Perspectives of primary care clinicians in Massachusetts on use of telemedicine with adults aged 65 and older during the COVID-19 pandemic.

To learn how to improve telemedicine for adults >65, we asked primary care clinicians ("PCPs") affiliated with one large Boston-area health system their views on using telemedicine (which included phone-only or video visits) with adults >65 during the COVID-19 pandemic. In open-ended questions, we asked PCPs to describe any challenges or useful experiences with telemedicine and suggestions for improving telemedicine as part of a larger web-based survey conducted between September 2020 and February 2021. Overall, 163/383 (42%) PCPs responded to the survey. Of these, 114 (70%) completed at least one open-ended question, 85% were non-Hispanic white, 59% were female, 75% were community-based, and 75% were in practice >20 years. We identified three major themes in participants' comments including the need to optimize telemedicine; integrate telemedicine within primary care; and that PCPs had disparate attitudes towards telemedicine for older adults. To optimize telemedicine, PCPs recommended more effective digital platforms, increased utilization of home medical equipment (e.g., blood pressure cuffs), and better coordination with caregivers. For integration, PCPs recommended targeting telemedicine for certain types of visits (e.g., chronic disease management), enabling video access, and reducing administrative burdens on PCPs. As for PCP attitudes, some felt telemedicine enhanced the doctor-patient relationship, improved the patient experience, and improved show rates. Others felt that telemedicine visits were incomplete without a physical exam, were less rewarding, and could be frustrating. Overall, PCPs saw a role for telemedicine in older adults' care but felt that more support is needed for these visits than currently offered.

Variation in Breast Cancer Risk Model Estimates Among Women in Their 40s Seen in Primary Care.

Background: The Gail, Breast Cancer Surveillance Consortium (BCSC), and Tyrer-Cuzick breast cancer risk prediction models are recommended for use in primary care. Calculating breast cancer risk is particularly important for women in their 40s when deciding on mammography, with some guidelines recommending screening for those with 5-year risk similar to women age 50 (≥1.1%). Yet, little is known about risk estimate agreement among models for these women. Materials and Methods: Four hundred nine Boston-area women 40-49 years of age completed a risk questionnaire before a primary care visit to compute their breast cancer risk. The kappa statistic was used to examine when (1) Gail and BCSC agreed on 5-year risk ≥1.1%; (2) Gail estimated 5-year risk ≥1.7% and Tyrer-Cuzick estimated 10-year risk ≥5% (guideline thresholds for recommending prevention medications); and when (3) Gail and Tyrer-Cuzick agreed on lifetime risk ≥20% (threshold for breast MRI using Tyrer-Cuzick). Results: Participant mean age was 44.1 years, 56.7% were non-Hispanic white, and 7.8% had a first-degree relative with breast cancer. Of 266 with breast density information to estimate both Gail and BCSC, the models agreed on 5-year risk being ≥1.1% for 36 women, kappa = 0.34 (95% confidence interval: 0.23-0.45). Gail and Tyrer-Cuzick estimates led to agreement about prevention medications for 8 women, kappa 0.41 (0.20-0.61), and models agreed on lifetime risk ≥20% for 3 women, kappa 0.08 (-0.01 to 0.16). Conclusions: There is weak agreement on breast cancer risk estimates generated by risk models recommended for primary care. Using different models may lead to different clinical recommendations for women in their 40s.

Managing the experience of breathlessness with Tai Chi: A qualitative analysis from a randomized controlled trial in COPD.

PURPOSE: Chronic obstructive pulmonary disease (COPD) is associated with dyspnea, decreased physical activity, and reduced quality-of-life. While pulmonary rehabilitation is helpful, maintenance of physical activity afterwards is problematic. We sought to explore qualitatively the multi-dimensional, biopsychosocial experience of patients with COPD who participated in Tai Chi (TC) vs. group walking to facilitate physical activity after pulmonary rehabilitation). METHODS: We analyzed semi-structured qualitative exit interviews (N = 81) from a randomized controlled trial comparing 6-months TC with a time-matched group walking intervention and usual care control (UC). Transcripts were reviewed by at least 2 independent reviewers utilizing a social constructivist framework and theoretical sampling approach. An in-depth analysis of an exemplar subset was performed to thematic saturation and captured emergent themes within and between groups. RESULTS: Focused analysis was conducted on 54 transcripts (N = 21 TC, N = 16 Walking, N = 17 UC). Participants were characterized by mean age 68.5 (±8.3) years, GOLD Stage = 3.0 (IQR 2.0-3.0), baseline FEV1 percent predicted 48.8% (±16.4), and 48.2% female. We identified predominant themes of breathlessness, and associated fear and embarrassment that limited physical activity across all groups. In both TC and walking, participants reported improvements in energy and endurance. Those in TC additionally shared improvements in breathing, mobility, and capacity for daily activities facilitated by body and breath awareness, emotional control and regulation of breathing, and an adaptive reframing of breathlessness. CONCLUSION: TC promoted physical and mental wellbeing by diminishing fear and embarrassment associated with breathlessness. Results highlight the multimodal characteristics of TC that may facilitate continued physical activity and improvement in quality of life.

NH2-terminal deletion of specific phosphorylation sites on PHOX2B disrupts the formation of enteric neurons in vivo.

Mutations in the paired-like homeobox 2 b (PHOX2B) gene are associated with congenital central hypoventilation syndrome (CCHS), which is a rare condition in which both autonomic dysregulation with hypoventilation and an enteric neuropathy may occur. The majority of patients with CCHS have a polyalanine repeat mutation (PARM) in PHOX2B, but a minority of patients have nonpolyalanine repeat mutations (NPARMs), some of which have been localized to exon 1. A PHOX2B-Y14X nonsense mutation previously generated in a human pluripotent stem cell (hPSC) line results in an NH2-terminus truncated product missing the first 17 or 20 amino acids, possibly due to translational reinitiation at an alternate ATG start site. This NH2-terminal truncation in the PHOX2B protein results in the loss of two key phosphorylation residues. Though the deletion does not affect the potential for PHOX2BY14X/Y14X mutant hPSC to differentiate into enteric neural crest cells (ENCCs) in culture, it impedes in vivo development of neurons in an in vivo model of human aganglionic small intestine.NEW & NOTEWORTHY A mutation that affects only 17-20 NH2-terminal amino acids in the paired-like homeobox 2 b (PHOX2B) gene hinders the subsequent in vivo establishment of intestinal neuronal cells, but not the in vitro differentiation of these cells.

Development of a Novel Intervention (Mindful Steps) to Promote Long-Term Walking Behavior in Chronic Cardiopulmonary Disease: Protocol for a Randomized Controlled Trial.

BACKGROUND: Despite current rehabilitation programs, long-term engagement in physical activity remains a significant challenge for patients with chronic obstructive pulmonary disease (COPD) and heart failure (HF). Novel strategies to promote physical activity in these populations are greatly needed. Emerging literature on the benefits of both mind-body interventions and web-based interventions provide the rationale for the development of the Mindful Steps intervention for increasing walking behavior. OBJECTIVE: This study aims to develop a novel multimodal mind-body exercise intervention through adaptation of an existing web-based physical activity intervention and incorporation of mind-body exercise, and to pilot test the delivery of the new intervention, Mindful Steps, in a randomized controlled feasibility trial in older adults with COPD and/or HF. METHODS: In phase 1, guided by a theoretical conceptual model and review of the literature on facilitators and barriers of physical activity in COPD and HF, we convened an expert panel of researchers, mind-body practitioners, and clinicians to inform development of the novel, multimodal intervention. In phase 2, we are conducting a pilot randomized controlled feasibility trial of the Mindful Steps intervention that includes in-person mind-body exercise classes, an educational website, online mind-body videos, and a pedometer with step-count feedback and goals to increase walking behavior in patients with COPD and/or HF. Outcomes include feasibility measures as well as patient-centered measures. RESULTS: The study is currently ongoing. Phase 1 intervention development was completed in March 2019, and phase 2 data collection began in April 2019. CONCLUSIONS: Through the integration of components from a web-based physical activity intervention and mind-body exercise, we created a novel, multimodal program to impact long-term physical activity engagement for individuals with COPD and HF. This developmental work and pilot study will provide valuable information needed to design a future clinical trial assessing efficacy of this multimodal approach. TRIAL REGISTRATION: ClinicalTrials.gov NCT03003780; https://clinicaltrials.gov/ct2/show/NCT03003780. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/27826.

The impact of Tai Chi and mind-body breathing in COPD: Insights from a qualitative sub-study of a randomized controlled trial.

PURPOSE: Chronic obstructive pulmonary disease (COPD) is associated with multiple psychosocial and behavioral factors. Prior research suggests that mind-body interventions may support the development and maintenance of healthy behaviors and improve health-related quality-of-life in such patients. We sought to qualitatively explore cognitive, psychosocial, and behavioral changes in patients with COPD who participated in two different mind-body interventions compared to an education control. METHODS: We analyzed semi-structured qualitative exit interviews from a prospective, randomized pilot trial (N = 123) investigating 12-weeks of Tai Chi (TC) vs. mind-body breathing (MBB) vs. education (EDU) control in patients with moderate-severe COPD. TC involved traditional movements, that integrate meditative breathing, while MBB focused mainly on meditative breathing techniques alone. Interviews were audio-recorded and transcribed verbatim. Qualitative analysis of randomly selected transcripts was performed by two independent reviewers using an iterative process to identify emergent themes informed by grounded theory methods until thematic saturation was reached. RESULTS: A total of 66 transcripts were reviewed (N = 22 TC, N = 22 MBB, N = 22 EDU). Participants were mean age = 68.1 years, GOLD Stage = 2.3, baseline FEV11 percent predicted mean (SD): 58% (13.4), 42.4% female. We identified six frequently mentioned themes: 1) overall awareness and understanding, 2) self-care knowledge, skills and behaviors, 3) behavior-related neurocognitive concepts, 4) physical function, 5) psychological well-being, and 6) social support/social function. Compared to EDU, more participants in TC and MBB noted improvements in awareness of self and the mind-body connection (e.g., body and breath awareness), knowledge of breathing techniques and integration of self-care skills with daily activities, self-efficacy for symptom management (particularly managing anxiety and dyspnea), acceptance of disease, physical function improvements (e.g., endurance, dyspnea, fatigue), and psychological well-being (particularly relaxation, emotion regulation and decreased reactivity). Compared to MBB, those in TC shared more intention to continue with self-care behaviors, physical activity self-efficacy, and improved flexibility. All three groups, including EDU, noted increased social support and knowledge of disease. Those in EDU, however, had fewer mentions of processes related to behavior change, and less concrete changes in neurocognitive, psychological, and physical function domains. CONCLUSIONS: Mind-body interventions including meditative breathing may impact behavior-related neurocognitive and emotional factors that improve self-care management and support positive behavioral changes in patients with COPD. TRIAL REGISTRATION: This trial is registered in Clinical Trials.gov, ID number NCT01551953.

Evaluation of a mammography decision aid for women 75 and older at risk for lower health literacy in a pretest-posttest trial.

OBJECTIVE: The evaluation of the effect of a mammography decision aid (DA) designed for older women at risk for lower health literacy (LHL) on their knowledge of mammography's benefits and harms and decisional conflict. METHODS: Using a pretest-posttest design, women > 75 years at risk for LHL reviewing a mammography DA before and after their [B] primary care provider visit. Women were recruited from an academic medical center and community health centers and clinics. RESULTS: Of 147 eligible women approached, 43 participated. Receipt of the DA significantly affected knowledge of mammography's benefits and harms [B] (pre-test (M = 3.75, SD = 1.05) to post-test (M = 4.42, SD = 1.19), p = .03). Receipt of the DA did not significantly affect decisional conflict (pre-test (M = 3.10, SD = .97) to post-test (M = 3.23, SD = 1.02), p = .71, higher scores = lower decisional conflict). The majority of the women (97%) indicated that the DA was helpful. CONCLUSIONS: Women found a mammography screening DA helpful and its use was associated with these women having increased knowledge of mammography's benefits and harms. PRACTICE IMPLICATIONS: With the shift toward shared decision-making for women > 75 years, there is a need to engage women of all literacy levels to participate in these decisions and have tools such as the one tested in this study.

Minimizing Variance in Gastroschisis Management Leads to Earlier Full Feeds in Delayed Closure.

BACKGROUND: Limited guidance exists regarding appropriate timing for feed initiation and advancement in gastroschisis. We hypothesized that implementation of a gastroschisis management protocol would allow for standardization of antibiotic and nutritional treatment for these patients. METHODS: We conducted a retrospective comparison of patients with simple gastroschisis at two pediatric hospitals before and after initiation of our gastroschisis care protocol. Complicated gastroschisis and early mortality were excluded. The control group extended from January 2012 to January 2014 and the protocol group from July 2014 to July 2016. Variables of interest included time to feed initiation, time to goal feeds, length of stay, and National Surgical Quality Improvement Program-defined complications. We performed a subgroup analysis for primary versus delayed gastroschisis closure. Statistical analyses, including F-tests for variance, were conducted in Prism. RESULTS: Forty-seven patients with simple gastroschisis were included (control = 22, protocol = 25). Protocol compliance was 76% with no increase in complication rates. There was no difference in length of stay or time from initiation to full feeds overall between the control and protocol groups. However, neonates who underwent delayed closure reached full feeds significantly earlier, averaging 9 d versus 15 d previously (P = 0.04). CONCLUSIONS: For infants undergoing delayed closure, the time to full feeds in this group now appears to match that of patients undergoing primary closure, indicating that delayed closure should not be a reason for slower advancement. Additional studies are needed to assess the impact of earlier full enteral nutrition on rare complications and rates of necrotizing enterocolitis.

Grading TESI: Crypt and villus formation in tissue-engineered small intestine alters with stem/progenitor cell source.

The small intestine has a remarkable ability to enhance its absorptive and digestive surface area through the formation of villi, a process known as villification. We sought to learn whether developing mouse and human tissue-engineered small intestine (TESI) followed known developmental biology routes to villification, such as Sonic hedgehog (SHH)/Indian hedgehog (IHH) and bone morphogenetic protein 4 (BMP4)/forkhead box F1 (FOXF1) signaling to identify targets to enhance the development of TESI. After generating TESI from prenatal and postnatal stem cell sources, we evaluated the effect of cell source derivation on villification with a grading scheme to approximate developmental stage. χ2 analysis compared the prevalence of TESI grade from each stem cell source. RNAscope probes detected genes known to direct villification and the development of the crypt-villus axis in mouse and human development. These were compared in TESI derived from various pluripotent and progenitor cell donor cell types as well as native human fetal and postnatal tissues. Prenatal and pluripotent cell sources form mature villus and crypt-like structures more frequently than postnatal donor sources, and there are alternate routes to villus formation. Human TESI recapitulates epithelial to mesenchymal crosstalk of several genes identified in development, with fetal and pluripotent donor-derived TESI arriving at villus formation following described developmental patterns. However, postnatal TESI is much less likely to form complete villus-crypt patterns and demonstrates alternate SHH/IHH and BMP4/FOXF1 signaling patterns. Grading TESI and other cellular constructs may assist discoveries to support future human therapies.NEW & NOTEWORTHY The small intestine can enhance its absorptive and digestive surface area through a process known as villification. Tissue-engineered small intestine achieves mature villification at varying levels of success between differing sources. We have developed a consistent grading schema of morphology and characterized it across multiple developmental pathways, allowing objective comparison between differing constructs and sources.

Thermal Injection Measurement (TIM) Adds Accuracy to Injections and Can Assess Cold Chain Management.

BACKGROUND: Inaccurate assessment of injected drug delivery may increase cost and morbidity or reduce efficacy. Yet currently most injections are evaluated solely by the formation of a visible wheal that might not truly estimate the actual area of effect. We hypothesized that thermal injection measurement (TIM) might verify appropriate temperature at the time of injection, as required for some temperature-sensitive vaccines and provide more accurate information about the area of delivery. METHODS: 0.1 mL of either iced (n = 11) or room temperature (n = 17) methylene blue solution was injected subcutaneously in mice under anesthesia and photos taken with an iPhone 7 built-in camera and Thermal Seek Camera phone plug-in. After 5 min, true values were determined at necropsy. RESULTS: TIM was closer in value to the measured area at necropsy than the area of the visualized skin wheal at both ice temperature and room temperature. The difference between the true value and thermal area assessment of iced solution averaged 0.15 cm2 as compared with the difference between the true value and wheal size, which averaged 0.27 cm2 (P = 0.04). At room temperature, this was maintained for thermal and visible wheal differences, 0.23 cm2 and 0.65 cm2, respectively (P = 0.0006). CONCLUSIONS: TIM can assess temperature at the time of injection and is more accurate than visual inspection. TIM could be applied to colorless injections and areas that are hard to visualize such as scar. As a portable phone plug-in, it might be a useful adjunct to aid the evaluation of injected drug delivery including in resource-limited settings.

Induced pluripotent stem cell-derived enteric neural crest cells repopulate human aganglionic tissue-engineered intestine to form key components of the enteric nervous system.

Models for enteric neuropathies, in which intestinal nerves are absent or injured, are required to evaluate possible cell therapies. However, existing options, including transgenic mice, are variable and fragile. Here immunocompromised mice were implanted with human pluripotent stem cell-derived tissue-engineered small intestine 10 weeks prior to a second survival surgery in which enteric nervous system precursor cells, or saline controls, were injected into the human intestinal organoid-derived tissue-engineered small intestine and analyzed 4 weeks later. Human intestinal organoid-derived tissue-engineered small intestine implants injected with saline as controls illustrated formation of intestinal epithelium and mesenchyme without an enteric nervous system. Second surgical introduction of human pluripotent stem cell-generated enteric nervous system precursors into developing human intestinal organoid-derived tissue-engineered small intestine implants resulted in proliferative migratory neuronal and glial cells, including multiple neuronal subtypes, and demonstrated function in contractility assays.

Dynamic modulation of innate immune response by varying dosages of lipopolysaccharide (LPS) in human monocytic cells.

Innate monocytes and macrophages can be dynamically programmed into distinct states depending upon the strength of external stimuli. Innate programming may bear significant relevance to the pathogenesis and resolution of human inflammatory diseases. However, systems analyses with regard to the dynamic programming of innate leukocytes are lacking. In this study, we focused on the dynamic responses of human promonocytic THP-1 cells to lipopolysaccharide (LPS). We observed that varying dosages of LPS differentially modulate the expression of selected pro- and anti- inflammatory mediators such as IL-6 and IL-33. Super-low dosages of LPS preferentially induced the pro-inflammatory mediator IL-6, while higher dosages of LPS induced both IL-6 and IL-33. Mechanistically, we demonstrated that super-low and high doses of LPS cause differential activation of GSK3 and Akt, as well as the transcription factors FoxO1 and CREB. Inhibition of GSK3 enabled THP-1 cells to express IL-33 when challenged with super-low dose LPS. On the other hand, activation of CREB with adenosine suppressed IL-6 expression. Taken together, our study reveals a dynamic modulation of monocytic cells in response to varying dosages of endotoxin, and may shed light on our understanding of the dynamic balance that controls pathogenesis and resolution of inflammatory diseases.

Innate immune programing by endotoxin and its pathological consequences.

Monocytes and macrophages play pivotal roles in inflammation and homeostasis. Recent studies suggest that dynamic programing of macrophages and monocytes may give rise to distinct "memory" states. Lipopolysaccharide (LPS), a classical pattern recognition molecule, dynamically programs innate immune responses. Emerging studies have revealed complex dynamics of cellular responses to LPS, with high doses causing acute, resolving inflammation, while lower doses are associated with low-grade and chronic non-resolving inflammation. These phenomena hint at dynamic complexities of intra-cellular signaling circuits downstream of the Toll-like receptor 4 (TLR4). In this review, we examine pathological effects of varying LPS doses with respect to the dynamics of innate immune responses and key molecular regulatory circuits responsible for these effects.

Causes and consequences of low grade endotoxemia and inflammatory diseases.

Increasing clinical observations reveal that persistent low-grade inflammation is associated with the pathogenesis of severe chronic diseases such as atherosclerosis, diabetes, and aging-related neurological diseases. Intriguingly, low levels of circulating Gram-negative bacterial endotoxin lipopolysaccharide (LPS) appear to be one of the key culprits in provoking a non-resolving low-grade inflammation. Adverse life styles, chronic infection, and aging can all contribute to the rise of circulating endotoxin levels and lead to low-grade endotoxemia. As a consequence, low-grade endotoxemia may skew host immune environment into a mild non-resolving pro-inflammatory state, which eventually leads to the pathogenesis and progression of inflammatory diseases. This review aims to highlight the recent progress in the causes and consequences of low-grade endotoxemia, as well as the emerging molecular mechanisms responsible.