Circulating Tumor DNA (ctDNA) Clearance May Predict Treatment Response in Neoadjuvant Colorectal Cancer Management.

Background: Circulating tumor DNA (ctDNA) is extracellular DNA released by tumors and has been proposed as a marker of residual disease as well as a predictor of disease recurrence in the adjuvant setting. However, data are lacking on the utility of this biomarker in the neoadjuvant setting. Methods: We performed a retrospective study of stage III and IV colorectal cancer patients receiving neoadjuvant treatment at a single institution. Results: Seventeen patients converted from a positive pre-neoadjuvant ctDNA to a negative ctDNA prior to surgery. Five patients remained persistently positive despite systemic treatment. ctDNA conversion was found to be associated with a higher incidence of favorable treatment effect scores on final surgical pathology. There was no difference in recurrence-free survival in this small population. Furthermore, no added benefit was identified for patients receiving additional neoadjuvant therapy after the time of positive to negative ctDNA conversion. Conclusions: This study highlights the potential utility of ctDNA and the need for prospective trials in the neoadjuvant setting to monitor treatment response and guide decisions on treatment duration.

The Effect of Web-Based Culinary Medicine to Enhance Protein Intake on Muscle Quality in Older Adults: Randomized Controlled Trial.

BACKGROUND: The most common age-related musculoskeletal disorder is sarcopenia. Sarcopenia is the progressive and generalized loss of muscle mass, strength, and function. The causes of sarcopenia can include insufficient nutritional status, which may be due to protein-energy malnutrition, anorexia, limited food access and eating ability, or malabsorption. In the United States, 15.51% of older adults have been diagnosed with sarcopenia. Culinary medicine (CM) is a novel evidence-based medical field that combines the science of medicine with food and cooking to prevent and treat potential chronic diseases. CM helps individuals learn and practice culinary skills while tasting new recipes. Therefore, this program could successfully reduce barriers to protein intake, enabling older adults to enhance their diet and muscle quality. OBJECTIVE: This study aimed to examine how a web-based CM intervention, emphasizing convenient ways to increase lean red meat intake, could improve protein intake with the promotion of physical activity to see how this intervention could affect older adults' muscle strength and mass. METHODS: A 16-week, single-center, parallel-group, randomized controlled trial was conducted to compare a web-based CM intervention group (CMG) with a control group (CG) while monitoring each group's muscle strength, muscle mass, and physical activity for muscle quality. The CMG received weekly web-based cooking demonstrations and biweekly nutrition education videos about enhancing protein intake, whereas the CG just received the recipe handout. Anthropometrics, muscle mass, muscle strength, dietary habits, physical activity, and cooking effectiveness were established at baseline and measured after the intervention. The final number of participants for the data analysis was 24 in the CMG and 23 in the CG. RESULTS: No between-group difference in muscle mass (P=.88) and strength (dominant P=.92 and nondominant P=.72) change from the prestudy visit was detected. No statistically significant difference in protein intake was seen between the groups (P=.50). A nonsignificant time-by-intervention interaction was observed for daily protein intake (P=.08). However, a statistically significant time effect was observed (P≤.001). Post hoc testing showed that daily protein intake was significantly higher at weeks 1 to 16 versus week 0 (P<.05). At week 16, the intake was 16.9 (95% CI 5.77-27.97) g higher than that at the prestudy visit. CONCLUSIONS: This study did not affect protein intake and muscle quality. Insufficient consistent protein intake, low physical activity, intervention adherence, and questionnaire accuracy could explain the results. These studies could include an interdisciplinary staff, different recruitment strategies, and different muscle mass measurements. Future research is needed to determine if this intervention is sustainable in the long term and should incorporate a follow-up to determine program efficacy on several long-term behavioral and health outcomes, including if the participants can sustain their heightened protein intake and how their cooking skills have changed. TRIAL REGISTRATION: ClinicalTrials.gov NCT05593978; https://clinicaltrials.gov/ct2/show/NCT05593978.

Designing self-tracking experiences: A qualitative study of the perceptions of barriers and facilitators to adopting digital health technology for automatic urine analysis at home.

Self-tracking technologies open new doors to previously unimaginable scenarios. The diagnosis of diseases years in advance, or supporting the health of astronauts on missions to Mars are just some of many example applications. During the COVID-19 pandemic, a wide range of self-monitoring protocols emerged, revealing opportunities but also challenges including difficulties in understanding how to self-use monitoring systems, struggling to recognize the benefit of such systems and a high likelihood of abandonment. In this paper, we explore the role that design plays in the creation of a user experience of self-tracking, with a focus on urine analysis at home. We investigate adoption factors and forms of data expression to overcome the presented challenges. By combining insights from related work, semi-structured interviews and indicative user-tests, we show the potential of pairing a traditional numerical data representation (data quantification) with a qualitative expression of the data (data qualification). Indeed, qualitative expressions have the potential to convey the complexity of the phenomena tracked, enabling deep meaning-making and emotional connection to personal data. At the same time, we also identify issues with this approach, which can require a longer learning curve and lead to rejection by users more accustomed to traditional, numerical approaches. Based on the results, several recommendations have been converted into an experimental proposition, which also presents future plans for the continuation of the project. This article presents the first fundamental step in creating a meaningful experience of self-tracking, taking into consideration the needs and expectations of future users.

Severe Hemolysis during Primaquine Radical Cure of Plasmodium vivax Malaria: Two Systematic Reviews and Individual Patient Data Descriptive Analyses.

Primaquine (PQ) kills Plasmodium vivax hypnozoites but can cause severe hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. We conducted two systematic reviews. The first used data from clinical trials to determine the variety of definitions and frequency of hematological serious adverse events (SAEs) related to PQ treatment of vivax malaria. The second used data from prospective studies and case reports to describe the clinical presentation, management, and outcome of severe PQ-associated hemolysis necessitating hospitalization. In the first review, SAEs were reported in 70 of 249 clinical trials. There were 34 hematological SAEs among 9,824 patients with P. vivax malaria treated with PQ, nine of which necessitated hospitalization or blood transfusion. Criteria used to define SAEs were diverse. In the second review, 21 of 8,487 articles screened reported 163 patients hospitalized after PQ radical cure; 79.9% of whom (123 of 154) were prescribed PQ at ≥ 0.5 mg/kg/day. Overall, 101 patients were categorized as having probable or possible severe PQ-associated hemolysis, 96.8% of whom were G6PD deficient (< 30% activity). The first symptoms of hemolysis were reported primarily on day 2 or 3 (45.5%), and all patients were hospitalized within 7 days of PQ commencement. A total of 57.9% of patients (77 of 133) had blood transfusion. Seven patients (6.9%) with probable or possible hemolysis died. Even when G6PD testing is available, enhanced monitoring for hemolysis is warranted after PQ treatment. Clinical review within the first 5 days of treatment may facilitate early detection and management of hemolysis. More robust definitions of severe PQ-associated hemolysis are required.

Effectiveness of Home-Based Exercise and Nutrition Programs for Senior Adults on Muscle Outcomes: A Scoping Review.

This scoping review investigates the volume of evidence for home-based exercise and nutrition programs and their effect on muscle quality among senior adults to inform implementation and future research. It aims to answer the research question: What are the evidence, challenges, and needs for research regarding a home-based exercise and nutrition intervention program to improve muscle outcomes in senior adults? This scoping review was conducted following the PRISMA extension for Scoping Review. The following databases were searched: PubMed, Scopus, MEDLINE, CINAHL, EMBASE, and the Cochrane Library. Applied filters were used to help condense the research articles. A total of 13 studies met the inclusion criteria for this scoping review. Most exercise interventions were either resistance or multi-component exercise programs. The nature of the nutrition intervention varied between different supplements, foods, education, or counseling. Muscle outcomes included muscle mass in nine studies, muscle function in all the studies, muscle strength in ten studies, and biochemical analyses in two studies. Two studies found improvements in muscle mass; two studies revealed improvements in all their muscle function tests; and three studies revealed improvements in muscle strength. Muscle biopsy in a study revealed enhanced muscle fibers, but both studies did not reveal any biomarker improvements. The scoping review findings revealed mixed results on the effectiveness of a home-based exercise and nutrition program. However, the current evidence does have many gaps to address before recommending this form of intervention for senior adults as an effective way to prevent and manage sarcopenia. Since this review identified multiple knowledge gaps, strengths, and limitations in this growing field, it can be a starting point to help build future study designs and interventions in this population.

Systematic review of the diagnosis and management of necrotising otitis externa: Highlighting the need for high-quality research.

OBJECTIVES: To present a systematic review and critical analysis of clinical studies for necrotising otitis externa (NOE), with the aim of informing best practice for diagnosis and management. DESIGN: Medline, Embase, Cochrane Library and Web of Science were searched from database inception until 30 April 2021 for all clinical articles on NOE. The review was registered on PROSPERO (ID: CRD42020128957) and conducted in accordance with PRISMA guidelines. RESULTS: Seventy articles, including 2274 patients were included in the final synthesis. Seventy-three percent were retrospective case series; the remainder were of low methodological quality. Case definitions varied widely. Median patient age was 69.2 years; 68% were male, 84% had diabetes and 10% had no reported immunosuppressive risk factor. Otalgia was almost universal (96%), with granulation (69%) and oedema (76%) the commonest signs reported. Pseudomonas aeruginosa was isolated in 62%, but a range of bacterial and fungal pathogens were reported and 14% grew no organism. Optimal imaging modality for diagnosis or follow-up was unclear. Median antimicrobial therapy duration was 7.2 weeks, with no definitive evidence for optimal regimens. Twenty-one percent had surgery with widely variable timing, indication, or procedure. One-year disease-specific mortality was 2%; treatment failure and relapse rates were 22% and 7%, respectively. CONCLUSION: There is a lack of robust, high-quality data to support best practice for diagnosis and management for this neglected condition. A minimum set of reporting requirements is proposed for future studies. A consensus case definition is urgently needed to facilitate high-quality research.

Behavior Change Effectiveness Using Nutrition Apps in People With Chronic Diseases: Scoping Review.

BACKGROUND: Cardiovascular disease, cancer, diabetes mellitus, and obesity are common chronic diseases, and their prevalence is reaching an epidemic level worldwide. As the impact of chronic diseases continues to increase, finding strategies to improve care, access to care, and patient empowerment becomes increasingly essential. Health care providers use mobile health (mHealth) to access clinical information, collaborate with care teams, communicate over long distances with patients, and facilitate real-time monitoring and interventions. However, these apps focus on improving general health care concerns, with limited apps focusing on specific chronic diseases and the nutrition involved in the disease state. Hence, available evidence on the effectiveness of mHealth apps toward behavior change to improve chronic disease outcomes is limited. OBJECTIVE: The objective of this scoping review was to provide an overview of behavior change effectiveness using mHealth nutrition interventions in people with chronic diseases (ie, cardiovascular disease, diabetes mellitus, cancer, and obesity). We further evaluated the behavior change techniques and theories or models used for behavior change, if any. METHODS: A scoping review was conducted through a systematic literature search in the MEDLINE, EBSCO, PubMed, ScienceDirect, and Scopus databases. Studies were excluded from the review if they did not involve an app or nutrition intervention, were written in a language other than English, were duplicates from other database searches, or were literature reviews. Following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 guidelines, the systematic review process included 4 steps: identification of records through the database search, screening of duplicate and excluded records, eligibility assessment of full-text records, and final analysis of included records. RESULTS: In total, 46 studies comprising 256,430 patients were included. There was diversity in the chronic disease state, study design, number of participants, in-app features, behavior change techniques, and behavior models used in the studies. In addition, our review found that less than half (19/46, 41%) of the studies based their nutrition apps on a behavioral theory or its constructs. Of the 46 studies, 11 (24%) measured maintenance of health behavior change, of which 7 (64%) sustained behavior change for approximately 6 to 12 months and 4 (36%) showed a decline in behavior change or discontinued app use. CONCLUSIONS: The results suggest that mHealth apps involving nutrition can significantly improve health outcomes in people with chronic diseases. Tailoring nutrition apps to specific populations is recommended for effective behavior change and improvement of health outcomes. In addition, some studies (7/46, 15%) showed sustained health behavior change, and some (4/46, 9%) showed a decline in the use of nutrition apps. These results indicate a need for further investigation on the sustainability of the health behavior change effectiveness of disease-specific nutrition apps.

Autoimmunity Is a Significant Feature of Idiopathic Pulmonary Arterial Hypertension.

Rationale: Autoimmunity is believed to play a role in idiopathic pulmonary arterial hypertension (IPAH). It is not clear whether this is causative or a bystander of disease and if it carries any prognostic or treatment significance. Objectives: To study autoimmunity in IPAH using a large cross-sectional cohort. Methods: Assessment of the circulating immune cell phenotype was undertaken using flow cytometry, and the profile of serum immunoglobulins was generated using a standardized multiplex array of 19 clinically validated autoantibodies in 473 cases and 946 control subjects. Additional glutathione S-transferase fusion array and ELISA data were used to identify a serum autoantibody to BMPR2 (bone morphogenetic protein receptor type 2). Clustering analyses and clinical correlations were used to determine associations between immunogenicity and clinical outcomes. Measurements and Main Results: Flow cytometric immune profiling demonstrates that IPAH is associated with an altered humoral immune response in addition to raised IgG3. Multiplexed autoantibodies were significantly raised in IPAH, and clustering demonstrated three distinct clusters: "high autoantibody," "low autoantibody," and a small "intermediate" cluster exhibiting high concentrations of ribonucleic protein complex. The high-autoantibody cluster had worse hemodynamics but improved survival. A small subset of patients demonstrated immunoglobulin reactivity to BMPR2. Conclusions: This study establishes aberrant immune regulation and presence of autoantibodies as key features in the profile of a significant proportion of patients with IPAH and is associated with clinical outcomes.

Genomic survey of edible cockle (Cerastoderma edule) in the Northeast Atlantic: A baseline for sustainable management of its wild resources.

Knowledge on correlations between environmental factors and genome divergence between populations of marine species is crucial for sustainable management of fisheries and wild populations. The edible cockle (Cerastoderma edule) is a marine bivalve distributed along the Northeast Atlantic coast of Europe and is an important resource from both commercial and ecological perspectives. We performed a population genomics screening using 2b-RAD genotyping on 9309 SNPs localized in the cockle's genome on a sample of 536 specimens pertaining to 14 beds in the Northeast Atlantic Ocean to analyse the genetic structure with regard to environmental variables. Larval dispersal modelling considering species behaviour and interannual/interseasonal variation in ocean conditions was carried out as an essential background to which compare genetic information. Cockle populations in the Northeast Atlantic displayed low but significant geographical differentiation between populations (F ST = 0.0240; p < 0.001), albeit not across generations. We identified 742 and 36 outlier SNPs related to divergent and balancing selection in all the geographical scenarios inspected, and sea temperature and salinity were the main environmental correlates suggested. Highly significant linkage disequilibrium was detected at specific genomic regions against the very low values observed across the whole genome. Two main genetic groups were identified, northwards and southwards of French Brittany. Larval dispersal modelling suggested a barrier for larval dispersal linked to the Ushant front that could explain these two genetic clusters. Further genetic subdivision was observed using outlier loci and considering larval advection. The northern group was divided into the Irish/Celtic Seas and the English Channel/North Sea, while the southern group was divided into three subgroups. This information represents the baseline for the management of cockles, designing conservation strategies, founding broodstock for depleted beds and producing suitable seed for aquaculture production.

Does the Good Behavior Game evoke negative peer pressure? Analyses in primary and secondary classrooms.

The Good Behavior Game (GBG) is a classroom management system that employs an interdependent group contingency, whereby students work as a team to win the game. Although previous anecdotal data have suggested that this arrangement may promote prosocial behavior, teachers may have concerns about its fairness and potential to evoke negative peer interactions (especially toward students who break the rules). We evaluated disruptive behaviors and social interactions during the GBG in a secondary classroom for students with emotional and behavioral disorders, as well as in a primary classroom for students with mild developmental disabilities. Results indicate that the GBG reduced disruptive behaviors; further, negative peer interactions decreased and positive interactions increased when the game was being played. Social validity results indicate that the majority of students thought the interdependent group contingency was fair.

History of High-Resolution Anoscopy.

High-resolution anoscopy (HRA) is a form of low-resolution anal microscopy currently utilized in the screening and management of anal squamous dysplasia. No randomized controlled trials, national or international guidelines exist on the use of HRA for this purpose. Much of our understanding of this entity has been adapted from the literature on cervical squamous dysplasia, including the technique of HRA itself. Epidemiologic evidence has shown that the prevalence and incidence of anal dysplasia is highest in HIV-positive populations. The history of this technique parallels the evolution of our understanding of anal dysplasia. To understand the history of the use of HRA and its place in the screening and management of anal squamous dysplasia, we discuss key advances in the understanding of human papillomavirus-related squamous dysplasia. We begin with early reports in the field establishing the link between this virus and squamous dysplasia, through the marked increase in anal cancer seen with the onset of the HIV epidemic, the identification of relevant populations at risk, the performance of the test itself, to its use today.

Hematopoietic stem cell transplantation alters susceptibility to pulmonary hypertension in Bmpr2-deficient mice.

Increasing evidence suggests that patients with pulmonary arterial hypertension (PAH) demonstrate abnormalities in the bone marrow (BM) and hematopoietic progenitor cells. In addition, PAH is associated with myeloproliferative diseases. We have previously demonstrated that low-dose lipopolysaccharide (LPS) is a potent stimulus for the development of PAH in the context of a genetic PAH mouse model of BMPR2 dysfunction. We hypothesized that the hematopoietic progenitor cells might be driving disease in this model. To test this hypothesis, we performed adoptive transfer of BM between wild-type (Ctrl) and heterozygous Bmpr2 null (Mut) mice. Sixteen weeks after BM reconstitution, mice were exposed to low-dose chronic LPS (0.5 mg/kg three times a week for six weeks). Mice underwent right heart catheterization and tissues were removed for histology. After chronic LPS dosing, Ctrl mice in receipt of Mut BM developed PAH, whereas Mut mice receiving Ctrl BM were protected from PAH. BM histology demonstrated an increase in megakaryocytes and there was an increase in circulating platelets in Ctrl mice receiving Mut BM. These findings demonstrate that the hematopoietic stem cell compartment is involved in the susceptibility to PAH in the Mut mouse. The results raise the possibility that hematopoietic stem cell transplantation might be a potential treatment strategy in genetic forms of PAH.

Microparticles Locally Deliver Active Interleukin-1 Receptor Antagonist In Vivo.

Despite significant research in therapeutic protein delivery, localized and sustained delivery of active therapeutic proteins remains a challenge. Delivery is a particular challenge for therapeutic proteins with a short half-life. Herein, localized delivery of interleukin-1 receptor antagonist (IL-1Ra) by mineral coated microparticles (MPs) is assessed in a healing rat medial collateral ligament (MCL). The local tissue concentration and systemic serum concentration of IL-1Ra, the anti-inflammatory activity of IL-1Ra delivered with MPs, and whether IL-1Ra loaded MPs (IL-1Ra MPs) are immunogenic in a healing ligament are also examined. IL-1Ra MPs significantly increase the local concentration of IL-1Ra compared to soluble IL-1Ra at 7 and 14 days after treatment but do not elevate the systemic concentration of IL-1Ra at these time points, indicating localized delivery of IL-1Ra. IL-1Ra MPs significantly reduce inflammation caused by the MPs themselves, indicating the IL-1Ra is active. Finally, IL-1Ra MPs do not induce a foreign body response and decrease the immunogenicity of human IL-1Ra in a healing rat MCL. Overall, mineral coated microparticles have the ability to locally deliver active therapeutic proteins for an extended period of time.

An evaluation of interdependent and independent group contingencies during the good behavior game.

The Good Behavior Game (GBG) uses an interdependent group contingency to improve classroom behavior. Despite the wealth of research on the effectiveness of the GBG, some teachers may have concerns about their students' abilities to work in teams, particularly if they have a history of poor social skills. We used an alternating treatments design to compare the relative effectiveness of the GBG with interdependent and independent group contingencies in a classroom for children with emotional and behavioral disorders. Our results showed that both versions of the GBG reduced verbal disruptions, inappropriate sitting, and off-task behaviors for all children. However, the majority of children preferred the interdependent arrangement. We discuss how these results may promote more widespread use of the GBG with children with substantial behavioral challenges.

Validating trial-based functional analyses in mainstream primary school classrooms.

There is growing evidence to support the use of trial-based functional analyses, particularly in classroom settings. However, there currently are no evaluations of this procedure with typically developing children. Furthermore, it is possible that refinements may be needed to adapt trial-based analyses to mainstream classrooms. This study was designed to expand the trial-based functional analysis literature by implementing the procedure in 2 mainstream primary school classrooms and validating the analysis through comparison of multiple treatment options, including some that were not indicated by the functional analysis. We also extended the procedure by including a peer-attention condition and obtaining data from teachers regarding the feasibility of the procedures. For all participants, functional analysis results helped to identify effective treatments. Furthermore, relative effects among treatments were accurately predicted by the functional analysis outcomes. Teachers reported that they understood the logic of functional analysis and found both analysis and treatment procedures to be easy and effective.

Generation and Culture of Blood Outgrowth Endothelial Cells from Human Peripheral Blood.

Historically, the limited availability of primary endothelial cells from patients with vascular disorders has hindered the study of the molecular mechanisms underlying endothelial dysfunction in these individuals. However, the recent identification of blood outgrowth endothelial cells (BOECs), generated from circulating endothelial progenitors in adult peripheral blood, may circumvent this limitation by offering an endothelial-like, primary cell surrogate for patient-derived endothelial cells. Beyond their value to understanding endothelial biology and disease modeling, BOECs have potential uses in endothelial cell transplantation therapies. They are also a suitable cellular substrate for the generation of induced pluripotent stem cells (iPSCs) via nuclear reprogramming, offering a number of advantages over other cell types. We describe a method for the reliable generation, culture and characterization of BOECs from adult peripheral blood for use in these and other applications. This approach (i) allows for the generation of patient-specific endothelial cells from a relatively small volume of adult peripheral blood and (ii) produces cells that are highly similar to primary endothelial cells in morphology, cell signaling and gene expression.

Phosphatidylinositol transfer protein, cytoplasmic 1 (PITPNC1) binds and transfers phosphatidic acid.

Phosphatidylinositol transfer proteins (PITPs) are versatile proteins required for signal transduction and membrane traffic. The best characterized mammalian PITPs are the Class I PITPs, PITPα (PITPNA) and PITPß (PITPNB), which are single domain proteins with a hydrophobic cavity that binds a phosphatidylinositol (PI) or phosphatidylcholine molecule. In this study, we report the lipid binding properties of an uncharacterized soluble PITP, phosphatidylinositol transfer protein, cytoplasmic 1 (PITPNC1) (alternative name, RdgBß), of the Class II family. We show that the lipid binding properties of this protein are distinct to Class I PITPs because, besides PI, RdgBß binds and transfers phosphatidic acid (PA) but hardly binds phosphatidylcholine. RdgBß when purified from Escherichia coli is preloaded with PA and phosphatidylglycerol. When RdgBß was incubated with permeabilized HL60 cells, phosphatidylglycerol was released, and PA and PI were now incorporated into RdgBß. After an increase in PA levels following activation of endogenous phospholipase D or after addition of bacterial phospholipase D, binding of PA to RdgBß was greater at the expense of PI binding. We propose that RdgBß, when containing PA, regulates an effector protein or can facilitate lipid transfer between membrane compartments.