Lowering the Acquisition of Multi-drug Resistant Organism (MDROs) with Pulsed-xenon (LAMP) Study: a cluster randomized controlled, double-blinded, interventional crossover trial.

BACKGROUND: Environmental disinfection is essential for reducing spread of healthcare associated infections (HAIs). Previous studies report conflicting results regarding the effects of ultraviolet light (UV) in reducing infections. This trial evaluated the impact of adding pulsed xenon UV (PX-UV) to standard terminal cleaning in reducing environmentally-implicated HAIs (eiHAIs). METHODS: The LAMP trial was conducted in 2 hospitals (15 inpatient wards) utilizing a cluster randomized controlled, double-blinded, interventional crossover trial comparing standard terminal cleaning followed by either pulsed xenon ultraviolet (PX-UV) disinfection (intervention arm) or sham disinfection (control arm). The primary outcome was incidence of eiHAIs from clinical microbiology tests on the 4th day of stay or later or within 3 days after discharge from the study unit. EiHAIs included clinical cultures positive for vancomycin-resistant enterococci (VRE), extended spectrum beta-lactamase-producing Escherichia coli or Klebsiella pneumonia, methicillin-resistant Staphylococcus aureus (MRSA), and Acinetobacter baumannii, and stool PCR positive for Clostridiodes difficile. FINDINGS: Between May 18, 2017 to Jan 7, 2020, 25,732 patients were included, with an incidence of 601 eiHAI and 180,954 patient days. There was no difference in the rate of eiHAIs in the intervention and sham arms (3.49 vs 3.17 infections/1000 patient days respectively, RR 1.10 CI (0.94, 1.29, p= 0.23)). Study results were similar when stratified by eiHAI type, hospital, and unit type. CONCLUSION: The LAMP study failed to demonstrate an effect of the addition of UV light disinfection following terminal cleaning on reductions in rates of eiHAIs. Further investigations targeting hospital environmental surfaces and the role of no touch technology to reduce HAIs are needed.

Differences in bone histomorphometry between White postmenopausal women with and without atypical femoral fracture after long-term bisphosphonate therapy.

Bone histomorphometric endpoints in transilial biopsies may be associated with an increased risk of atypical femoral fracture (AFF) in patients with osteoporosis who take antiresorptives, including bisphosphonates (BPs). One way to test this hypothesis is to evaluate bone histomorphometric endpoints in age-, gender-, and treatment time-matched patients who either had AFF or did not have AFF. In this study, we performed transiliac bone biopsies in 52 White postmenopausal women with (n = 20) and without (n = 32) AFFs, all of whom had been treated for osteoporosis continuously with alendronate for 4-17 yr. Despite the matched range of treatment duration (4-17 yr), AFF patients received alendronate for significantly longer time (10.7 yr) than non-AFF patients (8.0 yr) (P = .014). Bone histomorphometric endpoints reflecting microstructure and turnover were assessed in cancellous, intracortical, and endocortical envelopes from transilial biopsy specimens obtained from BP-treated patients 3-6 mo after AFF and from non-AFF patients with similar age-, gender-, and range of BP treatment duration. However, in both cancellous and intracortical envelopes, AFF patients had significantly lower wall thickness (W.Th) and higher osteoclast surface (Oc.S/BS) than non-AFF patients. In addition, AFF patients had significantly higher eroded surface (ES/BS) only in the intracortical envelope. None of the dynamic variables related to bone formation and turnover differed significantly between the groups. In conclusion, in the ilium of BP-treated patients with osteoporosis, AFF patients have lower thickness of superficial bone (lower W.Th) of the cancellous and cortical envelopes than non-AFF patients. AFF and non-AFF patients have a similar bone turnover rate in the ilium. Furthermore, in this population, as in previous work, AFF is more likely to occur in BP-treated patients with longer treatment duration.

Bisphosphonates (BPs) are widely used to prevent osteoporotic fracture and treat osteoporosis. However, prolonged use of BPs may increase the risk of atypical femoral fracture (AFF), and their pathogenesis remains unclear. This study compared the bone histomorphometric findings in cancellous and cortical bones between White osteoporotic women with (n = 20) and without AFF (n = 32), who had received BP treatment for a matched duration of 4­17 yr. The BP-treated patients with AFF had significantly lower wall thickness (W.Th) in both cancellous and cortical bones compared to BP-treated patients without AFF. There were no significant differences in bone formation, turnover, or mineral apposition rate between BP-treated AFF and non-AFF patients. In conclusion, our study results suggest that AFF risk is increased in BP-treated patients with smaller young and healthy superficial bone areas (indicated by lower W.Th). Surprisingly, we also discovered that patients with and without AFF have similar bone turnover rates, which contradicts previous beliefs. Our findings provide valuable insights into the potential factors contributing to AFF in BP-treated patients.

Colistin Monotherapy versus Combination Therapy for Carbapenem-Resistant Organisms.

BACKGROUND: Pneumonia and bloodstream infections (BSI) due to extensively drug-resistant (XDR) Acinetobacter baumannii, XDR Pseudomonas aeruginosa, and carbapenem-resistant Enterobacterales (CRE) are associated with high mortality rates, and therapeutic options remain limited. This trial assessed whether combination therapy with colistin and meropenem was superior to colistin monotherapy for the treatment of these infections. METHODS: The OVERCOME (Colistin Monotherapy versus Combination Therapy) trial was an international, randomized, double-blind, placebo-controlled trial. We randomly assigned participants to receive colistin (5 mg/kg once followed by 1.67 mg/kg every 8 hours) in combination with either meropenem (1000 mg every 8 hours) or matching placebo for the treatment of pneumonia and/or BSI caused by XDR A. baumannii, XDR P. aeruginosa, or CRE. The primary outcome was 28-day mortality, and secondary outcomes included clinical failure and microbiologic cure. RESULTS: Between 2012 and 2020, a total of 464 participants were randomly assigned to treatment, and 423 eligible patients comprised the modified intention-to-treat population. A. baumannii was the predominant trial pathogen (78%) and pneumonia the most common index infection (70%). Most patients were in the intensive care unit at the time of enrollment (69%). There was no difference in mortality (43 vs. 37%; P=0.17), clinical failure (65 vs. 58%; difference, 6.8 percentage points; 95% confidence interval [CI], -3.1 to 16.6), microbiologic cure (65 vs. 60%; difference, 4.8 percentage points; 95% CI, -5.6 to 15.2), or adverse events (acute kidney injury, 52 vs. 49% [P=0.55]; hypersensitivity reaction, 1 vs. 3% [P=0.22]; and neurotoxicity, 5 vs. 2% [P=0.29]) between patients receiving monotherapy and combination therapy, respectively. CONCLUSIONS: Combination therapy with colistin and meropenem was not superior to colistin monotherapy for the treatment of pneumonia or BSI caused by these pathogens. (Funded by the National Institute of Allergy and Infectious Diseases, Division of Microbiology and Infectious Diseases protocol 10-0065; ClinicalTrials.gov number, NCT01597973.).

Dynamic contrast enhanced (DCE) MRI estimation of vascular parameters using knowledge-based adaptive models.

We introduce and validate four adaptive models (AMs) to perform a physiologically based Nested-Model-Selection (NMS) estimation of such microvascular parameters as forward volumetric transfer constant, Ktrans, plasma volume fraction, vp, and extravascular, extracellular space, ve, directly from Dynamic Contrast-Enhanced (DCE) MRI raw information without the need for an Arterial-Input Function (AIF). In sixty-six immune-compromised-RNU rats implanted with human U-251 cancer cells, DCE-MRI studies estimated pharmacokinetic (PK) parameters using a group-averaged radiological AIF and an extended Patlak-based NMS paradigm. One-hundred-ninety features extracted from raw DCE-MRI information were used to construct and validate (nested-cross-validation, NCV) four AMs for estimation of model-based regions and their three PK parameters. An NMS-based a priori knowledge was used to fine-tune the AMs to improve their performance. Compared to the conventional analysis, AMs produced stable maps of vascular parameters and nested-model regions less impacted by AIF-dispersion. The performance (Correlation coefficient and Adjusted R-squared for NCV test cohorts) of the AMs were: 0.914/0.834, 0.825/0.720, 0.938/0.880, and 0.890/0.792 for predictions of nested model regions, vp, Ktrans, and ve, respectively. This study demonstrates an application of AMs that quickens and improves DCE-MRI based quantification of microvasculature properties of tumors and normal tissues relative to conventional approaches.

Effect of vitamin D metabolites on bone histomorphometry in healthy black and white women: An attempt to unravel the so-called vitamin D paradox in blacks.

An apparent vitamin D paradox, characterized by lower serum 25-hydroxyvitamin D (25(OH)D) levels and higher bone mineral density, is present in black population. In contrast, blacks have higher serum 1,25-dihydroxyvitamin D (1,25(OH)2D) levels. The effect of 1,25(OH)2D on the skeleton is not fully understood. We examined serum 25(OH)D, 1,25(OH)2D and bone histomorphometry in 50 black and white women (25 each) matched for age, menstrual status, and BMI. Histomorphometric indices related to bone structure, remodeling and mineralization were measured in cancellous bone in iliac bone biopsies. Data analyses led to the following results: 1) serum 25(OH)D was significantly lower and 1,25(OH)2D was significantly higher in black than in white women, but neither blacks nor whites revealed significant correlation between these two vitamin D metabolites. 2) there was no significant difference in PTH levels between blacks and whites. 3) except for greater trabecular thickness (Tb.Th) in blacks, there were no significant differences in other histomorphometric variables between the two ethnic groups. 4) osteoid surface (OS/BS), unlabeled osteoid surface (ulOS/BS), and osteoblast surface (ObS/BS) significantly correlated with serum 1,25(OH)2D levels. We conclude that lower serum 25(OH)D levels in blacks do not impair bone structure and remodeling, nor decrease bone mineralization. Higher serum 1,25(OH)2D levels in blacks may help preserve bone mass by stimulating bone formation via increasing osteoblast number and function, but moderately inhibit terminal bone mineralization as shown by higher ulOS/BS.

Characterization of the Response of 9L and U-251N Orthotopic Brain Tumors to 3D Conformal Radiation Therapy.

In a study employing MRI-guided stereotactic radiotherapy (SRS) in two orthotopic rodent brain tumor models, the radiation dose yielding 50% survival (the TCD50) was sought. Syngeneic 9L cells, or human U-251N cells, were implanted stereotactically in 136 Fischer 344 rats or 98 RNU athymic rats, respectively. At approximately 7 days after implantation for 9L, and 18 days for U-251N, rats were imaged with contrast-enhanced MRI (CE-MRI) and then irradiated using a Small Animal Radiation Research Platform (SARRP) operating at 220 kV and 13 mA with an effective energy of ∼70 keV and dose rate of ∼2.5 Gy per min. Radiation doses were delivered as single fractions. Cone-beam CT images were acquired before irradiation, and tumor volumes were defined using co-registered CE-MRI images. Treatment planning using MuriPlan software defined four non-coplanar arcs with an identical isocenter, subsequently accomplished by the SARRP. Thus, the treatment workflow emulated that of current clinical practice. The study endpoint was animal survival to 200 days. The TCD50 inferred from Kaplan-Meier survival estimation was approximately 25 Gy for 9L tumors and below 20 Gy, but within the 95% confidence interval in U-251N tumors. Cox proportional-hazards modeling did not suggest an effect of sex, with the caveat of wide confidence intervals. Having identified the radiation dose at which approximately half of a group of animals was cured, the biological parameters that accompany radiation response can be examined.

Pharmacist-Driven Transitions of Care Practice Model for Prescribing Oral Antimicrobials at Hospital Discharge.

Importance: Although prescribers face numerous patient-centered challenges during transitions of care (TOC) at hospital discharge, prolonged duration of antimicrobial therapy for common infections remains problematic, and resources are needed for antimicrobial stewardship throughout this period. Objective: To evaluate a pharmacist-driven intervention designed to improve selection and duration of oral antimicrobial therapy prescribed at hospital discharge for common infections. Design, Setting, and Participants: This quality improvement study used a nonrandomized stepped-wedge design with 3 study phases from September 1, 2018, to August 31, 2019. Seventeen distinct medicine, surgery, and specialty units from a health system in Southeast Michigan participated, including 1 academic tertiary hospital and 4 community hospitals. Hospitalized adults who had urinary, respiratory, skin and/or soft tissue, and intra-abdominal infections and were prescribed antimicrobials at discharge were included in the analysis. Data were analyzed from February 18, 2020, to February 28, 2022. Interventions: Clinical pharmacists engaged in a new standard of care for antimicrobial stewardship practices during TOC by identifying patients to be discharged with a prescription for oral antimicrobials and collaborating with primary teams to prescribe optimal therapy. Academic and community hospitals used both antimicrobial stewardship and clinical pharmacists in a multidisciplinary rounding model to discuss, document, and facilitate order entry of the antimicrobial prescription at discharge. Main Outcomes and Measures: The primary end point was frequency of optimized antimicrobial prescription at discharge. Health system guidelines developed from national guidelines and best practices for short-course therapies were used to evaluate optimal therapy. Results: A total of 800 patients prescribed oral antimicrobials at hospital discharge were included in the analysis (441 women [55.1%]; mean [SD] age, 66.8 [17.3] years): 400 in the preintervention period and 400 in the postintervention period. The most common diagnoses were pneumonia (264 [33.0%]), upper respiratory tract infection and/or acute exacerbation of chronic obstructive pulmonary disease (214 [26.8%]), and urinary tract infection (203 [25.4%]). Patients in the postintervention group were more likely to have an optimal antimicrobial prescription (time-adjusted generalized estimating equation odds ratio, 5.63 [95% CI, 3.69-8.60]). The absolute increase in optimal prescribing in the postintervention group was consistent in both academic (37.4% [95% CI, 27.5%-46.7%]) and community (43.2% [95% CI, 32.4%-52.8%]) TOC models. There were no differences in clinical resolution or mortality. Fewer severe antimicrobial-related adverse effects (time-adjusted generalized estimating equation odds ratio, 0.40 [95% CI, 0.18-0.88]) were identified in the postintervention (13 [3.2%]) compared with the preintervention (36 [9.0%]) groups. Conclusions and Relevance: The findings of this quality improvement study suggest that targeted antimicrobial stewardship interventions during TOC were associated with increased optimal, guideline-concordant antimicrobial prescriptions at discharge.

Bone Nanomechanical Properties and Relationship to Bone Turnover and Architecture in Patients With Atypical Femur Fractures: A Prospective Nested Case-Control Study.

Atypical femur fractures (AFFs) are well-established serious complication of long-term bisphosphonate and denosumab therapy in patients with osteopenia or osteoporosis. To elucidate underlying mechanism(s) for the development of AFF, we performed a nested case-control study to investigate bone tissue nanomechanical properties and prevailing bone microstructure and tissue-level remodeling status as assessed by bone histomorphometry. We hypothesized that there would be differences in nanomechanical properties between patients with and without AFF and that bone microstructure and remodeling would be related to nanomechanical properties. Thirty-two full-thickness transiliac bone biopsies were obtained from age- and sex-matched patients on long-term bisphosphonate therapy with (n = 16) and without an AFF (n = 16). Standard histomorphometric measurements were made in each sample on three different bone envelopes (cancellous, intracortical, and endosteal). Iliac bone wall thickness was significantly lower on all three bone surfaces in patients with AFF than in those without AFF. Surface-based bone formation rate was suppressed similarly in both groups in comparison to healthy premenopausal and postmenopausal women, with no significant difference between the two groups. Nanoindentation was used to assess material properties of cortical and cancellous bone separately. Elastic modulus was higher in cortical than in cancellous bone in patients with AFF as well as compared to the elastic modulus of cortical bone from non-AFF patients. However, the elastic modulus of the cancellous bone was not different between AFF and non-AFF groups or between cortical and cancellous bone of non-AFF patients. Resistance to plastic deformation was decreased in cortical bone in both AFF and non-AFF groups compared to cancellous bone, but to a greater extent in AFF patients. We conclude that long-term bisphosphonate therapy is associated with prolonged suppression of bone turnover resulting in altered cortical remodeling and tissue nanomechanical properties leading to AFF. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

The impact of initial tumor microenvironment on imaging phenotype.

Models of human cancer, to be useful, must replicate human disease with high fidelity. Our focus in this study is rat xenograft brain tumors as a model of human embedded cerebral tumors. A distinguishing signature of such tumors in humans, that of contrast-enhancement on imaging, is often not present when the human cells grow in rodents, despite the xenografts having nearly identical DNA signatures to the original tumor specimen. Although contrast enhancement was uniformly evident in all the human tumors from which the xenografts' cells were derived, we show that long-term contrast enhancement in the model tumors may be determined conditionally by the tumor microenvironment at the time of cell implantation. We demonstrate this phenomenon in one of two patient-derived orthotopic xenograft (PDOX) models using cancer stem-like cell (CSC)-enriched neurospheres from human tumor resection specimens, transplanted to groups of immune-compromised rats in the presence or absence of a collagen/fibrin scaffolding matrix, Matrigel. The rats were imaged by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and their brains were examined by histopathology. Targeted proteomics of the PDOX tumor specimens grown from CSC implanted with and without Matrigel showed that while the levels of the majority of proteins and post-translational modifications were comparable between contrast-enhancing and non-enhancing tumors, phosphorylation of Fox038 showed a differential expression. The results suggest key proteins determine contrast enhancement and suggest a path toward the development of better animal models of human glioma. Future work is needed to elucidate fully the molecular determinants of contrast-enhancement.

Reference Intervals for Bone Histomorphometric Measurements Based on Data from Healthy Premenopausal Women.

This study has established the normal reference intervals for bone histomorphometric measurements derived from healthy premenopausal women, which is rarely available. We presented the static and dynamic bone histomorphometric data from trans-iliac bone biopsies in 62 healthy premenopausal women (19 blacks and 43 whites, ages 20-53 years). There were no significant differences in age and BMI between black and white women. Since there was no significant difference in bone remodeling between the two ethnic groups, we pooled data of all 62 premenopausal women to establish normal reference intervals for bone histomorphometry. The results provide normal reference intervals for both static and dynamic histomorphometric variables in cancellous and cortical bone of the ilium. None of the bone remodeling-related variables correlated with age or BMI. This study provides reference intervals for bone histomorphometric measurements in both cancellous and cortical bone of the ilium, which would be helpful in the evaluation of bone health in women.

Effect of vitamin D nutrition on disease indices in patients with primary hyperparathyroidism.

In patients with primary hyperparathyroidism, the size of the adenoma is a major determinant of biochemical indices, disease severity, and manner of presentation. However, the large variation in adenoma weight, both within and between populations and a steady decline in parathyroid adenoma weights over time remain largely unexplained. Based on the results in a small number of patients almost two decades ago we proposed that vitamin D nutritional status of the patient explains both the disease manifestations and much of the variation in adenoma size. Accordingly, we examined the relationship between vitamin D nutrition, as assessed by serum levels of 25-hydroxyvitamin D, and parathyroid gland weight, the best available index of disease severity, in a large number of patients (n = 440) with primary hyperparathyroidism. A significant inverse relationship was found between serum 25-hydroxyvitamin D level and log adenoma weight (r = -0.361; p < 0.001). Also, the adenoma weight was significantly related directly to serum PTH, calcium, and alkaline phosphatase as dependent variables. In patients with vitamin D deficiency (defined as serum 25-hydroxyvitamin D levels 15 ng/mL or lower), gland weight, PTH, AP, and adjusted calcium were each significantly higher than in patients with 25-hydroxyvitamin D levels of 16 ng/mL or higher, but serum 1,25-dihydroxyvitamin D levels were similar in both groups. We interpret this to mean that suboptimal vitamin D nutrition stimulates parathyroid adenoma growth by a mechanism unrelated to 1,25-dihydroxyvitamin D deficiency. We conclude that variable vitamin D nutritional status in the population may partly explain the differences in disease presentation.

Castration-resistant prostate cancer: Androgen receptor inactivation induces telomere DNA damage, and damage response inhibition leads to cell death.

Telomere stability is important for cell viability, as cells with telomere DNA damage that is not repaired do not survive. We reported previously that androgen receptor (AR) antagonist induces telomere DNA damage in androgen-sensitive LNCaP prostate cancer cells; this triggers a DNA damage response (DDR) at telomeres that includes activation of ATM, and blocking ATM activation prevents telomere DNA repair and leads to cell death. Remarkably, AR antagonist induces telomere DNA damage and triggers ATM activation at telomeres also in 22Rv1 castration-resistant prostate cancer (CRPC) cells that are not growth inhibited by AR antagonist. Treatment with AR antagonist enzalutamide (ENZ) or ATM inhibitor (ATMi) by itself had no effect on growth in vitro or in vivo, but combined treatment with ENZ plus ATMi significantly inhibited cell survival in vitro and tumor growth in vivo. By inducing telomere DNA damage and activating a telomere DDR, an opportunity to inhibit DNA repair and promote cell death was created, even in CRPC cells. 22Rv1 cells express both full-length AR and AR splice variant AR-V7, but full-length AR was found to be the predominant form of AR associated with telomeres and required for telomere stability. Although 22Rv1 growth of untreated 22Rv1 cells appears to be driven by AR-V7, it is, ironically, expression of full-length AR that makes them sensitive to growth inhibition by combined treatment with ENZ plus ATMi. Notably, this combined treatment approach to induce telomere DNA damage and inhibit the DDR was effective in inducing cell death also in other CRPC cell lines (LNCaP/AR and C4-2B). Thus, the use of ENZ in combination with a DDR inhibitor, such as ATMi, may be effective in prolonging disease-free survival of patients with AR-positive metastatic CRPC, even those that co-express AR splice variant.

Response to survey directed to patient portal members differs by age, race, and healthcare utilization.

Health care systems are increasingly utilizing electronic medical record-associated patient portals to facilitate communication with patients and between providers and their patients. These patient portals are growing in recognition as potentially valuable research tools. While there is much information about the response rates and demographics of internet-based surveys as well as the demographics of patients who are portal members, not much is known about the response rate of internet-based surveys directed to a group of patient portal members or the demographics of which portal members respond to internet-based surveys issued within that specific population. The objective of these analyses was to determine the demographics of patient portal users who respond to an internet-based survey request. We hypothesized that respondents would more likely be: (1) older (65+), (2) European American, (3) married, (4) female, (5) college educated, (6) have higher medical care utilization, (7) have more comorbidities, and (8) have a private practice primary care physician (as opposed to a salaried group practice primary care physician). We found that our respondents tended to be older, of European geographic ancestry, and more frequent users of healthcare. While patient portal members are an easily identifiable and contactable group that are potentially valuable participants for research, it is important to understand that respondents to surveys solicited from this sampling frame may not be entirely representative. It will be important to develop strategies to more fully engage populations that represent the target population in order to increase overall and subgroup response rates.

Androgen Receptor and ALDH1 Expression Among Internationally Diverse Patient Populations.

PURPOSE: Population-based incidence rates of breast cancers that are negative for estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2/ neu (triple-negative breast cancer [TNBC]) are higher among African American (AA) compared with white American (WA) women, and TNBC prevalence is elevated among selected populations of African patients. The extent to which TNBC risk is related to East African versus West African ancestry, and whether these associations extend to expression of other biomarkers, is uncertain. METHODS: We used immunohistochemistry to evaluate estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2/ neu, androgen receptor and aldehyde dehydrogenase 1 (ALDH1) expression among WA (n = 153), AA (n = 76), Ethiopian (Eth)/East African (n = 90), and Ghanaian (Gh)/West African (n = 286) patients with breast cancer through an institutional review board-approved international research program. RESULTS: Mean age at diagnosis was 43, 49, 60, and 57 years for the Eth, Gh, AA, and WA patients, respectively. TNBC frequency was higher for AA and Gh patients (41% and 54%, respectively) compared with WA and Eth patients (23% and 15%, respectively; P < .001) Frequency of ALDH1 positivity was higher for AA and Gh patients (32% and 36%, respectively) compared with WA and Eth patients (23% and 17%, respectively; P = .007). Significant differences were observed for distribution of androgen receptor positivity: 71%, 55%, 42%, and 50% for the WA, AA, Gh, and Eth patients, respectively ( P = .008). CONCLUSION: Extent of African ancestry seems to be associated with particular breast cancer phenotypes. West African ancestry correlates with increased risk of TNBC and breast cancers that are positive for ALDH1.

Assessment of vertebral wedge strength using cancellous textural properties derived from digital tomosynthesis and density properties from dual energy X-ray absorptiometry and high resolution computed tomography.

The purpose of this study was to examine the potential of digital tomosynthesis (DTS) derived cancellous bone textural measures to predict vertebral strength under conditions simulating a wedge fracture. 40 vertebral bodies (T6, T8, T11, and L3 levels) from 5 male and 5 female cadaveric donors were utilized. The specimens were scanned using dual energy X-ray absorptiometry (DXA) and high resolution computed tomography (HRCT) to obtain measures of bone mineral density (BMD) and content (BMC), and DTS to obtain measures of bone texture. Using a custom loading apparatus designed to deliver a nonuniform displacement resulting in a wedge deformity similar to those observed clinically, the specimens were loaded to fracture and their fracture strength was recorded. Mixed model regressions were used to determine the associations between wedge strength and DTS derived textural variables, alone and in the presence of BMD or BMC information. DTS derived fractal, lacunarity and mean intercept length variables correlated with wedge strength, and individually explained up to 53% variability. DTS derived textural variables, notably fractal dimension and lacunarity, contributed to multiple regression models of wedge strength independently from BMC and BMD. The model from a scan orientation transverse to the spine axis and in the anterior-posterior view resulted in highest explanatory capability (R2adj = 0.91), with a scan orientation parallel to the spine axis and in the lateral view offering an alternative (R2adj = 0.88). In conclusion, DTS can be used to examine cancellous texture relevant to vertebral wedge strength, and potentially complement BMD in assessment of vertebral fracture risk.

Toward a noninvasive estimate of interstitial fluid pressure by dynamic contrast-enhanced MRI in a rat model of cerebral tumor.

PURPOSE: This study demonstrates a DCE-MRI estimate of tumor interstitial fluid pressure (TIFP) and hydraulic conductivity in a rat model of glioblastoma, with validation against an invasive wick-in-needle (WIN) technique. An elevated TIFP is considered a mark of aggressiveness, and a decreased TIFP a predictor of response to therapy. METHODS: The DCE-MRI studies were conducted in 36 athymic rats (controls and posttreatment animals) with implanted U251 cerebral tumors, and with TIFP measured using a WIN method. Using a model selection paradigm and a novel application of Patlak and Logan plots to DCE-MRI data, the MRI parameters required for estimating TIFP noninvasively were estimated. Two models, a fluid-mechanical model and a multivariate empirical model, were used for estimating TIFP, as verified against WIN-TIFP. RESULTS: Using DCE-MRI, the mean estimated hydraulic conductivity (MRI-K) in U251 tumors was (2.3 ± 3.1) × 10-5 (mm2 /mmHg-s) in control studies. Significant positive correlations were found between WIN-TIFP and MRI-TIFP in both mechanical and empirical models. For instance, in the control group of the fluid-mechanical model, MRI-TIFP was a strong predictor of WIN-TIFP (R2 = 0.76, p < .0001). A similar result was found in the bevacizumab-treated group of the empirical model (R2 = 0.93, p = .014). CONCLUSION: This research suggests that MRI dynamic studies contain enough information to noninvasively estimate TIFP in this, and possibly other, tumor models, and thus might be used to assess tumor aggressiveness and response to therapy.

Serum cholesterol trajectories in the 10 years prior to lymphoma diagnosis.

PURPOSE: Many studies suggest a role for cholesterol in cancer development. Serum cholesterol levels have been observed to be low in newly diagnosed lymphoma cases. The objective of these analyses was to examine the time-varying relationship of cholesterol with lymphomagenesis in the 10 years prior to diagnosis by lymphoma subtype. METHODS: Participants were selected from the combined membership of six National Cancer Institute-funded Cancer Research Network health plans from 1998 to 2008, excluding members with human immunodeficiency virus, cancer (except lymphoma), or organ transplants. Incident lymphoma cases within this population were ascertained and matched with up to five controls. Total serum cholesterol, high-density lipoprotein, and low-density lipoprotein were collected from plan databases. Multilevel, multivariable longitudinal models were fit after choosing the best polynomial order by deviance statistics for selected lymphoma histotypes to examine pre-diagnosis cholesterol trajectories: Hodgkin lymphoma (n = 519) and all non-Hodgkin lymphomas combined (n = 12,635) as well as six subtypes of the latter. RESULTS: For all categories, lymphoma cases had statistically significantly lower estimated total serum cholesterol, high-density lipoprotein, and low-density lipoprotein levels than controls in the years prior to diagnosis/index date. Between-group differences were most pronounced 3-4 years prior to diagnosis, when cases' cholesterol levels declined steeply. CONCLUSIONS: This analysis is the first to examine changes in serum cholesterol for a decade prior to lymphoma diagnosis. A drop in cholesterol levels was evident several years before diagnosis. Our results suggest that cholesterol-related pathways have an important relationship with lymphomagenesis and low cholesterol could be a preclinical lymphoma marker.

The association between placental histopathology and autism spectrum disorder.

INTRODUCTION: Research suggests that autism spectrum disorder (ASD) has its origins in utero. This study examines the association between evidence of placental histopathology and ASD. METHODS: Administrative claims data and medical records data were used to identify ASD cases (N = 55) and matched controls (N = 199) born at New York Methodist Hospital between 2007 and 2014 and subsequently seen in affiliated pediatrics clinics. Placentas from all births during this time period were reviewed as part of routine care. Data were analyzed using conditional logistic regression to account for the matched (gender, gestational age, and birth weight) design. RESULTS: Acute placental inflammation, regardless of type was associated with an increased risk of ASD (odds ratio [OR] = 3.14, 95% CI = 1.39, 6.95). Chronic uteroplacental vasculitis (OR = 7.13; 95% CI = 1.17, 43.38), the fetal inflammatory response in the chorionic plate vessels (OR = 5.12; 95% CI = 2.02, 12.96), and maternal vascular malperfusion pathology (OR = 12.29; 95% CI = 1.37, 110.69) were associated with an increased risk of ASD. Placental villous edema was associated with a decreased risk of ASD (OR = 0.05; 95% CI = 0.0005, 0.42). In subanalyses among male placentas acute inflammation overall, fetal inflammatory response in the chorionic plate vessels, and maternal vascular malperfusion pathology remained significantly associated with an increased risk of ASD whereas placental villous edema remained associated with a decreased risk of ASD. DISCUSSION: Histologic evidence of placental inflammation and maternal vascular malperfusion pathology are associated with ASD.

Methods to decrease variability in histological scoring in placentas from a cohort of preterm infants.

OBJECTIVE: Reliable semiquantitative assessment of histological placental acute inflammation is problematic, even among experts. Tissue samples in histology slides often show variability in the extent and location of neutrophil infiltrates. We sought to determine whether the variability in pathologists' scoring of neutrophil infiltrates in the placenta could be reduced by the use of 'regions of interest' (ROIs) that break the sample into smaller components. DESIGN: ROIs were identified within stained H&E slides from a cohort of 56 women. ROIs were scored using a semiquantitative scale (0-4) for the average number of neutrophils by at least two independent raters. SETTING: Preterm singleton births at Yale New Haven Hospital. PARTICIPANTS: This study used stained H&E placental slides from a cohort of 56 women with singleton pregnancies who had a clinically indicated amniocentesis within 24 hours of delivery. PRIMARY AND SECONDARY OUTCOME MEASURES: Interrater agreement was assessed with the intraclass correlation coefficient (ICC) and log-linear regression. Predictive validity was assessed using amniotic fluid protein profile scores (neutrophil defensin-2, neutrophil defensin-1, calgranulin C and calgranulin A). RESULTS: Excellent agreement by the ICC was found for the average neutrophil scores within a region of interest. Log-linear analyses suggest that even where there is disagreement, responses are positively associated along the diagonal. There was also strong evidence of predictive validity comparing pathologists' scores with amniotic fluid protein profile scores. CONCLUSIONS: Agreement among observers of semiquantitative neutrophil scoring through the use of digitised ROIs was demonstrated to be feasible with high reliability and validity.

Statin use and risk of multiple myeloma: An analysis from the cancer research network.

Animal and human data suggest statins may be protective against developing multiple myeloma; however, findings may be biased by the interrelationship with lipid levels. We investigated the association between statin use and risk of multiple myeloma in a large US population, with an emphasis on accounting for this potential bias. We conducted a case-control study nested within 6 US integrated healthcare systems participating in the National Cancer Institute-funded Cancer Research Network. Adults aged ≥40 years who were diagnosed with multiple myeloma from 1998-2008 were identified through cancer registries (N = 2,532). For each case, five controls were matched on age, sex, health plan, and membership duration prior to diagnosis/index date. Statin prescriptions were ascertained from electronic pharmacy records. To address potential biases related to lipid levels and medication prescribing practices, multivariable marginal structural models were used to model statin use (≥6 cumulative months) and risk of multiple myeloma, with examination of multiple latency periods. Statin use 48-72 months prior to diagnosis/index date was associated with a suggestive 20-28% reduced risk of developing multiple myeloma, compared to non-users. Recent initiation of statins was not associated with myeloma risk (risk ratio range 0.90-0.99 with 0-36 months latency). Older patients had more consistent protective associations across all latency periods (risk ratio range 0.67-0.87). Our results suggest that the association between statin use and multiple myeloma risk may vary by exposure window and age. Future research is warranted to investigate the timing of statin use in relation to myeloma diagnosis.