Altered peripheral blood leukocyte subpopulations, function, and gene expression in children with Down syndrome: implications for respiratory tract infection.

OBJECTIVES: We tested the hypothesis that aberrant expression of Hsa21-encoded interferon genes in peripheral blood immune cells would correlate to immune cell dysfunction in children with Down syndrome (DS). STUDY DESIGN: We performed flow cytometry to quantify peripheral blood leukocyte subtypes and measured their ability to migrate and phagocytose. In matched samples, we measured gene expression levels for constituents of interferon signaling pathways. We screened 49 children, of which 29 were individuals with DS. RESULTS: We show that the percentages of two peripheral blood myeloid cell subtypes (alternatively-activated macrophages and low-density granulocytes) in children with DS differed significantly from typical children, children with DS circulate a very different pattern of cytokines vs. typical individuals, and higher expression levels of type III interferon receptor Interleukin-10Rb in individuals with DS correlated with reduced migratory and phagocytic capacity of macrophages. CONCLUSIONS: Increased susceptibility to severe and chronic infection in children with DS may result from inappropriate numbers and subtypes of immune cells that are phenotypically and functionally altered due to trisomy 21 associated interferonopathy.

Combined immune checkpoint inhibition with durvalumab and tremelimumab with and without radiofrequency ablation in patients with advanced biliary tract carcinoma.

BACKGROUND: Current standard of care for advanced biliary tract cancer (BTC) is gemcitabine, cisplatin plus anti-PD1/PD-L1, but response rates are modest. The purpose of this study was to explore the efficacy and safety of durvalumab (anti-PD-L1) and tremelimumab (anti-CTLA-4), with and without an interventional radiology (IR) procedure in advanced BTC. METHODS: Eligible patients with advanced BTC who had received or refused at least one prior line of systemic therapy were treated with tremelimumab and durvalumab for four combined doses followed by monthly durvalumab alone with and without an IR procedure until the progression of disease or unacceptable toxicity. Objective response was assessed through CT or MRI by Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) every 8 weeks. Adverse events (AEs) were recorded and managed. The primary endpoint was 6-month progression-free survival (PFS). RESULTS: Twenty-three patients with advanced BTC were enrolled; 17 patients were assigned to treatment with durvalumab and tremelimumab (Durva/Treme); and 6 patients were treated with the combination of durvalumab, tremelimumab plus IR procedure (Durva/Treme + IR). The best clinical responses in the Durva/Treme arm were partial response (n = 1), stable disease (n = 5), progressive disease (n = 5), and in the Durva/Treme + IR arm: partial response (n = 0), stable disease (n = 3), progressive disease (n = 3). The median PFS was 2.2 months (95% CI: 1.3-3.1 months) in the Durva/Treme arm and 2.9 months (95% CI: 1.9-4.7 months) in the Durva/Treme + IR arm (p = 0.27). The median OS was 5.1 months (95% CI: 2.5-6.9 months) in the Durva/Treme arm and 5.8 months (95% CI: 2.9-40.1 months) in the Durva/Treme + IR arm (p = 0.31). The majority of AEs were grades 1-2. CONCLUSION: Durva/Treme and Durva/Treme + IR showed similar efficacy. With a manageable safety profile. Larger studies are needed to fully characterize the efficacy of Durva/Treme ± IR in advanced BTC.

Increased lethality of respiratory infection by Streptococcus pneumoniae in the Dp16 mouse model of Down syndrome.

Objectives: We sought to investigate whether the Dp16 mouse model of Down syndrome (DS) is more susceptible to severe and lethal respiratory tract infection by Streptococcus pneumoniae. Study Design: We infected controls and Dp16 mice with Streptococcus pneumoniae and measured survival rates. We compared cytokine production by primary lung cell cultures exposed to Streptococcus pneumoniae. We examined lung protein expression for interferon signaling related pathways. We characterized the histopathology and quantified the extent of bronchus-associated lymphoid tissue. Finally, we examined mouse tissues for the presence of oligomeric tau protein. Results: We found that the Dp16 mouse model of DS displayed significantly higher susceptibility to lethal respiratory infection with Streptococcus pneumoniae compared to control mice. Lung cells cultured from Dp16 mice displayed unique secreted cytokine profiles compared to control mice. The Dp16 mouse lungs were characterized by profound lobar pneumonia with massive diffuse consolidation involving nearly the entire lobe. Marked red hepatization was noted, and Dp16 mice lungs contained numerous bronchus-associated lymphoid tissues that were highly follicularized. Compared to uninfected mice, both control mice and Dp16 mice infected with Streptococcus pneumoniae showed evidence of oligomeric tau aggregates. Conclusions: Increased susceptibility to severe respiratory tract infection with Streptococcus pneumoniae in Dp16 mice closely phenocopies infection in individuals with DS. The increase does not appear to be linked to overexpression of mouse interferon genes syntenic to human chromosome 21.

Lung and Heart Biology of the Dp16 Mouse Model of down Syndrome: Implications for Studying Cardiopulmonary Disease.

(1) Background: We sought to investigate the baseline lung and heart biology of the Dp16 mouse model of Down syndrome (DS) as a prelude to the investigation of recurrent respiratory tract infection. (2) Methods: In controls vs. Dp16 mice, we compared peripheral blood cell and plasma analytes. We examined baseline gene expression in lungs and hearts for key parameters related to susceptibility of lung infection. We investigated lung and heart protein expression and performed lung morphometry. Finally, and for the first time each in a model of DS, we performed pulmonary function testing and a hemodynamic assessment of cardiac function. (3) Results: Dp16 mice circulate unique blood plasma cytokines and chemokines. Dp16 mouse lungs over-express the mRNA of triplicated genes, but not necessarily corresponding proteins. We found a sex-specific decrease in the protein expression of interferon α receptors, yet an increased signal transducer and activator of transcription (STAT)-3 and phospho-STAT3. Platelet-activating factor receptor protein was not elevated in Dp16 mice. The lungs of Dp16 mice showed increased stiffness and mean linear intercept and contained bronchus-associated lymphoid tissue. The heart ventricles of Dp16 mice displayed hypotonicity. Finally, Dp16 mice required more ketamine to achieve an anesthetized state. (4) Conclusions: The Dp16 mouse model of DS displays key aspects of lung heart biology akin to people with DS. As such, it has the potential to be an extremely valuable model of recurrent severe respiratory tract infection in DS.

Top advances of the year: Hepatobiliary cancers.

This commentary reviews top advances in hepatobiliary cancer research in 2021-2022, focusing on leveraging immunotherapeutics in combination with other therapies earlier in the disease course and targeted to patient's individualized biomarkers that may predict response or resistance to checkpoint inhibitors.

From Mouth to Muscle: Exploring the Potential Relationship between the Oral Microbiome and Cancer-Related Cachexia.

Cancer cachexia is a multifactorial wasting syndrome associated with skeletal muscle and adipose tissue loss, as well as decreased appetite. It affects approximately half of all cancer patients and leads to a decrease in treatment efficacy, quality of life, and survival. The human microbiota has been implicated in the onset and propagation of cancer cachexia. Dysbiosis, or the imbalance of the microbial communities, may lead to chronic systemic inflammation and contribute to the clinical phenotype of cachexia. Though the relationship between the gut microbiome, inflammation, and cachexia has been previously studied, the oral microbiome remains largely unexplored. As the initial point of digestion, the oral microbiome plays an important role in regulating systemic health. Oral dysbiosis leads to the upregulation of pro-inflammatory cytokines and an imbalance in natural flora, which in turn may contribute to muscle wasting associated with cachexia. Reinstating this equilibrium with the use of prebiotics and probiotics has the potential to improve the quality of life for patients suffering from cancer-related cachexia.

The oral microbiome, pancreatic cancer and human diversity in the age of precision medicine.

Pancreatic cancer is a deadly disease with limited diagnostic and treatment options. Not all populations are affected equally, as disparities exist in pancreatic cancer prevalence, treatment and outcomes. Recently, next-generation sequencing has facilitated a more comprehensive analysis of the human oral microbiome creating opportunity for its application in precision medicine. Oral microbial shifts occur in patients with pancreatic cancer, which may be appreciated years prior to their diagnosis. In addition, pathogenic bacteria common in the oral cavity have been found within pancreatic tumors. Despite these findings, much remains unknown about how or why the oral microbiome differs in patients with pancreatic cancer. As individuals develop, their oral microbiome reflects both their genotype and environmental influences. Genetics, race/ethnicity, smoking, socioeconomics and age affect the composition of the oral microbiota, which may ultimately play a role in pancreatic carcinogenesis. Multiple mechanisms have been proposed to explain the oral dysbiosis found in patients with pancreatic cancer though they have yet to be confirmed. With a better understanding of the interplay between the oral microbiome and pancreatic cancer, improved diagnostic and therapeutic approaches may be implemented to reduce healthcare disparities. Video Abstract.

The Use and Potential of Biomedical Detection Dogs During a Disease Outbreak.

Biomedical detection dogs offer incredible advantages during disease outbreaks that are presently unmatched by current technologies, however, dogs still face hurdles of implementation due to lack of inter-governmental cooperation and acceptance by the public health community. Here, we refine the definition of a biomedical detection dog, discuss the potential applications, capabilities, and limitations of biomedical detection dogs in disease outbreak scenarios, and the safety measures that must be considered before and during deployment. Finally, we provide recommendations on how to address and overcome the barriers to acceptance of biomedical detection dogs through a dedicated research and development investment in olfactory sciences.

Effectiveness of a Per-Meal Protein Prescription and Nutrition Education with versus without Diet Coaching on Dietary Protein Intake and Muscle Health in Middle-Aged Women.

Sufficient dietary protein intake is vital to maintaining muscle health with aging. Yet protein intake among adults is often inadequate. This study's main objective was to examine the impact of nutrition education (NE) and a per-meal protein prescription (PRx) with versus without diet coaching on protein intake. A secondary objective examined its effects on muscle health. Participants included 53 women, age 45-64 years. All participants received NE and PRx; those randomized to coached-group received 10-weeks of diet coaching. Assessments included: protein intake at baseline, weeks 4 and 12 and muscle health (muscle mass, grip strength, five-chair rise test, 4 mgait speed test). The Chi-square test examined percentages of participants meeting PRx between groups. Repeated measures analysis of variance assessed within group and intervention effects on protein intake and muscle health parameters. Protein intake (g/kg body weight) increased (p < 0.001): not-coached (n = 28) 0.8 ± 0.2 to 1.2 ± 0.3 and coached (n = 25) 1.0 ± 0.2 to 1.4 ± 0.3 with no significant difference between groups. A greater percentage of coached-group participants met (p = 0.04) breakfast (72%) and met (p < 0.001) three-meal (76%) PRx versus not-coached participants (25% and 53%, respectively). Participants in both groups exhibited significantly (p < 0.001) improved times for the five-chair rise test and 4 mgait speed test. Diet coaching in conjunction with a PRx and NE should be considered to assist individuals in improving protein intake through self-selection of protein-rich foods.

Palliative Medicine in Myelodysplastic Syndromes: Patients and Caregivers - A Qualitative Study.

OBJECTIVES: Evidence-based guidelines call for integration of palliative care within oncology from diagnosis. Misperceptions about palliative care have impeded implementation. Prior research has not examined perceptions about 'palliative care' versus 'supportive care' among patients and caregivers to whom this care is introduced routinely as part of comprehensive cancer care. We conducted a qualitative study of patients with myelodysplastic syndromes (MDS) and their informal caregivers to elicit perceptions of 'palliative care' and 'supportive care' before and after they received integrated primary/specialist palliative care from diagnosis. METHODS: Patients with newly diagnosed MDS and caregivers were interviewed about their understanding of 'palliative care' and 'supportive care' at diagnosis and follow-up. Interviews were audio-recorded, transcribed, and analysed by an interdisciplinary team. RESULTS: Forty-eight interviews were conducted in total, including with 21 patients and 13 caregivers at diagnosis, and 10 patients and 4 caregivers at follow-up. Initially, 28/34 participants (82%) associated 'palliative care' with death or fear/alarm. At follow-up, 11/14 participants (79%) recognised that 'palliative care' is not only for terminally ill patients, yet 13/14 participants (93%) still felt apprehensive about the term. Initially, 24/34 participants (71%) felt 'supportive care' sounded 'positive' and 12/14 participants (86%) reported this at follow-up. No participant associated 'supportive care' with death or fear/alarm at either time point. Among participants who had a preference, 'supportive care' was the preferred term initially and at follow-up. CONCLUSIONS: Patients with MDS and caregivers receiving integrated primary/specialist palliative care from diagnosis responded more favourably to and felt less apprehensive about 'supportive care', initially and at follow-up.

Using Transfer Trials to Teach Tacting to Children With Autism Spectrum Disorder.

Transfer trials are a component of discrete-trial training in which the therapist re-presents the initial instruction following a prompted trial to provide an opportunity for the learner to answer independently. Transfer trials may expedite the transfer of stimulus control, are commonly used by practitioners and researchers, and are often recommended as best practice by applied behavior analysis organizations. However, there is little research comparing the efficiency and efficacy of transfer trials to more traditional teaching procedures. The current study evaluated and compared transfer trials to a nontransfer trial procedure for two-component tacting with three children diagnosed with an autism spectrum disorder. Results indicated both procedures were both effective and efficient for teaching two-component tacts for all learners, supporting the inclusion of transfer trials in discrete-trial training.

The Gut Microbiome as a Component of the Gut-Brain Axis in Cognitive Health.

INTRODUCTION: The human microbiome, the microorganisms living in and on the body, plays a vital role in brain physiology and pathophysiology. The gut microbiome (GMB) has been identified as a link in the gut-brain axis moderating cognitive development and health. OBJECTIVES: The objectives of this scoping review are to discuss mechanisms of the microbiome-gut-brain axis in cognition, review the existing literature on the GMB and cognition, and discuss implications for nursing research. METHODS: We searched Pubmed using the terms "gut microbiome," "brain," and "cognition" and the terms "gut brain axis," "microbiome," and "cognition"; removed duplicates, studies not published in English, and unrelated publications; and added additional articles identified through references. We retained the 85 most relevant publications for this review. RESULTS: Common themes in the current literature include GMB components; interactions on cognitive development; effects of GMB-gut-brain interactions on cognition, mild cognitive impairment and Alzheimer's disease; effects of GMB interactions with physiologic stress on cognition in critical care; and GMB modification for improved cognition. Review of the literature on each of these topics reveals multiple theoretical mechanisms of action for GMB-gut-brain interaction that modify cognitive development and function across the lifespan. DISCUSSION: GMB components and dysbiosis have been implicated in many cognitive states, and specific microbiota constituents contribute to cognitive development, stability, and impairment. The study of these interactions is relevant to nursing research as it addresses the holistic human experience and microbiome constituents are modifiable, facilitating translation into the clinical setting.

Exploring how virtual primary care visits affect patient burden of treatment.

BACKGROUND: There is growing emphasis on the role of digital solutions in supporting chronic disease management. This has the potential to increase the burden patients experience in managing their health by offloading care from the health system to patients. This paper explores the effects of virtual visits on patient burden using an explicit framework measuring both the work patients do to care for their health and the challenges they experience that exacerbate burden. METHODS: This mixed methods study evaluates a large pilot implementation of virtual visits (video, audio, and asynchronous messaging with providers) in primary care in Ontario, Canada. Participants were recruited using convenience sampling from patients using a virtual visit platform to complete a semi-structured interview or a survey including a free-text response. We conducted 17 interviews and reviewed 427 free text responses related to explore patients' perceived value and burden of these visits. We used qualitative analyses to map patients' feedback on their experience to the framework on patient burden. MAIN FINDINGS: Virtual visits appear to reduce the work patients must do to manage their care by 1) improving access, convenience, and time needed for medical appointments, and 2) making it easier to access information and support for chronic disease management. Virtual visits also alleviate patients' perceived burden by improving continuity of care, experience of care, and providing some cost savings. CONCLUSIONS: Virtual visits reduced overall patient burden of treatment by decreasing the required patient effort of managing medical appointments and monitoring their health, and by minimizing challenges experienced when accessing care. For regions that want to improve patient experience of care, virtual visits are likely to be of benefit. There is need for further research on the generalizability of the findings herein, particularly for high-needs populations under-represented such as those of low socioeconomic status and those in rural and remote locations.

A cluster randomized controlled trial to assess the efficacy of a telehealth-based train-the-trainer mealtime intervention delivered by respite care center volunteers to caregivers of persons with dementia to improve nutritional outcomes and quality of life.

BACKGROUND: Persons with dementia with mild to moderate cognitive impairment are at risk for developing impairments with activities of daily living such as the ability to feed oneself, that negatively influence health. Lack of caregiver skills related to mealtime planning for persons with dementia and the ability to cope with dysfunctional behaviors are well-documented factors that influence nutritional status outcomes, lead to weight loss, poor quality of life, and impact their ability to remain at home. METHODS: A cluster randomized controlled trial with a parallel mixed methods evaluation processes will be conducted to examine the efficacy of a train-the-trainer program using non-paid volunteers in respite care centers to deliver a telehealth mealtime intervention guided by the theory-based C3P Model-Change the Person, Change the People, Change the Place (C3P). In this six-month study, dyads of caregivers and persons with mild to moderate dementia receiving respite care services will be randomized to receive either the telehealth intervention or enhanced usual care. Within the intervention group, dyads will be partnered with a C3P trained volunteer who will work with caregivers via videoconference to devise and implement mealtime plans. Under usual care, dyads will receive standardized educational materials modified from The Savvy Caregiver Program for Alzheimer's disease. The primary outcomes include weight maintenance or gain of the person with dementia and quality of life of the caregiver. A multi-level evaluation process utilizing respite center administrators and directors, volunteers, and caregivers will explore intervention fidelity, acceptability and sustainability. Using both the CONSORT and SPIRIT checklists as guidance, the comprehensive study design is more fully described in this manuscript. DISCUSSION: In this trial, we will lay the groundwork to examine the efficacy and sustainability of a train-the-trainer telehealth program that could be widely disseminated by national Alzheimer's organizations and readily adopted by community agencies to provide additional resources to assist families in managing mealtimes at home, while promoting the quality of life of both the caregiver and the person with dementia. TRIAL REGISTRATION: This study was registered with clinicaltrials.gov: NCT03622814 on August 9, 2018..

Burnout of the female dermatologist: How traditional burnout reduction strategies have failed women.

Dermatology is known as specialty that traditionally exhibits high levels of professional satisfaction, largely attributed to regular clinic hours and a lack of in-house call. Yet, the 2018 Medscape Dermatologist Lifestyle Survey showed that nearly one-third of dermatologists either currently experience or have experienced burnout during their careers. Although male and female dermatologists report similar burnout rates, 36% of female dermatologists reportedly work part-time compared with 14% of male dermatologists. The fact that female and male dermatologists experience similar rates of burnout even though women are more likely to work part-time suggests that female dermatologists might have additional or unique reasons for experiencing burnout compared with their male counterparts. Women in dermatology likely experience burnout, at least in part, as a result of stress from the demands of life outside of work. However, despite increasing interest in the development of burnout prevention strategies, efforts to reduce burnout have so far failed to acknowledge or address the unique reasons why female dermatologists may experience burnout. This article aims to better characterize causes of burnout that may disproportionately contribute to female burnout and to provide actionable steps to address burnout in female dermatologists.

Mass Cytometry Reveals Global Immune Remodeling with Multi-lineage Hypersensitivity to Type I Interferon in Down Syndrome.

People with Down syndrome (DS; trisomy 21) display a different disease spectrum relative to the general population, including lower rates of solid malignancies and higher incidence of neurological and autoimmune conditions. However, the mechanisms driving this unique clinical profile await elucidation. We completed a deep mapping of the immune system in adults with DS using mass cytometry to evaluate 100 immune cell types, which revealed global immune dysregulation consistent with chronic inflammation, including key changes in the myeloid and lymphoid cell compartments. Furthermore, measurement of interferon-inducible phosphorylation events revealed widespread hypersensitivity to interferon-α in DS, with cell-type-specific variations in downstream intracellular signaling. Mechanistically, this could be explained by overexpression of the interferon receptors encoded on chromosome 21, as demonstrated by increased IFNAR1 surface expression in all immune lineages tested. These results point to interferon-driven immune dysregulation as a likely contributor to the developmental and clinical hallmarks of DS.

Association of Cognitive Function with Amyloid-ß and Tau Proteins in the Vitreous Humor.

BACKGROUND: The eye may serve as source for diagnostic testing for early detection of Alzheimer's disease (AD). Examination of amyloid-ß (Aß) and tau protein content in human vitreous and its correlation to neuro-cognition may improve ocular-based AD detection methods. OBJECTIVE: To evaluate levels of Aß and tau protein in human vitreous humor and investigate the clinical predictive role of these proteins as early diagnostic markers of AD. METHODS: A prospective, single-center, multi-surgeon cohort study. Vitreous humor samples from 80 eyes were measured quantitatively for Aß40-42, pTau, and tTau. Linear regression was used to test associations between AD biomarker levels, Mini-Mental State Exam (MMSE), and serum apolipoprotein E (APOE) allele status, with adjustment for age, sex, and education level of patients. RESULTS: Lower MMSE scores were significantly associated with lower levels of vitreous Aß40 (p = 0.015), Aß42 (p = 0.0066), and tTau (p = 0.0085), and these biomarkers were not associated with any pre-existing eye conditions. Presence of the ɛ4 allele and the ɛ2 allele approached significance with reduced Aß40 level (p = 0.053) and increased p-Tau level (p = 0.056), respectively. CONCLUSION: Patients with poor cognitive function have significantly lower vitreous humor levels of AD-related biomarkers Aß40, Aß42, and tTau. These biomarkers do not correlate with underlying eye conditions, suggesting their specificity in association with cognitive change. This is the first study to our knowledge to correlate cognition with AD-related proteins in the vitreous humor. Results suggest ocular proteins may have a role for early dementia detection in individuals at risk for AD.