe clinical indications for diagnostic imaging of PDAC include diagnosis of the primary tumour, resectability assessment, evaluation of distant metastasis, and evaluation of treatment response. In the context of early detection, imaging strategies can be grouped into traditional and novel applications.Currently, the most common modalities to image the pancreas include CT, MRI, and endoscopic ultrasonography (EUS); however, access to these modalities is limited to diagnosis and staging. Over the past two decades, multiple studies have evaluated the accuracy of EUS, CT and MRI for detection of primary tumour in the pancreas, including their value in the context of early detection in high-risk cohorts  31,45,4,48. EvenIn the recent review, Arnone et al. investigated the role of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in PDAC, as its role is currently not clear and considered to be “under development” . In the MRI and MRCP are superior to CT in the assessment of ductal communication of the cystic lesions as well as depiction of internal characteristics such as septations and mural nodules, although both modalities are equivalent in early detection and characterisation. Moreover, MRI is preferable to CT for imaging surveillance of cystic lesions, particularly in young patients because of cumulative deleterious effects of ionizing radiation with CT. Thickened irregular septae, enhancing mural nodule, or solid components within the IPMN are suspicious for malignancy . SpecifiThe limitation of current imaging-based screens is that upon identification of potentially benign lesions, subsequent invasive evaluation by collecting tissue biopsies is still required to confirm diagnosis. Early diagnostics to identify carcinomas in situ are often challenging due to the detection limit of current radiological methods and how chronic pancreatitis shows similar fibrotic features to pancreatic cancer. Furthermore, morphologic tumour changes significant on imaging, appear much later than functional and metabolic changes. Thus, a considerable concern is that current imaging methods might not be adequate to identify tumours in the pancreas at an earlier stage when treatment would be optimal. A retrospective review of CT scans carried out for other indications showed no evidence of a pancreatic mass in most patients 6 months or earlier before the diagnosis of PDAC . Thus, tAmong the novel imaging modalities available for PDAC detection are functional imaging techniques.Diffusion weighted imaging (DWI) is a relatively new MRI technique that reflects changes in water mobility caused by interactions with cell membranes and macromolecules, and alterations in the tissue microenvironment. Therefore, DWI provides a tissue contrast that is different from that of conventional T1- and T2-weighted MRI images. In as much as DWI offers quantitative measurements of the diffusivity of water described by the apparent diffusion coefficient (ADC), it also represents microcirculation of blood flow. Therefore, in pancreatic cancer, ADC values are usually lower than in normal pancreatic tissue. Using DWI, Kamisawa et al., evaluated its clinical utility in patients with cancer and autoimmune pancreatitis, and assessed whether DWI could help differentiate cancer from pancreatitis . They deADC values reflect both molecular diffusion and microcirculation of blood (perfusion). The Intravoxel incoherent motion (IVIM) approach can separate signal attenuating effects of microcirculation (“pseudo-diffusion”) from molecular diffusion and thereby provide additional information to characterise focal pancreatic lesions, verifying more restricted diffusion in solid malignant tumours versus benign inflammatory ones . IVIM-baMRI can also provide other advanced techniques such as dynamic contrast enhanced MRI (DCE-MRI) for evaluation of perfusion. Potential major interest of functional imaging is to show early fibrotic and metabolic changes in pancreatic parenchyma, despite the absence of morphological changes. Granata et al. evaluated functional MRI to differentiate pancreatic tumours, peritumoural inflammatory tissue, and normal pancreatic parenchyma by means of DCE-MRI, diffusion kurtosis imaging, and IVIM DWI-derived parameters . Further13C pyruvate has been demonstrated in animal models and now in preliminary clinical studies [13C] pyruvate enables detection and monitoring of the progression of precursor lesions towards invasive PDAC  MRI has been proven feasible in experimental models, differentiating exocrine pancreas, pancreatitis, and pancreatic cancer tissue by the enzymatic conversion of pyruvate-to-lactate and pyruvate-to-alanine , and demonstrated that this relationship correlates with disease progression and treatment response [13C] MRI successfully differentiated pancreatic tumour tissue from surrounding tissue >30 s after the injection via [1-13C]lactate and [1-13C]alanine production [Hyperpolarised [1-response . Clinicaoduction .MR elastography (MRE), is another potential method to detect fibrosis. MRE, a multifrequency magnetic resonance elastography technique with noise-robust data post processing, has been introduced to the field of cancer imaging recently ,77. It pFunctional MRI techniques, therefore, have shown a potential to play an important role in earlier tumour detection of PDAC.There is increasing evidence that dual energy contrast enhanced CT is superior to monoenergy CT ,80. DualMolecular imaging has emerged as a potential way to identify smaller lesions, translating into the potential to diagnose at a much earlier stage than is available. Molecular imaging has the benefit of being able to identify differences between tumour and normal tissue on a molecular level, not based on morphological differences. Being able to combine molecular imaging with conventional imaging in, for example, molecular ultrasound, fluorescence endoscopy and PET/MRI, could have important implications for patient outcomes. Advanced molecular imaging has come to play an integral role in the management of gastro–entero–pancreatic neuroendocrine neoplasms. Somatostatin receptor targeting PET/MRI with liver-specific contrast agent has shown a strong potential for multiparametric evaluation of neuroendocrine neoplasms . So far,Nanotechnology has a potential to non-invasively differentiate between tumour and stromal elements in pancreatic cancer, thus nanoparticles could be used to target tumour elements and stromal elements of pancreatic cancer. Nanotechnology is defined as the manipulation of organic or inorganic materials to form structures on the scale of nanometres. Recently, advances in nanotechnology have provided great opportunities for strategies in advancing cancer diagnostics, imaging, and therapeutic drug delivery . NanoparThe quantitative analysis of medical images data and the extraction of imaging features, also called ‘radiomics’, represent an emerging approach in personalized medicine and advanced diagnostics, especially for disease characterization or outcome prediction. The interest towards radiomics is rapidly growing in the multidisciplinary cancer community as it shows an interesting pertinency and efficacy to answer several clinical questions arising in the management of patients affected by PDAC. In the recent systematic review by Casa et al. radiomics analysis showed to be a promising approach to evaluate PDAC from diagnosis to treatment response prediction . DespiteWhile exact benefit of PDAC screening remains unclear, screening of the general population is not recommended due to the low disease incidence and high costs. The main goal, therefore, is early detection of asymptomatic high-grade precursor lesions and non-invasive PDAC through targeted screening of high-risk populations to enable detection of resectable lesions. In effect, the task remains to identify the most at risk within this high-risk population. Due to relatively low incidence of PDAC, pooling of data from individual screening trials is needed to accumulate sufficient evidence of a clinical benefit. There has been recently significant improvement in pancreatic imaging using the multi-modality approach. Rapidly developing novel imaging techniques are expected to become widely used once their role in early detection of pancreatic cancer is established. Improved understanding of cancer precursors will shed light on the importance of early detection of such lesions, particularly in high-risk patients. The key to early detection is identifying high risk individuals, for whom imaging will be relevant, and using established imaging modalities with novel techniques in the setting of multi-modality approach. Finally, nanotechnology will have an important role in realising the goal for early detection and diagnostics of PDAC. Taken together, the future strategy may be the formation of multi-parametric risk models that combine imaging and clinical data, whereas artificial intelligence applied to imaging offers the possibility to detect early-stage cancer and thus extend survival for patients with PDAC.


The development of treatment biomarkers for psychiatric disorders has been challenging, particularly for heterogeneous neurodevelopmental conditions such as attention-deficit/hyperactivity disorder (ADHD). Promising findings are also rarely translated into clinical practice, especially with regard to treatment decisions and development of novel treatments. Despite this slow progress, the available neuroimaging, electrophysiological (EEG) and genetic literature provides a solid foundation for biomarker discovery. This article gives an updated review of promising treatment biomarkers for ADHD which may enhance personalized medicine and novel treatment development. The available literature points to promising pre-treatment profiles predicting efficacy of various pharmacological and non-pharmacological treatments for ADHD. These candidate predictive biomarkers, particularly those based on low-cost and non-invasive EEG assessments, show promise for the future stratification of patients to specific treatments. Studies with repeated biomarker assessments further show that different treatments produce distinct changes in brain profiles, which track treatment-related clinical improvements. These candidate monitoring/response biomarkers may aid future monitoring of treatment effects and point to mechanistic targets for novel treatments, such as neurotherapies. Nevertheless, existing research does not support any immediate clinical applications of treatment biomarkers for ADHD. Key barriers are the paucity of replications and external validations, the use of small and homogeneous samples of predominantly White children, and practical limitations, including the cost and technical requirements of biomarker assessments and their unknown feasibility and acceptability for people with ADHD. We conclude with a discussion of future directions and methodological changes to promote clinical translation and enhance personalized treatment decisions for diverse groups of individuals with ADHD. Biomarker discovery for psychiatric disorders and symptoms has been challenging, despite a clear need to guide clinical decisions –3 and a We first briefly discuss biomarker definitions and categories to provide a framework for the review. In 2001, the NIH Biomarkers Definitions Working Group defined a biomarker as “a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathologic processes, or biological responses to a therapeutic intervention. A biomarker can be a physiologic, pathologic, or anatomic characteristic or measurement that is thought to relate to some aspect of normal or abnormal biologic function or process” . While tGiven the wide variability in effectiveness and tolerability of available treatments, an important motivation for developing biomarkers has been to identify measures parsing this variability and aiding personalized treatment decisions. This is especially needed for treatments such as non-stimulants and non-pharmacological options, where effects may not be observed until weeks after treatment initiation. Here, we use the term “predictive biomarkers” based on BEST guidelines  Fig. 1)1), but rPre-treatment subcortical volumes have been associated with treatment response to methylphenidate (MPH), with responders showing smaller volumes than non-responders  in one sN = 7), reporting that greater decreases in regional homogeneity  within right postcentral gyrus and superior parietal lobe following a single MPH dose predicted lower ADHD severity at 8 weeks ) during resting states (eyes open or closed) is associated with better clinical outcomes following stimulant treatment , 35, 36 Fewer studies focused on non-stimulant medications. A 12-month study of ATX found broad pre-treatment increases in power in children classified as non-responders relative to controls, whereas responders only showed elevations in slower frequencies such as the delta (<4 Hz), theta and alpha (8–12 Hz) bands . Lower pAlthough most available studies of EEG predictive biomarkers have investigated pharmacological treatments, a notable non-pharmacological example is a novel 4-week double-blind, sham-controlled trigeminal nerve stimulation (TNS) trial, where lower pre-treatment resting-state right-frontal theta and alpha power predicted greater clinical improvement . FurtherOnly a few studies tested EEG predictors of more than one type of treatment , 56, 57.Another noteworthy exemplar based on different treatments is a recent multi-sample study of iAPF . Guided To summarize, while most of the EEG profiles predicting treatment outcomes have been examined only for stimulants, right frontal resting state spectral power, event-related power related to working memory and iAPF emerge as candidate predictive biomarkers that may aid future stratification and prediction of response to different treatments. Future studies will need to apply out-of-sample stratification and validation approaches prospectively to a wider portion of the ADHD population, treatments and EEG profiles.Genetic studies have also investigated biomarkers predicting treatment response, particularly to MPH Table . The firN = 7427) or stopping (N = 3370) MPH treatment or switching to non-stimulants (N = 1137) over 2 years [Given the known limitations of candidate gene approaches , more re 2 years . While n 2 years . In a su 2 years .Since each individual genetic marker only explains a tiny fraction of treatment response, three studies have investigated aggregate measures of genetic risk using polygenic risk scores (PRS) . PRS for ADHD was found to predict a favorable response to ADHD medication (MPH or ATX), explaining around 2% of the variance . The afoAdditionally, there has been interest in genetic markers that lie within the cytochrome P450 superfamily of enzymes. The cytochrome P450 system largely determines the metabolism of ATX and varies widely between individuals by genotype, and by race and ethnicity . PharmacTogether, initial findings suggest that stratifying individuals based on genetic markers, such as PRS and CNVs, may be useful to guide future treatment choice in a mechanistic manner. Future studies will need to use much larger samples, consider possible multiplicative effects of different genetic markers, investigate the effects of genetic biomarkers on response to multiple pharmacological and non-pharmacological treatments, and test the predictive utility of genetic biomarkers in combination with other biomarkers, such as the promising neuroimaging and EEG biomarkers discussed above.Another major application of treatment biomarkers is for treatment monitoring, with repeated biomarker assessments performed before and after treatment, in response to acute doses or over longer periods. Neuroimaging and EEG biomarkers reviewed in this section are consistent with the BEST monitoring biomarker category and response/pharmacodynamic biomarker category  also so.N = 131 adults with ADHD who underwent 12 months of MPH treatment reported no significant treatment-related changes in gray matter volume [Both acute and longer-term treatment effects on brain patterns have been documented using structural and functional magnetic resonance imaging in ADHD samples Table . Changesr volume .Table 4DA reasonably large literature, including studies using double-blind placebo-controlled designs in unmedicated youth with ADHD, has examined changes in brain functioning under acute doses of stimulant medication , 72–75 . AvailabA further body of work has examined the links between treatment-related improvements in ADHD symptoms and pre- to post-treatment changes in brain functioning over the course of clinical trials. ADHD symptom changes have been associated with changes in functional connectivity between bilateral medial frontal and left insular regions  and in fWith regard to non-pharmacological interventions, the aforementioned fMRI neurofeedback trial of the rIFG represents a notable example , 90. TheTogether, these findings provide initial evidence suggesting that distinct neuroimaging biomarkers may be useful for monitoring the longer-term effects of MPH, ATX and right IFG-neurofeedback . Nevertheless, limitations of this body of work include reliance of small sample sizes and lack of replications, as well as more practical limitations of MRI which limit its utility in clinical settings.Several studies have investigated the acute effects of medication on EEG profiles in individuals with ADHD  Table 55. Acute Studies investigating the longer-term effects of pharmacological treatment on EEG data have generally shown that stimulants ameliorate EEG patterns that differ between individuals with ADHD and neurotypical controls , 100–102Besides EEG studies of stimulants, 12-month ATX treatment produced decreases in EEG resting-state power in delta, theta, and alpha bands in responders but no changes in non-responders . SeveralVery few EEG studies have compared the effect of different treatments on EEG measures. While similar acute effects of MPH and ATX have been reported on EEG spectral power , a crossOverall, findings reviewed here suggests that EEG profiles, particularly event-related measures , are promising monitoring biomarkers. Future studies should replicate these encouraging findings in more heterogeneous samples and test the effects of multiple treatments. The application of source localization techniques is particularly promising for uncovering underlying brain mechanisms of EEG biomarkers and may also guide the development of novel non-pharmacological treatments .In this article we have reviewed progress in the discovery of treatment biomarkers for ADHD and their translation towards personalized treatment approaches, with a particular focus on predictive and monitoring/response biomarkers. Several pre-treatment profiles have been shown to predict response to pharmacological treatments for ADHD, with more preliminary but encouraging findings for response to non-pharmacological treatments. The most promising measures for treatment prediction are EEG measures such as iAPF and event-related beta power modulations, and genetic markers involved in PRS and CNVs, whereas the MRI literature has generally yielded more mixed findings largely based on small samples. These pre-treatment profiles represent candidate predictive biomarkers which, in the future, may assist in the stratification of patients with ADHD to specific treatments. Research leveraging repeated biomarker assessments further suggests that clinical response to ADHD treatments is underpinned by treatment-specific changes in brain profiles. These treatment-related changes have typically been consistent with the amelioration of neural patterns that are altered in children and adults with ADHD, although some evidence of “better than typical” post-treatment profiles have also been reported, suggesting potential compensatory mechanisms , 122. ThOverall, this body of research represents a solid research base for the development of biomarker approaches and for the future allocation of patients to existing and novel pharmacological and non-pharmacological treatments based on their individual behavioral and neurobiological profiles, consistent with the principles of precision and personalized medicine , 123. NeN < 100 participants for MRI/EEG studies), which are unlikely to allow for reliable estimates of the associations of genetic and brain biomarkers with measures of clinical effectiveness [First, there is a widespread lack of replication and out-of-sample validation of findings for most candidate predictive and monitoring/response biomarkers, with only a few notable exceptions . Most sttiveness , 126. Thtiveness , 128.Second, alongside increasing sample sizes and validation efforts, future research will be needed to increase the diversity of samples with regard to age, sex, comorbidities, ethnicity, race, and geographical region. As highlighted throughout our review, most evidence to date is based on samples of children (mainly boys) from White majority backgrounds and high-income countries, typically with few psychiatric and medical co-occurring conditions, even though comorbidities are the norm in patients with ADHD , 129. SeThird, most studies have examined associations between specific biomarkers and treatment outcomes using correlational and group-level analyses, but any biomarker is likely to individually explain only a small amount of variance in treatment response. Classifiers and machine learning algorithms are becoming particularly popular approaches to handle high dimensionality and maximize predictive accuracy of biomarkers , 136. ThFourth, although a key aim of personalized medicine is to determine which treatments may work best out of the available options for a given patient , 123, liFifth, since most of the available studies have conducted biomarker and clinical assessments only over a few weeks or months, we know very little about the clinical utility of biomarkers over longer time periods. Longitudinal work following patients with ADHD over multiple years has shown that remission from ADHD symptoms follows a highly non-linear trajectory for most patients , and it Sixth, very limited work has sought to establish the reliability, robustness and reproducibility of ADHD treatment biomarkers, although these are essential biomarker characteristics that are critical for future clinical application , 142. ThFinally, from a practical perspective, any neuroimaging, EEG, and genetic biomarker findings must not only be generalizable across patient subpopulations, but also across treatment sites and various testing equipment and procedures. The development of standardized biomarker testing protocols and training of healthcare professionals responsible for biomarker testing will be important challenges to face prior to clinical implementation. Further, the cost-effectiveness of brain and genetic markers is also yet to be determined from a health economics perspective, and will require pragmatic RCTs comparing the effectiveness and costs of biomarkers approaches vs. care as usual . These cIn conclusion, this article sought to highlight progress in the development of treatment biomarkers for ADHD and set clear guidance for future studies to move the field forward. Whereas most of the available research on ADHD biomarker to date has taken a primarily mechanistic approach, we hope that our recommendations will contribute to a shift toward more translational and clinically useful approaches, as well as more robust methodologies, and larger and more diverse samples. We believe that these steps will be essential to promote clinical translation of biomarker research and enhance personalized treatment decisions for diverse groups of individuals with ADHD.


Mucosal healing in the gut is an essential process when it comes to chronic inflammatory disorders such as inflammatory bowel diseases (IBD) but also to the creation of intestinal anastomosis. Despite an improvement of surgical techniques, the rates of anastomotic leakage remain substantial and represent a significant health-care and socio-economic burden. Recent research has focused on intrinsic factors such as mucosal linings and differences in the intestinal microbiota and identified specific endoluminal bacteria and epithelial proteins which influence intestinal wound healing and re-establishment of mucosal homeostasis. Despite the lack of large clinical studies, previous data indicate that the identified bacteria such as aerotolerant lactobacilli or wound-associated Akkermansia muciniphila as well as epithelial-expressed sialyl Lewis glycans or CD47 might be critical for wound and anastomotic healing in the gut, thus, providing a potential novel approach for future treatment strategies in colorectal surgery and IBD therapy. Since microbiota and mucosa are interacting closely, we outline the current discoveries about both subsets in this review together to demonstrate the significant interplay Impaired intestinal mucosal healing is a hallmark of inflammatory bowel diseases (IBD) and anastomotic leakage. Current IBD treatment mainly focuses on the immune system but the numbers of patients who still require surgery or suffer from side effects remain high . Since tThe selectively and dynamically permeable barrier between luminal components and the basolateral membrane is established and maintained by the epithelium consisting of enterocytes and goblet cells. Intercellular connections between the epithelial cells are formed by intercellular junctions, namely the tight junctions, adherence junctions, desmosomes and gap junctions , 7. The The increasing relevance of intestinal wound healing given and the significance of its dysregulation on patients , future Dysfunctional healing of the intestinal mucosa affects a large spectrum of patients resulting in a significant clinical relevance . ImportaThe coordination of the multi-step process of intestinal wound repair depends on the complex interplay between epithelial cells, immune cells and microbiota , 19. It via Pkp3, the authors also demonstrated a functional interplay between Dsc-2 and integrin β1 and β4, thus, arguing for Dsc-2 as a key contributor in intestinal mucosal healing. In contrast, Desmoglein-2, another desmosomal cadherin which interacts closely with Dsc-2, is required for intestinal barrier integrity  and hepatocyte growth factor (HGF) and their signaling pathways leading to mucosal restitution and cell proliferation , 22. Whintegrity , but no in vitro and in vivo  increased substantially in early regenerative mucosa. In this study Akkermansia muciniphilia was applied intrarectally and mice showed superior wound closure and increased proliferation of enterocytes compared to mice that received inert control. However, this effect was dependent on the presence of the Fpr1 gene, which encodes for a necessary protein for respiratory burst in neutrophils (Infiltrating immune cells, such as macrophages, are important components of the intestinal wound healing. Microbial metabolites or cell wall components affect the polarization of macrophaghes to a M2 state in a mouse model of colitis, augmenting intestinal wound healing . In caseeir guts . Microbieir guts , 56. In ammation . Furtheris model . In a motrophils .However, despite the great potential of the microbiota and mucosal healing, another important aspect of microbiota-associated wound healing is the potential association between microbial composition and inflammation-associated carcinogenesis. Due to the great effects on cell proliferation and barrier integration, specific microbial species have also been demonstrated to facilitate the formation of pre-neoplastic lesions with one study showing a different microbial diversity in patients with IBD-related colorectal cancer. The importance is further underlined by different incidences between IBD-related colon and small bowel cancers which might be related to differences in microbial compositions. Therefore, further research is necessary to address this issue to evaluate the impact of the microbial diversity on the overall IBD-cancer prognosis as well as to identify the potential of probiotics to limit the overgrowth of pathogenic microbial species.In a nutshell, there is consistently increasing evidence that intestinal wound healing is orchestrated by the microbial-epithelial interface . HoweverWhile the medical history teaches the pathophysiological misleading thesis of monomicrobial infections , the resin vivo experiments, thus, translation to clinical studies is necessary to evaluate the disease-specific relevance in detail. Based on the postulated results, the innovative approach of targeting mucosal healing for therapy of IBD or to support anastomotic healing looks to be particularly promising. However, relevant questions such as how to obtain adequate local levels of the applicated substance by either oral or intravenous administration remain to be answered. In case of anastomotic healing, local application or injection could be an interesting approach which needs to be evaluated as well. Moreover, while for sialyl Lewis glycans antibody-targeting by GM35 to block shedding of the v6 domain from CD44v6 is necessary to support wound healing (β1 integrin-dependent FAK-Src-p130Cas pathway is an alternative which can be translated to clinical aspects more easily. Importantly, striving for a limited local effect of the administered agent is particularly relevant for CD47 since it is an ubiquitously expressed protein and a systemic impact of medical targeting of CD47 cannot be completely estimated upfront.Besides addressing the microbiota, targeting proteins on intestinal epithelial cells such as desmosomes, CD47 or sialyl Lewis glycans relevant for epithelial migration and proliferation with novel medication has great potential as well and offers another target to improve intestinal mucosal healing –25, 28.  healing –25. PromFinally, and most importantly, further development of treatment strategies does not mean to leave established aspects and concepts such as anti-inflammatory and immunosuppressive medication behind but to complement the current therapeutic regimen. Therefore, optimal disease-specific therapy should consider all aspect of the pathophysiology including epithelial cells, immune cells and microbiota in the future and will combine different targets to address mucosal healing better and to improve patient outcome.Recent research has demonstrated a major role of intestinal epithelial cells as well as microbiota on adequate mucosal healing in the gut with a close interaction between both sites. All targets involve the key intrinsic parameters of intestinal wound healing: The systemic condition of the patient, the mucosal cells, resident and transmigrating immune cells, and the enteric microbiota, both commensal and pathogenic . However


The adverse effects of smoking on human health have been recognized for several decades, especially in the context of cancer. The ability of tobacco smoke components, including tobacco-specific carcinogens and additive compounds such as nicotine, to initiate or promote tumor growth have been described in hundreds of studies. These investigations have revealed the tumor-promoting activities of nicotine and other tobacco smoke components and have also recognized the ability of these agents to suppress the efficacy of cancer therapy; it is now clear that smoking can reduce the efficacy of most of the widely used therapeutic modalities, including immunotherapy, radiation therapy, and chemotherapy. Several studies examined if continued smoking after cancer diagnosis affected therapy response; it was found that while never smokers or non-smokers had the best response to therapy, those who quit smoking at the time of diagnosis had higher overall survival and reduced side-effects than those who continued to smoke. These studies also revealed the multiple mechanisms via which smoking enhances the growth and survival of tumors while suppressing therapy-induced cell death. In conclusion, smoking cessation during the course of cancer therapy markedly increases the chances of survival and the quality of life. Cancer places a huge burden on families and individuals across the world and is one of the leading causes of mortality worldwide . SeveralThe US Surgeon General report in 1964 formally outlined the various adverse effects of smoking on human health for the first time, especially the correlation between smoking and cancer incidence . SubsequIt has also become clear that smoking not only causes cancer but can also affect several facets of cancer biology. Thus, tobacco smoke and its components can initiate carcinogenesis, promote the progression and metastasis of cancer, and markedly reduce the efficacy of cancer therapy . IncreasImmunotherapy using immune checkpoint inhibitors is highly effective against lung cancers, including both small-cell and non-small-cell lung cancers . SeveralA recent case–control matched analysis compared the relative efficacy of first-line chemotherapy and immunotherapy in smokers and non-smokers. This study, conducted on 962 NSCLC patients who had received first-line Pembrolizumab and 462 patients who had been treated with first-line platinum-based chemotherapy, found that never smokers had a significantly higher risk of disease progression when treated with Pembrolizumab . There wThe biochemical mechanisms underlying the increased efficacy of immunotherapy in smokers have been explored by several groups, and factors other than increased mutational burden have been found to be involved. It has been established that those patients with PD-L1 expression in more than 50% of cells are more responsive to frontline immune checkpoint inhibitors . MultiplThe effects of smoking on immune cells in the context of cancer have been elucidated in multiple studies . It is kSeveral studies have demonstrated a clear correlation between smoking and the response to radiation or chemoradiation therapy in various cancers . While tA trial was conducted in 2012 based on reports that head and neck patients having higher levels of normoxia markers responded well to radiotherapy, while those with hypoxic markers, including low hemoglobin, responded poorly . Making The role of nicotinic acetylcholine receptors was evaluated in the context of resistance to radiation therapy, in an in-depth molecular analysis. Lin et al. (2019) reported that the nicotinic acetylcholine receptor subunit, α5, contributes to radiation resistance in oral squamous cell carcinomas . They foAdverse effects of smoking on cancer chemotherapy have been recognized for decades. One of the earliest studies, published by John Minna, Paul Bunn, and colleagues in 1980 , stratifEarlier studies also showed a correlation between the amount of lifetime smoking and therapy response. A retrospective study in Brazil  conducteSimilar high prevalence rates of smoking in cancer survivors have been reported, calling for more robust educational efforts in determining the deleterious effects of smoking on survivorship and quality of life. A study conducted on 1118 cancer survivors surveyed their awareness of the harms of continued smoking during therapy; surprisingly, a large proportion of the subjects were unaware that continued smoking leads to poor therapy response, enhanced surgical complications, and decreased overall quality of life . CurrentIn addition, studies have been conducted on how smoking affects treatment-related symptom burden. A study in 2011 examined how smoking affected the side-effects of cancer treatment on 947 patients who were scheduled to undergo chemotherapy or radiation pyrene, aldehydes, benzene, aromatic amines, etc. ,65. WhilSmokers metabolize chemotherapy drugs faster than non-smokers . When neOn the other hand, nicotine, which is the major addictive component of tobacco smoke, is a prime example of how a tobacco smoke component can promote tumor growth and metastasis without altering the genetic makeup of cells ,70. NicoNicotine by itself acts on cells through nicotinic acetylcholine receptors (nAChRs), which are expressed predominantly in neurons and neuro-muscular junctions ,76,77. TBased on the roles of nAChRs in promoting tumor growth, metastasis, angiogenesis, and drug resistance, it has been suggested that they may be potential targets for therapy ,86. SeveSeveral molecular mechanisms have been proposed for how smoking and nicotine in particular confer resistance to therapy. Earlier studies have described several molecular mechanisms that are driven by nAChR activation, especially certain specific subunits. While several different subunits have been demonstrated to be involved in resistance to therapy, especially α2/β3, α7, α5, etc., it is clear that the survival signals mediated by these subunits negate the effects of chemotherapy. For example, in cell culture models of NSCLC, it was found that pre-treatment with 1 μM nicotine efficiently suppressed apoptosis induced by several first-line chemotherapy agents, including cisplatin, gemcitabine, and taxanes . This inIn a similar vein, exposure to nicotine has been shown to activate the extracellular signal-regulated kinase (ERK) and protein kinase B (Akt kinase) pathways to promote the survival of colorectal cancer (CRC) cell lines ,89. NNK The tumor-promoting activities of nicotine involve the inactivation of tumor suppressors such as retinoblastoma tumor suppressor protein (Rb) and p53; in addition, tobacco smoke components can induce oncogenic proteins such as c-Myc and K-Ras . NicotinCancer stem cells, often referred to as tumor-initiating cells, have gained attention in the past decade as mediators of drug resistance ,95. CancAs mentioned above, smoking affects the levels of chemotherapy agents in the system by altering their metabolism. A review article published few years ago provides precise and detailed information on how specific chemotherapy agents and targeted therapies are affected by smoking . As outlE-cigarettes, or electronic nicotine dispersal systems, have been touted as healthier alternatives to cigarettes. The reasoning behind this line of thinking is that E-cigarettes contain nicotine along with stabilizing and flavoring agents and thus lack the classic tobacco carcinogens . E-cigarSeveral pharmaceutical agents that function by modulating various nAChR subunits have been approved by the FDA for smoking cessation; these include drugs such as varenicline, cytisine, and bupropion, which do not have any demonstrated adverse effects on therapy response. These agents have different properties and are generally safe for most smokers. In addition, behavioral therapies have been successfully used; these approaches totally avoid the use of nicotine or nicotine replacement as a strategy to facilitate cessation. From the known adverse effects of nicotine and other components in nicotine replacement therapies, it is more desirable to use one of the pharmacological agents or behavioral therapy.It is abundantly clear that smoking adversely affects the efficacy of anti-cancer therapies. Various components of tobacco smoke, including tobacco-specific carcinogens and nicotine, promote various survival signaling pathways in cancer cells and in the tumor microenvironment; further, they can alter the metabolism and degradation of drugs, reducing their effective concentrations and impacting their therapeutic benefit. In addition, the pro-inflammatory effects of tobacco smoke and nicotine alter the immune response and enhance the side-effects of therapy. These effects of tobacco smoke components, along with their negative effects on the overall physiology, result in poor survival outcomes.Continued smoking after cancer diagnosis has been strongly correlated with poor overall outcome, and smoking cessation after diagnosis improves response to therapy. These facts strongly support increased educational efforts to promote smoking cessation after cancer diagnosis. E-cigarettes and similar nicotine supplements might have adverse tumor-promoting effects over prolonged use, and ideally, using these agents for smoking cessation should be limited to the shortest duration possible. It can be imagined that increased education on the benefits of quitting smoking and the availability of resources to promote smoking cessation will continue to reduce the incidence of cancer and lead to further reductions in cancer-related mortality.


Non-suicidal self-injury (NSSI) has been linked with a higher risk of suicide attempts in autistic and non-autistic people. In the general population, NSSI may confer acquired capability for suicide by eroding one’s fear and avoidance of pain and death. The present study aimed to explore acquired capability as the mediator of increased suicide risk conferred by NSSI in autistic and non-autistic adults.n = 314, n = 312) completed an online survey exploring lifetime suicide attempts, experience with NSSI, and acquired capability for suicide. We explored relationships between lifetime incidence of NSSI and lifetime suicide attempts via three facets of acquired capability . In self-harming participants (224 autistic and 156 non-autistic), we explored whether particular types and features of NSSI might be especially associated with capability and through that with suicide: namely engagement in scratching, cutting, and self-hitting, and engaging in more numerous forms of NSSI.Autistic and non-autistic adults (While a higher frequency of NSSI was associated with all three facets of acquired capability, only reduced fear of death and mental rehearsal of suicide mediated an indirect relationship with lifetime suicide attempts. NSSI also directly predicted more numerous suicide attempts. Autistic people tended towards reduced fear of death and mental rehearsal regardless of NSSI status. Among self-harming autistic and non-autistic participants, cutting and an increased number of NSSI behaviours were associated with lifetime suicide attempts directly and indirectly via acquired capability. In both groups, self-hitting was associated with lifetime suicide attempts only via acquired capability.Our cross-sectional methodology negates inferences of directionality. While we controlled for age, our samples were poorly matched, with the autistic group two times older on average. The autistic sample, predominantly late-diagnosed, female and highly qualified, were unrepresentative of the whole autistic community.Our data suggest that acquired capability, as measured herein, is an incomplete explanation for the association between NSSI and suicide risk. A broader construct with stable and transient facets may offer greater explanatory power, but it is probable that other variables explain or provide additional means through which this association arises.The online version contains supplementary material available at 10.1186/s13229-022-00522-5. Non-suicidal self-injury (NSSI) describes deliberate and directly harmful behaviours  which inflict pain and/or damage to the body.There is emerging evidence that the same link between NSSI and later suicidality exists in the autistic population, who exhibit markedly higher rates of suicide attempts and deaths –11. HistThe fact that these papers assimilated NSSI within a broader concept of “suicidal thoughts and behaviours” disallows any attempt to examine NSSI as a specific risk marker for future suicide ideation, plans, attempts and deaths. There are, to our knowledge, just two studies which did report a specific association between non-suicidal NSSI and suicidal behaviour in autistic people , 31. OneThe association between self-injury that is distinctly non-suicidal and later suicide risk is an important feature in both autistic and non-autistic populations and requires explanation. In the general population, a putative mechanism was proposed in the form of acquired capability for suicide , 33: frofunction of that behaviour in predicting the transition from suicide ideation to attempts  = 14.13, p < 0.001); with reduced fear of death by suicide ; and with more mental rehearsal of suicide plans . The diagnosis did not moderate relationships between NSSI incidence and pain tolerance or reduced fear of death but was directly predictive of reduced fear of death by suicide . For the mental rehearsal aspect of acquired capability, diagnosis exerts both a main effect  and a moderating effect on its relationship with NSSI incidence . Respectively, these reflected that autistic status was associated with higher mental rehearsal of suicide plans and that the relationship between higher frequency of NSSI and greater mental rehearsal was stronger in non-autistic  than in autistic participants . These effects were independent of depression (positively associated with each facet of acquired capability), age (positively associated with reduced fear of death), and sex  was contributed to by higher lifetime incidence of NSSI , reduced fear of death , mental rehearsal of suicide , and depression . While greater lifetime incidence of NSSI predicted higher lifetime suicide attempts independent of the mediators (i.e. directly), it also exerts two indirect effects. In the first, a higher frequency of NSSI predicted higher suicide attempts via reduced fear of death by suicide, an effect significant in both autistic  and non-autistic participants . Higher frequency of NSSI also predicted suicide attempts via higher mental rehearsal of suicide plans; while this was significant for both autistic  and non-autistic participants , a significant index of moderated mediation  showed that the indirect effect of NSSI frequency on suicide attempts via mental rehearsal was stronger in non-autistic participants . Of additional interest was the effect of depression as a covariate which predicted greater endorsement of habituation to NSSI  and higher acquired capability . Only acquired capability, however, significantly predicted lifetime suicide attempts , with no direct or indirect effects of scratching. The data for non-autistic participants showed exactly the same picture  did not predict habituation (second mediator) or indeed acquired capability (the third mediator), the expected relationship between habituation and acquired capability was observed  was at the borderline of our adjusted alpha value (p < 0.0125). Endorsement of cutting was associated with acquired capability . Interestingly, the model predicting lifetime suicide attempts was contributed to not only by acquired capability  but by cutting as a direct effect , and explained considerably more of the variance in lifetime suicide attempts as compared to the preceding model with scratching as a predictor. In addition to predicting lifetime suicide attempts directly, cutting exert one  indirect effect on lifetime suicide attempts via habituation and then acquired capability sequentially , and a stronger one via acquired capability alone : these pathways are summarised in Fig. Though cutting was not associated with greater pain experienced during NSSI for autistic participants, the association between cutting and habituation  and acquired capability  in autistic participants. It was not directly associated with lifetime suicide attempts but did exert two indirect effects: one through habituation and then acquired capability sequentially , and one through acquired capability alone , as depicted in Fig. The last specific form of NSSI, endorsement of self-hitting, was associated with habituation , higher scores in acquired capability , and directly predicted a higher number of suicide attempts . In addition to directly predicting lifetime suicide attempts, a higher range of NSSI behaviours was associated with suicide attempts indirectly via acquired capability , as shown in Fig. Our final analyses focussed on the range or number of different NSSI behaviours participants engaged in. For autistic participants, a higher range of behaviours was associated with greater habituation . Ribeirpulation  note thacontribute to suicide ideation [However, the second interpretation of this finding suggests we need to look further beyond acquired or broader suicide capability to understand alternative means through which NSSI might influence suicide risk. Firstly, NSSI is associated with thwarted belongingness and perceived burdensomeness , 82, 83,ideation , 82, 83,ideation –88, someideation , 43. Of ideation , 90 rumiideation  and alexideation , 92 haveideation , 82, andideation , 94.It is likely, given their differences in pain perception –97 and lOn the assumption that an association does indeed exist between NSSI and later suicide risk, and that this connection is partially related to suicide capability, an important question is whether different NSSI behaviours differentially create suicide capability and whether they do so in a broad sense or only in relation to certain methods of suicide . Having direct effect of both cutting and NSSI range on lifetime suicide attempts is an important indication of other variables which might explain these relationships. In non-autistic people who self-injure, both of these predictors have been linked to more severe psychopathology, greater emotion regulation difficulties, and poorer impulse control [Interestingly, our binary endorsement of cutting and our continuous measure reflecting a range of NSSI behaviours behaved very similarly as variables: both were associated with habituation  and acquired capability; both directly predicted suicide attempts as well as exerting indirect effects via habituation and acquired capability sequentially, while cutting also exert an indirect effect via acquired capability alone. This is consistent with the previous literature examining these two predictors in non-autistic people. Among individual NSSI behaviours, cutting is particularly painful and provides immediate and lasting visual proof of physical damage, which is an important element of NSSI for some people –101. It  control , 106; th control . We cannInterestingly, self-hitting influenced lifetime suicide attempts only via acquired capability, thus conforming most closely to original ideas around this construct . Self-higeneral, rather than in relation to any one of these specific behaviours. The same is true of our measure of habituation to NSSI in general—but interestingly, our analyses of cutting and self-hitting both revealed two separate indirect effects of these predictors on lifetime suicide attempts, one via acquired capability alone and one via habituation and acquired capability sequentially . Interpretation of this finding can only be speculative at present, but as habituation only affected suicide attempts via acquired capability rather than independently, it is possible that this effect reflects the overlap between the two constructs: the habituation subscale of the NSSI-AT might be expected to relay most closely to pain tolerance, but less to fear of death or mental rehearsal. While these analyses are generally supportive of a pathway from NSSI to suicide via acquired capability, they corroborate our first analysis in reflecting the existence of additional mechanisms through which NSSI, and particular forms of NSSI, might influence suicidal behaviours.These analyses yielded several null findings and some unanswered questions other than the aforementioned direct effect. Severe scratching and/or pinching was unrelated to any other variables: it seems likely that this reflects the broad wording of this item on the NSSI-AT, which could conceivably apply to behaviours ranging in painfulness and destructiveness. Pain experienced during NSSI was not associated with any one predictor, mediator or with suicide attempts as an outcome. While this may reflect the aforementioned inconsistency around the role of pain tolerance in relation to acquired capability and suicide risk , it is fthrough suicide attempts as opposed to preceding them, given the increasing ease of subsequent attempts [necessary prerequisites for suicide but instead many possible factors and combinations of factors, distal and proximate, and that these fluctuate over time [The most prominent limitations of the present study relate to (a) the study design and operationalisation of variables, (b) the disparity between samples, and (c) their limited generalisability to wider populations. As pertains to the first of these points, our cross-sectional design was ill-equipped to test causal or directional hypotheses. While our analyses are suggestive of pathways between NSSI and lifetime suicide attempts via acquired capability, it is possible that capability was acquired attempts , 48, 98.ver time , 110. Lover time , 112 mayany population [Relatedly, our operationalisation of key variables may have been inadequate. The interpersonal theory of suicide is suggestive of a “dose–response” relationship between NSSI and acquitted capability, though this has not received appropriate experimental scrutiny. Our analyses relating to specific NSSI behaviours were limited by the use of binary variables, indicative only of the presence or absence of the behaviour but not its frequency, extent or history; nor did these binary variables reflect how other variables, like the type and intensity of pain, the presence or absence of blood, and an individual’s psychological state during NSSI, might moderate a process of acquiring suicide capability , 113. Oupulation , 57. Thepulation , 53, butlack of autism diagnosis in the comparison group, relying on self-report only. Potentially greater issues lie in both the disparity between our samples and their generalisability to autistic and non-autistic populations. While we attempted to control for age and for sex in group comparisons, our groups occupied different lifespan stages: non-autistic participants as emerging adults, and autistic participants as approaching or navigating midlife. While little is known about changes in suicidal behaviour and NSSI across autistic lifespans, we know that the nature of NSSI and suicidal behaviour varies across the lives of non-autistic people [The strength of our conclusions is limited by several issues concerning sampling and recruitment. Firstly, we did not clinically validate self-reported autism diagnosis or c people –117. OurWith regards generalisability, our convenience sample of non-autistic undergraduates furthermore comprises a very specific cohort unrepresentative of the non-autistic population generally . Our autOur findings suggest that acquired capability for suicide, most notably reduced fear of death and mental rehearsal of suicide plans, partially mediates the relationship between NSSI (and specific forms of NSSI) and more numerous lifetime suicide attempts. While this finding is poignant given the higher levels of acquired capability in the autistic sample , the emergence of direct effects between NSSI and lifetime suicide attempts indicates that additional mechanisms underpin this association. In that relationships between NSSI, suicidality, acquired capability and other potential mediators may operate bidirectionally, longitudinal and/or computational designs may afford greater insight into stable and innate, accumulated and dynamic risk factors which could give rise to NSSI, suicidality and other deleterious outcomes in autistic people.Additional file 1. Supplementary data analysis.


The exact pathogenesis of chronic obstructive pulmonary disease (COPD) remains largely unknown. While current management strategies are effective at stabilizing the disease or relief the symptoms, new approaches are required to target underlying disease process and reverse lung function deterioration. Recent research showed that pneumonia bacteria is critical in disease progression and gut microbiome is likely perturbed in COPD, which is usually accompanied by a decreased intestinal microbial diversity and a disturbance in immune system, contributing to a chronic inflammation. The cross-talk between gut microbes and lungs, termed as the “gut-lung axis,” is known to impact immune response and homeostasis in the airway. Although the gut and respiratory microbiota exhibit compositional differences, the gut and lung showed similarities in the origin of epithelia of both gastrointestinal and respiratory tracts, the anatomical structure, and early-life microbial colonization. Evidence showed that respiratory infection might be prevented, or at least dampened by regulating gut microbial ecosystem; thus, a promising yet understudied area of COPD management is nutrition-based preventive strategies. COPD patient is often deficient in nutrient such as antioxidant, vitamins, and fiber intake. However, further larger-scale randomized clinical trials (RCTs) are required to establish the role of these nutrition-based diet in COPD management. In this review, we highlight the important and complex interaction of microbiota and immune response on gut-lung axis. Further research into the modification and improvement of the gut microbiota and new interventions through diet, probiotics, vitamins, and fecal microbiota transplantation is extreme critical to provide new preventive therapies for COPD. Chronic obstructive pulmonary disease (COPD), which affects over 400 million people globally, is characterized by increasing breathlessness, chronic cough, and sputum production that are associated with irreversible progressive inflammatory condition and major lung destruction with airflow limitation . The claGrowing evidence revealed that dysbiosis of gut microbiota is considered as an important component in the pathophysiology of COPD . The gutvia the gut-lung axis. This review highlights the necessity to develop non-drug interventions as effective adjunctive treatment for COPD.Evidence from the gut-lung axis research on respiratory diseases such as asthma, COPD, cystic fibrosis, and respiratory infections suggested that respiratory diseases might be prevented or at least can be ameliorated by regulating gut microbial ecosystem through manipulation of gut microbiota . InterveBacteroidetes, Firmicutes, Proteobacteria, Actinobacteria, and Verrucomicrobia  permeability in AECOPD  suggeste in COPD . In an en sputum . Furthern sputum . These sCigarette smoking is the most significant risk factor for COPD . AlthougMalnutrition is an important but overlooked problem in COPD . Around Other risk factors such as chronic asthma, low birth weight, childhood respiratory tract infections, pulmonary tuberculosis, and occupational exposures to dusts have also been reported to contribute to the pathogenesis of COPD . The metvia gut immunity response. However, for those that escape from the clearance, some has been reported to transfer to circulation and travel to the lung, which results in activation of inflammation. The gut and lung microbiota can influence the function of NLRP3 inflammasome (The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing protein (NLRP3) inflammasome is generally activated by a range of stimuli and acts as a critical regulator in the innate immunity . The NLRammasome . In addiammasome . Activatammasome . In periammasome , suggestvia intravenously infusing canakinumab, a human anti-IL-1b monoclonal antibody, did not show statistical difference in forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) between treatment and placebo groups  failed to benefit COPD patients at moderate to severe stages. For instance, a 45-week monthly treatment on COPD patients o groups . Furthero groups . SimilarImmunoproteasome is a specialized type of proteasome required for intracellular protein degradation in immune cells. It also acts as a key regulator for immune cell differentiation, inflammatory activation, and autoimmunity. A recent study demonstrated that proteasome expression was upregulated in PBMCs isolated from severe COPD patients as compared to that from matching controls . The dis3) group to the DNA strands to regulate gene expression. DNMTs are highly sensitive to the availability of nutrients, and they are affected by metabolites produced by gut microbial species . Increased circulating TMAO level was associated with increased mortality of COPD patients, which was independent of disease severity . HoweverDiet is a readily modifiable factor for COPD patients. A direct association between Western diet and increased risk for COPD has been shown in both genders , indicatLactobacillus rhamnosus and Bifidobacteriumbre breve in COPD mice prevented the airway inflammation and lung damage (A recent study demonstrated that dietary supplementation of probiotics g damage . The proParabacteriodies goldsteinii (P. goldsteinii) was shown to reduce intestinal inflammation, enhance mitochondrial functions, ribosomal activities in colon, restore amino acids metabolism in sera, and inhibit lung infection, at least partially through inhibiting toll-like receptor 4 (TLR4) signaling pathway via the lipopolysaccharide derived from P. goldsteinii ; the Improvement Project of Specialized Diseases of Putuo District of China (2020tszb05).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.