Associations of semaglutide with incidence and recurrence of alcohol use disorder in real-world population.

Alcohol use disorders are among the top causes of the global burden of disease, yet therapeutic interventions are limited. Reduced desire to drink in patients treated with semaglutide has raised interest regarding its potential therapeutic benefits for alcohol use disorders. In this retrospective cohort study of electronic health records of 83,825 patients with obesity, we show that semaglutide compared with other anti-obesity medications is associated with a 50%-56% lower risk for both the incidence and recurrence of alcohol use disorder for a 12-month follow-up period. Consistent reductions were seen for patients stratified by gender, age group, race and in patients with and without type 2 diabetes. Similar findings are replicated in the study population with 598,803 patients with type 2 diabetes. These findings provide evidence of the potential benefit of semaglutide in AUD in real-world populations and call for further randomized clinicl trials.

Integrating predictive coding and a user-centric interface for enhanced auditing and quality in cancer registry data.

Data curation for a hospital-based cancer registry heavily relies on the labor-intensive manual abstraction process by cancer registrars to identify cancer-related information from free-text electronic health records. To streamline this process, a natural language processing system incorporating a hybrid of deep learning-based and rule-based approaches for identifying lung cancer registry-related concepts, along with a symbolic expert system that generates registry coding based on weighted rules, was developed. The system is integrated with the hospital information system at a medical center to provide cancer registrars with a patient journey visualization platform. The embedded system offers a comprehensive view of patient reports annotated with significant registry concepts to facilitate the manual coding process and elevate overall quality. Extensive evaluations, including comparisons with state-of-the-art methods, were conducted using a lung cancer dataset comprising 1428 patients from the medical center. The experimental results illustrate the effectiveness of the developed system, consistently achieving F1-scores of 0.85 and 1.00 across 30 coding items. Registrar feedback highlights the system's reliability as a tool for assisting and auditing the abstraction. By presenting key registry items along the timeline of a patient's reports with accurate code predictions, the system improves the quality of registrar outcomes and reduces the labor resources and time required for data abstraction. Our study highlights advancements in cancer registry coding practices, demonstrating that the proposed hybrid weighted neural-symbolic cancer registry system is reliable and efficient for assisting cancer registrars in the coding workflow and contributing to clinical outcomes.

Macrophage PET imaging in mouse models of cardiovascular disease and cancer with an apolipoprotein-inspired radiotracer.

Macrophages are key inflammatory mediators in many pathological conditions, including cardiovascular disease (CVD) and cancer, the leading causes of morbidity and mortality worldwide. This makes macrophage burden a valuable diagnostic marker and several strategies to monitor these cells have been reported. However, such strategies are often high-priced, non-specific, invasive, and/or not quantitative. Here, we developed a positron emission tomography (PET) radiotracer based on apolipoprotein A1 (ApoA1), the main protein component of high-density lipoprotein (HDL), which has an inherent affinity for macrophages. We radiolabeled an ApoA1-mimetic peptide (mA1) with zirconium-89 (89Zr) to generate a lipoprotein-avid PET probe (89Zr-mA1). We first characterized 89Zr-mA1's affinity for lipoproteins in vitro by size exclusion chromatography. To study 89Zr-mA1's in vivo behavior and interaction with endogenous lipoproteins, we performed extensive studies in wildtype C57BL/6 and Apoe-/- hypercholesterolemic mice. Subsequently, we used in vivo PET imaging to study macrophages in melanoma and myocardial infarction using mouse models. The tracer's cell specificity was assessed by histology and mass cytometry (CyTOF). Our data show that 89Zr-mA1 associates with lipoproteins in vitro. This is in line with our in vivo experiments, in which we observed longer 89Zr-mA1 circulation times in hypercholesterolemic mice compared to C57BL/6 controls. 89Zr-mA1 displayed a tissue distribution profile similar to ApoA1 and HDL, with high kidney and liver uptake as well as substantial signal in the bone marrow and spleen. The tracer also accumulated in tumors of melanoma-bearing mice and in the ischemic myocardium of infarcted animals. In these sites, CyTOF analyses revealed that natZr-mA1 was predominantly taken up by macrophages. Our results demonstrate that 89Zr-mA1 associates with lipoproteins and hence accumulates in macrophages in vivo. 89Zr-mA1's high uptake in these cells makes it a promising radiotracer for non-invasively and quantitatively studying conditions characterized by marked changes in macrophage burden.

Unplanned rehospitalisation due to medication harm following an Acute Myocardial Infarction.

Introduction The contribution of medication harm to rehospitalisation and adverse patient outcomes after an acute myocardial infarction (AMI) needs exploration. Rehospitalisation is costly to both patients and the healthcare facility. Following an AMI, patients are at risk of medication harm as they are often older, have multiple comorbidities and polypharmacy. This study aimed to quantify and evaluate medication harm causing unplanned rehospitalisation after an AMI. Methods This was a retrospective cohort study of patients discharged from a quaternary hospital post-AMI. All rehospitalisations within 18 months were identified using medical record review and coding data. The primary outcome measure was medication harm rehospitalisation. Preventability, causality and severity assessments of medication harm were conducted. Results A total of 1564 patients experienced an AMI and 415 (26.5%) were rehospitalised. Eighty-nine patients (5.7% of total population; 6.0% of those discharged) experienced a total of 101 medication harm events. Those with medication harm were older (p=0.007) and had higher rates of heart failure (p=0.005), chronic kidney disease (CKD) (p=0.046), chronic obstructive pulmonary disease (COPD) (p=0.037) and a prior history of ischaemic heart disease (p=0.005). Gastrointestinal (GI) bleeding, acute kidney injury (AKI) and hypotension were the most common medication harm events. Forty percent of events were avoidable and 84% were classed as 'serious'. Furosemide, antiplatelets and angiotensin-converting enzyme inhibitors (ACEi) were the most commonly implicated medications. The median time to medication harm rehospitalisation was 79 days (interquartile range [IQR]: 16-200 days). Conclusion Medication harm causes unplanned rehospitalisation in 5.7% of all AMI patients (1 in 17 patients; 6.0% of those discharged). The majority of harm was serious and occurred within the first 200 days of discharge. This study highlights that measures to attenuate the risk of medication harm rehospitalisation are essential, including post-discharge medication management.

A web-based tool for real-time adequacy assessment of kidney biopsies.

The escalating incidence of kidney biopsies providing insufficient tissue for diagnosis poses a dual challenge, straining the healthcare system and jeopardizing patients who may require rebiopsy or face the prospect of an inaccurate diagnosis due to an unsampled disease. Here, we introduce a web-based tool that can provide real-time, quantitative assessment of kidney biopsy adequacy directly from photographs taken with a smartphone camera. The software tool was developed using a deep learning-driven automated segmentation technique, trained on a dataset comprising nephropathologist-confirmed annotations of the kidney cortex on digital biopsy images. Our framework demonstrated favorable performance in segmenting the cortex via 5-fold cross-validation (Dice coefficient: 0.788±0.130) (n=100). Offering a bedside tool for kidney biopsy adequacy assessment has the potential to provide real-time guidance to the physicians performing medical kidney biopsies, reducing the necessity for re-biopsies. Our tool can be accessed through our web-based platform: http://www.biopsyadequacy.org.

Lisocabtagene maraleucel for treatment of relapsed and refractory primary mediastinal large B-cell lymphoma in an adolescent patient.

The safety and efficacy of CAR T-cell therapy are unknown in pediatric and adolescent patients with relapsed or refractory primary mediastinal large B-cell lymphoma (R/R PMBCL) which is associated with dismal prognosis. Here, we present a case report of a 16-year-old patient with R/R PMBCL treated with lisocabtagene maraleucel including correlative studies. Patient achieved complete response at 6 months without cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. She only experienced mild cytopenias, requiring filgrastim once. This report highlights the safety and efficacy of lisocabtagene maraleucel in this population, warranting prospective studies to improve clinical outcomes.

Comprehensive Factors for Predicting the Complications of Diabetes Mellitus: A Systematic Review.

BACKGROUND: This article focuses on extracting a standard feature set for predicting the complications of diabetes mellitus by systematically reviewing the literature. It is conducted and reported by following the guidelines of PRISMA, a well-known systematic review and meta-analysis method. The research articles included in this study are extracted using the search engine "Web of Science" over eight years. The most common complications of diabetes, diabetic neuropathy, retinopathy, nephropathy, and cardiovascular diseases are considered in the study. METHOD: The features used to predict the complications are identified and categorised by scrutinising the standards of electronic health records. RESULT: Overall, 102 research articles have been reviewed, resulting in 59 frequent features being identified. Nineteen attributes are recognised as a standard in all four considered complications, which are age, gender, ethnicity, weight, height, BMI, smoking history, HbA1c, SBP, eGFR, DBP, HDL, LDL, total cholesterol, triglyceride, use of insulin, duration of diabetes, family history of CVD, and diabetes. The existence of a well-accepted and updated feature set for health analytics models to predict the complications of diabetes mellitus is a vital and contemporary requirement. A widely accepted feature set is beneficial for benchmarking the risk factors of complications of diabetes. CONCLUSION: This study is a thorough literature review to provide a clear state of the art for academicians, clinicians, and other stakeholders regarding the risk factors and their importance.

Metacarpal Shortening with Intramedullary Screw Fixation: A Cadaveric Study.

Background Intramedullary screw fixation is a commonly used technique for the management of metacarpal fractures. However, compression across the fracture site can lead to unintentional shortening of the metacarpal. Questions/Purposes Our aim was to evaluate the risk of overshortening with differing intramedullary device designs for fixation of metacarpals. Methods The small finger metacarpal of nine fresh-frozen cadavers were included. A metacarpal neck fracture was simulated with a 5-mm osteotomy. Three different intramedullary screw designs were compared. Each screw was placed in a retrograde fashion into the intramedullary canal and the amount of shortening measured. Screws were reversed and the number of reverse turns with the screwdriver needed to release overshortening were measured. Results The average shortening at the osteotomy site was 2.5 mm. The mean shortening was 80%, 58%, and 12% for the partially threaded screw, fully threaded screw, and threaded nail, respectively. The mean differences of the distance shortened were statistically significant for the threaded nail compared with the partially and fully threaded screws. The partially threaded screw had the most shortening, while the threaded nail provided the least amount of shortening. When the screws were reversed, the screws did not disengage until the screw was fully removed from the osteotomy site. Conclusion The fully threaded nail demonstrates less shortening and possibly minimizes overshortening of fractures compared with partially threaded and fully threaded screw designs. Overshortening cannot be corrected by unscrewing the screw unless completely removed from the distal fragment. Clinical Relevance Orthopaedic surgeons may select intermedullary screws based on the design that is suited for the particular metacarpal fracture pattern.

Association of semaglutide with risk of suicidal ideation in a real-world cohort.

Concerns over reports of suicidal ideation associated with semaglutide treatment, a glucagon-like peptide 1 receptor (GLP1R) agonist medication for type 2 diabetes (T2DM) and obesity, has led to investigations by European regulatory agencies. In this retrospective cohort study of electronic health records from the TriNetX Analytics Network, we aimed to assess the associations of semaglutide with suicidal ideation compared to non-GLP1R agonist anti-obesity or anti-diabetes medications. The hazard ratios (HRs) and 95% confidence intervals (CIs) of incident and recurrent suicidal ideation were calculated for the 6-month follow-up by comparing propensity score-matched patient groups. The study population included 240,618 patients with overweight or obesity who were prescribed semaglutide or non-GLP1R agonist anti-obesity medications, with the findings replicated in 1,589,855 patients with T2DM. In patients with overweight or obesity (mean age 50.1 years, 72.6% female), semaglutide compared with non-GLP1R agonist anti-obesity medications was associated with lower risk for incident (HR = 0.27, 95% CI = 0.200.32-0.600.36) and recurrent (HR = 0.44, 95% CI = 0.32-0.60) suicidal ideation, consistent across sex, age and ethnicity stratification. Similar findings were replicated in patients with T2DM (mean age 57.5 years, 49.2% female). Our findings do not support higher risks of suicidal ideation with semaglutide compared with non-GLP1R agonist anti-obesity or anti-diabetes medications.

GLP-1 Receptor Agonists and Colorectal Cancer Risk in Drug-Naive Patients With Type 2 Diabetes, With and Without Overweight/Obesity.

This cohort study compares glucagon-like peptide 1 receptor agonists (GLP-1RAs) with 7 non­GLP-1RA antidiabetics among drug-naive patients with type 2 diabetes.

Gender differences in cardiovascular disease risk: Adolescence to young adulthood.

BACKGROUND AND AIMS: Gender differences in cardiovascular disease (CVD) have been well documented but rarely for young adults and the extent to which gender related lifestyle differences may contribute to gender differences in CVD risk experienced by young adults have not been reported. METHODS AND RESULTS: Data are from a long-running cohort study, the Mater-University of Queensland Study of Pregnancy (MUSP). We track gender differences in CVD related behaviours at 21 and 30 years (consumption of a Western Diet/Health-Oriented Diet, cigarette smoking, vigorous physical exercise, heavy alcohol consumption). At 30 years we compare males and females for CVD risk, and the extent to which lifestyle behaviours at 21 and 30 years contribute to CVD risk. At both 21 and 30 years of age, males more frequently consume a Western Diet and less often a Health Oriented Diet. By contrast, males are also much more likely to report engaging in vigorous physical activity. On most CVD markers, males exhibit much higher levels of risk than do females at both 21 and 30 years. At 30 years of age males have about five times the odds of being at high risk of CVD. Some lifestyle behaviours contribute to this additional risk. CONCLUSION: Young adult males much more frequently engage in most CVD related risk behaviours and males have a higher level of CVD risk. Gender differences in CVD risk remain high even after adjustment for CVD lifestyles, though dietary factors independently contribute to CVD risk at 30 years.

Selective prediction for extracting unstructured clinical data.

OBJECTIVE: While there are currently approaches to handle unstructured clinical data, such as manual abstraction and structured proxy variables, these methods may be time-consuming, not scalable, and imprecise. This article aims to determine whether selective prediction, which gives a model the option to abstain from generating a prediction, can improve the accuracy and efficiency of unstructured clinical data abstraction. MATERIALS AND METHODS: We trained selective classifiers (logistic regression, random forest, support vector machine) to extract 5 variables from clinical notes: depression (n = 1563), glioblastoma (GBM, n = 659), rectal adenocarcinoma (DRA, n = 601), and abdominoperineal resection (APR, n = 601) and low anterior resection (LAR, n = 601) of adenocarcinoma. We varied the cost of false positives (FP), false negatives (FN), and abstained notes and measured total misclassification cost. RESULTS: The depression selective classifiers abstained on anywhere from 0% to 97% of notes, and the change in total misclassification cost ranged from -58% to 9%. Selective classifiers abstained on 5%-43% of notes across the GBM and colorectal cancer models. The GBM selective classifier abstained on 43% of notes, which led to improvements in sensitivity (0.94 to 0.96), specificity (0.79 to 0.96), PPV (0.89 to 0.98), and NPV (0.88 to 0.91) when compared to a non-selective classifier and when compared to structured proxy variables. DISCUSSION: We showed that selective classifiers outperformed both non-selective classifiers and structured proxy variables for extracting data from unstructured clinical notes. CONCLUSION: Selective prediction should be considered when abstaining is preferable to making an incorrect prediction.

Combined direct/indirect detection allows identification of DNA termini in diverse sequencing datasets and supports a multiple-initiation-site model for HIV plus-strand synthesis.

Replication of genetic material involves the creation of characteristic termini. Determining these termini is important to refine our understanding of the mechanisms involved in maintaining the genomes of cellular organisms and viruses. Here we describe a computational approach combining direct and indirect readouts to detect termini from next-generation short-read sequencing. While a direct inference of termini can come from mapping the most prominent start positions of captured DNA fragments, this approach is insufficient in cases where the DNA termini are not captured, whether for biological or technical reasons. Thus, a complementary (indirect) approach to terminus detection can be applied, taking advantage of the imbalance in coverage between forward and reverse sequence reads near termini. A resulting metric ("strand bias") can be used to detect termini even where termini are naturally blocked from capture or ends are not captured during library preparation (e.g., in tagmentation-based protocols). Applying this analysis to datasets where known DNA termini are present, such as from linear double-stranded viral genomes, yielded distinct strand bias signals corresponding to these termini. To evaluate the potential to analyze a more complex situation, we applied the analysis to examine DNA termini present early after HIV infection in a cell culture model. We observed both the known termini expected based on standard models of HIV reverse transcription (the U5-right-end and U3-left-end termini) as well as a signal corresponding to a previously described additional initiation site for plus-strand synthesis (cPPT [central polypurine tract]). Interestingly, we also detected putative terminus signals at additional sites. The strongest of these are a set that share several characteristics with the previously characterized plus-strand initiation sites (the cPPT and 3' PPT [polypurine tract] sites): (i) an observed spike in directly captured cDNA ends, an indirect terminus signal evident in localized strand bias, (iii) a preference for location on the plus-strand, (iv) an upstream purine-rich motif, and (v) a decrease in terminus signal at late time points after infection. These characteristics are consistent in duplicate samples in two different genotypes (wild type and integrase-lacking HIV). The observation of distinct internal termini associated with multiple purine-rich regions raises a possibility that multiple internal initiations of plus-strand synthesis might contribute to HIV replication.

[ST266 inhibits neointimal hyperplasia after arterial balloon injury in rats].

Objective    To examine the effect of Human Amnion-Derived Multipotent Progenitor (AMP) cells and their novel ST266 secretome on neointimal hyperplasia after arterial balloon injury in rats.Material and Methods    Sprague-Dawley male rats were randomly divided into four groups (n=7): Control (PBS) group, systemic ST266 group, systemic AMP group and local AMP implant group. Neointimal hyperplasia was induced in the iliac using a 2F Fogarty embolectomy catheter. After surgery, the rats in the ST266 group were treated with 0.1, 0.5, or 1ml ST266 iv daily. In the systemic AMP groups, a single dose (SD) of 0.5 ×106 or 1×106 AMP cells was injected via the inferior vena cava after arterial balloon injury. In local AMP implant groups, 1×106, 5×106, or 20×106 AMP cells were implanted in 300 µl Matrigel (Mtgl) around the iliac artery after balloon injury. The iliac arteries were removed for histologic analysis at 28 days after the surgery. Re-endothelialization index was measured at 10 days after balloon injury.Results    ST266 (1 ml) group had a lower level of the Neointima / Neointima+Media ratio (N / N+M) 0.3±0.1 vs 0.5±0.1, p=0.004) and luminal stenosis (LS) percentage (18.2±1.9 % vs 39.2±5.8 %, p=0.008) compared with the control group. Single-dose AMP (1×106) decreased LS compared to the control group (19.5±5.4 % vs 39.2±5.8 %, p=0.033). Significant reduction in N / N+M were found between implanted AMPs (20×106) and the control group (0.4±0.1 vs 0.5±0.1, p=0.003) and the Mtgl-only group (0.5±0.1, p=0.007). Implanted AMPs (20×106) decreased the LS compared with both the control (39.2±5.8 %, p=0.001) and Mtgl-only group (37.5±8.6 %, p=0.016). ST266 (1 ml) significantly increased the re-endothelialization index compared to the control (0.4±0.1 vs 0.1±0.1, p=0.002).Conclusion    ST266 and AMP cells reduce neointimal formation and increase the re-endothelialization index after arterial balloon injury. ST266 is potentially a novel, therapeutic agent to prevent vascular restenosis in human.

Are Orthopedic Fellowship Programs Giving Out Too Many Interviews? A Retrospective Analysis Suggests They Are.

Background: The orthopedic surgery fellowship match process is associated with substantial stress and expense, yet the optimal number of interviews for fellowships to offer has not been evaluated. Purpose: We sought to evaluate the number of orthopedic surgery fellowship interviews given and construct a model to determine the appropriate number of interviews to offer based on specialty and program size. Methods: We conducted a retrospective study of 6 orthopedic fellowship specialties; data were obtained from San Francisco Match and covered the 5-year period from 2014 to 2018. The orthopedic fellowship subspecialties included adult reconstruction/oncology, foot and ankle, pediatrics, spine, sports medicine, and trauma. We excluded shoulder and elbow (less than 5 years of data) and hand and upper extremity (alternative matching process). Parameters included number of programs, number of spots per program, number of ranked applicants per program (mean ± SD), and difference in number of interviews offered and ranked applicants per program (mean ± SD). Multiple regression analysis was used to create an equation for determining the optimal number of interviews for the programs. Results: Of 1377 orthopedic fellowship programs analyzed, 1370 (99.50%) conducted interviews beyond the number of ranked applicants. Programs ranked an overall mean of 20.10 ± 10.17 applicants with an overall mean of 11.60 ± 8.62 additional interviews offered. Sports medicine had the highest mean ranked applicants (23.21 ± 9.77) and pediatrics had the lowest mean ranked applicants (15.74 ± 7.76). The most additional interviews were given in adult reconstruction (14.80 ± 9.92) and the least were given in pediatrics (8.32 ± 7.17). The predictive equation was reported as Y = ß1x1 + ß2x2 (Y = ranked applicants, x1 = spots open, and x2 = last rank). Conclusion: Programs in 6 orthopedic subspecialties in the fellowship match process appear to consistently offer more interviews than necessary. We have developed a model to help programs predict the optimal number of fellowship applicants to interview. Future studies need to validate the model, especially with anticipated increases of the virtual interview format.

Xanthogranulomatous inflammation requiring small bowel anastomosis revision: A case report.

BACKGROUND: Xanthogranulomatous inflammation (XGI) is an uncommon process involving an accumulation of inflammatory cells, commonly lipid-laden macrophages. XGI has been described to occur throughout the body but only rarely in the lower gastrointestinal tract. We describe a case of XGI contributing to chronic obstructive symptoms in the terminal ileum, in which the patient had an initial diagnostic laparoscopy, continued to have symptoms, then proceeded to have the definitive treatment. To our knowledge, this is the first report of XGI associated with a prior small bowel anastomosis. CASE SUMMARY: We report the case of a 42-year-old female who presented with intermittent epigastric pain and subjective fevers. She had undergone a laparoscopic small bowel resection for Meckel's diverticulum five years prior. Her workup was notable for computed tomography scan demonstrating mild inflammation and surrounding stranding at the level of the prior anastomosis. She underwent a laparotomy, resection of the prior anastomosis and re-anastomosis, with final histopathological examination findings consistent with mural XGI. CONCLUSION: XGI can occur at the site of a prior bowel anastomosis and cause chronic obstructive symptoms.

Application of estimand framework in ICH E9 (R1) to safety evaluation.

Defining the right question of interest is important to a clinical study. ICH E9 (R1) introduces the framework of an estimand and its five attributes, which provide a basis for connecting different components of a study with its clinical questions. Most of the applications of the estimand framework focus on efficacy instead of safety assessment. In this paper, we expand the estimand framework into the safety evaluation and compare/contrast the similarity and differences between safety and efficacy estimand. Furthermore, we present and discuss applications of a safety estimand to oncology trials and pooled data analyses. At last, we also discuss the potential usage of safety estimand to handle the impacts of COVID-19 pandemic on safety assessment.

Human T2D-Associated Gene IMP2/IGF2BP2 Promotes the Commitment of Mesenchymal Stem Cells Into Adipogenic Lineage.

Excessive adiposity is the main cause of obesity and type two diabetes (T2D). Variants in human IMP2/IGF2BP2 gene are associated with increased risk of T2D. However, little is known about its role in adipogenesis and in insulin resistance. Here, we investigate the function of IMP2 during adipocyte development. Mice with Imp2 deletion in mesenchymal stem cells (MSC) are resistant to diet-induced obesity without glucose and insulin tolerance affected. Imp2 is essential for the early commitment of adipocyte-derived stem cells (ADSC) into preadipocytes, but the deletion of Imp2 in MSC is not required for the proliferation and terminal differentiation of committed preadipocytes. Mechanistically, Imp2 binds Wnt receptor Fzd8 mRNA and promotes its degradation by recruiting CCR4-NOT deadenylase complex in an mTOR-dependent manner. Our data demonstrate that Imp2 is required for maintaining white adipose tissue homeostasis through controlling mRNA stability in ADSC. However, the contribution of IMP2 to insulin resistance, a main risk of T2D, is not evident.

Fiber density and matrix stiffness modulate distinct cell migration modes in a 3D stroma mimetic composite hydrogel.

The peritumoral stroma is a complex 3D tissue that provides cells with myriad biophysical and biochemical cues. Histologic observations suggest that during metastatic spread of carcinomas, these cues influence transformed epithelial cells, prompting a diversity of migration modes spanning single cell and multicellular phenotypes. Purported consequences of these variations in tumor escape strategies include differential metastatic capability and therapy resistance. Therefore, understanding how cues from the peritumoral stromal microenvironment regulate migration mode has both prognostic and therapeutic value. Here, we utilize a synthetic stromal mimetic in which matrix fiber density and bulk hydrogel mechanics can be orthogonally tuned to investigate the contribution of these two key matrix attributes on MCF10A migration mode phenotypes, epithelial-mesenchymal transition (EMT), and invasive potential. We develop an automated computational image analysis framework to extract migratory phenotypes from fluorescent images and determine 3D migration metrics relevant to metastatic spread. Using this analysis, we find that matrix fiber density and bulk hydrogel mechanics distinctly contribute to a variety of MCF10A migration modes including amoeboid, single mesenchymal, clusters, and strands. We identify combinations of physical and soluble cues that induce a variety of migration modes originating from the same MCF10A spheroid and use these settings to examine a functional consequence of migration mode -resistance to apoptosis. We find that cells migrating as strands are more resistant to staurosporine-induced apoptosis than either disconnected clusters or individual invading cells. Improved models of the peritumoral stromal microenvironment and understanding of the relationships between matrix attributes and cell migration mode can aid ongoing efforts to identify effective cancer therapeutics that address cell plasticity-based therapy resistances. STATEMENT OF SIGNIFICANCE: Stromal extracellular matrix structure dictates both cell homeostasis and activation towards migratory phenotypes. However decoupling the effects of myriad biophysical cues has been difficult to achieve. Here, we encapsulate electrospun fiber segments within an amorphous hydrogel to create a fiber-reinforced hydrogel composite in which fiber density and hydrogel stiffness can be orthogonally tuned. Quantification of 3D cell migration reveal these two parameters uniquely contribute to a diversity of migration phenotypes spanning amoeboid, single mesenchymal, multicellular cluster, and collective strand. By tuning biophysical and biochemical cues to elicit heterogeneous migration phenotypes, we find that collective strands best resist apoptosis. This work establishes a composite approach to modulate fibrous topography and bulk hydrogel mechanics and identified biomaterial parameters to direct distinct 3D cell migration phenotypes.

SARS-CoV-2 primary and breakthrough infections in patients with cancer: Implications for patient care.

Initial reports of SARS-CoV-2 caused COVID-19 suggested that patients with malignant diseases were at increased risk for infection and its severe consequences. In order to provide early United States population-based assessments of SARS-CoV-2 primary infections in unvaccinated patients with hematologic malignancies or cancer, and SARS-CoV-2 breakthrough infections in vaccinated patients with hematologic malignancies or cancer, we conducted retrospective studies using two, unique nationwide electronic health records (EHR) databases. Using these massive databases to provide highly statistically significant data, our studies demonstrated that, compared to patients without malignancies, risk for COVID-19 was increased in patients with all cancers and with all hematologic malignancies. Risks varied with specific types of malignancy. Patients with hematologic malignancies or cancer were at greatest risk for COVID-19 during the first year after diagnosis. Risk for infection was increased for patients 65 years and older, compared to younger patients and among Black patients compared to white patients. When patients with hematologic malignancies or cancer were vaccinated against SARS-CoV-2, their risk for breakthrough infections was decreased relative to primary infections but remained elevated relative to vaccinated patients without malignancies. Compared to vaccinated patients without malignancies, vaccinated patients with hematologic malignancy or cancer showed increased risk for infection at earlier post vaccination time points. As with primary infections, risk for breakthrough infections was greatest in patients during their first year of hematologic malignancy or cancer. There were no signs of racial disparities among vaccinated patients with hematologic malignancies or cancer. These results provide the population basis to understand the significance of subsequent immunologic studies showing relative defective and delayed immunoresponsiveness to SARS-CoV-2 vaccines among patients with hematologic malignancies and cancers. These studies further provide the basis for recommendations regarding COVID-19 vaccination, vigilance and maintaining mitigation strategies in patients with hematologic malignancies and cancers.