Shared decision-making needs, barriers, and facilitators of patients with newly diagnosed advanced cancer in the hospital: a multi-level, mixed-methods study.

PURPOSE: Little is known about the shared decision-making (SDM) needs, barriers, and facilitators of patients with newly diagnosed advanced cancer in the hospital. Understanding this may improve SDM and cancer care quality in this vulnerable population. METHODS: A single-site, mixed-methods study of hospitalized patients with newly diagnosed advanced cancer, caregivers, and oncologists was conducted. After discharge, patient ± caregiver semi-structured interviews exploring SDM needs, barriers, and facilitators regarding their most important upcoming cancer-related decision were conducted. Oncologists were surveyed about patient knowledge and SDM needs using closed- and open-ended questions, respectively. Thematic analysis was performed for qualitative data with a focus on themes unique to or amplified by hospitalization. Descriptive statistics and the Chi-squared test were performed for quantitative data. RESULTS: Patients and caregivers reported high SDM needs surrounding treatment and prognostic information, leading to decisional conflict. Eight themes emerged: anticipated cancer treatment decisions, variable control preferences in decision-making, high cancer-related information needs and uncertainty, barriers and facilitators to information gathering during and post hospitalization, and decision-making facilitators. Among 32 oncologists, most (56%) reported patients were poorly informed about treatment and prognosis. Oncologists reported variable expectations about patient knowledge after hospitalization, facilitators to patient decision-making, and patient uncertainty while awaiting an outpatient oncologist appointment. CONCLUSION: Patients newly diagnosed with advanced cancer in the hospital have high SDM needs and experience decisional conflict. This may be due to barriers unique to or exacerbated by hospitalization. Further research is needed to develop strategies to address these barriers and enhance the facilitators identified in this study.

Systemic calcineurin inhibitors tacrolimus and voclosporin: A review of off-label dermatologic uses.

BACKGROUND: Systemic calcineurin inhibitors, cyclosporine, tacrolimus, and voclosporin, have been utilized in various dermatologic conditions. Although there have been numerous off-label dermatologic indications with published guidelines for cyclosporine, there is no established strong consensus for tacrolimus and voclosporin. OBJECTIVE: To conduct a review of off-label use of systemic tacrolimus and voclosporin in various dermatoses to better inform treatment methods. METHODS: A literature search was conducted using PubMed and Google Scholar. Relevant clinical trials, observational studies, case series, and reports regarding off-label dermatologic uses of systemic tacrolimus and voclosporin were included. RESULTS: Tacrolimus shows promise for numerous dermatologic conditions, including psoriasis, atopic dermatitis/eczema, pyoderma gangrenosum, chronic urticaria, and Behcet's disease. Randomized controlled trial data are only available for voclosporin in psoriasis, which showed efficacy but did not meet noninferiority to cyclosporine. LIMITATIONS: Data were limited and extracted from published papers. Studies differed in methodology, and nonstandardized outcomes limited the conclusions drawn. CONCLUSIONS: In comparison to cyclosporine, tacrolimus can be considered for treatment-refractory disease or in patients with cardiovascular risk factors or inflammatory bowel disease. Voclosporin has only been utilized in psoriasis currently, and clinical trials in psoriasis show voclosporin's efficacy. Voclosporin can be considered for patients with lupus nephritis.

The Association between Caffeine Intake and the Colonic Mucosa-Associated Gut Microbiota in Humans-A Preliminary Investigation.

We examined the association between caffeine and coffee intake and the community composition and structure of colonic microbiota. A total of 34 polyp-free adults donated 97 colonic biopsies. Microbial DNA was sequenced for the 16S rRNA gene V4 region. The amplicon sequence variant was assigned using DADA2 and SILVA. Food consumption was ascertained using a food frequency questionnaire. We compared the relative abundance of taxonomies by low (<82.9 mg) vs. high (≥82.9 mg) caffeine intake and by never or <2 cups vs. 2 cups vs. ≥3 cups coffee intake. False discovery rate-adjusted p values (q values) <0.05 indicated statistical significance. Multivariable negative binomial regression models were used to estimate the incidence rate ratio and its 95% confidence interval of having a non-zero count of certain bacteria by intake level. Higher caffeine and coffee intake was related to higher alpha diversity (Shannon index p < 0.001), higher relative abundance of Faecalibacterium and Alistipes, and lower relative abundance of Erysipelatoclostridium (q values < 0.05). After adjustment of vitamin B2 in multivariate analysis, the significant inverse association between Erysipelatoclostridium count and caffeine intake remained statistically significant. Our preliminary study could not evaluate other prebiotics in coffee.

Intravascular schwannoma: A review of a rare diagnosis.

While schwannoma is one of the most common types of benign peripheral nerve tumors in adults, a very unique and specific variant of schwannoma, the intravascular variant, is exceedingly rare. There have only been three previously published cases of intravascular schwannomas. Here we describe a fourth case of an intravascular schwannoma in a 47-year-old man with an enlarging subcutaneous nodule on his posterior calf. This is the second case of an intravascular schwannoma contained within a vein. Also included is an overview of intravascular schwannomas, including a description and discussion of the histopathological diagnosis, differential diagnoses, and schwannoma variants.

Predictive Modeling for Voxel-Based Quantification of Imaging-Based Subtypes of Pancreatic Ductal Adenocarcinoma (PDAC): A Multi-Institutional Study.

Previously, we characterized qualitative imaging-based subtypes of pancreatic ductal adenocarcinoma (PDAC) on computed tomography (CT) scans. Conspicuous (high delta) PDAC tumors are more likely to have aggressive biology and poorer clinical outcomes compared to inconspicuous (low delta) tumors. Here, we developed a quantitative classification of this imaging-based subtype (quantitative delta; q-delta). Retrospectively, baseline pancreatic protocol CT scans of three cohorts (cohort#1 = 101, cohort#2 = 90 and cohort#3 = 16 [external validation]) of patients with PDAC were qualitatively classified into high and low delta. We used a voxel-based method to volumetrically quantify tumor enhancement while referencing normal-pancreatic-parenchyma and used machine learning-based analysis to build a predictive model. In addition, we quantified the stromal content using hematoxylin- and eosin-stained treatment-naïve PDAC sections. Analyses revealed that PDAC quantitative enhancement values are predictive of the qualitative delta scoring and were used to build a classification model (q-delta). Compared to high q-delta, low q-delta tumors were associated with improved outcomes, and the q-delta class was an independent prognostic factor for survival. In addition, low q-delta tumors had higher stromal content and lower cellularity compared to high q-delta tumors. Our results suggest that q-delta classification provides a clinically and biologically relevant tool that may be integrated into ongoing and future clinical trials.

Imaging-Based Subtypes of Pancreatic Ductal Adenocarcinoma Exhibit Differential Growth and Metabolic Patterns in the Pre-Diagnostic Period: Implications for Early Detection.

BACKGROUND: Previously, we characterized subtypes of pancreatic ductal adenocarcinoma (PDAC) on computed-tomography (CT) scans, whereby conspicuous (high delta) PDAC tumors are more likely to have aggressive biology and poorer clinical outcomes compared to inconspicuous (low delta) tumors. Here, we hypothesized that these imaging-based subtypes would exhibit different growth-rates and distinctive metabolic effects in the period prior to PDAC diagnosis. MATERIALS AND METHODS: Retrospectively, we evaluated 55 patients who developed PDAC as a second primary cancer and underwent serial pre-diagnostic (T0) and diagnostic (T1) CT-scans. We scored the PDAC tumors into high and low delta on T1 and, serially, obtained the biaxial measurements of the pancreatic lesions (T0-T1). We used the Gompertz-function to model the growth-kinetics and estimate the tumor growth-rate constant (α) which was used for tumor binary classification, followed by cross-validation of the classifier accuracy. We used maximum-likelihood estimation to estimate initiation-time from a single cell (10-6 mm3) to a 10 mm3 tumor mass. Finally, we serially quantified the subcutaneous-abdominal-fat (SAF), visceral-abdominal-fat (VAF), and muscles volumes (cm3) on CT-scans, and recorded the change in blood glucose (BG) levels. T-test, likelihood-ratio, Cox proportional-hazards, and Kaplan-Meier were used for statistical analysis and p-value <0.05 was considered significant. RESULTS: Compared to high delta tumors, low delta tumors had significantly slower average growth-rate constants (0.024 month-1 vs. 0.088 month-1, p<0.0001) and longer average initiation-times (14 years vs. 5 years, p<0.0001). α demonstrated high accuracy (area under the curve (AUC)=0.85) in classifying the tumors into high and low delta, with an optimal cut-off of 0.034 month-1. Leave-one-out-cross-validation showed 80% accuracy in predicting the delta-class (AUC=0.84). High delta tumors exhibited accelerated SAF, VAF, and muscle wasting (p <0.001), and BG disturbance (p<0.01) compared to low delta tumors. Patients with low delta tumors had better PDAC-specific progression-free survival (log-rank, p<0.0001), earlier stage tumors (p=0.005), and higher likelihood to receive resection after PDAC diagnosis (p=0.008), compared to those with high delta tumors. CONCLUSION: Imaging-based subtypes of PDAC exhibit distinct growth, metabolic, and clinical profiles during the pre-diagnostic period. Our results suggest that heterogeneous disease biology may be an important consideration in early detection strategies for PDAC.

Alcohol use alters the colonic mucosa-associated gut microbiota in humans.

Alcohol misuse is a risk factor for many adverse health outcomes. Alcohol misuse has been associated with an imbalance of gut microbiota in preclinical models and alcoholic diseases. We hypothesized that daily alcohol use would change the community composition and structure of the human colonic gut microbiota. Thirty-four polyp-free individuals donated 97 snap-frozen colonic biopsies. Microbial DNA was sequenced for the 16S ribosomal RNA gene hypervariable region 4. The SILVA database was used for operational taxonomic unit classification. Alcohol use was assessed using a food frequency questionnaire. We compared the biodiversity and relative abundance of the taxa among never drinkers (ND, n = 9), former drinkers (FD, n = 10), current light drinkers (LD, <2 drinks daily, n = 9), and current heavy drinkers (HD, ≥2 drinks daily, n = 6). False discovery rate-adjusted P values (q values) < .05 indicated statistical significance. HD had the lowest α diversity (Shannon index q value < 0.001), and HD's microbial composition differed the most from the other groups (P value = .002). LD had the highest relative abundance of Akkermansia (q values < 0.001). HD had the lowest relative abundance of Subdoligranulum, Roseburia, and Lachnospiraceaeunc91005 but the highest relative abundance of Lachnospiraceaeunc8895 (all q values < 0.05). The multivariable negative binomial regression model supported these observations. ND and FD had a similar microbial profile. Heavy alcohol use was associated with impaired gut microbiota that may partially mediate its effect on health outcomes.

BCG-Prime and boost with Esx-5 secretion system deletion mutant leads to better protection against clinical strains of Mycobacterium tuberculosis.

Although vaccination with BCG prevents disseminated forms of childhood tuberculosis (TB), it does not protect against pulmonary infection or Mycobacterium tuberculosis (Mtb) transmission. In this study, we generated a complete deletion mutant of the Mtb Esx-5 type VII secretion system (Mtb Δesx-5). Mtb Δesx-5 was highly attenuated and safe in immunocompromised mice. When tested as a vaccine candidate to boost BCG-primed immunity, Mtb Δesx-5 improved protection against highly virulent Mtb strains in the murine and guinea pig models of TB. Enhanced protection provided by heterologous BCG-prime plus Mtb Δesx-5 boost regimen was associated with increased pulmonary influx of central memory T cells (TCM), follicular helper T cells (TFH) and activated monocytes. Conversely, lower numbers of T cells expressing exhaustion markers were observed in vaccinated animals. Our results suggest that boosting BCG-primed immunity with Mtb Δesx-5 is a potential approach to improve protective immunity against Mtb. Further insight into the mechanism of action of this novel prime-boost approach is warranted.

Implementation of a Medical School Elective Course Incorporating Case-Based Learning: a Pilot Study.

INTRODUCTION: Case-based learning (CBL) is a pedagogical method using clinical case studies to reinforce learning topics. A pilot elective course incorporating CBL was offered for first-year medical students. The purpose of this study is to (1) describe the logistics of implementing the course and (2) evaluate its reception among medical students on its efficacy in learning basic science class material. METHOD: An 8-week elective course was offered to medical students from 2012 to 2017. Specialists facilitated case discussions synthesizing material from didactic lectures with clinical scenarios. End-of-term surveys with multiple choice and free response questions were distributed to students and described using summary statistics. RESULTS: There were 13 cohorts of enrollees, and the average number of students enrolled per cohort was 45.6, out of an average class size of 186 (24.5%, range 36-60). One hundred ninety-eight (64.2%) students reported that the course considerably changed or greatly expanded knowledge. Three hundred two (89.1%) students felt it met a majority of or exceeded expectations. Two hundred eighty-seven (80.2%) responses indicated interest in taking the course again or recommending it to others. One hundred six responses (27.1%) indicated preference for CBL over traditional lectures, and 177 (45.3%) were interested to see CBL integrated into the curriculum. CONCLUSIONS: Overall, this CBL elective course was well-received and perceived as effective for better learning class material by students. Additionally, students were receptive to case-based learning and integrating this style of learning into a preclinical curriculum without entirely replacing didactic-based learning. These findings may encourage more medical schools to explore incorporating CBL in the curriculum.

Creating customized oral stents for head and neck radiotherapy using 3D scanning and printing.

BACKGROUND: To evaluate and establish a digital workflow for the custom designing and 3D printing of mouth opening tongue-depressing (MOTD) stents for patients receiving radiotherapy for head and neck cancer. METHODS: We retrospectively identified 3 patients who received radiation therapy (RT) for primary head and neck cancers with MOTD stents. We compared two methods for obtaining the digital impressions of patients' teeth. The first method involved segmentation from computed tomography (CT) scans, as previously established by our group, and the second method used 3D scanning of the patients' articulated stone models that were made during the conventional stent fabrication process. Three independent observers repeated the process to obtain digital impressions which provided data to design customized MOTD stents. For each method, we evaluated the time efficiency, dice similarity coefficient (DSC) for reproducibility, and the 3D printed stents' accuracy. For the 3D scanning method, we evaluated the registration process using manual and automatic approaches. RESULTS: For all patients, the 3D scanning method demonstrated a significant advantage over the CT scanning method in terms of time efficiency with over 60% reduction in time consumed (p < 0.0001) and reproducibility with significantly higher DSC (p < 0.001). The printed stents were tested over the articulated dental stone models, and the trueness of fit and accuracy of dental anatomy was found to be significantly better for MOTD stents made using the 3D scanning method. The automated registration showed higher accuracy with errors < 0.001 mm compared to manual registration. CONCLUSIONS: We developed an efficient workflow for custom designing and 3D-printing MOTD radiation stents. This workflow represents a considerable improvement over the CT-derived segmentation method. The application of this rapid and efficient digital workflow into radiation oncology practices can expand the use of these toxicity sparing devices to practices that do not currently have the support to make them.

Increasing access to specialty care for rare diseases: a case study using a foundation sponsored clinic network for patients with neurofibromatosis 1, neurofibromatosis 2, and schwannomatosis.

BACKGROUND: Our primary aim was to assess the ability of a non-profit foundation-sponsored clinic network to facilitate access to specialized care for patients with neurofibromatoses (NF), a group of neurogenetic disorders including NF1, NF2, and schwannomatosis (SWN). Our secondary aim was to identify how our findings in NF could be applied more broadly to other rare diseases. METHODS: We retrospectively reviewed aggregate data on patient volume reported by specialty NF clinics in a nonprofit network from 2008 to 2015. We classified clinics as high or low volume for disease type (NF1 and NF2/schwannomatosis) and pediatric/adult care. We compared clinic-level data to self-reported patient-level data from a large online patient registry. RESULTS: Between 2008 and 2015, the number of certified NF clinics grew from 32 to 50, and annual patient volume rose from 6776 to 10,245 patients (13% of the total estimated U.S. NF patient population). For patient registry participants (n = 4476), the median driving distance to the nearest network clinic was 51.3 miles. Driving distances to reach high-volume centers were elevated for adults compared to children (295.8 vs. 67.9 miles), and schwannomatosis and NF2 patients compared to NF1 patients (310.9 vs. 368.1 vs. 161.7 miles). Of registry participants reporting their location of care (n = 2271), only 43.2% received care in a network specialty clinic, with especially low rates of attendance in the Southwest and Far West. CONCLUSIONS: While the number of certified NF clinics and volume of patients seen in these clinics has increased, many NF patients still do not attend specialty clinics and/or travel a significant distance for care. Geographic access to care is more limited for adults, patients with rarer conditions, and patients in the Western U.S. Potential measures to improve access to specialty care for people living with NF and other rare diseases are discussed.

Development and Pilot Evaluation of a Novel Dignity-Conserving End-of-Life (EoL) Care Model for Nursing Homes in Chinese Societies.

PURPOSE OF THE STUDY: The provision of end-of-life (EoL) care in long-term-care settings remains largely underdeveloped in most Chinese societies, and nursing home residents often fail to obtain good care as they approach death. This paper systematically describes the development and implementation mechanisms of a novel Dignity-Conserving EoL Care model that has been successfully adopted by three nursing homes in Hong Kong and presents preliminary evidence of its effectiveness on enhancing dignity and quality of life (QoL) of terminally ill residents. DESIGN AND METHODS: Nine terminally ill nursing home residents completed the McGill Quality of Life Questionnaire and the Nursing Facilities Quality of Life Questionnaire at baseline and 6 months post-EoL program enrollment. Wilcoxon signed rank test was used to detect significance changes in each QoL domains across time. RESULTS: Although significant deterioration was recorded for physical QoL, significant improvement was observed for social QoL. Moreover, a clear trend toward significant improvements was identified for the QoL domains of individuality and relationships. IMPLICATIONS: A holistic and compassionate caring environment, together with the core principles of family-centered care, interagency and interdisciplinary teamwork, as well as cultural-specific psycho-socio-spiritual support, are all essential elements for optimizing QoL and promoting death with dignity for nursing home residents facing morality. This study provides a useful framework to facilitate the future development of EoL care in long-term-care settings in the Chinese context.

Conditional depletion of KasA, a key enzyme of mycolic acid biosynthesis, leads to mycobacterial cell lysis.

Inhibition or inactivation of InhA, a fatty acid synthase II (FASII) enzyme, leads to mycobacterial cell lysis. To determine whether inactivation of other enzymes of the mycolic acid-synthesizing FASII complex also leads to lysis, we characterized the essentiality of two beta-ketoacyl-acyl carrier protein synthases, KasA and KasB, in Mycobacterium smegmatis. Using specialized transduction for allelic exchange, null kasB mutants, but not kasA mutants, could be generated in Mycobacterium smegmatis, suggesting that unlike kasB, kasA is essential. To confirm the essentiality of kasA, and to detail the molecular events that occur following depletion of KasA, we developed CESTET (conditional expression specialized transduction essentiality test), a genetic tool that combines conditional gene expression and specialized transduction. Using CESTET, we were able to generate conditional null inhA and kasA mutants. We studied the effects of depletion of KasA in M. smegmatis using the former strain as a reference. Depletion of either InhA or KasA led to cell lysis, but with different biochemical and morphological events prior to lysis. While InhA depletion led to the induction of an 80-kDa complex containing both KasA and AcpM, the mycobacterial acyl carrier protein, KasA depletion did not induce the same complex. Depletion of either InhA or KasA led to inhibition of alpha and epoxy mycolate biosynthesis and to accumulation of alpha'-mycolates. Furthermore, scanning electron micrographs revealed that KasA depletion resulted in the cell surface having a "crumpled" appearance, in contrast to the blebs observed on InhA depletion. Thus, our studies support the further exploration of KasA as a target for mycobacterial-drug development.

The primary mechanism of attenuation of bacillus Calmette-Guerin is a loss of secreted lytic function required for invasion of lung interstitial tissue.

Tuberculosis remains a leading cause of death worldwide, despite the availability of effective chemotherapy and a vaccine. Bacillus Calmette-Guérin (BCG), the tuberculosis vaccine, is an attenuated mutant of Mycobacterium bovis that was isolated after serial subcultures, yet the functional basis for this attenuation has never been elucidated. A single region (RD1), which is absent in all BCG substrains, was deleted from virulent M. bovis and Mycobacterium tuberculosis strains, and the resulting DeltaRD1 mutants were significantly attenuated for virulence in both immunocompromised and immunocompetent mice. The M. tuberculosis DeltaRD1 mutants were also shown to protect mice against aerosol challenge, in a similar manner to BCG. Interestingly, the DeltaRD1 mutants failed to cause cytolysis of pneumocytes, a phenotype that had been previously used to distinguish virulent M. tuberculosis from BCG. A specific transposon mutation, which disrupts the Rv3874 Rv3875 (cfp-10 esat-6) operon of RD1, also caused loss of the cytolytic phenotype in both pneumocytes and macrophages. This mutation resulted in the attenuation of virulence in mice, as the result of reduced tissue invasiveness. Moreover, specific deletion of each transcriptional unit of RD1 revealed that three independent transcriptional units are required for virulence, two of which are involved in the secretion of ESAT-6 (6-kDa early secretory antigenic target). We conclude that the primary attenuating mechanism of bacillus Calmette-Guérin is the loss of cytolytic activity mediated by secreted ESAT-6, which results in reduced tissue invasiveness.