Developing hydrogels for gene therapy and tissue engineering.

Hydrogels are a class of highly absorbent and easily modified polymer materials suitable for use as slow-release carriers for drugs. Gene therapy is highly specific and can overcome the limitations of traditional tissue engineering techniques and has significant advantages in tissue repair. However, therapeutic genes are often affected by cellular barriers and enzyme sensitivity, and carrier loading of therapeutic genes is essential. Therapeutic gene hydrogels can well overcome these difficulties. Moreover, gene-therapeutic hydrogels have made considerable progress. This review summarizes the recent research on carrier gene hydrogels for the treatment of tissue damage through a summary of the most current research frontiers. We initially introduce the classification of hydrogels and their cross-linking methods, followed by a detailed overview of the types and modifications of therapeutic genes, a detailed discussion on the loading of therapeutic genes in hydrogels and their characterization features, a summary of the design of hydrogels for therapeutic gene release, and an overview of their applications in tissue engineering. Finally, we provide comments and look forward to the shortcomings and future directions of hydrogels for gene therapy. We hope that this article will provide researchers in related fields with more comprehensive and systematic strategies for tissue engineering repair and further promote the development of the field of hydrogels for gene therapy.

Multi-omics Analyses Reveal Function of Apolipoprotein E in Alternative Splicing and Tumor Immune Microenvironment in Kidney Renal Clear Cell Carcinoma via Pan-cancer Analysis.

Apolipoprotein E (APOE) regulates lipid metabolism, associated with the development of various cancers. However, its precise prognostic significance and functions in alternative splicing and the tumor immune microenvironment remain unclear. In this study, we extracted APOE expression in pan-cancer from TCGA and analyzed mRNA transcriptome, cell lines, and protein levels. Furthermore, we analyzed the alternative splicing expression of the APOE gene transcript with prognostic profiles using the OncoSplicing database. We obtained 73 common APOE genes to perform functional enrichment analysis, assess the correlation between genes and immune cells using TIMER, EPIC, and ssGSEA methods, and examine the prognostic significance using the UALCAN database. Finally, single-cell data was employed to assess the correlation between APOE genes and cell functions. Our findings revealed that APOE expression varies across different tumor types and cancer cell lines. The alternative splicing analysis demonstrated that APOE transcript expression levels have prognostic value in cancers such as LGG, KIRC, and KIRP. Functional enrichment analysis indicated significant associations between APOE and various immune cells, such as macrophages, CD8 T cells, and NK cells, with significant implications for prognosis. Moreover, single-cell data indicated that APOE was primarily expressed in renal epithelial cells among stromal cells and in macrophages among immune cells, significantly negatively correlated with five functional states. Our study represents the first comprehensive exploration of APOE's function in pan-cancers and identifies APOE as a potential biomarker in cancer pathogenesis, prognosis, and immune therapeutic target.

Differentiation between Phyllodes Tumors and Fibroadenomas through Breast Ultrasound: Deep-Learning Model Outperforms Ultrasound Physicians.

The preoperative differentiation of breast phyllodes tumors (PTs) from fibroadenomas (FAs) plays a critical role in identifying an appropriate surgical treatment. Although several imaging modalities are available, reliable differentiation between PT and FA remains a great challenge for radiologists in clinical work. Artificial intelligence (AI)-assisted diagnosis has shown promise in distinguishing PT from FA. However, a very small sample size was adopted in previous studies. In this work, we retrospectively enrolled 656 breast tumors (372 FAs and 284 PTs) with 1945 ultrasound images in total. Two experienced ultrasound physicians independently evaluated the ultrasound images. Meanwhile, three deep-learning models (i.e., ResNet, VGG, and GoogLeNet) were applied to classify FAs and PTs. The robustness of the models was evaluated by fivefold cross validation. The performance of each model was assessed by using the receiver operating characteristic (ROC) curve. The area under the curve (AUC), accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were also calculated. Among the three models, the ResNet model yielded the highest AUC value, of 0.91, with an accuracy value of 95.3%, a sensitivity value of 96.2%, and a specificity value of 94.7% in the testing data set. In contrast, the two physicians yielded an average AUC value of 0.69, an accuracy value of 70.7%, a sensitivity value of 54.4%, and a specificity value of 53.2%. Our findings indicate that the diagnostic performance of deep learning is better than that of physicians in the distinction of PTs from FAs. This further suggests that AI is a valuable tool for aiding clinical diagnosis, thereby advancing precision therapy.

A Novel Deep-Learning Method with Channel Attention Mechanism for Underwater Target Recognition.

The core of underwater acoustic recognition is to extract the spectral features of targets. The running speed and track of the targets usually result in a Doppler shift, which poses significant challenges for recognizing targets with different Doppler frequencies. This paper proposes deep learning with a channel attention mechanism approach for underwater acoustic recognition. It is based on three crucial designs. Feature structures can obtain high-dimensional underwater acoustic data. The feature extraction model is the most important. First, we develop a ResNet to extract the deep abstraction spectral features of the targets. Then, the channel attention mechanism is introduced in the camResNet to enhance the energy of stable spectral features of residual convolution. This is conducive to subtly represent the inherent characteristics of the targets. Moreover, a feature classification approach based on one-dimensional convolution is applied to recognize targets. We evaluate our approach on challenging data containing four kinds of underwater acoustic targets with different working conditions. Our experiments show that the proposed approach achieves the best recognition accuracy (98.2%) compared with the other approaches. Moreover, the proposed approach is better than the ResNet with a widely used channel attention mechanism for data with different working conditions.

Response of the somatosensory cortex following thermal stimuli to dental implants.

In the current study, we investigated the cortical response of the somatosensory cortex following thermal stimuli to dental implants. Five implants were inserted at the site of the left upper canine with immediate implant placement protocols in five cats. Intrinsic signal optical imaging was applied to measure the cortical responses evoked by thermal sensing via dental implants. The cortical response evoked by 60 g of tactile stimulus to implants was also examined. The response strength and activated location were compared between implants and natural teeth. Thermal stimuli via the implant could evoke reliable cortical responses in the tooth-related region. However, the response amplitude evoked by the cold stimuli applied to the implants was significantly lower than that evoked by the cold stimuli applied to the natural teeth, indicating that the implants were less sensitive to thermal change than the natural tooth. The response evoked by tactile stimuli to implants was significantly stronger than that evoked by cold stimuli. Thermal and tactile stimuli activated the same location of the tooth-related somatosensory cortex in both the implants and natural teeth. Therefore, the thermal change in implants could be detected at the cortical response level. Multimodal sensory integration of thermal and tactile functions existed for implants.

High Expression of THBS1 Leads to a Poor Prognosis in Papillary Thyroid Cancer and Suppresses the Anti-Tumor Immune Microenvironment.

Objectives: To study the role of thrombospondin-1 (THBS1) in papillary thyroid cancer (PTC) prognosis and the immune microenvironment. Methods: A retrospective cohort study was designed, and data from The Cancer Genome Atlas database and PTC tissues from Fudan University Shanghai Cancer Center were used. Weighted gene co-expression network analysis was performed to build a THBS1-immune-related gene prognostic index (T-I index). Results: High THBS1 expression was correlated with advanced TNM stage, higher recurrence risk, and shorter progression-free interval. High THBS1 expression correlated with MAPK and PD1 pathways indicating a tumor promoting and immunity-inhibiting tendency. The T-I index showed a powerful capacity to predict progression-free survival and immunotherapy benefit. Conclusion: High expression of THBS1 leads to a poor prognosis in PTCs and suppresses the anti-tumor immune microenvironment.

Outcomes of Talar Osteochondral and Transchondral Lesions Using an Algorithmic Approach Based on Size, Location, and Subchondral Plate Integrity: A 10-Year Study on 204 Lesions.

The management of transchondral and osteochondral talar lesions has evolved, with microfracturing originally considered the best initial treatment. Despite talar lesions being a tri-dimensional defect, most studies use 2-dimensional parameters to grade them. We propose in this study that tri-dimensional sizing may be more appropriate in evaluation for treatment. The present study evaluated the outcomes of treatment of talar lesions performed by a single surgeon, creating and using an algorithm based on volume, location, and integrity of the subchondral plate. The lesions were classified as "small" (up to 125 mm3), "medium" (125 mm3-1500 mm3), and "large" (>1500 mm3) based upon evaluation of the preoperative magnetic resonance imagining. Location of the lesion was also noted on a 9-region grid pattern of the talar dome. These 3 parameters dictated whether a lesion required microfracturing or retrograde drilling, autogenous or allogenous bone graft, and whether an open versus an arthroscopic approach was required. Over a 10-year period, surgery was performed on 204 lesions. Overall, the average time to return to activity was 7.93 ± 5.00 (range 2-36) months. The average preoperative American Orthopaedic Foot and Ankle score was 76.44 ± 10.98 (range 52-86), and the average postoperative American Orthopaedic Foot and Ankle score was 96.12 ± 3.46 (range 81-100), p = .0001. By using the proposed algorithm, the outcome and return to activity for most patients can be better predicted, regardless of the size or location of the osteochondral lesion. The treatment algorithm implemented in the present investigation yielded overall acceptable results, with only 7 of the 204 lesions needing additional surgery.

The role of gingival mechanoreceptors in the tactile function of dental implants.

Dental implants seem to restore some degree of tactile function. The aim of this study was to investigate the role of gingival mechanoreceptors in dental-implant osseoperception at the cortical-response level. The gingiva of the upper-left canine implant was stripped off under local anesthesia in five cats. We used intrinsic-signal optical imaging (ISOI) to measure the population-response characteristics of the feline oral-related cortex when separately applying punctate mechanical stimuli to the left canine implant and right intact natural canine. These response characteristics were compared under local anesthesia after removal of the gingiva. Under local anesthesia, the signal strength of the implant was significantly weaker than that of the tooth under weak but not under strong stimulus. After the gingiva was stripped off, the signal strength of the implant was significantly weaker than that of the tooth at all strengths of stimulus. Based on the evoked cortical responses, the gingiva was involved in the maximal tactile function of the implant.

Incidence of Lung Cancer Among Never-Smoking Asian American, Native Hawaiian, and Pacific Islander Females.

BACKGROUND: Although lung cancer incidence rates according to smoking status, sex, and detailed race/ethnicity have not been available, it is estimated that more than half of Asian American, Native Hawaiian, and Pacific Islander (AANHPI) females with lung cancer have never smoked. METHODS: We calculated age-adjusted incidence rates for lung cancer according to smoking status and detailed race/ethnicity among females, focusing on AANHPI ethnic groups, and assessed relative incidence across racial/ethnic groups. We used a large-scale dataset that integrates data from electronic health records from 2 large health-care systems-Sutter Health in Northern California and Kaiser Permanente Hawai'i-linked to state cancer registries for incident lung cancer diagnoses between 2000 and 2013. The study population included 1 222 694 females (n = 244 147 AANHPI), 3297 of which were diagnosed with lung cancer (n = 535 AANHPI). RESULTS: Incidence of lung cancer among never-smoking AANHPI as an aggregate group was 17.1 per 100 000 (95% confidence interval [CI] = 14.9 to 19.4) but varied widely across ethnic groups. Never-smoking Chinese American females had the highest rate (22.8 per 100 000, 95% CI = 17.3 to 29.1). Except for Japanese American females, incidence among every never-smoking AANHPI female ethnic group was higher than that of never-smoking non-Hispanic White females, from 66% greater among Native Hawaiian females (incidence rate ratio = 1.66, 95% CI = 1.03 to 2.56) to more than 100% greater among Chinese American females (incidence rate ratio = 2.26, 95% CI = 1.67 to 3.02). CONCLUSIONS: Our study revealed high rates of lung cancer among most never-smoking AANHPI female ethnic groups. Our approach illustrates the use of innovative data integration to dispel the myth that AANHPI females are at overall reduced risk of lung cancer and demonstrates the need to disaggregate this highly diverse population.

Tactile sensation of natural teeth and dental implants in the somatosensory cortex.

PURPOSE: This study aimed to investigate the cortical response characteristics evoked by natural teeth and implants. METHODS: Five cats were subjected to intrinsic signal optical imaging to measure the cortical responses evoked by natural teeth and implants. The difference in tactile sensation between the implant and natural tooth was compared in detail at the cortical response level. RESULTS: Some similarities were observed between the implants and natural teeth. The stimulating-response curves of the implants and natural teeth were generally S-curves, and both implants and natural teeth preferred labial-lingual direction stimulation. The implants and natural teeth differed in terms of their tactile sensitivity: implants were weaker than natural teeth in terms of both static and dynamic sensitivity. However, after saturation, there was no significant difference in tactile strength between implants and natural teeth. CONCLUSION: Both natural teeth and implants are able to distinguish the tactile strength and stimulation direction. Although implants are less sensitive than the natural tooth, the maximal tactile function and directional preference of implants are similar to those of natural teeth.

Road to Better Work-Life Balance? Lean Redesigns and Daily Work Time among Primary Care Physicians.

PURPOSE: To assess the impact of Lean primary care redesigns on the amount of time that physicians spent working each day. METHODS: This observational study was based on 92 million time-stamped Epic® EHR access logs captured among 317 primary care physicians in a large ambulatory care delivery system. Seventeen clinic facilities housing 46 primary care departments were included for study. We conducted interrupted time series analysis to monitor changes in physician work patterns over 6 years. Key measures included total daily work time; time spent on "desktop medicine" outside the exam room; time spent with patients during office visits; time still working after clinic, i.e., after seeing the last patient each day; and remote work time. RESULTS: The amount of time that physicians spent on desktop EHR activities throughout the day, including after clinic hours, decreased by 10.9% (95% CI: -22.2, -2.03) and 8.3% (95% CI: -13.8, -2.12), respectively, during the first year of Lean implementation. Total daily work hours among physicians, which included both desktop activity and time in office visits, decreased by 20% (95% CI: -29.2, -9.60) by the third year of Lean implementation. CONCLUSIONS: These findings suggest that Lean redesign may be associated with time savings for primary care physicians. However, since this was an observational analysis, further study is warranted (e.g., randomized trial) -to determine the impact of Lean interventions on physician work experiences.

Application of preoperative ultrasound features combined with clinical factors in predicting HER2-positive subtype (non-luminal) breast cancer.

BACKGROUND: Human epidermal growth factor receptor2+ subtype breast cancer has a high degree of malignancy and a poor prognosis. The aim of this study is to develop a prediction model for the human epidermal growth factor receptor2+ subtype (non-luminal) of breast cancer based on the clinical and ultrasound features related with estrogen receptor, progesterone receptor, and human epidermal growth factor receptor2. METHODS: We collected clinical data and reviewed preoperative ultrasound images of enrolled breast cancers from September 2017 to August 2020. We divided the data into in three groups as follows. Group I: estrogen receptor ± , Group II: progesterone receptor ± and Group III: human epidermal growth factor receptor2 ± . Univariate and multivariate logistic regression analyses were used to analyze the clinical and ultrasound features related with biomarkers among these groups. A model to predict human epidermal growth factor receptor2+ subtype was then developed based on the results of multivariate regression analyses, and the efficacy was evaluated using the area under receiver operating characteristic curve, accuracy, sensitivity, specificity. RESULTS: The human epidermal growth factor receptor2+ subtype accounted for 138 cases (11.8%) in the training set and 51 cases (10.1%) in the test set. In the multivariate regression analysis, age ≤ 50 years was an independent predictor of progesterone receptor + (p = 0.007), and posterior enhancement was a negative predictor of progesterone receptor + (p = 0.013) in Group II; palpable axillary lymph node, round, irregular shape and calcifications were independent predictors of the positivity for human epidermal growth factor receptor-2 in Group III (p = 0.001, p = 0.007, p = 0.010, p < 0.001, respectively). In Group I, shape was the only factor related to estrogen receptor status in the univariate analysis (p < 0.05). The area under receiver operating characteristic curve, accuracy, sensitivity, specificity of the model to predict human epidermal growth factor receptor2+ subtype breast cancer was 0.697, 60.14%, 72.46%, 58.49% and 0.725, 72.06%, 64.71%, 72.89% in the training and test sets, respectively. CONCLUSIONS: Our study established a model to predict the human epidermal growth factor receptor2-positive subtype with moderate performance. And the results demonstrated that clinical and ultrasound features were significantly associated with biomarkers.

Exploring Somatic Alteration Associating With Aggressive Behaviors of Papillary Thyroid Carcinomas by Targeted Sequencing.

Wisely differentiating high-risk papillary thyroid carcinoma (PTC) patients from low-risk PTC patients preoperatively is necessary when comes to making a personalized treatment plan. It is not easy to stratify the risk of patients according to sonography or lab results before surgery. This study aims to seek out potential mutation gene markers that may be helpful in stratifying the risk of PTC. A custom panel of 439 PTC relevant and classic tumor metabolic pathway relevant genes was designed. Targeted capture sequencing was performed on 35 pairs of samples from 35 PTC tumors and 35 para-tumor thyroid tissues obtained during surgery. Variant calling and detection of cancer gene mutations were identified by bio-information analysis. Ingenuity Pathway Analysis (IPA) was performed to do functional enrichment analysis of high-frequency mutant genes. Immunohistochemistry (IHC) was performed on 6 PTC patients to explore the expression of protein associated with interested genes. Event-free survival (EFS) was calculated to determine which genes might affect the prognosis of patients. We have identified 32 high-frequency mutant genes in PTC including BRAF. RBL2 was found to be significantly correlated to event-free survival, FOXO1, MUC6, PCDHB9, NOTCH1, FIZ1, and RTN1 were significantly associated with EFS, while BRAF mutant was not correlated to any of the prognosis indicators. Our findings in this study might open more choices when designing thyroid gene panels used in FNA samples to diagnose PTC and predict the potentially aggressive behavior of PTC.

Investigating the role of gingiva in the tactile function of teeth at the cortical level.

The role of the gingiva in the tactile perception of teeth is unclear, and the physiological basis of tooth tactile function needs to be examined at the cortical response level. In the presented study, gingiva from the upper left canine was removed under local anesthesia from five cats. Intrinsic signal optical imaging was used to measure population response characteristics of the cat oral-related cortex when punctate mechanical stimuli were separately applied to the left gingiva-stripped canine and right intact canine. Then, their response characteristics were compared. There were no significant differences in the cortical response strength between the anesthetized and unanesthetized canines. Signal strength of the gingiva-stripped tooth was significantly weaker than that of the intact tooth at low stimulus strength. However, no significant differences between the gingiva-stripped tooth and intact tooth were found after saturation. Based on the evoked cortical responses, the gingiva is involved in low-intensity tactile perception of teeth, which could explain the reason why chronic gingivitis results in the paresthesia of natural teeth.

Insertional Achilles Tendinopathy: Analysis of 166 Procedures and Return to Activity.

The surgical procedure for Insertional Achilles tendinopathy (IAT) varies widely with no consensus as to approach and documenting return to activity (RTA). This study presents outcomes of surgery for IAT by a single surgeon, documenting activity level and return to activity. From January 2001 through January 2018, 166 procedures were reviewed. Surgery included debridement of the Achilles insertion, resection of the superior calcaneus and bursa, and re-attachment with suture anchors. There were 110 males and 56 females. The majority of patients in the entire cohort were runners (n = 54). The average age of the cohort was 50.3 ± 12.1 years (range 20-80). Average follow-up was 114.0 ± 63.5 months (range 6-222 months). Average RTA for males and females were 6.43 months and 7.22 months, (p = .2), respectively. There was no difference in RTA between patients who had calcific tendinosis (n = 84) and noncalcific tendinosis (n = 82). Complications were 2 infections, 2 DVTs, and 17 deep suture reactions with a total complication rate of 12.6%; there were no re-ruptures postoperatively. There was no significant difference in number of complications between absorbable and nonabsorbable suture in the anchors (p = .41). The average RM score was 1.5 ± 0.7. The RM scores were better for males (p = .002), but there were no differences in RTA or complications between sexes. Overall, 95.8% of the procedures resulted in improved outcome and ability to return to activity including sports. This retrospective investigation shows surgical intervention for IAT yields good results with an average return to activity including sports in approximately 7 months.

Acute Achilles Tendon Rupture Repair in Athletically Active Patients: Results on 188 Tendons.

We report on the outcome of acute Achilles tendon ruptures by a single surgeon using open and percutaneous techniques was performed. This prospective study included 186 patients with 188 ruptured Achilles tendons. A traditional open technique was primarily performed on patients from January 2001 to December 2011. From January 2012 to January 2018, a percutaneous repair was primarily performed. Outcome measures included the Roles and Maudsley (RM) score, ability to perform a single leg heel raise, calf atrophy and return to activity. There were 149 males (average age 42.5 ± 12.7 years) and 39 females (average age 41.7 ± 11.4 years). Of the 188 ruptured tendons (92 repairs on the right Achilles and 96 on the left), 103 were repaired percutaneously and 85 had open repairs. There were 18 (9.6%) complications. Three re-ruptures occurred, one following open and two following percutaneous repairs, all within 12 weeks of the original repair. Two patients developed a Venousthromboembolism (1.0%). Thirteen patients had suture reactions; three infections (1.6%), 11 wound complications (5.8%), and 3 required surgical excision of the suture material (1.6%). Non-absorbable sutures were associated with more wound complications and were more frequently used in open repairs (p = .003). Patients who underwent open repair experienced more wound complications (p = .0001). Patients who underwent percutaneous repair using absorbable suture experienced a lower rate of overall complications (p = .0007). Basketball (n = 29) was the most common sport during which ruptures occurred. Return to activity (RTA) was 8.2 ± 2.9 months. There was no difference for RTA between males and females (p = .54) and RM scores (p= .69), nor surgical technique, and no difference for RTA based on the desired activity (p = .47). 123 of the 188 patients returned to their desired activity (65.5%). There was a statistically significant evidence of a positive association between inability to perform heel-raises and decreased activity (p = .01).

Integrating Electronic Health Record, Cancer Registry, and Geospatial Data to Study Lung Cancer in Asian American, Native Hawaiian, and Pacific Islander Ethnic Groups.

BACKGROUND: A relatively high proportion of Asian American, Native Hawaiian, and Pacific Islander (AANHPI) females with lung cancer have never smoked. We used an integrative data approach to assemble a large-scale cohort to study lung cancer risk among AANHPIs by smoking status with attention to representation of specific AANHPI ethnic groups. METHODS: We leveraged electronic health records (EHRs) from two healthcare systems-Sutter Health in northern California and Kaiser Permanente Hawai'i-that have high representation of AANHPI populations. We linked EHR data on lung cancer risk factors (i.e., smoking, lung diseases, infections, reproductive factors, and body size) to data on incident lung cancer diagnoses from statewide population-based cancer registries of California and Hawai'i for the period between 2000 and 2013. Geocoded address data were linked to data on neighborhood contextual factors and regional air pollutants. RESULTS: The dataset comprises over 2.2 million adult females and males of any race/ethnicity. Over 250,000 are AANHPI females (19.6% of the female study population). Smoking status is available for over 95% of individuals. The dataset includes 7,274 lung cancer cases, including 613 cases among AANHPI females. Prevalence of never-smoking status varied greatly among AANHPI females with incident lung cancer, from 85.7% among Asian Indian to 14.4% among Native Hawaiian females. CONCLUSION: We have developed a large, multilevel dataset particularly well-suited to conduct prospective studies of lung cancer risk among AANHPI females who never smoked. IMPACT: The integrative data approach is an effective way to conduct cancer research assessing multilevel factors on cancer outcomes among small populations.

Patient experiences after implementing lean primary care redesigns.

OBJECTIVE: To examine the effect of Lean primary care redesigns on patient satisfaction with care and timeliness of care received. DATA/SETTING: We used patient surveys and time-stamped electronic health record (EHR) data in a large ambulatory care system. DESIGN: Lean-based changes to clinical spaces and care team workflows were implemented in one pilot site and then scaled to all primary care departments across the system. Redesigns included standardizing equipment and patient education materials in examination rooms, streamlining call management functions, co-locating physician and medical assistant dyads in a shared workspace, and creating new care team workflows. We used a non-randomized stepped-wedge study design and segmented regression with interrupted time series analysis to examine Lean impacts on patient outcomes. DATA COLLECTION: We analyzed patient satisfaction ratings and wait times as documented by the EHR. These longitudinal data were collected for 317 physician-led teams in 46 primary care departments from January 2011 to December 2016. PRINCIPAL FINDINGS: After implementation of Lean redesigns, patients reported a 44.8 percent increase in satisfaction with the adequacy of time spent with care providers during office visits (P < .05). They also reported 71.6 percent higher satisfaction with their care provider's ability to listen to their concerns, and a 55.4 percent increase in perceived staff helpfulness at the visit (P < .01). Based on monthly EHR data, the amount of time elapsed between a patient request for a routine appointment and the scheduled visit day decreased from baseline by an average 2 percent per month (P < .01). On the day of the visit, patient wait times to be seen also decreased gradually by an average 1.2 percent per month (P < .05). CONCLUSIONS: Patient experiences of care after Lean implementations have not been widely studied in primary care settings. We found that Lean redesign yielded improvements that may strengthen clinical operations while enhancing value for patients.

History of Cholecystectomy and Risk of Clostridium Difficile Infection.

BACKGROUND: Cholecystectomy affects bile acid physiology. There is growing evidence that both primary and secondary bile acids play a role in the pathogenesis of Clostridium difficile infections (CDIs). AIMS: The aim of this study is to elucidate the relationship and risk of CDI in patients with cholecystectomy. METHODS: We performed a matched cohort study of patients in an integrated healthcare system in Northern California from January 2000 to December 2018. Patients with cholecystectomy (cases, n = 12,617) identified based on Current Procedure Terminology codes were age- and sex-matched to patients without cholecystectomy (controls, n = 37,851). We excluded those with history of CDI at baseline and calculated the hazard ratio (HR) for development of CDI after adjusting for confounders. RESULTS: We found total of 351 incident CDI during average of 4.66 years of follow-up among cases and controls. In multivariate analysis, cholecystectomy was associated with elevated risk of CDI (HR 1.53, 95% confidence interval 1.14-2.04) compared with controls. Stratified analysis shows this effect does not differ according use of proton pump inhibitors (Pinteraction = 0.142), antibiotics (Pinteraction = 0.387), and hospitalization (Pinteraction = 0.252). CONCLUSIONS: Cholecystectomy is associated with mild increased risk of incident CDI, but this effect is not influenced by use of proton pump inhibitors, antibiotics, or hospitalization. Future prospective studies should be conducted to validate these findings and evaluate bile acid changes after a cholecystectomy.

Population-Based Registry Linkages to Improve Validity of Electronic Health Record-Based Cancer Research.

BACKGROUND: There is tremendous potential to leverage the value gained from integrating electronic health records (EHR) and population-based cancer registry data for research. Registries provide diagnosis details, tumor characteristics, and treatment summaries, while EHRs contain rich clinical detail. A carefully conducted cancer registry linkage may also be used to improve the internal and external validity of inferences made from EHR-based studies. METHODS: We linked the EHRs of a large, multispecialty, mixed-payer health care system with the statewide cancer registry and assessed the validity of our linked population. For internal validity, we identify patients that might be "missed" in a linkage, threatening the internal validity of an EHR study population. For generalizability, we compared linked cases with all other cancer patients in the 22-county EHR catchment region. RESULTS: From an EHR population of 4.5 million, we identified 306,554 patients with cancer, 26% of the catchment region patients with cancer; 22.7% of linked patients were diagnosed with cancer after they migrated away from our health care system highlighting an advantage of system-wide linkage. We observed demographic differences between EHR patients and non-EHR patients in the surrounding region and demonstrated use of selection probabilities with model-based standardization to improve generalizability. CONCLUSIONS: Our experiences set the foundation to encourage and inform researchers interested in working with EHRs for cancer research as well as provide context for leveraging linkages to assess and improve validity and generalizability. IMPACT: Researchers conducting linkages may benefit from considering one or more of these approaches to establish and evaluate the validity of their EHR-based populations.See all articles in this CEBP Focus section, "Modernizing Population Science."