NASH is a potentially progressive form of NAFLD characterized by hepatocyte injury and liver inflammation which can cause fibrosis. Currently, there are limited data on the patient experience of NASH. Our aim was to use both literature review and patient interviews to understand the signs/symptoms and life impacts of NASH fibrosis stages F1–F4 that are important to patients, as well as begin to investigate the applicability of an instrument  that may be used to capture patients’ experiences. The literature review identified concepts (signs/symptoms and impacts) related to NASH fibrosis stages F1–F4 and the NASH-specific patient-reported outcome instrument (NASH-CHECK) for reporting patient experience of NASH. Interviews with 22 patients from Canada and the USA with NASH fibrosis stages F1–F4 revealed 27 signs/symptoms and 32 impacts that they felt were important, including fatigue, pain in the abdomen, worry, and frustration. Three concepts reported during patient interviews were not identified in the literature review. No concepts appeared to be exclusive to a specific fibrosis stage or presence/absence of obesity and no linear trends were identified between fibrosis stage or presence/absence of obesity and level of disturbance reported for concepts. The patient interviews supported the concepts included in the NASH-CHECK overall, demonstrating that it could be used to report the patient experience of NASH fibrosis stages F1–F4. Interviews with patients with NASH fibrosis stages F1–F4 revealed patients can self-report and elaborate on signs/symptoms and impacts related to the disease regardless of fibrosis stage. The NASH-CHECK was identified as a suitable instrument that could be used by patients with fibrosis stages F1–F4.  NASH is a chronic and potentially progressive liver disease and a severe form of NAFLD. The condition is estimated to affect 1.5%–6.5% of the global population.A number of comorbidities associated with the development of NAFLD also increase the likelihood of progressive fibrosis in those with NASH, including type 2 diabetes, obesity, and high blood pressure.NASH has traditionally been considered an asymptomatic disease, making diagnosis and monitoring challenging. Clinicians typically rely on histological diagnosis from invasive liver biopsies to diagnose patients with NASH. Although histological indicators of disease severity are important markers of NASH and risk of progression, they do not measure the impacts of the disease, or of treatments, that may be most important to patients. Understanding how symptoms and the life impacts of NASH affect patients’ well-being is increasingly recognized as important for individuals to make more informed decisions about their care, as well as for designing endpoints that measure changes in patients’ health-related quality of life in clinical trials of treatment or studies of the personal impact of NASH progression. Patients with NASH may report a variety of symptoms and disease-related impacts on their lives, including physical and psychological issues or social difficulties that negatively affect their quality of life.Patient-reported outcomes (PROs) can be used as an important tool to document patients’ experiences of diseases or treatments, directly from the patients and without interpretation by clinicians or other individuals.PRO instruments can be developed to record and quantify responses from patients. By asking patients about their medical condition experience, it is possible to create and improve PRO instruments so that their content is most applicable and relevant to patients. Qualitative patient interviews can be used to develop and establish the content validity of PRO instruments.The overall goal of this study was to explore and document the concepts (signs/symptoms and impacts) that are relevant and important to patients with NASH fibrosis stages F1–F4.A targeted literature review (TLR) was performed to identify concepts relevant to patients with NASH fibrosis stages F1–F4 and to identify potential PRO instruments that may be used to capture their experiences of NASH. A preliminary conceptual model was created of the signs/symptoms  and impacts (effects of the symptoms experienced by the patients) identified as most relevant to patients with NASH fibrosis stages F1–F4. Qualitative concept elicitation interviews were conducted with patients with NASH fibrosis stages F1–F4, and the findings used to update the conceptual model. The concepts identified during the patient interviews were also compared with the PRO instrument identified during the TLR to establish whether it is appropriate for patients with NASH fibrosis stages F1–F4. An overview of the study design is in Figure http://links.lww.com/HC9/A89). The searches were restricted to English language publications and articles published between April 2, 2009, and April 2, 2019. The article abstracts initially identified were screened against the exclusion criteria given in Supporting Table S2 (http://links.lww.com/HC9/A89). Blog searches were also conducted on the websites PatientsLikeMe, Fatty Liver Foundation, Health Unlocked, and American Liver Foundation in which the patient clearly stated a diagnosis of NASH or NAFLD. A preliminary conceptual model of the experience of patients with NASH was created based on the concepts identified through the TLR. Concepts were grouped into “signs and symptoms,” “immediate impacts,” and “general impacts.”A TLR was performed to provide a deeper understanding of the concepts underlying patients’ experiences of NASH and explore any existing, relevant instruments that attempt to capture these experiences. The targeted search was executed using PubMed to identify literature on the signs, symptoms, and impacts of NASH. The search criteria used included the search terms “nonalcoholic steatohepatitis” and “nonalcoholic fatty liver disease” for disease, as well as “signs,” “symptoms,” “patient-reported outcomes,” and “conceptual model” for outcomes of interest . Patients received an honorarium upon completion of the interview process.Patients were recruited through a clinical study team at the University of Calgary, Calgary, Alberta, Canada, or with assistance from Global Perspectives—Patient Search & Engagement, Norwich, England. Patients were recruited via telephone calls by the site coordinator or clinicians as well as through clinician referral by Global Perspectives. Patients completed an informed consent form, and their physicians completed the confirmation of diagnosis form. Eligible patients were from the USA or Canada, aged over 18 years, and had a confirmed NASH fibrosis diagnosis . Patients with NASH fibrosis stages F1–F3 had to have been receiving stable treatments that could affect NASH for a minimum of 12 months before biopsy if treatment had been initiated. A summary of patient eligibility criteria and any treatment taken for comorbid conditions is given in Supporting Tables S3 and S4  and University of Calgary’s Conjoint Health Research Ethics Board . This study was conducted in accordance with the ethical principles of The Declaration of Helsinki and is consistent with Good Clinical Practice and the regulations of the United States Food and Drug Administration, applicable laws, and the institutional review board requirements.Concept elicitation interviews were conducted by 2 interviewers  experienced in performing concept elicitation interviews. The interview approach was consistent with recommended guidelines provided by the International Society for Pharmacoeconomics and Outcomes Research Good Research Practices Task Force.Deidentified transcripts were generated from all recorded interviews. Coding of the audio transcripts was performed by Rakshit Patil and Meredith Venerus of IQVIA, who followed coding rules that were established before coding began. One primary coder was responsible for coding all interviews and a second coder coded the interview transcripts until an intercoder agreement of 0.7 or more was achieved in at least 3 transcripts.The preliminary conceptual model created from the TLR was updated based on patient responses. New concepts identified as salient were added to the conceptual model. Concepts from the preliminary conceptual model reported by <20% of patients were removed.The applicability of existing PRO instrument(s) identified during the TLR was also explored. The content validity of PRO instruments was evaluated to assess whether there is existing evidence to support their use in the NASH population. The concepts identified as salient from the concept elicitation interviews were compared with items present in the PRO instrument to confirm the suitability of the instrument for patients with NASH fibrosis stages F1–F4.http://links.lww.com/HC9/A89). This was supplemented with 8 congress posters presented at the 2019 European Association for the Study of the Liver conference . In addition, 22 patient forum/blog posts were identified for inclusion. A total of 40 concepts relevant to NASH were selected from the articles and congress presentations; 22 symptoms and 18 impacts.Following an initial search, 596 article abstracts (full-text publications and congress abstracts) were identified for possible inclusion; after review, 12 articles were identified as highly relevant to the patient experience of NASH/NAFLD Of the 14 PRO instruments reviewed, 3 were developed specifically for NASH. The NASH-specific PRO instrument (NASH-CHECK) and chronic liver disease questionnaire-NASH/NAFLD (CLDQ-NAFLD/NASH) were identified as potentially the most suitable for patients with NASH fibrosis stages F1–F4. The NASH-CHECK,A total of 22 patients across liver fibrosis stages F1–F4  were interviewed in this study (Table The concept elicitation interviews identified 59 concepts (27 signs/symptoms and 32 impacts), including 3 that were not identified during the TLR . Most signs/symptoms and impacts were mentioned when the interviewers asked follow-up questions rather than spontaneously by the patients. Of the reported concepts, 32.2% of signs/symptoms and 26.5% of impacts were mentioned spontaneously. The 22 interviews were grouped chronologically into 5 waves  to identify the saturation of concepts. The majority of signs/symptoms (88%) and impacts (91%) were reported in the first wave of interviews. Saturation was achieved after the second and third waves for signs/symptoms and impacts, respectively, supporting that few or no new concepts would have been identified through additional interviews.http://links.lww.com/HC9/A89). Of the reported signs/symptoms, 4  had average disturbance ratings between 7.7 and 10 but were reported by <15% of patients. Although loss of appetite/feeling full quickly and dermatological issues were frequently reported by patients , they had average disturbance scores of <5 . For impacts, one concept  was given a score >5 (5.5) but was reported by <20% of patients.Ten signs/symptoms were identified as salient, with the most salient including fatigue/low energy, pain in the abdomen/liver area, and gastrointestinal problems/gassy Figure A. SixteeOf the reported signs/symptoms and impacts, none were exclusive to a specific fibrosis stage of NASH, and patients across all NASH fibrosis stages required probing for over half of their reported concepts. The average number of signs/symptoms reported by patients with NASH fibrosis stage F1, F2, F3, and F4 was 9.5, 8.0, 11.0, and 12.2, respectively. The average number of impacts reported for patients with NASH fibrosis stage F1, F2, F3, and F4 was 16.3, 8.0, 17.9, and 19.4, respectively. The small size of the populations meant differences in salience are only suggestive of differences between fibrosis stages. The reported concepts suggest some were salient only for patients with fibrosis stages F1–F3 or F4 (Table 2). Although obese and nonobese patients reported similar concepts, patients who were obese reported some concepts as more disturbing than did nonobese patients, leading to the salience of certain concepts for obese patients but not for nonobese patients with NASH. The small size of the populations in this study means differences in salience are only suggestive that there are differences between obese and nonobese populations. Obese patients reported 7 signs/symptoms and 15 impacts as salient that nonobese patients did not .The preliminary conceptual model was updated based upon the concepts identified during concept elicitation interviews Figure . Three ihttp://links.lww.com/HC9/A89). The salient signs/symptoms not included in the NASH-CHECK were dizziness, gastrointestinal problems/gassy , joint pain, nausea/vomiting, and shortness of breath, and the impacts not included in the NASH-CHECK were frustration and irritability.Salient concepts identified during concept elicitation were compared with items from the NASH-CHECK, which was selected during the TLR as the most appropriate PRO instrument for assessing the patients’ experiences of NASH. Similar concepts reported during the patient interviews were grouped together for comparison with items in the NASH-CHECK. Eighteen of the salient concepts  were covered by the NASH-CHECK either directly or indirectly  cognitive problems, swelling, cold extremities, and hair loss, and (impacts) psychological/psychiatric issues]. Differences in concept disturbance between patients may indicate variation in individuals with NASH and how they experience the condition.Some of the concepts reported in this study may not have been the direct result of NASH itself but instead caused or influenced by other comorbidities. Symptoms reported as highly disturbing by only a few patients in this study, such as swelling, cold extremities, and hair loss, are also recognized in patients with hypothyroidism and so could be indicative of this condition—NAFLD has been found to be prevalent in patients with clinical hypothyroidism and could potentially directly or indirectly impact the pathogenesis of NAFLD and NASH.Of the impacts reported, decreased social functioning was identified as a salient impact irrespective of fibrosis stage or whether patients were obese. Loneliness frequently occurs in patients with chronic conditions and has been associated with morbidity and mortality.It is important to understand the complete patient experience of NASH, not just its impact on the liver, so that appropriate PRO instruments can be developed. These instruments may then be used to better understand the impact NASH has on patients and could ultimately be used to determine treatment endpoints in clinical trials that may be highly relevant to the patient, despite appearing to be separate from traditional liver disease endpoints. The NASH-CHECK was created by the LITMUS group, whose main aim is to develop and validate biomarkers that achieve a regulatory qualification and can be used for diagnosing and/or monitoring the progression of NAFLD/NASH and fibrosis stage.Patient interviews to develop the NASH-CHECKThe study was restricted in the geographic locations of the patients who participated, and the majority of patients were White non-Hispanic, limiting the ethnic diversity of the study. The small size of the subgroups makes it difficult to make any firm conclusions about the characteristics of and differences between each fibrosis stage, and risks data being skewed by a single patient. A considerable number of symptoms and impacts were elicited only via probing by the interviewer; while we acknowledge this as a limitation, given the nature of NASH and the lack of knowledge in both patients and the general medical community around patient experience of the condition, we are cautious in drawing any inferences regarding the importance/salience of the symptoms/impacts that had to be probed. Over half of patients had diabetes and/or obesity, which could have contributed to some of the concepts being reported as salient. A lack of understanding about NASH could have caused patients to struggle to differentiate between concepts related to NASH and to their comorbid conditions. However, including patients with such comorbidities benefits the study as they are typical conditions experienced by patients with NASH. The study was also conducted during the COVID-19 pandemic so reporting of concepts may have been affected by the encouragement of these individuals to self-isolate (worsening impacts related to self-isolating and patients being more aware of their symptoms). However, a heightened awareness of symptoms could allow some that would otherwise be unrecognized to be identified, allowing a more complete understanding of the condition.This study highlights that patients can self-report and elaborate on signs/symptoms and impacts associated with NASH, regardless of fibrosis stage. However, due to the small sample size, further studies are required to confirm whether this is consistent across patients with NASH, including those from different countries. By identifying concepts that required updating, or were not included in the preliminary conceptual model, the study demonstrates the benefit of talking directly to patients about their experience of NASH. While comorbid conditions, such as obesity and diabetes, may influence the signs/symptoms and impacts reported by patients, these are still important to recognize as part of the patient experience of NASH. The identification of items in the NASH-CHECK that predominantly overlapped with the concepts from this study demonstrates the suitability of the NASH-CHECK for holistically understanding the patient experience of NASH fibrosis stages F1–F4.


The widespread use of live attenuated vaccines using strains that belong to Cluster II might have accounted for these changes in the relative distribution between Clusters.To clarify the genetic diversity of the porcine reproductive and respiratory syndrome virus (PRRSV) in Japan in recent years, we determined the nucleotide sequence of open reading frame 5 of 2482 PRRSV sequences obtained from samples collected from pigs between January 2018 and December 2020. As a result of molecular phylogenetic analysis, Cluster II represented the largest proportion (44.9–50.6%) throughout the study period, followed by Cluster IV (34.0–40.8%), Cluster III (7.8–12.1%), Cluster I (3.1–6.7%), and Cluster V (0.1–0.2%). The relative distributions between Clusters varied between geographic regions and between years: in 2018, Cluster II was the most prevalent in all regions. In 2019, Cluster II was dominant in the Hokkaido and Tohoku regions, while in other regions Cluster IV was dominant. In 2020, Cluster IV was dominant in the Kanto/Tosan and Kyushu/Okinawa regions, whilst in other regions Cluster II was predominant. Compared with a previous study, the proportions of genome sequences classified in Clusters II and IV significantly increased ( Arteriviridae, order Nidovirales [The porcine reproductive and respiratory syndrome virus (PRRSV) causes porcine reproductive and respiratory syndrome (PRRS), which is characterized by reproductive failure in sows and respiratory disease in piglets . PRRSV iovirales . PRRSV iovirales . PRRS waovirales  and subsovirales . PRRS haovirales , and theovirales . There aovirales ,10,11,12It has also been suggested that PRRSV is associated with and is one of the key pathogens of the Porcine Respiratory Disease Complex (PRDC) ,14,15, aThe diagnosis of PRRS depends on the measurements of enzyme-linked immune-sorbent assay (ELISA) antibody titers and the detection of the PRRSV antibody by a immunoperoxidase monolayer assay or an immunofluorescence assay of blood or serum samples collected from pigs at different production stages; detection of PRRSV genes by reverse transcription-polymerase chain reaction test (RT-PCR); the detection of antigens in the lungs and tonsils by immunohistochemical staining; and the isolation of PRRSV using porcine alveolar macrophages ,19,20,21PRRSV contains at least nine open reading frames (ORFs) including ORFs 1a and 1b, ORFs 2a and 2b, and ORFs 3–7 . Among tThis study aimed to identify the diversity of Type II PRRSV genes and epidemic types distributed in Japan in recent years by determining the nucleotide sequences of the ORF5 genes using sequences from samples collected in Japan between January 2018 and December 2020.A total of 2482 PRRSV nucleotide sequences of the ORF5 genes detected from samples collected from pigs during the years from 2018 to 2020 were used for molecular phylogenetic analysis based on the method described in a previous study . The numMolecular Evolutionary Genetic Analysis (MEGA) software version 7.0  was used to create a phylogenetic tree for each PRRSV sequence for which the ORF5 gene region was sequenced . Of the ® PRRS strain , Ingelvac® PRRS MLV strain , EDRD-1 strain , Jpn5-37 strain , and Jos1 strain  were used as the reference strains for Clusters I, II, III, IV and V, respectively. For Cluster I, Fostera® PRRS strain , which has been available in Japan since 2018, was also used as a reference strain. EDRD-1, Jpn5-37 and Jos1 were the first wild type isolates detected for each Cluster in Japan and commonly used as reference for phylogenetic analysis  , a graphp-values less than 0.05 were considered statistically significant.A chi-square test was used to investigate if there was a significant difference between the relative distributions of PRRSV sequences classified in the Clusters in this study and previous studies, and between Clusters in the respective geographic regions. When comparing the identity distributions of sequences classified in each Cluster between years, the Shapiro–Wilk test was first used to check the normality of the identity distribution within Clusters. If the sequences within Clusters were normally distributed in terms of identity, one-way analysis of variance (ANOVA) was performed to draw a comparison between the years. If normality was not assumed for any of the three years, the Kruskal–Wallis test was used for between-year comparisons, followed by Steel–Dwass multiple comparisons in post-hoc tests. All All the PRRSV sequences detected in this study were of the North American type, also called PRRSV Type II. The relative distribution between Clusters for the three study years at the national level are shown in The relative distributions between the Clusters for the seven geographic regions  for each of the three years 2018, 2019, and 2020, are shown in ® PRRS MLV and Fostera® PRRS, Ingelvac® PRRS MLV, EDRD-1, and Jpn5-37 and Jos1 strain as reference strains, respectively.® PRRS MLV strain  to the Prime PacV strain A. They aeference B, with o® PRRS MLV strain throughout the study years  and a significant decrease in the proportion of Cluster III (p < 0.01)  with some sequences presenting an identity of up to 90.6%. Although the Jpn5-37 strain has been experimentally proven to be highly virulent [Our study revealed that the relative distributions between the Clusters of PRRSV were relatively stable during the three years, with Clusters II and IV representing the largest proportions, followed by Clusters III, I, and V. A previous study reported that Cluster III represented the highest proportion based on the analysis of PRRSV strains detected in 2007 and 2008 . Althougain Jpn5- with som® PRRS strain, one of the reference strains for Cluster I in our study, is a vaccine strain approved and marketed in Japan since 2018 and it has been used by pig farmers for PRRS control. This might have resulted in the detection of many viruses closely related to Fostera® PRRS during the study period. To the contrary, there were no Cluster I sequences detected in this study that were closely related to Prime Pac® PRRS MLV, another reference strain. This is most likely because Prime Pac® PRRS MLV has not been approved and used commercially in Japan.Interestingly, the identity distributions to the reference strain of the sequences classified as Clusters I and II might be consistent with known vaccination practices in Japan. The Fostera® PRRS MLV strain. This is most probably because this vaccine has been approved in Japan for more than 20 years and is still widely used by many pig farmers to protect their pig herds from the field strains of PRRSV that cause clinical diseases. The widespread use of this vaccine might have led to the increase in Cluster II strains. Currently, the only modified live PRRS vaccines used on pig farms in Japan are Fostera® PRRS, produced using a Cluster I strain, and Ingelvac® PRRS MLV, produced using a Cluster II strain. As shown in a previous study in the United States [Regarding Cluster II, the majority of the sequences classified in this Cluster revealed over 95% sequence identity with the Ingelvacd States , the conNo significant change was observed in the identity distribution of the Cluster III sequences over the study period, suggesting that no significant genetic change from the reference strain occurred during these three years. The EDRD-1 strain used as the reference strain for Cluster III in this study was detected in Japan in 1993. The long period that has elapsed since then might have lowered the identity of this Cluster’s sequences compared with Clusters I and II’s sequences, for which the vaccine strain was used as the reference strain. The identity of the sequences classified in Cluster IV with the reference strain was low, suggesting that the strains have been propagated and mutated repeatedly from the time they were first detected in Japan to the present. Two sequences and one sequence classified in Cluster IV in this study were close to a strain detected in Austria (AY875854) and a strain detected in Denmark, respectively, (AF095515), each with an identity being above 99%. However, no epidemiological evidence was available that could possibly link these sequences with pigs imported from either of these countries. The number of Cluster V sequences detected in this study was too small to draw inference using statistical analysis.In this study, we used MEGA to create a phylogenetic tree for each of the PRRSV strains for which the ORF5 gene region was sequenced. However, there are other methods used to describe virus diversity and evolution such as the lineage system using a Bayesian Markov chain Monte Carlo (BMCMC) method ,40. FurtOur study indicated that PRRSVs on pig farms in Japan have a high degree of genetic diversity and that this diversity has increased over time in the past decade. In addition, our study revealed that the epidemic type of PRRSV has changed over the past decade. A recent study conducted in Canada using whole-genome sequencing was more successful than ORF5 sequencing, in obtaining strain classification and interpretation of results in 9.10% of clinical samples . The who


Knowledge-based treatment planning (KBP) solutions can be used to assist in the planning process by automatically generating patient-specific optimization objectives. A KBP model is typically derived from treatment plans with a similar planning methodology, for example beam angles. An end-user might deviate from this methodology for a variety of reasons. The effect of such deviations on KBP plan quality has not been widely explored. We therefore studied this using a human-interaction free proton planning solution to create comparative plans with the default angles used when building the model, and altered beam angle arrangements. Because normal tissue complication probability (NTCP) can be used to select patients for proton therapy, this was used as the primary outcome metric for plan quality. The results show that the beam angle and number of beams only had a small effect on the plan NTCP. This suggests that the model is robust to the various beam arrangements within the range described in this analysis, although a method that automatically further adapts the KBP planning objectives further decreased the NTCP by 1–3%.Knowledge-based planning solutions have brought significant improvements in treatment planning. However, the performance of a proton-specific knowledge-based planning model in creating knowledge-based plans (KBPs) with beam angles differing from those used to train the model remains unexplored. We used a previously validated RapidPlanPT model and scripting to create nine KBPs, one with default and eight with altered beam angles, for 10 recent oropharynx cancer patients. The altered-angle plans were compared against the default-angle ones in terms of grade 2 dysphagia and xerostomia normal tissue complication probability (NTCP), mean doses of several organs at risk, and dose homogeneity index (HI). As KBP could be suboptimal, a proof of principle automatic iterative optimizer (AIO) was added with the aim of reducing the plan NTCP. There were no statistically significant differences in NTCP or HI between default- and altered-angle KBPs, and the altered-angle plans showed a <1% reduction in NTCP. AIO was able to reduce the sum of grade 2 NTCPs in 66/90 cases with mean a reduction of 3.5 ± 1.8%. While the altered-angle plans saw greater benefit from AIO, both default- and altered-angle plans could be improved, indicating that the KBP model alone was not completely optimal to achieve the lowest NTCP. Overall, the data showed that the model was robust to the various beam arrangements within the range described in this analysis. The radiotherapy treatment planning process is laborious, subjective, and prone to both inter- and intra-institutional variations ,2. KnowlIt has already been demonstrated that if the geometric data differ significantly from the training data, plans may be suboptimal , and if If RapidPlanPT produces suboptimal KBPs when applied to plans with non-standard beam arrangement, it should be possible to optimize these plans further than their default-arrangement counterparts. For this purpose, we introduce a proof of principle automatic iterative optimizer (AIO), implemented using the Eclipse Scripting Application Programming Interface  ,16, taskIn summary, in this study, we use a previously introduced automated knowledge-based planning solution and a previously validated RapidPlanPT model to generate KBPs with both default and altered beam angle arrangements without human interaction . We demoTen recent HNC patients with locally advanced oropharynx cancer, previously treated with 2-arc VMAT, were arbitrarily selected for the study. All patients had given signed consent that their data could be used within the department’s research program, and the institutional medical ethics committee exempted this work from requiring their official approval.B/PTVE) in 35 fractions. Additionally, a 5 mm wide ring (PTVO) around PTVB was subtracted from PTVE to facilitate a steep dose fall-off.All plans in this study were automatically generated using the previously described automated knowledge-based planning solution a 12]. I. I12]. IThe KBPs with RapidPlanPT-generated line objectives were non-robustly optimized using Varian Eclipse nonlinear universal proton optimizer (NUPO) 16.0.2 with multifield optimization using proximal/distal/lateral target margins of 2/3/5 mm. The OAR dose objectives were as follows: maximum of 50 and 54 Gy to spinal cord and brain stem expanded with 3 mm margin, respectively, but preferably lower; as low as possible mean dose to both parotid and submandibular glands, oral cavity, and individual swallowing muscles .B V95% = 98%. The RapidPlanPT model had been trained on 50 manually planned 3-field IMPT plans based on patients not included in this study, and it has previously been shown to produce high quality KBPs [The dose calculation was performed using proton convolution superposition algorithm 16.0.2, and the plans were normalized to PTVity KBPs .We designed a proof of principle automatic iterative optimizer (AIO) solution for further optimization of the KBPs in an iterative manner. When performed manually, the treatment planner would adjust the optimization objectives to find the lowest achievable OAR doses and the trade-off between OAR sparing and PTV dose homogeneity ,24. AIO B plus margin . These structures are used in the AIO process to drive the dose down in OARout while avoiding both underdosing and hot spots within OARin.In order to prevent underdosing of parts of the target overlapping with OARs in the AIO-produced plans, a set of helper structures were introduced by splitting the NTCP-related OARs into portions within and without PTVB maximum dose (DMax) to facilitate the optimization process, as reduced PTV homogeneity can lead to significantly lower OAR doses [out and maximum dose objectives for OARin are added. The mean dose objectives of the OARout are set to the respective mean dose minus a reduction dose (x) with priority comparable to the pre-existing OAR objective priorities. Likewise, the OARin objectives are set to PTVB target dose with priorities comparable to the PTVB objective priorities. Underdosing in the PTVB is avoided by giving its minimum dose objectives higher priority than the OARin objectives. The initial value of reduction dose x is set to 0/2.5/5 Gy, depending on the initial dose homogeneity so that the more homogeneous plans are optimized more aggressively.As a starting point, AIO uses an optimized treatment plan, a KBP in this case, checking that the plan has a sufficient margin in PTVAR doses . If the B DMax < 109%) and there is little reduction in OAR DMean, the reduction dose is increased for all OARout. If the objective reduction was too aggressive, i.e., PTVB DMax > 110%, the reduction factor is reduced. Finally, the mean dose objectives are updated to DMean–x according to the latest optimizer dose, and the process is iterated until the PTVB homogeneity threshold is reached. The resulting treatment plans (AIO-KBPs) are expected to have better NTCP values with slightly degraded dose homogeneity.Once the new optimization objectives are added, the plan is optimized, followed by dose calculation and normalization using the process described for KBP creation. If the resulting plan has not reached the homogeneity threshold , conformity index (CI), and plan NTCP. The HI and CI were defined respectively asx% is the dose to x% of the PTVB, Dp is the prescription dose to PTVB (70 Gy), Vx% is the isodose volume receiving at least x% of dose, and VPTV is the volume of PTVB. The NTCPs (grade 2 and 3 dysphagia and xerostomia at 6 months after the treatment) were evaluated according to models adopted by the Dutch radiation oncology society [Σ.The altered-angle KBPs and AIO-KBPs were compared to the default-angle ones by computing the PTV society . Model dp < 0.05.The HI and NTCP were also used to compare AIO-KBPs to the respective KBPs, and to study whether the altered- and default-angle plans behaved differently in the optimization. The statistical significance of the results is evaluated using two-sided Wilcoxon signed rank test at Σ, HI, or CI between default- and altered-angle KBPs, and the altered-angle plans showed at most <1% reduction in NTCPΣ. However, there were 13 altered-angle plans with HI reduction >1.The KBPs with altered beam angles produced by the automated knowledge-based planning solution, before AIO was applied, had on average slightly worse NTCP metrics and a slightly better homogeneity index . The patFor all OAR, the differences in default- and altered-angle KBP mean doses were mainly between ±2 Gy, with individual plans seeing differences up to ±6 Gy in the oral cavity, superior pharyngeal constrictor muscle, and spinal cord. A graph of OAR-wise mean dose results is presented in Σ in 66 out of 90 KBPs, and improved NTCPΣ by an average of 3.5 ± 1.8% .AIO managed to reduce NTCP5 ± 1.8% . GeneralΣ values . Dysphaghe plans a,b. In mhe plans . IndividNone of the OAR were systematically reduced in any of the AIO plans, but were instead increased by <1 Gy in about 25% of cases. None of the OAR (NTCP-related or otherwise) saw mean dose increases over 5 Gy, apart from the oral cavity, the mean dose for which was increased by over 5 Gy in two cases c,d.On average, AIO converged in about six iterations, which corresponds to about 20 min of processing time.Σ reduction achievable with altered beam angles also increased from <1 to almost 4% . The largest variation in dysphagia over the beam angles was for patients six and seven, where the size of PTVB and its location in relation to the pharyngeal constrictor muscles and oral cavity increases the effect of beam angles on the NTCP. The NTCP values in AIO plans were more evenly distributed, with 45 and 40 out of 80 grade 2 dysphagia and xerostomia endpoints, respectively, being lower for the default-angle plans , indicating that the optimizer was forced to make more aggressive trade-offs between PTV homogeneity and OAR dose in default-angle plans. As with pre-AIO KBPs, the best beam angle arrangement varied from patient to patient, but the differences were slightly more noticeable in the AIO plans  but had little to no effect on CI, with all plans having a CI between 1.03 and 1.06. The AIO process successfully reduced NTCPΣ in 5/6 KBPs, with a maximum reduction of 3.9%. The effect of AIO processing on HI was inconclusive; in 2/3 patients, HI was increased by <1, but for one patient it was reduced by a similar amount. The CI was increased on average by 0.05 for all plans. A graph of the results is presented in Supplementary Material S4.When applied to prospective beam arrangements with increased number of fields, the performance of both RapidPlanPT and AIO varied. Increasing the number of beams to four or five improved NTCPΣ, but on average, the standard beam angles were the best choice. Adding AIO further reduced the NTCPΣ on average by about 3% for all beam angles, depending on the initial quality of the KBP. Increasing the number of fields did not substantially lower the NTCPΣ.This study evaluated the performance of RapidPlanPT when creating KBPs with beam angle arrangements differing from those in the training set. A previously demonstrated RapidPlanPT model and automated KBP-creation pipeline, as well as a novel proof-of-principle automated iterative optimizer (AIO), were employed to create a total of 90 KBPs for 10 HNC patients without human interference. Our results demonstrate that changing the beam angles could occasionally lead to <1% lower NTCPTo place this study in context, RapidPlanPT has been previously studied by Delaney et al. and Xu et al., demonstrating its clinical feasibility with models trained on plans with standardized (former) and varying (latter) beam angle arrangements ,10. Our Σ reductions of 2–4%. This may be clinically relevant when set against the threshold of a 15+% reduction in NTCPΣ (for grade 2+ toxicity) that can lead to patients being selected for proton therapy in the Netherlands [B volumes, and thus less overlap between PTV and NTCP-relevant OARs . This would indicate that, for clinical practice, where manually choosing and testing even a moderate number of different beam angles is time consuming and laborious, there is little benefit to be gained for NTCP from fine-tuning the patient-specific beam angles. Instead, using a template arrangement, and performing crude alterations to it based on the relative OAR location and potential avoidance regions, such as the dental amalgam, would be more efficient. Automated beam angle optimization, while expected to confer a small benefit, nonetheless merits consideration as a part of a comprehensive approach to automation and plan-quality improvement [For 13/80 altered-angle AIO plans, there were NTCProvement . In addiΣ per added field, even after the AIO process. The effect on homogeneity was inconclusive, with KBPs showing little to no benefit, and AIO plans showing moderate improvements for two patients, and a worse HI for the third.We also studied the effect of increasing the number of beams to four or five by generating these KBPs for three patients. Earlier studies have found a larger number of fields to have either minor or no effect on OAR sparing, PTV coverage, or plan robustness ,29,30. OThe major limitations of this study were the lack of robust optimization and the associated beam path considerations, as well as the plans being optimized for lowest OAR dose instead of for the highest homogeneity or conformity and lowest NTCP. Optimizing the plan robustly could lead to more significant differences between beam angle arrangements, especially in cases where the beam path is through highly inhomogeneous tissue, or there are critical OAR close to the target . SimilarΣ in 66 out of 90 KBPs, reducing it by 2.9 and 3.6% for default- and altered-angle KBPs, respectively. This highlights that there is frequently room for improvement in plans and presumably reflects the fact that the plans used to generate the KBP model were themselves not maximally optimized. Such data highlight a wider role for approaches such as AIO, which not only emphasize automation  but also focus on the generation of high-quality patient-specific plans. While the use of KBP is generally advised against in the case of plans that are considered outliers  because this would create sub-optimal optimization objectives, adding AIO could probably solve this problem. The plans that could not be improved either had high initial PTVB DMax, leading to them being directly discarded from AIO (13 plans), or were ones in which the first iteration failed to find a solution that would reduce NTCPΣ without violating the 110% PTV DMax threshold (11 plans). In future, a separate AIO routine to increase PTVB homogeneity at the cost of OAR dose could be realized to address these plans. On average, the process took about six iterations, or 20 min, to converge. The maximum number of iterations was capped at 10, as it was found that after this point there was very little improvement, especially when used together with a more aggressive initial reduction dose for plans with low initial PTVB DMax. A major bottleneck in the process was, however, the need for dose calculation following each optimization round to check whether the end conditions had been met. This was due to the optimizer-reported maximum dose differing from the calculated and normalized dose by more than our 1% target margin. If the AIO process could be made less sensitive to this difference, and the dose calculation steps could be omitted from the iteration process, the processing time would fall by about 25%.Our proof-of-principle AIO process was able to improve the NTCPIn addition to speed, AIO would benefit also from other improvements to make it more clinically relevant: If the optimization objectives could be adjusted during the optimization engine processing, as is possible via the graphical user interface of NUPO, a lot of time could be saved on not having to instantiate it between each iteration . Furthermore, a more holistic solution for constraints and end conditions would be required to ensure that an acceptable plan quality is maintained. One possibility, and an interesting topic for future research, would be a clinical goals-based “wish-list” of dosimetric objectives that AIO could seek to fulfill during processing . While wA KBP model to create head and neck cancer proton plans has been shown to be robust to beam arrangements that differ substantially from those used in the plans on which the model was based. Further automated optimization of KBP plans with default and altered beam angles showed that many could be improved to some extent or another. This suggests that the plans used to generate the model were not fully optimized for reduction of specific NTCP and HI parameters. Furthermore, plans consisting of more beams could be generated using KBP + AIO, but increasing the number of beams only led to clinically insignificant reductions in the NTCP.


In addition, methods currently used to assess the home environment do not capture real-time data on potentially modifiable environmental exposures or their effect on asthma symptoms.It is estimated that over 60% of adults with asthma have uncontrolled symptoms, representing a substantial health and economic impact. The effects of the home environment and exposure to volatile organic compounds (VOCs) and fine particulate matter (PM2.5), and lung function in terms of forced expiratory volume in 1 second (FEV1%); (2) assess the frequency and level of residential environmental exposures  via self-reported data and home monitoring objective measures; (3) assess the level of asthma control as indicated by self-reported asthma symptoms and lung function; and (4) explore associations of self-reported and objective measures of residential environmental exposures with self-reported and objective measures of asthma control.The aims of this study are to (1) determine the feasibility and usability of ecological momentary assessment (EMA) to assess self-report residential environmental exposures and asthma symptoms, home monitoring of objective environmental exposures (total VOCs and PM2.5, and FEV1%, respectively. EMA data will be collected using a personal smartphone and EMA software platform. Participants will be sent scheduled and random EMA notifications to assess asthma symptoms, environmental exposures, lung function, and mitigation strategies. After the 14-day data collection period, participants will respond to survey items related to acceptability, appropriateness, and feasibility.We will recruit 50 adults with asthma who have completed our online Global COVID-19 Asthma Study, indicated willingness to be contacted for future studies, reported high use of disinfectant/cleaning products, and have asthma that is not well controlled. Participants will receive an indoor air quality monitor and a home spirometer to measure VOCs, PMThis study was funded in March 2021. We pilot tested our procedures and began recruitment in April 2022. The anticipated completion of the study is 2023.Findings from this feasibility study will support a powered study to address the impact of home environmental exposures on asthma symptoms and develop tailored, home-based asthma interventions that are responsive to the changing home environment and home routines.ClinicalTrials.gov NCT05224076; https://clinicaltrials.gov/ct2/show/NCT05224076DERR1-10.2196/39887 Asthma is a disease of chronic airway inflammation that affects 1 in 12 adults in the United States .Adults usually spend the majority of their day indoors (~15 hours/day) ,5, and dVOCs are widely used as ingredients in household products, including cleaning, disinfecting, cosmetic, degreasing, and hobby products. Early in the pandemic, it was recommended to disinfect surfaces with a US Environmental Protection Agency (EPA)–registered household disinfectant . While t2.5) were highest indoors in homes (versus outdoors or in offices) on weekends when participants wearing personal air quality monitors were at home for longer periods [2.5 have been shown to affect cardiovascular health, anxiety, cognitive function, and respiratory health [2.5 on asthma are still unclear [2.5 [PM are small particles or liquid droplets that include acids, organic chemicals, metals, soils, dust, and allergens . Common  periods , thus suy health . However unclear . Increasear [2.5 -21. Exis2.5). These validated sensors and EMA provide real-time environmental exposure data; however, they have yet to be used to examine the home air quality of adults with asthma and its associations with symptoms in real time [Collecting home air quality data and asthma symptoms typically rely on subjective patient report, which is impacted by recall bias and resource-intensive methods, such as collection of environmental samples from homes. These methods have made it difficult to fully assess the impact of potentially modifiable home environmental exposures on asthma symptoms in real time or provide practical and timely interventions to reduce exposures and disease burden. Ecological momentary assessment (EMA) allows for the collection of time-dependent, real-time data on self-report measures. Thus, EMA reduces potential biases and enhances ecological validity by taking measurements in real time in the settings where they occur, providing high-quality longitudinal data. EMA has been increasingly applied to diseases impacted by lifestyle and outdoor environmental exposures, including studies of asthma-related exposures -5. Yet, eal time -25.2.5. This design will allow us to alert participants of high levels of VOCs and PM2.5 and collect real-time data on exposure and asthma symptoms. Daily and exposure-related lung function will be measured with a low-cost home spirometer. Finally, we will examine the effect of residential environmental exposures that may be related to time spent at home and the associations between these exposures and asthma control. In this paper, we will describe the study protocol and outline how multiple commercially available technologies that measure air quality, lung function, and EMA were harmoniously blended and refined prior to pilot testing.Accordingly, this study aims to assess the feasibility and usability of EMA to capture the context of real-time behaviors and environmental exposures that impact indoor environments. In addition, this study assesses the feasibility and usability of providing participants with an indoor air quality monitor (Awair Omni) to continuously capture total VOCs and PMResearch efforts that focus on indoor home environments are essential to elucidate the possible extent of exposures that can impact asthma outcomes and further exacerbate the risk of hospitalization in a time when home and health care resources continue to be strained. We illustrate the goals of our feasibility study and the impacts we intend to accomplish using the Translational Research Framework ,27. ThisObjectives1%); (2) assess the frequency and level of residential environmental exposures  via self-reported data and home monitoring objective measures; (3) assess the level of asthma control as indicated by self-reported asthma symptoms and lung function; and (4) explore associations of self-reported and objective measures of residential environmental exposures with self-reported and objective measures of asthma control.The aims of this study are to (1) determine the feasibility and usability of EMA to assess self-report residential environmental exposures and asthma symptoms, home monitoring of objective environmental exposures , and lung function in terms of forced expiratory volume in 1 second , respectively. EMA survey data will be collected using a personal smartphone and the PiLR Health software platform [We will recruit 50 adults with asthma who completed our online Global COVID-19 Asthma Study (GCAS), indicated willingness to be contacted for future research, reported high use of disinfectant/cleaning products, and have suboptimally controlled asthma . Participlatform . ParticiAll studies were conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines and approved by the relevant institutional review boards at the University of Kansas (STUDY00145830), University of Louisville (21.0466), University of Illinois Chicago (2020-0851), and University of Chicago (22-0767).2.5, temperature, humidity, carbon dioxide, ambient light, and ambient noise [2.5 levels  at home, such as forced vital capacity (FVC), FEVume loop . The sysThis study builds on data collected from the GCAS, a cross-sectional online survey we conducted in 2020 to examine how the COVID-19 pandemic affected the prevalence of disinfectant use among adults with asthma and to assess the association between the frequency of disinfectant use and asthma control as measured by the Asthma Control Test (ACT) . Over 13Eligibility criteria include GCAS participants who (1) indicated willingness to be contacted for future research and provided an email address or phone number and (2) reported high use of disinfectant/cleaning products since COVID-19 (≥5 per week) and current ACT ≤19 or ≥2 asthma exacerbations in the past 12 months. The commonly used and validated ACT includes 5 items addressing asthma symptoms, use of rescue medications, and effect of asthma on daily functioning. Responses are summed for total ACT score with scores ≤19 indicating asthma that is not well controlled ,41. Non-A total of 50 individuals with at least 20%-40% of the sample representing individuals who self-identify as being of a minority race/ethnicity  who meet the eligibility criteria will be randomly selected and invited to participate in this study via email or phone. Invites will be sent to selected individuals on a staggered timeline based on response rate and positive participation interest. Participants will be randomized within their participant category . Participants within each category will be randomly assigned an order number using a random number generator in Excel (Microsoft). Participants will be recruited in the order of their random assignment until we have recruited a total of 50.Using the randomized order assignment, invitations will be sent to 2 to 5 individuals from each group at a time, with the intent of enrolling initially up to 5 participants at any 1 time. If fewer than 5 consent to participate in any wave of invitations, invitations will be sent to the next potential participants in the randomized order assignment. We will scale up to 10 to 15 enrolled participants once we have passed the initial start-up period. The staggered recruitment process will be repeated until 50 individuals including at least 20%-40% minorities have completed study participation. Recruitment will focus on equal numbers from each participant category . However, given the smaller initial pool, if we are unable to recruit 25 minority participants, additional participants will be recruited from the White participant pool until a total of 50 participants are enrolled.Interested individuals will be directed to a Research Electronic Data Capture (REDCap) survey link to confirm willingness to participate, verify eligibility, and provide current contact information. REDCap will be formatted to automatically send 2 additional email invitations 1 week apart if no response is received. If no response is received after the second email invitation and a phone number is provided, a phone call contact will be attempted. If no phone number is provided, a third follow-up email will be sent. A total of 3 contact attempts over a 3-week period with 1 week between each contact will be made to each invited individual. We will randomly select replacements if no response is received after 3 contact attempts, lack of interest is indicated, or inclusion/exclusion criteria are not met.2.5 levels as captured by Awair Omni. The first triggered survey  will be sent to participants as soon as elevated levels of VOCs or PM2.5 levels are detected to assess behaviors or environmental changes that may have caused elevation, ask participants to report any asthma symptoms they are experiencing, and remind them to use their spirometer. The second triggered survey  will follow 1 hour after the trigger event  and will assess interventions by participants to improve the indoor air quality or reduce their exposure  and any ongoing asthma symptoms. All these surveys were built on the PiLR dashboard by study team members after receiving orientation by PiLR staff. After creating the surveys, research team members were added as “participants” to allow for rigorous testing of the surveys, prompts, skip logics, and so on. Sending EMA surveys triggered by Awair Omni readings required significant programming conducted by PiLR staff. Primary considerations for scheduling the triggered surveys were timing of the survey prompt relative to the event  while reducing burden on participant for the number of prompts received . Real-time data resulted in frequent prompts to respond to the same event, whereas 5-minute averages could result in delay of a few minutes between actual event and the deployment of the survey prompt. Several team members received Awair Omni devices and used them to assess the functionality and potential burden on participants and test the link between Awair Omni readings and EMA triggered surveys to ensure that the proper link is established and real-time data on VOCs and PM2.5 are captured that will trigger EMA surveys.Four types of EMA surveys will be sent to participants: a daily morning survey  inquiring whether participants had asthma symptoms and requesting participants use their ZEPHYRx spirometer; 2 daily random surveys  to assess disinfectant use and asthma symptoms and remind those with asthma symptoms to use their spirometer; and 2 triggered surveys based on elevated VOCs and/or PMHow-to guides were developed to describe the set-up and use of each research tool. The goal was to create a seamless guide with step-by-step pictures so a participant could easily follow and pinpoint any missteps. The currently available user guides from the specific companies  were used as templates, with additional specificity added as needed. For each device, research team members downloaded the app, set up the device, took screenshots of the processes, and wrote step-by-step instructions of the set-up. Issues faced while developing the guides included variations between phone types  and software updates that occurred during testing requiring adjustments in the guides. An asthma-focused community advisory board hosted and led by the Chicago Asthma Consortium was utilized to review the guides and provide feedback. This feedback was incorporated into each guide. Suggestions included having study team contact information readily available in case of any issues and using highlighted boxes to relay important information.Measures that will be administered at baseline via REDCap are outlined in Adult Asthma History includes 5 items adapted from the Behavioral Risk Factor Surveillance System Survey  and 3 itAdult Asthma Adherence Questionnaire includes 5 items on following a prescribed asthma medication plan and barriers to following that plan .Health Behaviors includes items addressing exercise, use of alcohol, vaping products, marijuana, and cigarettes.Home Environmental Exposure data include time typically spent at home, exposure to residential secondhand smoke, use of hand sanitizer, disinfectants, room where most time is spent in the home, potential asthma triggers in that room , potential asthma triggers in the room participants sleep in, and cleaning products used in the shower/tub, kitchen, and on furniture. Additional data will include frequency of cleaning these areas, exposure to fragrances in the home, use of dryer sheets, presence of plants in the home, use of allergy control covers for pillows and mattress, pets in the home, heating, ventilation, use of a humidifier, having an attached garage, and use of pesticides in the home ,45.Demographics include where participants live, education level, occupation, ZIP code, health insurance, rent/own home, type of home, number of people in the home, number of bedrooms, 8 items addressing feelings of worry/tiredness/anxiety, self-rated physical health, comorbidities, height/weight, COVID-19 exposure/infection status, COVID-19 vaccine status, face mask, impact of COVID-19 on finances/employment, and an open-ended question to address any additional concerns. In terms of emotional support the PROMIS_SF_V2 Short Form 4A measures perceived feelings of support, being cared for, and valued (4 items) . Higher Perceived Stress Scale includes 4 items measuring the degree to which situations in one’s life are appraised as stressful. Higher scores indicate an increased level of perceived stress .Open-ended questions will be asked to identify any troubleshooting areas, determine if adjustments need to be made, and assess ease of use of the app/devices. Participants will be asked how things went with each of the study tools . Additional things to be asked include feedback on the set-up materials provided prior to data collection, interactions with research staff, queries if a participant is nonresponsive to EMA prompts, and an open-ended general item about how the study is going. Interactions will be recorded and reviewed by the research team to identify patterns as well as any adjustments that are needed.At the end of the 14-day data collection period, participants will be asked to respond to a short REDCap survey assessing usability of the Awair Omni indoor air quality monitor (10 items), PiLR EMA Health app (10 items), and the ZEPHYRx home spirometer (10 items), with response ranging from 1 (strongly agree) to 5 (strongly disagree). After each section, there will be an open-ended item for participants to comment on what they liked or did not like about each study tool . A random sample of 20 participants will be interviewed to further explore these factors using 4 open-ended questions: (1) “How did the study work for you?” (2) “Tell us what you liked/didn’t like about the indoor air quality monitor.” (3) “How did you feel about the integration of the various tools  in the study?” (4) “Is there anything else you’d like to tell us?”Each day of observation will be divided into 4 periods between 6 AM and 10 AM that will be 4 hours each. Data from event-contingent prompts as well as fixed  prompts will be analyzed. Multiple event–contingent prompts may occur within the same 4-hour window, in which case data will be averaged across all event-contingent prompts during that period. The daily morning survey is scheduled so that it will always occur within the first 4-hour window of the day, and the random prompts are scheduled so only 1 will occur within any of the 4-hour windows.To address the first aim of this study, we will assess compliance in 4 areas: survey response, spirometry use, interventions to reduce exposure, and air quality monitoring. Survey response compliances will be measured using EMA prompts and defined by the total number of completed prompts of each type out of the number of EMA prompts of each type received. Behavioral compliance to use of the spirometer will be assessed as the number of times the participant used the spirometer out of the number of times the participant was prompted to use it. Compliance to completing interventions to reduce exposure following an air quality event will be assessed using completed follow-up surveys as the number of times the participant reported taking action to reduce exposure out of the number of event-contingent surveys where the participant indicated they were in the home at the time of the event. Air quality monitoring compliance will be assessed as the duration the indoor air quality monitor is used by each participant out of the total study time. Compliance in all 4 areas will be assessed for the entire study period as well as within the 4-hour daily windows.The quantitative participant assessment of acceptability, appropriateness, and feasibility will be analyzed descriptively. Differences in use and acceptance by participant demographics will be examined to identify factors  that may make participants more or less likely to use the monitors or respond to prompts. Qualitative interview data will be transcribed and uploaded to Dedoose qualitative analysis software  for content analysis.2.5 levels exceed optimal levels, average daily levels, average levels per time, and fluctuations in VOC and PM2.5. We will identify possible environmental triggers that contribute to high levels of VOCs and PM2.5 and event-contingent prompts.To address the second aim of this study, we will analyze baseline data on the current use and frequency of disinfectants/cleaners and exposure to environmental triggers . Real-time self-reported data on disinfectant use throughout the study period obtained through the EMA studies will be analyzed for total use during the study period as well as trends within and across the daily time intervals . We will determine the prevalence of disinfectant use and frequency (percent of EMA prompts at which disinfectant use is reported). We will also obtain data from the Awair Omni dashboard to determine the number of times VOC and PM1% predicted within 30 minutes of each event-contingent prompt. Asthma control will also be evaluated using EMA by exploring differences in variability in lung function.To address the third aim of this study, we will determine the baseline level of asthma control as reported by the ACT. We will use EMA to determine the level of asthma control over the study period as indicated by (A) asthma symptoms reported at each prompt and over the 14 days, (B) number of time periods in which participants report asthma symptoms, and (C) lung function as measured by FEV2.5 exposure, (2) time-level exposure frequency variables defined by the number of times VOC and PM2.5 levels reach or exceed the threshold for the optimal readings per week, (3) time-level exposure level variables defined by the average scores of VOC and PM2.5 levels in the time windows considered in the analysis, and (4) time-level exposure duration variables defined by the total time within the time windows that the VOC and PM2.5 levels were elevated. The outcome variables that we will consider include occurrence of any asthma symptoms, inhaler use, and FEV1% predicted within 30 minutes from the event-contingent prompt.We will use the data collected using the EMA approach to evaluate the fourth aim of this study. EMA data are multilevel, with time windows (level 1) nested in individual participant information (level 2). The exposure variables will include (1) baseline person-level variables such as self-reported use and frequency of disinfectant/cleaner use and PM1%. We will control for both level 1 variables  and level 2 variables . Using available time stamps from the indoor air quality monitor, EMA, and the spirometer, we will also explore average lag time between an event-contingent prompt and self-reported asthma symptoms using multilevel survival analyses.We will use multilevel binary logistic regression to examine the associations between the exposure variables and binary outcome variables. We will also use multilevel linear regression to examine associations between the exposure variables and predicted FEVThis project received funding in March 2021. The first year of this project has been spent focusing on determining the feasibility and usability of using an EMA to assess self-report of residential environmental exposures, home monitoring or environmental exposures, and lung function. This has involved creating participant research materials and developing and coordinating 4 diverse software platforms: REDCAp surveys, ZEPHYRx spirometer, Awair Omni home air quality monitor, and PiLR EMA. We pilot tested our procedures and began recruitment in March 2022. We anticipate study completion in 2023.2.5 in the home environment on asthma in several ways. First, it addresses how increased cleaning and disinfecting practices could impact asthma control in people with asthma. This consideration is particularly relevant considering the COVID-19 pandemic, during which people have dramatically increased their use of disinfectants. This study also addresses the methodological shortcomings of previous studies of the home environment of adults with asthma, as we uniquely use real-time collection of symptoms data with EMA to examine the effects of environmental triggers on adult asthma symptoms, real-time objective residential exposure data , and we collect an objective measure of asthma control with the measurement of lung function.This study contributes to our knowledge of the real-time impact of VOCs and PMThis study has several strengths. First, it builds on an ongoing study and will be conducted with individuals who have agreed to be recruited for future studies and thus facilitate enrollment. Second, participants will be drawn from a wide geographic area in the United States, which increases broad representation of participants. We will gather real-time environmental exposure data and indicators of asthma control in unregulated indoor home spaces without actual in-person contact. Findings from this study have the potential to impact recommendations for indoor use of disinfectants/cleaners for those with asthma and guide further research.There are a number of challenges we anticipate as we launch this feasibility study. First is the presence of the digital divide and the extent to which we may encounter it. The concept of the digital divide acknowledges that communities across nations have differing levels of access to technology, including smartphones, internet, and broadband infrastructure, which may be related to geography , generational differences, comfort level with technology, and finances. As part of the feasibility design, we will document the impact of this differing access to better address challenges of the digital divide and promote inclusion of varied communities in future studies involving the indoor home environment and technology platforms.Along with documenting the extent of the digital divide encountered in this study, our team is interested in addressing any ethical concerns that arise with using multiple technology platforms in the indoor home environment. Real-time data collected by Wi-Fi and Bluetooth–enabled devices may bring about unique ethical concerns that must be addressed to ensure privacy and confidentiality. Our team will address any ethical concerns in real time with the guidance of our institutional review board, and we will strive to share best practice when bringing such technology into homes with our research participants as partners in this process. The feasibility design of this study will allow us to purposefully address any challenges that may arise in a larger, powered study.Findings from this study will provide preliminary data for a powered study to develop innovative intervention strategies for people with asthma and address the impact of changes in environmental exposures related to COVID-19, thereby enhancing our preparedness for future infectious disease outbreaks. This has implications for risk reduction in people with asthma to help improve asthma self-management using personal monitors and sensors for individually tailored exposure profiles.


Opioid-induced constipation (OIC) is one of the most prevalent adverse events associated with cancer patients who receive opioid analgesics for moderate to severe pain. Acupuncture may be an effective treatment for OIC. We designed this trial to assess the efficacy and safety of electroacupuncture for OIC in cancer patients.This is a multicenter, sham-controlled, parallel-group, subject- and assessor-blinded randomized trial. A total of 100 cancer patients with OIC will be randomly assigned to either the electroacupuncture group or the sham electroacupuncture group at a ratio of 1:1. Patients in each group will receive a total of 24-session treatment over 8 weeks, three sessions a week and 30 min each session. Thereafter, patients will be followed up for another 8 weeks. The primary outcome will be the proportion of responders, defined as a patient who has ≥3 spontaneous bowel movements (SBMs)/wk and ≥ increase of 1 SBM from baseline simultaneously for at least 6 out of 8 weeks of the treatment period. The secondary outcomes will include the mean weekly SBMs and complete spontaneous bowel movements, the mean Bristol Stool Form Scale score for stool consistency, the mean score for straining of SBM, the total and subscale scores of Patient Assessment of Constipation-Symptom questionnaires, and the total and subscale scores of Patient Assessment of Constipation-Quality of Life questionnaire. Patients' global assessment of treatment effectiveness, patients' expectation toward the effectiveness of acupuncture and safety of acupuncture will also be assessed. All efficacy analyses will be performed in the intention-to-treat population.To improve the adherence to intervention protocols, the majority of the participants will be recruited from an inpatient setting. The results will help to determine the clinical effects and safety of electroacupuncture for the treatment of OIC among patients with cancer.www.ClinicalTrials.gov, identifier: NCT03797586, registered on 4 January 2019, https://clinicaltrials.gov/ct2/show/NCT03797586. Approximately 70–80% of patients with advanced diseases are tortured by moderate to severe pain . Opioid via activating somatic and peripheral nerves, sending an afferent signal to the nucleus tractus solitarii, and then resulting in an enhanced vagal efferent flow to the GI tract  in functional constipation , 23. FurGI tract . CurrentThis is a multicenter, prospective, sham-controlled, parallel-group, subject- and assessor-blinded, randomized, superiority trial. The protocol of this study was developed according to the Recommendations for Interventional Trials (SPIRIT)  and the This trial is scheduled to be performed at six hospitals in China mainland from May 2019 to October 2022. A total of 100 OIC participants with cancer will be publicly recruited from inpatient and outpatient departments through posters and networks in the Guizhou University of Traditional Chinese Medicine, Zhejiang Hospital, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Hengyang Hospital Affiliated to Hunan University of Chinese Medicine, Wangjing Hospital affiliated to China Academy of Chinese Medical Sciences, and Yantai Hospital of Traditional Chinese Medicine. The study will use competitive recruitment. Guang'anmen Hospital affiliated to China Academy of Chinese Medical Sciences will be responsible for study design, data interpretation and writing of report. The duration of the trial for each participant will be 17 weeks: 1- week baseline assessment (run-out period), 8- week treatment, and 8- week follow-up.Web-based central randomization will be performed by the Linkermed Pharm Technology Co. Ltd . Participants will be randomly allocated, in a 1:1 ratio, to either the EA or the SA group using permuted block-randomization and stratified by center. Acupuncturists at each site will log in the central randomization system to apply for the randomization number and group allocation. Participants, outcome evaluators, and data analysts will be blinded to the group assignments. The acupuncturists who perform the treatment will not be blinded due to the nature of the acupuncture treatment.One hundred cancer patients with OIC will be included in the study. Research assistants will be in charge of recruitment. Researchers will inform the participants of the possible benefits and risks associated with this trial. Oncologists or gastroenterologists will be responsible for diagnosing OIC and evaluating the status of participant . Participants will be required to sign informed consent before enrolment and will be free to withdraw from the trial at any time.(1) Cancer patients must meet the Rome IV  diagnost(2) Patients recruited in this trial must have a history of OIC symptoms for at least 1 week;(3) Patients must be ≥18 years of age and ≤ 85 years of age;(4) Patient's cancer condition must be stable with a life expectancy that is more than 6 months;(5) Patients must have an Eastern Cooperative Oncology Group (ECOG)  performa(6) Patients must have been receiving a stably maintained opioid regimen, consisting of a total daily dose of 30–1,000 mg oral morphine equivalents for at least 2 weeks prior to screening for cancer pain. Furthermore, it must be anticipated that the opioid will be maintained for at least 10 weeks;(7) The SBM frequency of the patients must be ≤ 2 times a week when laxatives are not being taken;(8) Patients must be capable of oral intake of drugs, food and beverages;(9) Provision of written informed consent before inclusion.Patients who fulfill any of the following criteria will be excluded:(1) Patients diagnosed with clinically significant abnormal defecation due to functional disorders or structural abnormalities of the gastrointestinal tract and other tissues related to gastrointestinal tract (not including OIC): inflammatory bowel disease, rectal prolapse, gastrointestinal obstruction, peritoneal metastasis, or peritoneal tumor at the time of enrollment;(2) Patients with a history of gastrointestinal tract operation, abdominal operation, or abdominal adhesion within 1 month prior to screening; history of intestinal obstruction within 3 months prior to screening;(3) Diagnosis of active diverticular disease; or severe hemorrhoid; or anal fissure; or artificial rectum or anus;(4) Patients with an intraperitoneal catheter or those that use a feeding tube to maintain vital signs;(5) Diagnosis of pelvic disorder, which are considered to have obvious effects on the intestinal transport of feces ;(6) Patients that are being treated with a new cancer chemotherapy, which had never been administered in the past, within 14 days of the screening or are scheduled to receive such therapy during the study;(7) Patients that received radiotherapy within 28 days of the screening or are scheduled to receive such therapy during the study;(8) Patients that underwent a surgery or intervention that is considered to have an obvious effect on the gastrointestinal functions within 28 days of the screening or are scheduled to receive surgery or intervention which is considered to have obvious effects on the gastrointestinal functions during the study, or scheduled to receive surgery or intervention which will be anticipated to prevent the patients from completing the trial;(9) Patients with uncontrolled hyperthyroidism, severe hypertension, heart disease, systematic infection or blood coagulation disorders (hypercoagulation status or hemorrhagic tendency);(10) Patients that consumed >4 additional opioid doses per day, for breakthrough pain, for more than 3 days during the baseline period, or if their maintenance opioid dosing regimen was modified during this period;(11) Patients with severe cancerous pain  refractory to opioid therapy;(12) Patients with a history of opioid discontinuation due to severe adverse events or patients that are suspected to discontinue opioid use due to the potential risk of adverse events;(13) Patients that received an opioid receptor antagonist or agonist within 1 month of the screening, or those who are scheduled to receive such therapy during the study;(14) Patients with a history of nerve neurolysis;(15) Patients with severe cognitive impairment, aphasia, or psychiatric disorders; abdominal aortic aneurysm; hepatomegaly; or splenomegaly;(16) Patients that have received acupuncture within 3 months of the screening;(17) Other patients who are considered ineligible for the study by the investigator on the basis of concomitant therapy and medical findings.Nomenclature and location of acupuncture points  and SDZ-V EA apparatus  in this trial. The planned treatment protocol is based on our previous trials regarding acupuncture for functional constipation , 30. Bile points  drafted The local skin will be routinely sterilized while the patient is in a supine position. For ST25 and SP14, 0.30 × 50 mm or 0.30 × 75 mm needles will be gently vertically inserted to the muscle layer of the abdominal wall, where patients will feel sharp pain and acupuncturists will feel resistance from the needle tip. For ST37, 0.30 × 40 mm needles will be vertically inserted ~15 mm deep, followed by three-time manipulation of even lifting and twisting method to elicit the sensation of deqi . Paired The patients in the SA group will receive minimal needling at non-acupoints as bilateral sham ST25, SP14, and ST37. The sham ST25 and SP14 are located 2 cm horizontally outward of the points stimulaed in the EA group. The sham ST37 point is located outward of ST37 in the middle of the stomach and gallbladder channel. After sterilization of the skin, 0.30 × 40 mm needles will be directly inserted about 2–3 mm until they can stand up when attached by the alligator clips. No manipulation will be used and no deqi sensation will be elicited at any of the sham points. The bilateral sham ST25, SP14, and ST37 points will be attached by the same EA apparatus with a continuous wave of 10 Hz and current intensity of 0.1–0.2 mA for 30 min with only the initial 30 s on.Patients in both groups will receive 24 treatment sessions over an 8-week period . Each session will last for 30 min. Patients will be treated separately to prevent between-patient communication. Patients will be followed up for another 8 weeks after the treatment stopped.During the trial, other medication or intervention for OIC will be discouraged. However, if a patient has no bowel movement for 72 consecutive hours, only bisacodyl  or a 110 ml glycerol enema will be permitted as a rescue medication. Details of drug use (time and frequency) will be recorded.The patients will be asked to keep a patient diary every day for 13 weeks: 1 week as baseline before randomization (run-out period before baseline), 8 weeks during the treatment period and 4 weeks (weeks 13–16) during the follow-up period. The content of the diary includes the bowel movements, the stool consistency, degree of difficulty in defecation, the rescue medicine drugs and duration of usage, and the intensity of cancerous pain. The diary will be collected weekly during the 8-week treatment period and collected at the end of week 16 during the follow-up period. The outcome evaluators will examine the contents of the diary and determine the SBM and the frequency accordingly.The primary outcome of this study is the proportion of responders, defined as a patient that has ≥3 SBMs/wk and ≥ increase of 1 SBM from baseline simultaneously for at least 6 out of 8 weeks of the treatment period. SBM is defined as a bowel movement that occurred without any medication or intervention to assist within the previous 24 h . A bowelThe secondary outcomes of this study include the following items:(1) Changes in the mean weekly SBMs from the baseline during weeks 1–8 and 13–16. The mean weekly SBMs equals the total frequency of SBMs divided by the numbers of week(s) recorded;(2) The proportion of patients with ≥3 mean weekly SBMs during weeks 1–8 and 13–16;(3) The proportion of patients with an increase of ≥1 mean weekly SBM from the baseline during weeks 1–8 and 13–16;(4) A change in the mean weekly CSBMs from the baseline during weeks 1–8 and 13–16. A CSBM is defined as an SBM with the feeling of complete evacuation . The mea(5) The proportion of patients with ≥3 mean weekly CSBMs during weeks 1–8 and 13–16;(6) The proportion of patients with an increase of ≥1 mean weekly CSBM from the baseline during weeks 1–8 and 13–16;(7) A change in the mean Bristol Stool Form Scale score for stool consistency of SBMs from the baseline during weeks 1–8 and 13–16. For stool consistency, each patient will be asked to record their stool consistency according to the Bristol Stool Form Scale  on the f(8) A change in the mean score for the straining of SBMs from the baseline during weeks 1–8 and 13–16. For assessment of the straining of SBMs, each patient will be asked to rate his/her score of straining, using the following five-point scale : not at (9) A change in the total and subscale score of the Patient Assessment of Constipation-Symptom (PAC-SYM) questionnaire from the baseline at weeks 8 and 16. The PAC-SYM is a questionnaire used to evaluate the severity of chronic constipation in the past 2 weeks. It consists of 12 items, which are subdivided into abdominal (four items), rectal (three items), and stool (five items) scales . The sco(10) A change in the total and subscale scores of the Patient Assessment of Constipation-Quality of Life (PAC-QOL) questionnaires from the baseline at weeks 8 and 16. The PAC-QOL is a 28-item self-reported questionnaire to assess the burden of constipation on patients' everyday functioning and wellbeing in the 2 weeks (14 days) prior to assessment . This qu(11) Patients' global assessment of treatment efficacy. Each patient will be asked to rate his/her efficacy of treatment using the following 7-point self-reporting scale: markedly worse (1), moderately worse (2), slightly worse (3), no change (4), slightly improved (5), moderately improved (6), and markedly improved (7). Scales with seven response categories are easy to use and have shown a high reliability and validity . This qu(12) The proportion of patients using rescue medicine and the mean frequency of rescue medicine use per week during weeks 1–8 and 9–16; Other Pre-specified Outcome Measures(13) The proportion of patients discontinuing the opioid, and those with a ≥30% weekly mean increase or decrease in the dose of opioid from baseline during weeks 1–8 and 9–16.(14) The proportion of patients with a change from baseline in anti-tumor therapy that could impair the defecation during weeks 1–8 and 9–16.(15) Patients' belief in the efficacy of acupuncture. Participants will be asked to answer the following questions at baseline: “Do you think acupuncture will be effective in treating the disease in general?” and “Do you think acupuncture will be effective in improving the OIC?” For each question, patients will choose one of the following answers: “unclear/whatever,” “Yes,” or “No;”(16) Blinding assessment. The blinding is regarded as successful when a patient guesses EA is the acupuncture modality they have received. Patients will be informed before the randomization that they will have a chance of 50% to receive EA or SA. They will also be told that the electrical stimulation in both groups are relatively weak, and they may fail to sense the stimulation gradually during the treatment process out of the tolerance in human body. Within 5 min after any treatment in the 8th week, the patients will be asked to answer the following question: “Is EA the acupuncture modality that you have received?” Patients will choose one of the following answers: “Yes,” or “No.”All AEs will be recorded throughout the whole trial in Adverse Event Form (AEF) by patients themselves and outcome assessors. AEs will be categorized as treatment-related  or non-treatment-related. Detailed information regarding AEs and serious adverse events (SAEs)—including the name, onset date, intensity, relationship with acupuncture and outcome—will be recorded. Safety assessments also include an 11-point NRS to evaluate the intensity of cancer pain. The mean and largest intensity of cancer pain during the preceding week will be evaluated at baseline, as well as weeks 2, 4, 6, 8, and 16. SAEs , if occurs, will be immediately reported to the principle investigator and the Medical Ethics Committee of Guang'anmen Hospital, based on which a decision to terminate or adjust the trial will be made.Assuming a responder proportion (based on the unpublished preliminary data collected from 10 participants with EA group and 10 SA controls) of 45.4% in the EA group and 14.0% in the SA group, we estimated that a sample size of 100 patients will provide 90% power to detect a 31.4% or greater difference in responder proportions between groups with at a two-sided alpha level of 0.05 and 20% loss to follow-up.All efficacy analyses will be performed in the intention-to-treat (ITT) population, which is defined as all randomized participants. Safety analyses will be conducted among randomized patients who received at least one treatment session. Missing data on the primary outcome will be imputed using the multiple imputation method under the missing at random assumption. In case of relevant differences in baseline variables between the two groups, those unbalanced variables will be used as covariates for the analysis of the primary outcome. Subgroup analyses of efficacy will be performed according to individual opioid dose at baseline.x2 test. Confidence interval (CIs) will be calculated using the Clopper-Pearson method. For other Categorical variables, comparisons between treatment groups will assess using the Fisher exact test or Wilcoxon rank-sum test as appropriate. Continuous variables will be performed using the t-test or Wilcoxon rank-sum test as appropriate. AE incidences for each treatment group will be compared using Fisher's exact test.The primary outcome will be evaluated using the All staff members will undergo training prior to the trial. The acupuncturists in this trial will have an acupuncture license with at least 2-year acupuncture experience. Monitors will check the case report forms and the acupuncture operation regularly. To improve adherence to intervention protocols, the majority of patients will come from the inpatient setting. The outcomes will be evaluated by independent assessors who are unaware of the group allocation. The data will be input by a clinical research coordinator according to the contents of CRF using the Electronic Data Capture System (EDC), which will be monitored by Clinical Research Associate. Detailed documentation of drop-outs and withdrawals, including the reasons, will be obtained throughout the trial. All of the investigators will always maintain a strict privacy policy to protect confidentiality before, during and after the trial.The research question was first proposed by two cancer patients suffering OIC. Once the patient has completed the trial, the burden of the intervention will be assessed by patients themselves. All participants will obtain the copy of the completed manuscript if they would like to receive a copy of the trial results.ClinicalTrials.gov (NCT03797586). All eligible patients will be fully informed the duration and procedure of this study, the right to decline to participate during screening period or withdraw from the research at any time. They will have enough time to ask details of the trial and decide whether to participate or not. Any modifications to the protocol that may impact the conduct of the study will be agreed upon by the study investigators and approved by the local ethics committee prior to implementation. Participants will be asked to provide the informed consent form prior to enrollment. The findings of the study will be disseminated by publications in an international peer-reviewed medical journal, with online access. We also plan to present it in relevant national/international conferences.This study was planned in accordance with the Helsinki Declaration and has been approved by the Ethical Committee of the Guang'anmen Hospital, China Academy of Chinese Medical Sciences . The trial was registered at Constipation is one of the most common and bothersome symptoms among cancer patients receiving opioid for pain management. Some patients would choose to endure the pain rather than the constipation cause by long-term opioid therapy . TherefoOIC is characterized by a reduction in bowel movement frequency, straining, and a feeling of incomplete evacuation that is associated with opioid use. In this trial, we will not limit the type of cancer. Our major reason is because it is difficult to recruit when cancer is limited to certain types. Only those patients with good general condition diagnosed with OIC will be included. Oncologists or gastroenterologists are responsible for diagnosing OIC and judging the life expectancy of participant. One of the reasons is that in studies conducted with patients in poor general condition are difficult to maintain the follow up. Considering the severity and irreversibility of OIC, we will select SBMs rather than CSBMs as the primary outcome in this trial. SBMs may also provide an objective reflection of bowel movement improvement for OIC, and has been selected as the primary outcome measurement in several trials  among boAs this trial is targeted at cancer patients who are receiving opioid prescriptions for pain management, it will be a challenge for them to comply well with the frequent attendance to hospital at the treatment and follow-up periods. Hence, the majority of patients will be recruited in the inpatient setting, and the 8-week treatment period and 8-week follow-up period have been designed to be relatively short. The use of rescue medication will further reduce dropout rates. The trial also has several limitations. First, all patients recruited in this study are Chinese, some of whom may have prior experience with acupuncture. The intervention in this trial is EA involving manual acupuncture and electrical stimulation. In order to achieve maintain the blinding of patients, we chose minimal needling at non-acupoints with electrical stimulation for 30 s as the control methods. SA thus may have a few biological effects, which may lead to a false negative result. Second, the acupuncturist will not be blinded to the group allocation due to the nature of the acupuncture. This might result in bias and influence the results. Third, as this study was conducted primarily in the inpatient settings, our results may not be generalized to all OIC populations.Trial status: Recruitment started in May 2019, and is currently ongoing.The studies involving human participants were reviewed and approved by Institutional Review Boards of Guang'anmen Hospital in China. The patients/participants provided their written informed consent to participate in this study.ZL and WW conceived the idea of this trial and the design this study. YL is responsible for statistical analysis. This manuscript was drafted by WW and XW and revised by YL, ZL, YS, XL, and YY. All authors have read and approved the final manuscript.This study was supported and funded by the 2019 National Administration of Traditional Chinese Medicine Project of building evidence-based practice capacity for TCM–Project BEBPC-TCM (No. 2019XZZX-ZJ). The funders had no role in the planning, study design, execution, or analysis of the work.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.