Evaluating the Effectiveness of Personalized Medicine With Software.

We present methodological advances in understanding the effectiveness of personalized medicine models and supply easy-to-use open-source software. Personalized medicine involves the systematic use of individual patient characteristics to determine which treatment option is most likely to result in a better average outcome for the patient. Why is personalized medicine not done more in practice? One of many reasons is because practitioners do not have any easy way to holistically evaluate whether their personalization procedure does better than the standard of care, termed improvement. Our software, "Personalized Treatment Evaluator" (the R package PTE), provides inference for improvement out-of-sample in many clinical scenarios. We also extend current methodology by allowing evaluation of improvement in the case where the endpoint is binary or survival. In the software, the practitioner inputs 1) data from a single-stage randomized trial with one continuous, incidence or survival endpoint and 2) an educated guess of a functional form of a model for the endpoint constructed from domain knowledge. The bootstrap is then employed on data unseen during model fitting to provide confidence intervals for the improvement for the average future patient (assuming future patients are similar to the patients in the trial). One may also test against a null scenario where the hypothesized personalization are not more useful than a standard of care. We demonstrate our method's promise on simulated data as well as on data from a randomized comparative trial investigating two treatments for depression.

Discrimination of SARS-CoV-2 infected patient samples by detection dogs: A proof of concept study.

While the world awaits a widely available COVID-19 vaccine, availability of testing is limited in many regions and can be further compounded by shortages of reagents, prolonged processing time and delayed results. One approach to rapid testing is to leverage the volatile organic compound (VOC) signature of SARS-CoV-2 infection. Detection dogs, a biological sensor of VOCs, were utilized to investigate whether SARS-CoV-2 positive urine and saliva patient samples had a unique odor signature. The virus was inactivated in all training samples with either detergent or heat treatment. Using detergent-inactivated urine samples, dogs were initially trained to find samples collected from hospitalized patients confirmed with SARS-CoV-2 infection, while ignoring samples collected from controls. Dogs were then tested on their ability to spontaneously recognize heat-treated urine samples as well as heat-treated saliva from hospitalized SARS-CoV-2 positive patients. Dogs successfully discriminated between infected and uninfected urine samples, regardless of the inactivation protocol, as well as heat-treated saliva samples. Generalization to novel samples was limited, particularly after intensive training with a restricted sample set. A unique odor associated with SARS-CoV-2 infection present in human urine as well as saliva, provides impetus for the development of odor-based screening, either by electronic, chemical, or biological sensing methods. The use of dogs for screening in an operational setting will require training with a large number of novel SARS-CoV-2 positive and confirmed negative samples.

The Endemic Amid the Pandemic: Seeking Help for Violence Against Women in the Initial Phases of COVID-19.

During the first months of the COVID-19 pandemic, governments instituted a series of measures to control the spread of the virus. The measures were widely believed to increase women's risk of violent victimization, most of which is by an intimate partner. We examined help-seeking during this period in a large U.S. city and used an interrupted time series analysis to assess the effects of three government interventions on domestic violence and sexual assault hotline calls and on "911" calls regarding domestic violence, assault, and rape. Declaration of an emergency appeared to reduce victim calls to the rape crisis hotline and the few "911" calls about rape. School closure was associated with a reduction in "911" calls about assault and rape and victim calls to the domestic violence hotline. Implementation of stay-at-home orders was associated with a gradual increase in domestic violence hotline calls. Although "911" calls regarding assault fell by nearly half, calls to police for domestic violence were unchanged. In sum, there was a decrease in help-seeking for sexual assault and assault in general but not for domestic violence during the initial phases of the COVID-19 outbreak. The analysis underscores the importance of distinguishing between the violence itself, calls to police, and calls to helplines when claims are made about changes over time in violence against women. The opportunities and constraints for each can differ widely under usual circumstances, circumstances that were altered by public health interventions related to the pandemic.

A Randomized Cross-Over Field Study of Pre-Hydration Strategies in Dogs Tracking in Hot Environments.

The objective of this study was to evaluate 4 pre-exercise hydration strategies (oral water, chicken-flavored water, chicken-flavored oral electrolyte solution, and subcutaneous electrolyte solution) in working dogs conducting rigorous tracking operations in hot and arid conditions. In a randomized cross-over field study, 7 Border Patrol Search, Trauma, and Rescue (BORSTAR) Unit dogs working/training out of Fort Bliss in El Paso, Texas were randomly assigned to one of 4 different hydration strategy treatments each day for 4 days of study participation. Dogs were provided hydration treatment prior to running 2 separate one-mile tracks and were offered water while tracking. Body weight, blood, and urine were collected at the beginning of the study day and at the completion of each track. Core body temperatures were recorded using internal temperature sensing capsules. The impact of hydration strategy on change in weight, peak temperature, and serum chemical, hematological, and urinary parameters were analyzed using the COIN procedure in Ra. Compared to the other 3 hydration strategies, dogs receiving chicken-flavored water had higher blood creatine kinase values at the end of the second track (p = 0.0361). Otherwise, hydration strategy had minimal effects on blood or urine parameters. Total fluid intake was lower with water only compared to the other three hydration strategies. Dogs developed elevated core body temperatures (median 41°C; 106°F) without signs of heat exhaustion or heat stroke. Alternate hydration strategies increased total fluid intake compared to water alone; however, chicken-flavored water resulted in increased markers of muscle injury suggesting electrolyte-enriched strategies may have an advantage as a hydration strategy. Additionally, electrolyte-enriched fluids before exercise may help these dogs maintain lower peak temperatures.

Machine Learning Algorithms in Suicide Prevention: Clinician Interpretations as Barriers to Implementation.

OBJECTIVE: Machine learning algorithms in electronic medical records can classify patients by suicide risk, but no research has explored clinicians' perceptions of suicide risk flags generated by these algorithms, which may affect algorithm implementation. The objective of this study was to evaluate clinician perceptions of suicide risk flags. METHODS: Participants (n = 139; 68 with complete data) were mental health clinicians recruited to complete online surveys from October 2018 to April 2019. RESULTS: Most participants preferred to know which features resulted in a patient receiving a suicide flag (94.12%) and reported that knowing those features would influence their treatment (88.24%). Clinicians were more likely to report that some algorithm features (increased thoughts of suicide) would alter their clinical decisions more than others (age, physical health conditions; χ² = 270.84, P < .001). Clinicians were more likely to report that they would create a safety/crisis response plan in response to a suicide risk flag compared to other interventions (χ² = 227.02, P < .001), and 21% reported that they would complete a no-suicide contract following a suicide risk flag. CONCLUSIONS: Clinicians overwhelmingly reported that suicide risk flags in electronic medical records would alter their clinical decision making. However, clinicians' likelihood of acting in response to a suicide risk flag was tied to which features were highlighted rather than the presence of the risk flag alone. Thus, the utility of a suicide risk algorithm will be reduced if clinical features underlying the algorithm are hidden from clinicians or if clinicians do not view the clinical features as intuitively meaningful predictors of suicide risk.

After the gun: examining police visits and intimate partner violence following incidents involving a firearm.

Laws have been enacted to keep firearms out of the hands of abusers. In this study, we examined one such effort-removal of a firearm at the scene of intimate partner violence (IPV)-to assess the subsequent occurrence and number of IPV incidents responded to by police and subsequent risk of injury to the victim. Using the 28,977 IPV calls in one large U.S. city to which officers responded during the 2013 calendar year, we identified 220 first-time incidents in which offenders used (i.e., brandished, pistol whipped, shot) a pistol, revolver, rifle, or shotgun. Officers reported removing a firearm from 52 (24%) of the offenders. After using full propensity score matching to control for potential confounders, logistic and Poisson regressions were used to assess differences between those from whom a firearm was removed and those whose firearm was not removed. Firearm removal at the scene of an IPV incident appears to increase the likelihood of subsequent IPV reports to police and suggestive evidence that subsequent injury to the victim might increase as well. The offender shifting from threats with a firearm to physical violence and a change (an increase as well as a decrease) in victim willingness to summon police may account for the findings.

Covariance adjustments for the analysis of randomized field experiments.

BACKGROUND: It has become common practice to analyze randomized experiments using linear regression with covariates. Improved precision of treatment effect estimates is the usual motivation. In a series of important articles, David Freedman showed that this approach can be badly flawed. Recent work by Winston Lin offers partial remedies, but important problems remain. RESULTS: In this article, we address those problems through a reformulation of the Neyman causal model. We provide a practical estimator and valid standard errors for the average treatment effect. Proper generalizations to well-defined populations can follow. CONCLUSION: In most applications, the use of covariates to improve precision is not worth the trouble.

Evidence-based versus junk-based evaluation research: some lessons from 35 years of the evaluation review.

Along with the late Howard Freeman, Richard Berk was a founding editor of Evaluation Review (then Evaluation Quarterly) in 1977. He resigned as editor of this journal at the end of 2010. In this article, he reflects on his experiences.

CXCL7-Mediated Stimulation of Lymphangiogenic Factors VEGF-C, VEGF-D in Human Breast Cancer Cells.

Increased expression of lymphangiogenesis factors VEGF-C/D and heparanase has been correlated with the invasion of cancer. Furthermore, chemokines may modify matrix to facilitate metastasis, and they are associated with VEGF-C and heparanase. The chemokine CXCL7 binds heparin and the G-protein-linked receptor CXCR2. We investigated the effect of CXCR2 blockade on the expression of VEGF-C/D, heparanase, and on invasion. CXCL7 siRNA and a specific antagonist of CXCR2 (SB225002) were used to treat CXCL7 stably transfected MCF10AT cells. Matrigel invasion assays were performed. VEGF-C/D expression and secretion were determined by real-time PCR and ELISA assay, and heparanase activity was quantified by ELISA. SB225002 blocked VEGF-C/D expression and secretion (P < .01). CXCL7 siRNA knockdown decreased heparanase (P < .01). Both SB225002 and CXCL7 siRNA reduced the Matrigel invasion (P < .01). The MAP kinase signaling pathway was not involved. The CXCL7/CXCR2 axis is important for cell invasion and the expression of VEGF-C/D and heparanase, all linked to invasion.

Biofilms and chronic otitis media: an initial exploration into the role of biofilms in the pathogenesis of chronic otitis media.

PURPOSE: The aim of the study was to compare the extent of biofilm infection in percentage of mucosal surface area of adenoids removed from children with otitis media with effusion (OME) vs those with recurrent acute otitis media (RAOM) and obstructive sleep apnea (OSA). MATERIALS AND METHODS: Comparative microanatomical investigation of adenoid mucosa using scanning electron microscopy obtained from 30 children with OME, RAOM, and OSA was used in this study. Seventeen males and 13 females ranging in age from 9 months to 10 years were included in this study. Percentage of biofilm surface area involvement was the main measure. RESULTS: Adenoids removed from patients with OME had moderately dense mature biofilms covering the mucosal surface with a mean of 27.7% of their mucosal surface covered with mature biofilms. These results were distinct from results obtained from patients diagnosed with RAOM and OSA with means of 97.6% and 0.10% of their mucosal surfaces covered with mature biofilms, respectively. These differences were statistically significant at P < .0001. CONCLUSIONS: Adenoids removed from patients with OME were characterized by distinctly different percentage of biofilm mucosal surface area coverage, with significantly more biofilm presence than OSA patients but significantly less biofilm presence than RAOM patients. Although previous investigations have supported a dominant role of nasopharyngeal biofilms in RAOM pathogenesis, these results suggest nasopharyngeal biofilms may play a different role in the pathogenesis of OME and that this clinical entity may be more multifactorial in nature.

Immunohistochemical analysis of ocular platelet basic protein expression during infection with Pseudomonas aeruginosa.

Platelet basic protein (PBP) and several of its derivatives are known to express a wide range of biological characteristics. It is the precursor of connective tissue activating peptide (CTAP-III), beta thromboglobulin (beta-TG) and neutrophil activating peptide (NAP-2), which is the proteolytic derived end product. The temporal ocular expression of the chemokine PBP before and during corneal infection over several days by Pseudomonas aeruginosa was examined by immunohistochemistry. Prior to corneal infection, immunohistochemical staining demonstrated the constitutive expression of PBP in the cornea, lens and retina. PBP expression was present in the corneal epithelium, stromal fibroblasts and endothelium. There was a temporal increase in PBP expression in the cornea after infection. The entire cornea exhibited extensive cellular infiltration by positive PBP staining infiltrating cells within 6 days post-infection. The cornea, lens and retina underwent extensive degradation within 5-6 days post-infection with some apparent selective increase in PBP staining in the lens and retina.

Biofilm density in the pediatric nasopharynx: recurrent acute otitis media versus obstructive sleep apnea.

OBJECTIVES: We compared the biofilm surface density of adenoids removed from children with recurrent acute otitis media (RAOM) to that of adenoids removed from children with a diagnosis of obstructive sleep apnea (OSA). METHODS: We performed a comparative microanatomic study of adenoid mucosa using scanning electron microscopy in patients with diagnoses of RAOM and OSA (27 female and 41 male; age range, 3 months to 15 years). RESULTS: The adenoids removed from patients with RAOM had dense, mature biofilms covering nearly their entire mucosal surfaces. More specifically, the adenoids removed from patients with RAOM had an average of 93.53% of their mucosal surface covered, versus an average of 1.01% coverage on the adenoids removed from patients with OSA. These differences were statistically significant (p < 0.0001). CONCLUSIONS: The adenoids removed from patients with RAOM had almost their entire mucosal surface covered with biofilms, versus scant coverage for patients with OSA. Recurrent acute otitis media is notoriously resistant to antibiotic treatment, and aspirates of middle ear fluid repeatedly yield negative cultures. It is these properties that have led biofilms to become increasingly implicated in the pathogenesis of RAOM. Thus, the resistance of biofilms to antimicrobials, together with their planktonic shedding of organisms, may be an important mechanism in the development of RAOM.

Identification of adenoid biofilms with middle ear pathogens in otitis-prone children utilizing SEM and FISH.

OBJECTIVES: Biofilms have been implicated in the development of several chronic infections. We sought to demonstrate middle ear pathogens in adenoid biofilms using scanning electron microscopy (SEM) and fluorescent in situ hybridization (FISH) with confocal laser scanning microscopy (CLSM). METHODS: Comparative micro-anatomic investigation of adenoid mucosa using SEM and FISH with confocal scanning laser microscopic (CLSM) imaging from patients with recurrent acute otitis media (RAOM). RESULTS: All otitis-prone children demonstrated biofilm surface area presence greater than 85% by SEM. FISH accompanied by CLSM imaging also demonstrated patchy biofilms All biofilms contained middle ear pathogens and were frequent in polymicrobial distributions: 4 of 6, 4 of 6 and 3 of 6 samples contained Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis, respectively. CONCLUSIONS: Dense adenoid biofilms may act as a reservoir for reinfection of the tubotympanum. Aspiration of planktonic middle ear pathogens existing in resistant adenoid biofilms during a viral upper respiratory tract infection may be an important event in the development of RAOM.

Demonstration of nasopharyngeal and middle ear mucosal biofilms in an animal model of acute otitis media.

OBJECTIVES: We performed this study to determine the role of nasopharyngeal and middle ear (ME) biofilms in acute otitis media (AOM). METHODS: Sixty female 6-month-old chinchillas, free of ME disease, were utilized. Experimental animals were inoculated with influenza A followed by Streptococcus pneumoniae 7 days later. Control animals were inoculated with Sorensen's phosphate buffer. Daily otoscopy and tympanometry was performed, and the animals were painlessly sacrificed on days 1, 2, 5, 8, and 14. All mucosae were harvested and prepared for scanning electron microscopy. RESULTS: The ME inflammation, initially detected on day 2 after bacterial inoculation, peaked on day 8. Eight percent of the dually inoculated chinchillas displayed type B tympanograms, and 40% displayed type C. Otoscopic evaluation of tympanic membrane inflammation was rated from 0 to 4 (0 = normal and 4 = severe drainage and/or inflammation) according to an otoscopic grading system. Ten percent of the experimental chinchillas had a grade 2 score, 20% had grade 3, and 6.7% had grade 4. The controls demonstrated no abnormal tympanometric or otoscopic findings. Scanning electron microscopic imaging showed dense biofilms on 83% of the nasopharynges and 67% of the MEs on day 8 in the experimental animals. All animals with ME biofilms had biofilms in the nasopharynx. The controls did not demonstrate biofilm formation. CONCLUSIONS: The study parallels the natural pathogenesis of AOM in humans. The demonstration of mucosal biofilms in both the nasopharynx (58%) and the ME (47%) of animals with ME inflammation and/or infection lends further support to the importance of mucosal biofilms in the pathogenesis of AOM.

Increased invasion through basement membrane by CXCL7-transfected breast cells.

BACKGROUND: CXC chemokines may modify breast cancer cells and surrounding extracellular matrix to facilitate metastasis. CXCL7 is heparin binding, has heparanase activity, and is a ligand to CXCR2, a G-protein-linked receptor. METHODS: Isogenic cell lines, malignant MCF10CA1a.cl1 cells, and premalignant MCF10AT cells were used. CXCR2 and CXCL7 expression levels were quantified by reverse transcriptionase-polymerase chain reaction and Western blot. MCF10AT cells were stably transfected with CXCL7, and matrigel invasion assays were performed. Antibody to CXCL7 was used to inhibit invasion. CXCL7 secretion by transfectants and heparanase activity were quantified by enzyme-linked immunosorbent assay. RESULTS: CXCL7 and CXCR2 expression were significantly higher in malignant MCF10CA1a.cl1 cells than in premalignant MCF10AT cells. Secreted CXCL7, secreted heparanase activity, and invasiveness were all increased in CXCL7-transfected MCF10AT cells. CXCL7 antibody inhibited invasion of CXCL7-transfected MCF10AT cells. CONCLUSIONS: Malignant MCF10CA1a.cl1 cells express more CXCL7 and CXCR2 than premalignant MCF10AT cells. CXCL7-transfected MCF10AT cells are as invasive as malignant breast cancer cells.

Weighting regressions by propensity scores.

Regressions can be weighted by propensity scores in order to reduce bias. However, weighting is likely to increase random error in the estimates, and to bias the estimated standard errors downward, even when selection mechanisms are well understood. Moreover, in some cases, weighting will increase the bias in estimated causal parameters. If investigators have a good causal model, it seems better just to fit the model without weights. If the causal model is improperly specified, there can be significant problems in retrieving the situation by weighting, although weighting may help under some circumstances.

Expression patterns of lymphangiogenic and angiogenic factors in a model of breast ductal carcinoma in situ.

BACKGROUND: Foci of invasion are found in greater than 20% of excised specimens of breast ductal carcinoma in situ (DCIS). Since lymphangiogenesis markers are associated with the potential for increased lymph node metastasis, the purpose of the current study was to determine expression of lymphangiogenesis molecular markers in a model of aggressive DCIS. METHODS: From the MCF10A xenograft model, comedo type MCF10DCIS.com cells, premalignant MCF10AT, and invasive MCF10CA1a.cl1 cells were tested. Invasion was tested by Matrigel invasion assays (Becton-Dickinson, Bedford, MA). Gene expression was determined by reverse transcriptase-polymerase chain reaction and protein expression by immunoblot, normalized to beta-actin. RESULTS: MCF10DCIS.com cells were 4-fold more invasive than MCF10AT cells (P < .01), and expressed several-fold more mRNA and protein than MCF10AT and MCF10CA1a.cl1 cells for vascular endothelial growth factor C, vascular endothelial growth factor D, and lymphatic vessel endothelial hyaluronan receptor 1 (P < .01). CONCLUSIONS: A subset of comedo-type DCIS cells are invasive, and expression of lymphangiogenesis markers is greater at the mRNA and protein levels than by invasive cancer cells (P < .01). These additional molecular markers may characterize aggressive DCIS more precisely.

Biofilm surface area in the pediatric nasopharynx: Chronic rhinosinusitis vs obstructive sleep apnea.

OBJECTIVE: To compare the percentage of mucosal surface area of adenoids infected with biofilms removed from children with chronic rhinosinusitis (CRS) vs children with obstructive sleep apnea (OSA). DESIGN: Comparative microanatomical investigation of adenoid mucosa from patients with CRS and OSA using scanning electron microscopy. SETTING: University-affiliated hospitals and ambulatory surgery center. PATIENTS: Four girls and 12 boys ranging in age from 3 months to 10 years. MAIN OUTCOME MEASURE: Measurements of biofilm coverage of the entire adenoidal surface. RESULTS: Adenoids removed from patients with CRS had dense mature biofilms covering the mucosal surface; they had a mean of 94.9% of their mucosal surface covered with mature biofilms, compared with a mean of 1.9% coverage on the adenoids removed from patients with OSA. This difference was statistically significant at P < .001. CONCLUSIONS: Adenoids removed from patients with CRS had almost their entire mucosal surface covered with biofilms vs scant coverage for patients with OSA. Biofilms in the nasopharynx of children with CRS may act as a chronic reservoir for bacterial pathogens resistant to standard antibiotics. The mechanical debridement of the nasopharyngeal biofilms may explain the observed clinical benefit associated with adenoidectomy in this subset of pediatric patients.

Identification of adenoid biofilms in chronic rhinosinusitis.

OBJECTIVE: To compare the percent mucosal surface area of adenoids removed from children with chronic rhinosinusitis (CRS) and those with obstructive sleep apnea (OSA) infected with biofilms. DESIGN: Comparative micro-anatomic investigation of adenoid mucosa using scanning electron microscopy from patients with CRS and OSA. SUBJECTS: 4 females and 12 males ranging from 3 months to 10 years of age. RESULTS: Adenoids removed from patients with CRS had dense mature biofilms covering the mucosal surface. More specifically, adenoids removed from patients with CRS had an average of 94.9% of their mucosal surface covered with mature biofilms vs. an average of 1.9% coverage on the adenoids removed from patients with OSA. These differences were statistically significant at the p<0.001 level. CONCLUSIONS: It is well established that adenoidectomy is useful in the treatment of CRS resistant to antibiotics. Adenoids removed from patients with CRS had almost their entire mucosal surface covered with biofilms vs. scant coverage for patients with OSA (p<0.001). Decreased metabolic activity, decreased growth rate, and transmission of resistance genes all contribute to the antibiotic resistant nature of the biofilms. These metabolically sessile communities shed planktonic microorganisms on an intermittent basis. Therefore biofilms in the nasopharynx of children with CRS may act as a chronic reservoir for bacterial pathogens resistant to standard antibiotics. Also, the mechanical debridement of the nasopharyngeal biofilms may explain the observed clinical benefit associated with adenoidectomy in this subset of pediatric patients.