Pseudomonas aeruginosa ventricular assist device infections: findings from ineffective phage therapies in five cases.

Left ventricular assist devices (LVAD) are increasingly used for management of heart failure; infection remains a frequent complication. Phage therapy has been successful in a variety of antibiotic refractory infections and is of interest in treating LVAD infections. We performed a retrospective review of four patients that underwent five separate courses of intravenous (IV) phage therapy with concomitant antibiotic for treatment of endovascular Pseudomonas aeruginosa LVAD infection. We assessed phage susceptibility, bacterial strain sequencing, serum neutralization, biofilm activity, and shelf-life of phage preparations. Five treatments of one to four wild-type virulent phage(s) were administered for 14-51 days after informed consent and regulatory approval. There was no successful outcome. Breakthrough bacteremia occurred in four of five treatments. Two patients died from the underlying infection. We noted a variable decline in phage susceptibility following three of five treatments, four of four tested developed serum neutralization, and prophage presence was confirmed in isolates of two tested patients. Two phage preparations showed an initial titer drop. Phage biofilm activity was confirmed in two. Phage susceptibility alone was not predictive of clinical efficacy in P. aeruginosa endovascular LVAD infection. IV phage was associated with serum neutralization in most cases though lack of clinical effect may be multifactorial including presence of multiple bacterial isolates with varying phage susceptibility, presence of prophages, decline in phage titers, and possible lack of biofilm activity. Breakthrough bacteremia occurred frequently (while the organism remained susceptible to administered phage) and is an important safety consideration.

Association of endoscopic biopsy sampling methods with detection of precursor lesions of gastric cancer.

BACKGROUND AND AIMS: The yield of various endoscopic biopsy sampling methods for detection of precursor lesions of noncardia gastric cancer in a real-world setting remains unclear. Our objective was to evaluate the association of endoscopic biopsy sampling methods with detection of gastric intestinal metaplasia (GIM) and gastric dysplasia (GD). METHODS: We conducted a case-control study of adult patients who underwent EGD with biopsy sampling between 2010 and 2021 in a racially and ethnically diverse U.S. healthcare system. Cases were patients with histopathologic findings of GIM and/or GD. Control subjects were matched 1:1 by age, procedure date, and medical center. We compared the detection of GIM and GD using 4 different biopsy sampling methods: unspecified, specified stomach location, 2+2, and the Sydney protocol. Additionally, we assessed trends in use of sampling methods (Cochrane-Armitage) and identified patient and endoscopist factors associated with their use (logistic regression). RESULTS: We identified 20,938 GIM and 455 GD matched pairs. A greater proportion of GIM cases were detected using 2+2 (31.3% vs 25.3%, P < .0001) and the Sydney protocol (9.1% vs 1.0%, P < .0001) compared with control subjects. Similarly, a greater proportion of GD cases were detected using the Sydney protocol (15.6% vs .4%, P < .0001). We observed an increasing trend in the use of the Sydney protocol during the study period (3.8%-16.1% in cases, P < .0001; 1%-1.1% in control subjects, P = .005). Male and Asian American patients were more likely to undergo 2+2 or the Sydney protocol, whereas female and Hispanic endoscopists were more likely to perform sampling using these protocols. CONCLUSIONS: The application of the Sydney protocol is associated with an increased detection of precursor lesions of gastric cancer in routine clinical practice.

Derivation and External Validation of Machine Learning-Based Model for Detection of Pancreatic Cancer.

INTRODUCTION: There is currently no widely accepted approach to screening for pancreatic cancer (PC). We aimed to develop and validate a risk prediction model for pancreatic ductal adenocarcinoma (PDAC), the most common form of PC, across 2 health systems using electronic health records. METHODS: This retrospective cohort study consisted of patients aged 50-84 years having at least 1 clinic-based visit over a 10-year study period at Kaiser Permanente Southern California (model training, internal validation) and the Veterans Affairs (VA, external testing). Random survival forests models were built to identify the most relevant predictors from >500 variables and to predict risk of PDAC within 18 months of cohort entry. RESULTS: The Kaiser Permanente Southern California cohort consisted of 1.8 million patients (mean age 61.6) with 1,792 PDAC cases. The 18-month incidence rate of PDAC was 0.77 (95% confidence interval 0.73-0.80)/1,000 person-years. The final main model contained age, abdominal pain, weight change, HbA1c, and alanine transaminase change (c-index: mean = 0.77, SD = 0.02; calibration test: P value 0.4, SD 0.3). The final early detection model comprised the same features as those selected by the main model except for abdominal pain (c-index: 0.77 and SD 0.4; calibration test: P value 0.3 and SD 0.3). The VA testing cohort consisted of 2.7 million patients (mean age 66.1) with an 18-month incidence rate of 1.27 (1.23-1.30)/1,000 person-years. The recalibrated main and early detection models based on VA testing data sets achieved a mean c-index of 0.71 (SD 0.002) and 0.68 (SD 0.003), respectively. DISCUSSION: Using widely available parameters in electronic health records, we developed and externally validated parsimonious machine learning-based models for detection of PC. These models may be suitable for real-time clinical application.

Machine learning versus regression for prediction of sporadic pancreatic cancer.

BACKGROUND/OBJECTIVES: There is currently no widely accepted approach to identify patients at increased risk for sporadic pancreatic cancer (PC). We aimed to compare the performance of two machine-learning models with a regression-based model in predicting pancreatic ductal adenocarcinoma (PDAC), the most common form of PC. METHODS: This retrospective cohort study consisted of patients 50-84 years of age enrolled in either Kaiser Permanente Southern California (KPSC, model training, internal validation) or the Veterans Affairs (VA, external testing) between 2008 and 2017. The performance of random survival forests (RSF) and eXtreme gradient boosting (XGB) models were compared to that of COX proportional hazards regression (COX). Heterogeneity of the three models were assessed. RESULTS: The KPSC and the VA cohorts consisted of 1.8 and 2.7 million patients with 1792 and 4582 incident PDAC cases within 18 months, respectively. Predictors selected into all three models included age, abdominal pain, weight change, and glycated hemoglobin (A1c). Additionally, RSF selected change in alanine transaminase (ALT), whereas the XGB and COX selected the rate of change in ALT. The COX model appeared to have lower AUC (KPSC: 0.737, 95% CI 0.710-0.764; VA: 0.706, 0.699-0.714), compared to those of RSF (KPSC: 0.767, 0.744-0.791; VA: 0.731, 0.724-0.739) and XGB (KPSC: 0.779, 0.755-0.802; VA: 0.742, 0.735-0.750). Among patients with top 5% predicted risk from all three models (N = 29,663), 117 developed PDAC, of which RSF, XGB and COX captured 84 (9 unique), 87 (4 unique), 87 (19 unique) cases, respectively. CONCLUSIONS: The three models complement each other, but each has unique contributions.

Eribulin normalizes pancreatic cancer-associated fibroblasts by simulating selected features of TGFß inhibition.

BACKGROUND: Less than 11% of pancreatic cancer patients survive 5-years post-diagnosis. The unique biology of pancreatic cancer includes a significant expansion of its desmoplastic tumor microenvironment, wherein cancer-associated fibroblasts (CAFs) and their self-produced extracellular matrix are key components. CAF functions are both tumor-supportive and tumor-suppressive, while normal fibroblastic cells are solely tumor-suppressive. Knowing that CAF-eliminating drugs are ineffective and can accelerate cancer progression, therapies that "normalize" CAF function are highly pursued. Eribulin is a well-tolerated anti-microtubule drug used to treat a plethora of neoplasias, including advanced/metastatic cancers. Importantly, eribulin can inhibit epithelial to mesenchymal transition via a mechanism akin to blocking pathways induced by transforming growth factor-beta (TGFß). Notably, canonical TGFß signaling also plays a pivotal role in CAF activation, which is necessary for the development and maintenance of desmoplasia. Hence, we hypothesized that eribulin could modulate, and perhaps "normalize" CAF function. METHODS: To test this premise, we used a well-established in vivo-mimetic fibroblastic cell-derived extracellular matrix (CDM) system and gauged the effects of eribulin on human pancreatic CAFs and cancer cells. This pathophysiologic fibroblast/matrix functional unit was also used to query eribulin effects on CDM-regulated pancreatic cancer cell survival and invasive spread. RESULTS: Demonstrated that intact CAF CDMs modestly restricted eribulin from obstructing pancreatic cancer cell growth. Nonetheless, eribulin-treated CAFs generated CDMs that limited nutrient-deprived pancreatic cancer cell survival, similar to reported tumor-suppressive CDMs generated by TGFß-deficient CAFs. CONCLUSIONS: Data from this study support the central proposed premise suggesting that eribulin could be used as a CAF/matrix-normalizing drug.

Severity of Diabetic Retinopathy and the Risk of Future Cerebrovascular Disease, Cardiovascular Disease, and All-Cause Mortality.

PURPOSE: To determine the relationship between the severity of diabetic retinopathy and the future risk of cerebrovascular accident (CVA), myocardial infarction (MI), congestive heart failure (CHF), and all-cause mortality in patients with type 2 diabetes mellitus. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients with type 2 diabetes who underwent diabetic retinopathy screening via fundus photography. METHODS: The relationship between retinopathy status and the 5-year risk of first-time CVA, MI, CHF, and all-cause mortality was investigated using multivariate Cox proportional hazards regressions that controlled for age, gender, race or ethnicity, hemoglobin A1c, duration of diabetes, high-density lipoprotein level, low-density lipoprotein level, history of hypertension, systolic blood pressure, diastolic blood pressure, tobacco use, statin use, body mass index, urine microalbumin-to-creatinine ratio, and estimated glomerular filtration rate. MAIN OUTCOME MEASURES: Five-year risk of first-time CVA, MI, CHF, and all-cause mortality. RESULTS: Seventy-seven thousand three hundred seventy-six patients were included in this study. The average age was 59.8 years with 53.6% male, 31.2% non-Hispanic White, and 41.4% Hispanic patients. Diabetic retinopathy was significantly associated with all outcomes on multivariate analysis. Compared with patients with no retinopathy, those with minimal nonproliferative diabetic retinopathy (NPDR) had a higher risk of CVA (hazard ratio [HR], 1.31; 95% confidence interval [CI], 1.18-1.46), MI (HR, 1.30; 95% CI, 1.15-1.46), CHF (HR, 1.29; 95% CI, 1.19-1.40), and death (HR, 1.15; 95% CI, 1.05-1.25). Similarly, patients with moderate to severe NPDR had a higher risk of each outcome (CVA: HR, 1.56; 95% CI, 1.29-1.89; MI: HR, 1.92; 95% CI, 1.57-2.34; CHF: HR, 1.90; 95% CI, 1.66-2.18, and death: HR, 1.55; 95% CI, 1.32-1.82), as did patients with proliferative diabetic retinopathy (CVA: HR, 2.53; 95% CI, 1.84-3.48; MI: HR, 1.89; 95% CI, 1.26-2.83; CHF: HR, 1.96; 95% CI, 1.47-2.59; and death: HR, 1.87; 95% CI, 1.36-2.56). CONCLUSIONS: Diabetic retinopathy is significantly associated with future risk of CVA, MI, CHF, and death, with higher degrees of retinopathy appearing to carry a heightened risk for each outcome. Retinal information may provide valuable insights into patients' risk of future vascular disease and death.

Patient and Physician Perspectives of Deprescribing Potentially Inappropriate Medications in Older Adults with a History of Falls: a Qualitative Study.

BACKGROUND: High-risk medications pose serious safety risks to older adults, including increasing the risk of falls. Deprescribing potentially inappropriate medications (PIMs) in older adults who have experienced a fall is a key element of fall reduction strategies. However, continued use of PIMs in older adults is common, and clinicians may face substantial deprescribing barriers. OBJECTIVE: Explore patient and clinician experiences with and perceptions of deprescribing PIMs in patients with a history of falls. DESIGN: We led guided patient feedback sessions to explore deprescribing scenarios with patient stakeholders and conducted semi-structured interviews with primary care physicians (PCPs) to explore knowledge and awareness of fall risk guidelines, deprescribing experiences, and barriers and facilitators to deprescribing. PARTICIPANTS: PCPs from Kaiser Permanente Southern California (KPSC) and patient members of the KPSC Regional Patient Advisory Committee. APPROACH: We used maximum variation sampling to identify PCPs with patients who had a fall, then categorized the resulting PIM dispense distribution for those patients into high and low frequency. We analyzed the data using a hybrid deductive-inductive approach. Coders applied initial deductively derived codes to the data, simultaneously using an open-code inductive approach to capture emergent themes. KEY RESULTS: Physicians perceived deprescribing discussions as potentially contentious, even among patients with falls. Physicians reported varying comfort levels with deprescribing strategies: some felt that the conversations might be better suited to others (e.g., pharmacists), while others had well-planned negotiation strategies. Patients reported lack of clarity as to the reasons and goals of deprescribing and poor understanding of the seriousness of falls. CONCLUSIONS: Our study suggests that key barriers to deprescribing include PCP trepidation about raising a contentious topic and insufficient patient awareness of the potential seriousness of falls. Findings suggest the need for multifaceted, multilevel deprescribing approaches with clinician training strategies, patient educational resources, and a focus on building trusting patient-clinician relationships.

Physician adjudication of angioedema diagnosis codes in a population of patients with heart failure prescribed angiotensin-converting enzyme inhibitor therapy.

PURPOSE: Our objective was to calculate the positive predictive value (PPV) of the ICD-9 diagnosis code for angioedema when physicians adjudicate the events by electronic health record review. Our secondary objective was to evaluate the inter-rater reliability of physician adjudication. METHODS: Patients from the Cardiovascular Research Network previously diagnosed with heart failure who were started on angiotensin-converting enzyme inhibitors (ACEI) during the study period (July 1, 2006 through September 30, 2015) were included. A team of two physicians per participating site adjudicated possible events using electronic health records for all patients coded for angioedema for a total of five sites. The PPV was calculated as the number of physician-adjudicated cases divided by all cases with the diagnosis code of angioedema (ICD-9-CM code 995.1) meeting the inclusion criteria. The inter-rater reliability of physician teams, or kappa statistic, was also calculated. RESULTS: There were 38 061 adults with heart failure initiating ACEI in the study (21 489 patient-years). Of 114 coded events that were adjudicated by physicians, 98 angioedema events were confirmed for a PPV of 86% (95% CI: 80%, 92%). The kappa statistic based on physician inter-rater reliability was 0.65 (95% CI: 0.47, 0.82). CONCLUSIONS: ICD-9 diagnosis code of 995.1 (angioneurotic edema, not elsewhere classified) is highly predictive of angioedema in adults with heart failure exposed to ACEI.

Fixed-Dose Combination Medications for Treating Hypertension: A Review of Effectiveness, Safety, and Challenges.

PURPOSE OF REVIEW: To summarize the recent evidence on the effectiveness and safety of antihypertensive fixed-dose combination (FDC) medications, and to describe the facilitators and barriers to implementing FDCs in US clinical practice. RECENT FINDINGS: Recent clinical practice guidelines include FDC use for treating high BP. Clinical trials in recent years support the use of antihypertensive FDCs including low-dose triple- and quadruple-therapy FDCs. Initiating a low-to-standard dose dual-therapy FDCs showed better BP control than initiating treatment with a standard-dose monotherapy, and triple-therapy FDCs produced better BP control rates than dual-therapy FDCs. Retrospective cohort studies showed that FDCs are associated with increased medication adherence, reduced clinical inertia, decreased time to BP control, and improved cardiovascular outcomes. We further discussed barriers and facilitators of wider implementation of antihypertensive FDCs in clinical practice. FDC treatment for hypertension is not commonly used despite historical and recent data which support the effectiveness, safety, and benefits of FDCs. Simplified and protocolized treatment algorithms, team-based care, shared decision-making principles are crucial to successful utilization and implementation of FDC in clinical practice.

Follow-up of Abnormal Estimated GFR Results Within a Large Integrated Health Care Delivery System: A Mixed-Methods Study.

BACKGROUND: Timely follow-up of abnormal laboratory results is important for high-quality care. We sought to identify risk factors, facilitators, and barriers to timely follow-up of an abnormal estimated glomerular filtration rate (eGFR) for the diagnosis of chronic kidney disease. STUDY DESIGN: Mixed-methods study: retrospective electronic health record (EHR) analyses, physician interviews. SETTING & PARTICIPANTS: Large integrated health care delivery system. Quantitative analyses included 244,540 patients 21 years or older with incident abnormal eGFRs from January 1, 2010, to December 31, 2015, ordered by 7,164 providers. Qualitative analyses included 15 physician interviews. EXPOSURES: Patient-, physician-, and system-level factors. OUTCOME: Timely follow-up of incident abnormal eGFRs, defined as repeat eGFR obtained within 60 to 150 days, follow-up testing before 60 days that indicated normal kidney function, or diagnosis before 60 days of chronic kidney disease or kidney cancer. ANALYTICAL APPROACH: Multivariable robust Poisson regression models accounting for clustering within provider were used to estimate risk ratios (RRs) and 95% CIs for lack of timely follow-up. Team coding was used to identify themes from physician interviews. RESULTS: 58% of patients lacked timely follow-up of their incident abnormal eGFRs (ie, had a care gap). An abnormal creatinine result flag in the EHR was associated with better follow-up (RR for care gap, 0.65; 95% CI, 0.64-0.66). Patient online portal use and physician panel size were weakly associated with follow-up. Patients seen by providers behind on managing their EHR message box were at higher risk for care gaps. Physician interviews identified system-level (eg, panel size and assistance in managing laboratory results) and provider-level (eg, proficiency using EHR tools) factors that influence laboratory result management. LIMITATIONS: Unable to capture intentional delays in follow-up testing. CONCLUSIONS: Timely follow-up of abnormal results remains challenging in an EHR-based integrated health care delivery system. Strategies improving provider EHR message box management and leveraging health information technology (eg, flagging abnormal eGFR results), making organizational/staffing changes (eg, increasing the role of nurses in managing laboratory results), and boosting patient engagement through better patient portals may improve test follow-up.

Preoperative Vision and Surgeon Volume as Predictors of Visual Outcomes after Cataract Surgery.

PURPOSE: To evaluate the relationship between preoperative vision and surgeon volume with visual outcomes after cataract surgery. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients aged ≥18 years old enrolled in the Kaiser Permanente Southern California Health Plan who underwent cataract surgery by nontrainee surgeons. METHODS: Patients who underwent cataract surgery between January 1, 2013 and December 31, 2015, were included. A multivariate analysis using Generalized Additive Mixed Models was performed to determine the relationship between surgeon volume and postoperative visual acuity after controlling for patient age, preoperative visual acuity, history of diabetes, and history of diabetic retinopathy. Modeling was done for the relationship between preoperative vision and visual outcomes while controlling for surgeon volume, patient age, history of diabetes, and history of diabetic retinopathy. MAIN OUTCOME MEASURE: Absolute letter change and percentage of patients to achieve ≥5 Early Treatment Diabetic Retinopathy Study (ETDRS) letter gain postoperatively. RESULTS: There were 103 920 cataract surgeries performed by 136 surgeons included in this analysis. Patients whose surgeons performed <91.0 surgeries/year (95% confidence interval [CI], 61.1-139; P < 0.05) gained fewer letters postoperatively than the overall average, whereas those whose surgeons performed >91 but <227 surgeries/year (95% CI, 169-∞; P < 0.05) gained more letters than average. Although statistically significant, the difference between the lowest and highest performing surgeons was approximately 1.25 letters. Surgeons who performed <110 surgeries/year (95% CI, 81.7-149; P < 0.05) had fewer patients who gained ≥5 letters. Surgeons who performed >110 but <293 surgeries/year (95% CI, 232-∞; P < 0.05) were approximately 15% more likely to have patients who gained ≥5 letters. Patients with preoperative vision <74.7 letters (95% CI, 74.7-74.8; P < 0.05) and <75.8 letters (95% CI, 75.8-75.9; P < 0.05) gained more letters and were more likely to gain ≥5 letters postoperatively, respectively. CONCLUSIONS: Patients whose vision is approximately 20/32 or worse are more likely to have significant visual gains after cataract surgery. Although statistically significant differences exist in postoperative vision based on surgeon volume, these do not appear to be clinically meaningful. Overall, visual outcomes are functionally comparable across a wide range of surgeon volumes.

TREATMENT PATTERNS AND 2-YEAR VISION OUTCOMES WITH BEVACIZUMAB IN DIABETIC MACULAR EDEMA: An Analysis From a Large U.S. Integrated Health Care System.

PURPOSE: To assess health care utilization and vision outcomes over 2 years in patients receiving bevacizumab treatment in clinical practice for diabetic macular edema. METHODS: Patients with newly diagnosed diabetic macular edema who received an intravitreal bevacizumab injection within 12 months of initial diagnosis were identified from Kaiser Permanente's 350,000 patients with diabetes mellitus treated between 2008 and 2013. Snellen best-corrected visual acuity (BCVA), number of intravitreal injections, and patient characteristics were abstracted from the electronic record. The main outcome measure was change in BCVA. RESULTS: Three hundred and nine patients met the inclusion criteria and had 2 years of follow-up after their first bevacizumab injection. These patients had a mean of 3.1 injections (range, 1-17) during the 2-year follow-up. Mean BCVA improvement was 5.4 letters at 12 months and 5.3 letters at 24 months. Only 29.8% of patients demonstrated ≥3 lines of vision improvement from baseline, whereas 12.3% had ≥3 lines of vision loss from baseline at 24 months. CONCLUSION: This is the largest U.S. clinical practice-based study of bevacizumab use in diabetic macular edema. Consistent with national studies, the frequency of injection was low. Average BCVA improvement was lower than in anti-vascular endothelial growth factor trials. Significant BCVA improvement was achieved in approximately 30% of patients with newly diagnosed diabetic macular edema.

Rapid Bench to Bedside Therapeutic Bacteriophage Production.

It has been over 100 years since bacteriophages (phages) were used as a human therapeutic. Since then, phage production has dramatically evolved. Current phage preparations have fewer adverse effects due to their low bacterial toxin content. As a result, therapeutic phages have become a predominant class of new antimicrobials and are being widely used for compassionate treatment of multidrug-resistant (MDR) infections. We describe herein a protocol for the production and ultrapurification of phages. By this technique, it is possible for a lab experienced with the process to produce >109 plaque-forming units (PFU) per mL of Gram-negative phages that meet FDA endotoxins limits for intravenous infusions in as little as 48 hours. We provide illustrations of the process and tips on how to safely remove bacterial toxins from phage lysates. Although dependent on the phage strain, the approach described can rapidly generate and purify phages for a variety of applications.

Identifying Symptoms Prior to Pancreatic Ductal Adenocarcinoma Diagnosis in Real-World Care Settings: Natural Language Processing Approach.

BACKGROUND: Pancreatic cancer is the third leading cause of cancer deaths in the United States. Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer, accounting for up to 90% of all cases. Patient-reported symptoms are often the triggers of cancer diagnosis and therefore, understanding the PDAC-associated symptoms and the timing of symptom onset could facilitate early detection of PDAC. OBJECTIVE: This paper aims to develop a natural language processing (NLP) algorithm to capture symptoms associated with PDAC from clinical notes within a large integrated health care system. METHODS: We used unstructured data within 2 years prior to PDAC diagnosis between 2010 and 2019 and among matched patients without PDAC to identify 17 PDAC-related symptoms. Related terms and phrases were first compiled from publicly available resources and then recursively reviewed and enriched with input from clinicians and chart review. A computerized NLP algorithm was iteratively developed and fine-trained via multiple rounds of chart review followed by adjudication. Finally, the developed algorithm was applied to the validation data set to assess performance and to the study implementation notes. RESULTS: A total of 408,147 and 709,789 notes were retrieved from 2611 patients with PDAC and 10,085 matched patients without PDAC, respectively. In descending order, the symptom distribution of the study implementation notes ranged from 4.98% for abdominal or epigastric pain to 0.05% for upper extremity deep vein thrombosis in the PDAC group, and from 1.75% for back pain to 0.01% for pale stool in the non-PDAC group. Validation of the NLP algorithm against adjudicated chart review results of 1000 notes showed that precision ranged from 98.9% (jaundice) to 84% (upper extremity deep vein thrombosis), recall ranged from 98.1% (weight loss) to 82.8% (epigastric bloating), and F1-scores ranged from 0.97 (jaundice) to 0.86 (depression). CONCLUSIONS: The developed and validated NLP algorithm could be used for the early detection of PDAC.

Stomach Cancer Prediction Model (SCoPM): An approach to risk stratification in a diverse U.S. population.

BACKGROUND AND AIMS: Population-based screening for gastric cancer (GC) in low prevalence nations is not recommended. The objective of this study was to develop a risk-prediction model to identify high-risk patients who could potentially benefit from targeted screening in a racial/ethnically diverse regional US population. METHODS: We performed a retrospective cohort study from Kaiser Permanente Southern California from January 2008-June 2018 among individuals age ≥50 years. Patients with prior GC or follow-up <30 days were excluded. Censoring occurred at GC, death, age 85 years, disenrollment, end of 5-year follow-up, or study conclusion. Cross-validated LASSO regression models were developed to identify the strongest of 20 candidate predictors (clinical, demographic, and laboratory parameters). Records from 12 of the medical service areas were used for training/initial validation while records from a separate medical service area were used for testing. RESULTS: 1,844,643 individuals formed the study cohort (1,555,392 training and validation, 289,251 testing). Mean age was 61.9 years with 53.3% female. GC incidence was 2.1 (95% CI 2.0-2.2) cases per 10,000 person-years (pyr). Higher incidence was seen with family history: 4.8/10,000 pyr, history of gastric ulcer: 5.3/10,000 pyr, H. pylori: 3.6/10,000 pyr and anemia: 5.3/10,000 pyr. The final model included age, gender, race/ethnicity, smoking, proton-pump inhibitor, family history of gastric cancer, history of gastric ulcer, H. pylori infection, and baseline hemoglobin. The means and standard deviations (SD) of c-index in validation and testing datasets were 0.75 (SD 0.03) and 0.76 (SD 0.02), respectively. CONCLUSIONS: This prediction model may serve as an aid for pre-endoscopic assessment of GC risk for identification of a high-risk population that could benefit from targeted screening.

Pulsed low-dose-rate radiation (PLDR) reduces the tumor-promoting responses induced by conventional chemoradiation in pancreatic cancer-associated fibroblasts.

Pancreatic cancer is becoming increasingly deadly, with treatment options limited due to, among others, the complex tumor microenvironment (TME). This short communications study investigates pulsed low-dose-rate radiation (PLDR) as a potential alternative to conventional radiotherapy for pancreatic cancer neoadjuvant treatment. Our ex vivo research demonstrates that PLDR, in combination with chemotherapy, promotes a shift from tumor-promoting to tumor-suppressing properties in a key component of the pancreatic cancer microenvironment we called CAFu (cancer-associated fibroblasts and selfgenerated extracellular matrix functional units). This beneficial effect translates to reduced desmoplasia (fibrous tumor expansion) and suggests PLDR's potential to improve total neoadjuvant therapy effectiveness. To comprehensively assess this functional shift, we developed the HOST-Factor, a single score integrating multiple biomarkers. This tool provides a more accurate picture of CAFu function compared to individual biomarkers and could be valuable for guiding and monitoring future therapeutic strategies. Our findings support the ongoing NCT04452357 clinical trial testing PLDR safety and TME normalization potential in pancreatic cancer patients. The HOST-Factor will be used in samples collected from this trial to validate its potential as a key tool for personalized medicine in this aggressive disease.

Netrin G1 Ligand is a new stromal immunomodulator that promotes pancreatic cancer.

Understanding pancreatic cancer biology is fundamental for identifying new targets and for developing more effective therapies. In particular, the contribution of the stromal microenvironment to pancreatic cancer tumorigenesis requires further exploration. Here, we report the stromal roles of the synaptic protein Netrin G1 Ligand (NGL-1) in pancreatic cancer, uncovering its pro-tumor functions in cancer-associated fibroblasts and in immune cells. We observed that the stromal expression of NGL-1 inversely correlated with patients' overall survival. Moreover, germline knockout (KO) mice for NGL-1 presented decreased tumor burden, with a microenvironment that is less supportive of tumor growth. Of note, tumors from NGL-1 KO mice produced less immunosuppressive cytokines and displayed an increased percentage of CD8 + T cells than those from control mice, while preserving the physical structure of the tumor microenvironment. These effects were shown to be mediated by NGL-1 in both immune cells and in the local stroma, in a TGF-ß-dependent manner. While myeloid cells lacking NGL-1 decreased the production of immunosuppressive cytokines, NGL-1 KO T cells showed increased proliferation rates and overall polyfunctionality compared to control T cells. CAFs lacking NGL-1 were less immunosuppressive than controls, with overall decreased production of pro-tumor cytokines and compromised ability to inhibit CD8 + T cells activation. Mechanistically, these CAFs downregulated components of the TGF-ß pathway, AP-1 and NFAT transcription factor families, resulting in a less tumor-supportive phenotype. Finally, targeting NGL-1 genetically or using a functionally antagonistic small peptide phenocopied the effects of chemotherapy, while modulating the immunosuppressive tumor microenvironment (TME), rather than eliminating it. We propose NGL-1 as a new local stroma and immunomodulatory molecule, with pro-tumor roles in pancreatic cancer. Statement of Significance: Here we uncovered the pro-tumor roles of the synaptic protein NGL-1 in the tumor microenvironment of pancreatic cancer, defining a new target that simultaneously modulates tumor cell, fibroblast, and immune cell functions. This study reports a new pathway where NGL-1 controls TGF-ß, AP-1 transcription factor members and NFAT1, modulating the immunosuppressive microenvironment in pancreatic cancer. Our findings highlight NGL-1 as a new stromal immunomodulator in pancreatic cancer.

Heterologous expression of the C-terminal antigenic domain of the malaria vaccine candidate Pfs48/45 in the green algae Chlamydomonas reinhardtii.

Malaria is a widespread and infectious disease that is a leading cause of death in many parts of the world. Eradication of malaria has been a major world health goal for decades, but one that still remains elusive. Other diseases have been eradicated using vaccination, but traditional vaccination methods have thus far been unsuccessful for malaria. Infection by Plasmodium species, the causative agent of malaria, is currently treated with drug-based therapies, but an increase in drug resistance has led to the need for new methods of treatment. A promising strategy for malaria treatment is to combine transmission blocking vaccines (TBVs) that prevent spread of disease with drug-based therapies to treat infected individuals. TBVs can be developed against surface protein antigens that are expressed during parasite reproduction in the mosquito. When the mosquito ingests blood from a vaccinated individual harboring the Plasmodium parasite, the antibodies generated by vaccination prevent completion of the parasites life-cycle. Animal studies have shown that immunization with Pfs48/45 results in the production of malaria transmission blocking antibodies; however, the development of this vaccine candidate has been hindered by poor expression in both prokaryotic and eukaryotic hosts. Recently, the chloroplast of Chlamydomonas reinhardtii has been used to express complex recombinant proteins. In this study, we show that the C-terminal antigenic region of the Pfs48/45 antigen can be expressed in the chloroplast of the green algae C. reinhardtii and that this recombinant protein has a conformation recognized by known transmission blocking antibodies. Production of this protein in algae has the potential to scale to the very large volumes required to meet the needs of millions at risk for contracting malaria.

Immunogenicity of bacteriophages.

Hundreds of trillions of diverse bacteriophages (phages) peacefully thrive within and on the human body. However, whether and how phages influence their mammalian hosts is poorly understood. In this review, we explore current knowledge and present growing evidence that direct interactions between phages and mammalian cells often induce host inflammatory and antiviral immune responses. We show evidence that, like viruses of the eukaryotic host, phages are actively internalized by host cells and activate conserved viral detection receptors. This interaction often generates proinflammatory cytokine secretion and recruitment of adaptive immune programs. However, significant variability exists in phage-immune interactions, suggesting an important role for structural phage characteristics. The factors leading to the differential immunogenicity of phages remain largely unknown but are highly influenced by their human and bacterial hosts.

Controllers or Bare Hands? A Controlled Evaluation of Input Techniques on Interaction Performance and Exertion in Virtual Reality.

Virtual Reality (VR) systems have traditionally required users to operate the user interface with controllers in mid-air. More recent VR systems, however, integrate cameras to track the headset's position inside the environment as well as the user's hands when possible. This allows users to directly interact with virtual content in mid-air just by reaching out, thus discarding the need for hand-held physical controllers. However, it is unclear which of these two modalities-controller-based or free-hand interaction-is more suitable for efficient input, accurate interaction, and long-term use under reliable tracking conditions. While interacting with hand-held controllers introduces weight, it also requires less finger movement to invoke actions (e.g., pressing a button) and allows users to hold on to a physical object during virtual interaction. In this paper, we investigate the effect of VR input modality (controller vs. free-hand interaction) on physical exertion, agency, task performance, and motor behavior across two mid-air interaction techniques (touch, raycast) and tasks (selection, trajectory-tracing). Participants reported less physical exertion, felt more in control, and were faster and more accurate when using VR controllers compared to free-hand interaction in the raycast setting. Regarding personal preference, participants chose VR controllers for raycast but free-hand interaction for mid-air touch. Our correlation analysis revealed that participants' physical exertion increased with selection speed, quantity of arm motion, variation in motion speed, and bad postures, following ergonomics metrics such as consumed endurance and rapid upper limb assessment. We also found a negative correlation between physical exertion and the participant's sense of agency, and between physical exertion and task accuracy.