Clinical trial of a probiotic and herbal supplement for lung health.

Introduction: Dysbiosis of the gut microbiome may augment lung disease via the gut-lung axis. Proteobacteria may contribute to tissue proteolysis followed by neutrophil recruitment, lung tissue injury, and perpetuation of chronic inflammation. To study the effects of probiotics across the gut-lung axis, we sought to determine if a Lactobacillus probiotic and herbal blend was safe and well-tolerated in healthy volunteers and asthmatic patients. Methods: We conducted a 1-month randomized, open-label clinical trial in Cork, Ireland with healthy and asthmatic patients who took the blend twice a day. The primary endpoint was safety with exploratory endpoints including quality of life, lung function, gut microbiome ecology, and inflammatory biomarkers. Results: All subjects tolerated the blend without adverse events. Asthmatic subjects who took the blend showed significant improvements in lung function as measured by forced expiratory volume and serum short chain fatty acid levels from baseline to Week 4. The gut microbiome of asthmatic subjects differed significantly from controls, with the most prominent difference in the relative abundance of the proteobacteria Escherichia coli. Administration of the probiotic maintained overall microbial community architecture with the only significant difference being an increase in absolute abundance of the probiotic strains measured by strain-specific PCR. Conclusion: This study supports the safety and efficacy potential of a Lactobacillus probiotic plus herbal blend to act on the gut-lung axis. However, due to the lack of a control group, a longer blinded, placebo-controlled study will be warranted to confirm the efficacy improvements observed in this trial. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT05173168.

A comparison of simulation and traditional local anesthesia teaching methods among dental hygiene students.

BACKGROUND: The COVID-19 pandemic forced dental educators to quickly modify the teaching-learning platform without testing outcomes of alternative teaching methods prior to implementation. One critical course affected was the teaching of local anesthesia (LA) that moved from practicing injections using the traditional student-to-student method to the simulation model using manikins. PURPOSE: This study compared two LA teaching methods (student-to-student versus simulation) in two consecutive cohorts before and during the pandemic to assess differences in students' skill level and self-confidence. METHODS: This quasi-experimental study recruited a convenience sample of dental hygiene students at the University of Minnesota during 2020 and 2021. Consent was collected prior to student-to-student injection practice and survey distribution. Data collected were clinical and summative clinical assessments to determine LA skill level, and student surveys to assess self-confidence. Analyses included descriptive statistics, linear models within and between cohorts, and inductive analysis for qualitative survey responses. RESULTS: Fifty of 57 students (88%) completed the survey, and 54 (95%) consented access to their clinical assessments. Skill level was significantly higher for the simulation cohort compared to the student-to-student cohort on the LA summative clinical assessment (59.0 vs. 55.6, p = 0.004). No differences were found in self-confidence between cohorts. A positive association was found between students' self-confidence and skill levels for both cohorts, but only student-to-student cohort results were statistically significant (student-to-student: r = 0.44, p = 0.02; simulation: r = 0.24, p = 0.26). CONCLUSION: Results support incorporating simulation manikin teaching methods for LA with a student-to-student partner component.

Preparation of Radiolabeled Antibodies for Nuclear Medicine Applications in Immuno-Oncology.

The mixed patient responses to antibodies targeting immune checkpoint proteins (e.g., CTLA-4, PD-1, PD-L1) have generated tremendous interest in discovering biomarkers that predict which patients will best respond to these treatments. To complement molecular biomarkers obtained from biopsies, the nuclear medicine community has begun developing radiopharmaceuticals that may provide a more holistic assessment of the biological character of all disease sites in patients. On the leading edge of clinical translation are a spectrum of radiolabeled antibodies targeting immune checkpoint proteins or T cell-specific antigens. The adoption of these reagents requires development of efficient and versatile methods for antibody bioconjugation and radiochemistry. We report herein protocols for the preparation of an anti-PD-L1 IgG1 (termed C4) labeled with zirconium-89. The approach is time and cost economical, high yielding, and adaptable to numerous antibody clones and platforms of interest to the immune-oncology community. Included also are representative methods for characterizing the pharmacology of the antibody post bioconjugation, and conducting an in vivo assessment of radiotracer biodistribution in tumor bearing mouse models.

Effects of Rhythmic Sensory Stimulation on Ehlers-Danlos Syndrome: A Pilot Study.

Ehlers-Danlos syndrome (EDS) is a connective tissue disorder characterized by joint hypermobility and skin extensibility and is often accompanied by chronic pain. Rhythmic sensory stimulation (RSS) can be defined as the stimulation of the senses in a periodic manner within a range of low frequencies. Music plus sound delivered through a vibroacoustic device is a form of RSS and has demonstrated utility in managing pain. In this current study, we conducted an open-label pilot study of 15 patients with hypermobile EDS using RSS as the intervention. Posttreatment improvements were seen in 11 of the 15 patients (73%), whereas 3 of the 15 patients (20%) experienced worse outcomes. Of the 14 patients that completed the experiment, 6 participants (43%) were classified as "responders" to the device while 8 participants (57%) were classified as "nonresponders." Responders demonstrated significant improvements in pain interference (51.5 ± 16 preintervention vs. 43.5 ± 16.4 postintervention BPI score) and depression symptoms (34.0 ± 15.9 preintervention vs. 26.8 ± 12.1 postintervention CESD score). Poststudy interviews confirm the improvements of pain interference, mood, and bowel symptoms. Furthermore, analysis of medical conditions within the responder group indicates that the presence of depression, anxiety, irritable bowel syndrome, and fibromyalgia may indicate a greater likelihood for patients to benefit with vibroacoustic applications. These results indicate a possible potential for RSS, delivered using a vibroacoustic device, in managing pain-related symptoms. Further research is necessary to elucidate the exact mechanism behind the physiological benefits of RSS.

Synthesis and Initial Biological Evaluation of Boron-Containing Prostate-Specific Membrane Antigen Ligands for Treatment of Prostate Cancer Using Boron Neutron Capture Therapy.

Boron neutron capture therapy (BNCT) is a therapeutic modality which has been used for the treatment of cancers, including brain and head and neck tumors. For effective treatment via BNCT, efficient and selective delivery of a high boron dose to cancer cells is needed. Prostate-specific membrane antigen (PSMA) is a target for prostate cancer imaging and drug delivery. In this study, we conjugated boronic acid or carborane functional groups to a well-established PSMA inhibitor scaffold to deliver boron to prostate cancer cells and prostate tumor xenograft models. Eight boron-containing PSMA inhibitors were synthesized. All of these compounds showed a strong binding affinity to PSMA in a competition radioligand binding assay (IC50 from 555.7 to 20.3 nM). Three selected compounds 1a, 1d, and 1f were administered to mice, and their in vivo blocking of 68Ga-PSMA-11 uptake was demonstrated through a positron emission tomography (PET) imaging and biodistribution experiment. Biodistribution analysis demonstrated boron uptake of 4-7 µg/g in 22Rv1 prostate xenograft tumors and similar tumor/muscle ratios compared to the ratio for the most commonly used BNCT compound, 4-borono-l-phenylalanine (BPA). Taken together, these data suggest a potential role for PSMA targeted BNCT agents in prostate cancer therapy following suitable optimization.

Understanding the medication prior-authorization process: A case study of patients and clinical staff from a large rural integrated health delivery system.

PURPOSE: The barriers and solutions to the current prior-authorization (PA) process at an integrated health system were evaluated. METHODS: Focus groups were conducted with patients at an integrated health system who also had insurance from an affiliated health plan and at least 1 denial for a medication in the past year. Semistructured interviews were conducted with medical staff (physicians, office staff, and PA experts). Both focus groups and interviews were audio-recorded and transcribed. Inductive analysis was used to code transcripts and develop themes. RESULTS: Three focus groups were conducted with 13 patients, and 9 medical staff (3 staff physicians, 2 office staff, and 4 PA staff) who have interactions with the PA process interviewed. Several themes were identified including the complexity of the PA process, consequences experienced, and ineffective communication between key stakeholders. A cross-cutting theme was that stakeholders expressed feelings of frustration, anxiety, and anger throughout the PA process. All stakeholders offered insights on how the process could be improved to better facilitate their preferences, such as access to the list of medications that require PA and the need for a patient advocate. CONCLUSION: Results of this study revealed that the PA process was frustrating, upsetting, and infuriating to patients and medical staff involved in the process. Three main themes identified included the complexity of the PA process, consequences experienced from the PA process, and ineffective communication between stakeholders.

Measuring Dynamic Changes in the Labile Iron Pool in Vivo with a Reactivity-Based Probe for Positron Emission Tomography.

Redox cycling of iron powers various enzyme functions crucial for life, making the study of iron acquisition, storage, and disposition in the whole organism a worthy topic of inquiry. However, despite its important role in biology and disease, imaging iron in animals with oxidation-state specificity remains an outstanding problem in biology and medicine. Here we report a first-generation reactivity-based probe of labile ferrous iron suitable for positron emission tomography studies in live animals. The responses of this reagent to systemic changes in labile iron disposition were revealed using iron supplementation and sequestration treatments in mice, while the potential of this approach for in vivo imaging of cancer was demonstrated using genetically and pathologically diverse mouse models, including spontaneous tumors arising in a genetically engineered model of prostate cancer driven by loss of PTEN.

Impact of long-term androgen deprivation therapy on PSMA ligand PET/CT in patients with castration-sensitive prostate cancer.

PURPOSE: Since the introduction of PSMA PET/CT with 68Ga-PSMA-11, this modality for imaging prostate cancer (PC) has spread worldwide. Preclinical studies have demonstrated that short-term androgen deprivation therapy (ADT) can significantly increase PSMA expression on PC cells. Additionally, retrospective clinical data in large patient cohorts suggest a positive association between ongoing ADT and a pathological PSMA PET/CT scan. The present evaluation was conducted to further analyse the influence of long-term ADT on PSMA PET/CT findings. METHODS: A retrospective analysis was performed of all 1,704 patients who underwent a 68Ga-PSMA-11 PET/CT scan at our institution from 2011 to 2017 to detect PC. Of 306 patients scanned at least twice, 10 had started and continued ADT with a continuous clinical response between the two PSMA PET/CT scans. These ten patients were included in the current analysis which compared the tracer uptake intensity and volume of PC lesions on PSMA PET/CT before and during ongoing ADT. RESULTS: Overall, 31 PC lesions were visible in all ten patients before initiation of ADT. However, during ongoing ADT (duration 42-369 days, median 230 days), only 14 lesions were visible in eight of the ten patients. The average tracer uptake values decreased in 71% and increased in 12.9% of the PC lesions. Of all lesions, 33.3% were still visible in six patients with a complete PSA response (≤0.1 ng/ml). CONCLUSION: Continuous long-term ADT significantly reduces the visibility of castration-sensitive PC on PSMA PET/CT. If the objective is visualization of the maximum possible extent of disease, we recommend referring patients for PSMA PET/CT before starting ADT.

ProvenCare-Psoriasis: A disease management model to optimize care.

There are a variety of evidence-based treatments available for psoriasis. The transition of this evidence into practice is challenging. In this article, we describe the design of our disease management approach for Psoriasis (ProvenCare®) and present preliminary evidence of the effect of its implementation. In designing our approach, we identified three barriers to optimal care: 1) lack of a standardized and discrete disease activity measure within the electronic health record, 2) lack of a system-wide, standardized approach to care, and 3) non-uniform financial access to appropriate non-pharmacologic treatments. We implemented several solutions, which collectively form our approach. We standardized the documentation of clinical data such as body surface area (BSA), created a disease management algorithm for psoriasis, and aligned incentives to facilitate the implementation of the algorithm. This approach provides more coordinated, cost effective care for psoriasis, while being acceptable to key stakeholders. Future work will examine the effect of the implementation of our approach on important clinical and patient outcomes.

Imaging PD-L1 Expression with ImmunoPET.

High sensitivity imaging tools could provide a more holistic view of target antigen expression to improve the identification of patients who might benefit from cancer immunotherapy. We developed for immunoPET a novel recombinant human IgG1 (termed C4) that potently binds an extracellular epitope on human and mouse PD-L1 and radiolabeled the antibody with zirconium-89. Small animal PET/CT studies showed that 89Zr-C4 detected antigen levels on a patient derived xenograft (PDX) established from a non-small-cell lung cancer (NSCLC) patient before an 8-month response to anti-PD-1 and anti-CTLA4 therapy. Importantly, the concentration of antigen is beneath the detection limit of previously developed anti-PD-L1 radiotracers, including radiolabeled atezolizumab. We also show that 89Zr-C4 can specifically detect antigen in human NSCLC and prostate cancer models endogenously expressing a broad range of PD-L1. 89Zr-C4 detects mouse PD-L1 expression changes in immunocompetent mice, suggesting that endogenous PD-1/2 will not confound human imaging. Lastly, we found that 89Zr-C4 could detect acute changes in tumor expression of PD-L1 due to standard of care chemotherapies. In summary, we present evidence that low levels of PD-L1 in clinically relevant cancer models can be imaged with immunoPET using a novel recombinant human antibody.

Medication therapy disease management: Geisinger's approach to population health management.

PURPOSE: Pharmacists' involvement in a population health initiative focused on chronic disease management is described. SUMMARY: Geisinger Health System has cultivated a culture of innovation in population health management, as highlighted by its ambulatory care pharmacy program, the Medication Therapy Disease Management (MTDM) program. Initiated in 1996, the MTDM program leverages pharmacists' pharmacotherapy expertise to optimize care and improve outcomes. MTDM program pharmacists are trained and credentialed to manage over 16 conditions, including atrial fibrillation (AF) and multiple sclerosis (MS). Over a 15-year period, Geisinger Health Plan (GHP)-insured patients with AF whose warfarin therapy was managed by the MTDM program had, on average, 18% fewer emergency department (ED) visits and 18% fewer hospitalizations per year than GHP enrollees with AF who did not receive MTDM services, with 23% lower annual total care costs. Over a 2-year period, GHP-insured patients with MS whose pharmacotherapy was managed by pharmacists averaged 28% fewer annual ED visits than non-pharmacist-managed patients; however, the mean annual total care cost was 21% higher among MTDM clinic patients. CONCLUSION: The Geisinger MTDM program has evolved over 20 years from a single pharmacist-run anticoagulation clinic into a large program focused on managing the health of an ever-growing population. Initial challenges in integrating pharmacists into the Geisinger patient care framework as clinical experts were overcome by demonstrating the MTDM program's positive impact on patient outcomes.

Clinical and economic consequences of statin intolerance in the United States: Results from an integrated health system.

BACKGROUND: Although statins are considered safe and effective, they have been associated with statin intolerance (SI) in clinical and observational studies. OBJECTIVE: The objective of this study was to describe the clinical and economic consequences of SI through comparison of an SI cohort of patients with matched controls. METHODS: This study used data extracted from an integrated health system's electronic health records from 2008 to 2014. Adults with SI were matched to controls using a propensity score. Patients were hierarchically classified into 6 mutually exclusive cardiovascular (CV)-risk categories: recent acute coronary syndrome (ACS; ≤12 months preindex), coronary heart disease, ischemic stroke, peripheral artery disease, diabetes, or primary prevention. The study endpoints, low-density lipoprotein cholesterol (LDL-C) goal attainment, medical costs, and time to first CV event were compared using conditional logistic regression, generalized linear, and Cox proportional hazards models, respectively. RESULTS: Patients with SI (n = 5190) were matched with controls (n = 15,570). Patients with SI incurred higher medical costs and were less likely to reach LDL-C goals than controls. Patients with SI were at higher risk for revascularization procedures in all CV risk categories except ACS, and those in the diabetes risk category were at higher risk for any CV event. There was a lower risk of all-cause death among patients with SI. CONCLUSIONS: Patients with SI were less likely to reach LDL-C goals, incurred higher health care costs, and experienced a higher risk for nonfatal CV events than patients without SI. Alternative management strategies are needed to better treat high CV risk patients.

68Ga-PSMA-11 PET Imaging of Response to Androgen Receptor Inhibition: First Human Experience.

The purpose of this work was to evaluate the effect of androgen receptor (AR) inhibition on prostate-specific membrane antigen (PSMA) uptake imaged using 68Ga-PSMA-11 PET in a mouse xenograft model and in a patient with castration-sensitive prostate cancer. METHODS: We imaged 3 groups of 4 mice bearing LNCaP-AR xenografts before and 7 d after treatment with ARN-509, orchiectomy, or control vehicle. Additionally, we imaged one patient with castration-sensitive prostate cancer before and 4 wk after treatment with androgen deprivation therapy (ADT). Uptake on pre- and posttreatment imaging was measured and compared. RESULTS: PSMA uptake increased 1.5- to 2.0-fold in the xenograft mouse model after treatment with both orchiectomy and ARN-509 but not with vehicle. Patient imaging demonstrated a 7-fold increase in PSMA uptake after the initiation of ADT. Thirteen of 22 lesions in the imaged patient were visualized on PSMA PET only after treatment with ADT. CONCLUSION: Inhibition of the AR can increase PSMA expression in prostate cancer metastases and increase the number of lesions visualized using PSMA PET. The effect seen in cell and animal models can be recapitulated in humans. A better understanding of the temporal changes in PSMA expression is needed to leverage this effect for both improved diagnosis and improved therapy.

Short-Term Effects of Rhythmic Sensory Stimulation in Alzheimer's Disease: An Exploratory Pilot Study.

This study assessed the effect of stimulating the somatosensory system of Alzheimer's disease (AD) patients at three stages of their illness with 40 Hz sound. In this AB cross-over study design, 18 participants (6 mild, 6 moderate, 6 severe) each participated in 13 sessions: one intake and 12 treatment. Treatment A consisted of 40 Hz sound stimulation and Treatment B consisted of visual stimulation using DVDs, each provided twice a week over 6 weeks for a total of 6 times per treatment. Outcome measures included: St. Louis University Mental Status Test (SLUMS), Observed Emotion Rating Scale, and behavioral observation by the researcher. Data were submitted to regression analysis for the series of 6 SLUMS scores in treatment A and 6 scores in B with comparison by group. The slopes for the full sample and subgroups in the 40 Hz treatment were all significant beyond alpha = 0.05, while those for the DVD were not. A thematic analysis of qualitative observations supported the statistical findings. 40 Hz treatment appeared to have the strongest impact on persons with mild and moderate AD. Results are promising in terms of a potential new treatment for persons with AD, and further research is needed.

Presence of calcium-binding motifs in PilY1 homologs correlates with Ca-mediated twitching motility and evolutionary history across diverse bacteria.

Twitching motility, involving type IV pili, is essential for host colonization and virulence of many pathogenic bacteria. Studies of PilY1, a tip-associated type IV pili protein, indicate that PilY1 functions as a switch between pilus extension and retraction, resulting in twitching motility. Recent work detected a calcium-binding motif in PilY1 of some animal bacterial pathogens and demonstrated that binding of calcium to PilY1 with this motif regulates twitching. Though studies of PilY1 in non-animal pathogens are limited, our group demonstrated that twitching motility in the plant pathogen Xylella fastidiosa, which contains three PilY1 homologs, is increased by calcium supplementation. A study was conducted to investigate the phylogenetic relationship between multiple PilY1 homologs, the presence of calcium-binding motifs therein, and calcium-mediated twitching motility across diverse bacteria. Strains analyzed contained one to three PilY1 homologs, but phylogenetic analyses indicated that PilY1 homologs containing the calcium-binding motif Dx[DN]xDGxxD are phylogenetically divergent from other PilY1 homologs. Plant-associated bacteria included in these analyses were then examined for a calcium-mediated twitching response. Results indicate that bacteria must have at least one PilY1 homolog containing the Dx[DN]xDGxxD motif to display a calcium-mediated increase in twitching motility, which likely reflects an adaption to environmental calcium concentrations.

Lung cancer: needs assessment, treatment and therapies.

Lung cancer is the most common cancer in the world. Globally, the annual diagnosis rate of new cases is approximately 1.6 million. The latest figures for the UK show that there are approximately 39000 cases each year and that lung cancer accounts for about 22% of all cancer deaths (Cancer Research UK, 2013a). This article will look at the latest national recommendations for managing and treating non-small cell lung cancer, which accounts for about 80% of lung cancers, as well as emerging therapies. It is not within the scope of this article to discuss each type and aspect of lung cancer in detail and further reading is encouraged.

Functional tissue-engineered valves from cell-remodeled fibrin with commissural alignment of cell-produced collagen.

Heart valve replacements composed of living tissue that can adapt, repair, and grow with a patient would provide a more clinically beneficial option than current inert replacements. Bioartificial valves were produced by entrapping human dermal fibroblasts within a fibrin gel. Using a mold design that presents appropriate mechanical constraints to the cell-induced fibrin gel compaction, gross fiber alignment (commissure-to-commissure alignment in the leaflets and circumferential alignment in the root) and the basic geometry of a native aortic valve were obtained. After static incubation on the mold in complete medium supplemented with transforming growth factor beta 1, insulin, and ascorbate, collagen fibers produced by the entrapped cells were found to coalign with the fibrin based on histological analyses. The resultant tensile mechanical properties were anisotropic. Ultimate tensile strength and tensile modulus of the leaflets in the commissural direction were 0.53 and 2.34 MPa, respectively. The constructs were capable of withstanding backpressure commensurate with porcine aortic valves in regurgitation tests (330 mmHg) and opened and closed under physiological pressure swings of 10 and 20 mmHg, respectively. These data support proof of principle of using cell-remodeled fibrin gel to produce tissue-engineered valve replacements.

Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines.

The nervous system senses peripheral damage through nociceptive neurons that transmit a pain signal. TRPA1 is a member of the Transient Receptor Potential (TRP) family of ion channels and is expressed in nociceptive neurons. TRPA1 is activated by a variety of noxious stimuli, including cold temperatures, pungent natural compounds, and environmental irritants. How such diverse stimuli activate TRPA1 is not known. We observed that most compounds known to activate TRPA1 are able to covalently bind cysteine residues. Here we use click chemistry to show that derivatives of two such compounds, mustard oil and cinnamaldehyde, covalently bind mouse TRPA1. Structurally unrelated cysteine-modifying agents such as iodoacetamide (IA) and (2-aminoethyl)methanethiosulphonate (MTSEA) also bind and activate TRPA1. We identified by mass spectrometry fourteen cytosolic TRPA1 cysteines labelled by IA, three of which are required for normal channel function. In excised patches, reactive compounds activated TRPA1 currents that were maintained at least 10 min after washout of the compound in calcium-free solutions. Finally, activation of TRPA1 by disulphide-bond-forming MTSEA is blocked by the reducing agent dithiothreitol (DTT). Collectively, our data indicate that covalent modification of reactive cysteines within TRPA1 can cause channel activation, rapidly signalling potential tissue damage through the pain pathway.

The safety and usefulness of high-dose-rate endoluminal brachytherapy as a boost in the treatment of patients with esophageal cancer with external beam radiation with or without chemotherapy.

PURPOSE: This study reports the results of a single-institution experience with high-dose-rate brachytherapy (HDRBT) used as a boost in the treatment of esophageal cancer with external beam radiation therapy (ERT) with or without chemotherapy. METHODS AND MATERIALS: Patients without evidence of metastatic disease were identified. HDRBT was given before ERT with a dose of 20 Gy in 5 fractions. Patients with a Karnofsky performance of more than 70 received treatment with 50 Gy in 25 fractions and concurrent 5-fluorouracil and cis-platinum during Weeks 1 and 5, whereas patients with a Karnofsky performance of less than 70 were treated with radiation therapy alone with 35 Gy in 14 fractions. RESULTS: Fifty-three patients received HDRBT treatment with combined ERT and chemotherapy and 17 patients with ERT alone. The incidence of acute bone marrow toxicity was 55% Grade 2 and 15% Grade 3, and 85% of patients had Grade 2 esophagitis. With a median follow-up time of 26 months, the median survival was 21 months; the 2-year local recurrence was 25%, and the 5-year survival rate was 28%. CONCLUSION: HDRBT is safe and beneficial for local control in the radical treatment of patients with esophageal cancer.