Assessing the Impact of 2-Step Clostridioides difficile Testing at the Healthcare Facility Level.

BACKGROUND: Two-step testing for Clostridioides difficile infection (CDI) aims to improve diagnostic specificity but may also influence reported epidemiology and patterns of treatment. Some providers fear that 2-step testing may result in adverse outcomes if C. difficile is underdiagnosed. METHODS: Our primary objective was to assess the impact of 2-step testing on reported incidence of hospital-onset CDI (HO-CDI). As secondary objectives, we assessed the impact of 2-step testing on C. difficile-specific antibiotic use and colectomy rates as proxies for harm from underdiagnosis or delayed treatment. This longitudinal cohort study included 2 657 324 patient-days across 8 regional hospitals from July 2017 through March 2022. Impact of 2-step testing was assessed by time series analysis with generalized estimating equation regression models. RESULTS: Two-step testing was associated with a level decrease in HO-CDI incidence (incidence rate ratio, 0.53 [95% confidence interval {CI}, .48-.60]; P < .001), a similar level decrease in utilization rates for oral vancomycin and fidaxomicin (utilization rate ratio, 0.63 [95% CI, .58-.70]; P < .001), and no significant level (rate ratio, 1.16 [95% CI, .93-1.43]; P = .18) or trend (rate ratio, 0.85 [95% CI, .52-1.39]; P = .51) change in emergent colectomy rates. CONCLUSIONS: Two-step testing is associated with decreased reported incidence of HO-CDI, likely by improving diagnostic specificity. The parallel decrease in C. difficile-specific antibiotic use offers indirect reassurance against underdiagnosis of C. difficile infections still requiring treatment by clinician assessment. Similarly, the absence of any significant change in colectomy rates offers indirect reassurance against any rise in fulminant C. difficile requiring surgical management.

Manipulation of sucrose phloem and embryo loading affects pea leaf metabolism, carbon and nitrogen partitioning to sinks as well as seed storage pools.

Seed development largely depends on the long-distance transport of sucrose from photosynthetically active source leaves to seed sinks. This source-to-sink carbon allocation occurs in the phloem and requires the loading of sucrose into the leaf phloem and, at the sink end, its import into the growing embryo. Both tasks are achieved through the function of SUT sucrose transporters. In this study, we used vegetable peas (Pisum sativum L.), harvested for human consumption as immature seeds, as our model crop and simultaneously overexpressed the endogenous SUT1 transporter in the leaf phloem and in cotyledon epidermal cells where import into the embryo occurs. Using this 'Push-and-Pull' approach, the transgenic SUT1 plants displayed increased sucrose phloem loading and carbon movement from source to sink causing higher sucrose levels in developing pea seeds. The enhanced sucrose partitioning further led to improved photosynthesis rates, increased leaf nitrogen assimilation, and enhanced source-to-sink transport of amino acids. Embryo loading with amino acids was also increased in SUT1-overexpressors resulting in higher protein levels in immature seeds. Further, transgenic plants grown until desiccation produced more seed protein and starch, as well as higher seed yields than the wild-type plants. Together, the results demonstrate that the SUT1-overexpressing plants with enhanced sucrose allocation to sinks adjust leaf carbon and nitrogen metabolism, and amino acid partitioning in order to accommodate the increased assimilate demand of growing seeds. We further provide evidence that the combined Push-and-Pull approach for enhancing carbon transport is a successful strategy for improving seed yields and nutritional quality in legumes.

CDC's Hospital-Onset Clostridioides difficile Prevention Framework in a Regional Hospital Network.

Importance: Despite modest reductions in the incidence of hospital-onset Clostridioides difficile infection (HO-CDI), CDI remains a leading cause of health care-associated infection. As no single intervention has proven highly effective on its own, a multifaceted approach to controlling HO-CDI is needed. Objective: To assess the effectiveness of the Centers for Disease Control and Prevention's Strategies to Prevent Clostridioides difficile Infection in Acute Care Facilities Framework (hereafter, the Framework) in reducing HO-CDI incidence. Design, Setting, and Participants: This quality improvement study was performed within the Duke Infection Control Outreach Network from July 1, 2019, through March 31, 2022. In all, 20 hospitals in the network participated in an implementation study of the Framework recommendations, and 26 hospitals did not participate and served as controls. The Framework has 39 discrete intervention categories organized into 5 focal areas for CDI prevention: (1) isolation and contact precautions, (2) CDI confirmation, (3) environmental cleaning, (4) infrastructure development, and (5) antimicrobial stewardship engagement. Exposures: Monthly teleconferences supporting Framework implementation for the participating hospitals. Main Outcomes and Measures: Primary outcomes were HO-CDI incidence trends at participating hospitals compared with controls and postintervention HO-CDI incidence at intervention sites compared with rates during the 24 months before the intervention. Results: The study sample included a total of 2184 HO-CDI cases and 7 269 429 patient-days. In the intervention cohort of 20 participating hospitals, there were 1403 HO-CDI cases and 3 513 755 patient-days, with a median (IQR) HO-CDI incidence of 2.8 (2.0-4.3) cases per 10 000 patient-days. The first analysis included an additional 3 755 674 patient-days and 781 HO-CDI cases among the 26 controls, with a median (IQR) HO-CDI incidence of 1.1 (0.7-2.7) case per 10 000 patient-days. The second analysis included an additional 2 538 874 patient-days and 1751 HO-CDI cases, with a median (IQR) HO-CDI incidence of 5.9 (2.7-8.9) cases per 10 000 patient-days, from participating hospitals 24 months before the intervention. In the first analysis, intervention sites had a steeper decline in HO-CDI incidence over time relative to controls (yearly incidence rate ratio [IRR], 0.79 [95% CI, 0.67-0.94]; P = .01), but the decline was not temporally associated with study participation. In the second analysis, HO-CDI incidence was declining in participating hospitals before the intervention, and the rate of decline did not change during the intervention. The degree to which hospitals implemented the Framework was associated with steeper declines in HO-CDI incidence (yearly IRR, 0.95 [95% CI, 0.90-0.99]; P = .03). Conclusions and Relevance: In this quality improvement study of a regional hospital network, implementation of the Framework was not temporally associated with declining HO-CDI incidence. Further study of the effectiveness of multimodal prevention measures for controlling HO-CDI is warranted.

Burnout and staff turnover among certified nursing assistants working in acute care hospitals during the COVID-19 pandemic.

INTRODUCTION: Healthcare worker burnout is a growing problem in the United States which affects healthcare workers themselves, as well as the healthcare system as a whole. The goal of this qualitative assessment was to understand factors that may lead to healthcare worker burnout and turnover through focus groups with Certified Nursing Assistants who worked in acute care hospitals during the COVID-19 pandemic. METHODS: Eight focus group discussions lasting approximately 30 minutes each were held remotely from October 2022-January 2023 with current and former Certified Nursing Assistants who worked during the COVID-19 pandemic in acute care hospitals. Participants were recruited through various sources such as social media and outreach through professional organizations. The focus groups utilized open-ended prompts including topics such as challenges experienced during the pandemic, what could have improved their experiences working during the pandemic, and motivations for continuing or leaving their career in healthcare. The focus groups were coded using an immersion-crystallization technique and summarized using NVivo and Microsoft Excel. Participant demographic information was summarized overall and by current work status. RESULTS: The focus groups included 58 Certified Nursing Assistants; 33 (57%) were current Certified Nursing Assistants and 25 (43%) were Certified Nursing Assistants who no longer work in healthcare. Throughout the focus groups, five convergent themes emerged, including staffing challenges, respect and recognition for Certified Nursing Assistants, the physical and mental toll of the job, facility leadership support, and pay and incentives. CONCLUSIONS: Focus group discussions with Certified Nursing Assistants identified factors at individual and organizational levels that might contribute to burnout and staff turnover in healthcare settings. Suggestions from participants on improving their experiences included ensuring staff know they are valued, being included in conversations with leadership, and improving access to mental health resources.

Making a C-DIFFerence: Implementation of a prevention collaborative to reduce hospital-onset Clostridioides difficile infection rates.

Objective: To assist hospitals in reducing Clostridioides difficile infections (CDI), the Centers for Disease Control and Prevention (CDC) implemented a collaborative using the CDC CDI prevention strategies and the Targeted Assessment for Prevention (TAP) Strategy as foundational frameworks. Setting: Acute-care hospitals. Methods: We invited 400 hospitals with the highest cumulative attributable differences (CADs) to the 12-month collaborative, with monthly webinars, coaching calls, and deployment of the CDC CDI TAP facility assessments. Infection prevention barriers, gaps identified, and interventions implemented were qualitatively coded by categorizing them to respective CDI prevention strategies. Standardized infection ratios (SIRs) were reviewed to measure outcomes. Results: Overall, 76 hospitals participated, most often reporting CDI testing as their greatest barrier to achieving reduction (61%). In total, 5,673 TAP assessments were collected across 46 (61%) hospitals. Most hospitals (98%) identified at least 1 gap related to testing and at least 1 gap related to infrastructure to support prevention. Among 14 follow-up hospitals, 64% implemented interventions related to infrastructure to support prevention (eg, establishing champions, reviewing individual CDIs) and 86% implemented testing interventions (eg, 2-step testing, testing algorithms). The SIR decrease between the pre-collaborative and post-collaborative periods was significant among participants (16.7%; P < .001) but less than that among nonparticipants (25.1%; P < .001). Conclusions: This article describes gaps identified and interventions implemented during a comprehensive CDI prevention collaborative in targeted hospitals, highlighting potential future areas of focus for CDI prevention efforts as well as reported challenges and barriers to prevention of one of the most common healthcare-associated infections affecting hospitals and patients nationwide.

Chemically recyclable thermoplastics from reversible-deactivation polymerization of cyclic acetals.

Identifying plastics capable of chemical recycling to monomer (CRM) is the foremost challenge in creating a sustainable circular plastic economy. Polyacetals are promising candidates for CRM but lack useful tensile strengths owing to the low molecular weights produced using current uncontrolled cationic ring-opening polymerization (CROP) methods. Here, we present reversible-deactivation CROP of cyclic acetals using a commercial halomethyl ether initiator and an indium(III) bromide catalyst. Using this method, we synthesize poly(1,3-dioxolane) (PDXL), which demonstrates tensile strength comparable to some commodity polyolefins. Depolymerization of PDXL using strong acid catalysts returns monomer in near-quantitative yield and even proceeds from a commodity plastic waste mixture. Our efficient polymerization method affords a tough thermoplastic that can undergo selective depolymerization to monomer.

Unnecessary antibiotic prescribing in pediatric ambulatory care visits for bronchitis and bronchiolitis in the United States, 2006-2015.

Antibiotics are not indicated for the treatment of bronchitis and bronchiolitis. Using a nationally representative database from 2006-2015, we found that antibiotics were prescribed in 58% of outpatient visits for bronchitis and bronchiolitis in children, serving as a possible baseline for the expanded HEDIS 2020 measure regarding antibiotic prescribing for bronchitis.

A qualitative assessment of factors affecting nursing home caregiving staff experiences during the COVID-19 pandemic.

BACKGROUND: A large portion of COVID-19 cases and deaths in the United States have occurred in nursing homes; however, current literature including the frontline perspective of staff working in nursing homes is limited. The objective of this qualitative assessment was to better understand what individual and facility level factors may have contributed to the impact of COVID-19 on Certified Nursing Assistants (CNAs) and Environmental Services (EVS) staff working in nursing homes. METHODS: Based on a simple random sample from the National Healthcare Safety Network (NHSN), 7,520 facilities were emailed invitations requesting one CNA and/or one EVS staff member for participation in a voluntary focus group over Zoom. Facility characteristics were obtained via NHSN and publicly available sources; participant demographics were collected via SurveyMonkey during registration and polling during focus groups. Qualitative information was coded using NVIVO and Excel. RESULTS: Throughout April 2021, 23 focus groups including 110 participants from 84 facilities were conducted homogenous by participant role. Staffing problems were a recurring theme reported. Participants often cited the toll the pandemic took on their emotional well-being, describing increased stress, responsibilities, and time needed to complete their jobs. The lack of consistent and systematic guidance resulting in frequently changing infection prevention protocols was also reported across focus groups. CONCLUSIONS: Addressing concerns of low wages and lack of financial incentives may have the potential to attract and retain employees to help alleviate nursing home staff shortages. Additionally, access to mental health resources could help nursing home staff cope with the emotional burden of the COVID-19 pandemic. These frontline staff members provided invaluable insight and should be included in improvement efforts to support nursing homes recovering from the impact of COVID-19 as well as future pandemic planning.

Gaps in infection prevention practices for catheter-associated urinary tract infections and central line-associated bloodstream infections as identified by the Targeted Assessment for Prevention Strategy.

BACKGROUND: Catheter-associated urinary tract infections (CAUTI) and central line-associated bloodstream infections (CLABSI) represent a substantial portion of health care-associated infections (HAIs) reported in the United States. The Targeted Assessment for Prevention Strategy is a quality improvement framework to reduce health care-associated infections. Data from the Targeted Assessment for Prevention Facility Assessments were used to determine common infection prevention gaps for CAUTI and CLABSI. METHODS: Data from 2,044 CAUTI and 1,680 CLABSI assessments were included in the analysis. Items were defined as potential gaps if ≥33% respondents answered Unknown, ≥33% No, or ≥50% No or Unknown or Never, Rarely, Sometimes, or Unknown to questions pertaining to those areas. Review of response frequencies and stratification by respondent role were performed to highlight opportunities for improvement. RESULTS: Across CAUTI and CLABSI assessments, lack of physician champions (<35% Yes) and nurse champions (<55% Yes), along with lack of awareness of competency assessments, audits, and feedback were reported. Lack of practices to facilitate timely removal of urinary catheters were identified for CAUTI and issues with select device insertion practices, such as maintaining aseptic technique, were perceived as areas for improvement for CLABSI. CONCLUSIONS: These data suggest common gaps in critical components of infection prevention and control programs. The identification of these gaps has the potential to inform targeted CAUTI and CLABSI prevention efforts.

Medical and psychology students' knowledge and attitudes regarding aging and sexuality.

The current study surveys medical and doctoral psychology students (N = 100) from an urban northeastern university regarding knowledge and attitudes toward elderly sexuality and aging using the Facts on Aging Quiz, the Aging Sexuality Knowledge and Attitudes Scale, and measures of interest in gerontology, academic/clinical exposure to aging and sexuality, and contact with elders. The current study found that psychology students demonstrated greater aging knowledge than medical students; however, both groups showed gaps in knowledge about sexuality. Married students had greater academic/clinical exposure and greater knowledge about aging but less permissive attitudes toward elderly sexuality. Generally, knowledge about aging was the strongest correlate of knowledge about sexuality. Level of knowledge about sexuality was not associated with attitudes. Attitudes toward sexuality and aging may be more strongly tied to demographic variables reflective of religious beliefs or adherence to sociocultural norms.

Targeting Nitrogen Metabolism and Transport Processes to Improve Plant Nitrogen Use Efficiency.

In agricultural cropping systems, relatively large amounts of nitrogen (N) are applied for plant growth and development, and to achieve high yields. However, with increasing N application, plant N use efficiency generally decreases, which results in losses of N into the environment and subsequently detrimental consequences for both ecosystems and human health. A strategy for reducing N input and environmental losses while maintaining or increasing plant performance is the development of crops that effectively obtain, distribute, and utilize the available N. Generally, N is acquired from the soil in the inorganic forms of nitrate or ammonium and assimilated in roots or leaves as amino acids. The amino acids may be used within the source organs, but they are also the principal N compounds transported from source to sink in support of metabolism and growth. N uptake, synthesis of amino acids, and their partitioning within sources and toward sinks, as well as N utilization within sinks represent potential bottlenecks in the effective use of N for vegetative and reproductive growth. This review addresses recent discoveries in N metabolism and transport and their relevance for improving N use efficiency under high and low N conditions.

Association of Patient-Reported Difficulty with Adherence with Achievement of Clinical Targets Among Hemodialysis Patients.

BACKGROUND: Non-adherence to dialysis recommendations is common and associated with poor outcomes. We used data from a cohort of in-center hemodialysis patients to determine whether patients' reported difficulties with adherence were associated with achievement of clinical targets for treatment recommendations. PATIENTS AND METHODS: We included 799 in-center patients receiving hemodialysis from February 2010 to October 2016 at Emory Dialysis (Atlanta, GA, USA). Patient-reported difficulty with adherence (yes vs no) across multiple domains (coming to dialysis, completing dialysis sessions, fluid restrictions, diet restrictions, taking medications) was obtained from baseline social worker assessments. Achievement of clinical targets for coming to dialysis (missing ≥3 expected sessions), completing dialysis sessions (shortening >3 sessions by ≥15 min), fluid restrictions (mean interdialytic weight gain ≥3 kg), diet restrictions (mean potassium ≥5.0 mEq/L, mean phosphate >5.5 mg/dL), and taking medications (mean phosphate >5.5 mg/dL) was estimated over the following 12 weeks, using electronic medical record data. Crude agreement was assessed, and multivariable logistic regression was used to estimate the associations between these measures. RESULTS: Agreement between reported difficulty in adherence and failure to achieve clinical targets was generally poor across all domains (percent agreement: 52.9-65.3%). After adjustment, patients reporting difficulty with fluid restrictions were 62% more likely to have mean interdialytic weight gain ≥3 kg than those not reporting difficulty (OR: 1.62, 95% CI: 1.08, 2.43). Patients reporting difficulty with coming to dialysis were 41% more likely to miss ≥3 expected dialysis sessions over 12 weeks (OR: 1.41, 95% CI: 0.96, 2.07); however, this association was not statistically significant. There were no significant associations between reported difficulty and failure to achieve clinical targets in other categories. CONCLUSION: While reported difficulty with only fluid restrictions and coming to dialysis were associated with failure to achieve clinical targets in our study, the general lack of agreement between reported difficulty with adherence and failure to achieve clinical targets highlights a gap that could be explored to develop and target educational interventions aimed at increasing adherence among dialysis patients.

Epidemiological considerations in transgender health: A systematic review with focus on higher quality data.

Background: High quality data pertaining to the size of the transgender and gender diverse (TGD) population are scant, however, several recently published studies may provide more reliable contemporary estimates. Aims: To summarize the estimated number and proportion of TGD individuals overall and across age groups, based on most accurate data. Methods: This systematic review focused on recent studies (published from 2009 through 2019) that utilized sound methodology in assessing the proportion of TGD people in the general population. Publications were included if they used clear definitions of TGD status, and calculated proportions based on a well-defined sampling frame. Nineteen eligible publications represented two broad categories of studies: those that used data from large health care systems; and those that identified TGD individuals from population surveys. Results: Among health system-based studies, TGD persons were identified using relevant diagnostic codes or clinical notes. The proportions of individuals with a TGD-relevant diagnosis or other recorded evidence ranged between 17 and 33 per 100,000 enrollees. In population surveys TGD status was ascertained based on self-report with either narrow or broad definitions. The survey-based estimates were orders of magnitude higher and consistent across studies using similar definitions. When the surveys specifically inquired about 'transgender' identity, the estimates ranged from 0.3% to 0.5% among adults, and from 1.2% to 2.7% among children and adolescents. When the definition was expanded to include broader manifestations of 'gender diversity', the corresponding proportions increased to 0.5-4.5% among adults and 2.5-8.4% among children and adolescents. Upward temporal trends in the proportion of TGD people were consistently observed. Conclusions: Current data indicate that people who self-identify as TGD represent a sizable and increasing proportion of the general population. This proportion may differ, depending on inclusion criteria, age, and geographic location, but well-conducted studies of similar type and design tend to produce comparable results.

Miscible Polyether/Poly(ether-acetal) Electrolyte Blends.

This study shows that it is possible to obtain homogeneous mixtures of two chemically distinct polymers with a lithium salt for electrolytic applications. This approach is motivated by the success of using mixtures of organic solvents in modern lithium-ion batteries. The properties of mixtures of a polyether, poly(ethylene oxide) (PEO), a poly(ether-acetal), poly(1,3,6-trioxocane) (P(2EO-MO)), and lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) salt were studied by small-angle neutron scattering (SANS) and electrochemical characterization in symmetric cells. The SANS data are used to determine the miscibility window and quantify the effect of added salt on the thermodynamic interactions between the polymers. In the absence of salt, PEO/P(2EO-MO) blends are homogeneous and characterized by attractive interactions, i.e., a negative Flory-Huggins interaction parameter, χ. The addition of small amounts of salt results in a positive effective Flory-Huggins interaction parameter, χ eff, and macrophase separation. Surprisingly, miscible blends and negative χ eff parameters are obtained when the salt concentration is increased beyond a critical value. The electrochemical properties of PEO/P(2EO-MO)/LiTFSI blends at a given salt concentration were close to those obtained in PEO/LiTFSI electrolytes at the same salt concentration. This suggests that in the presence of PEO the electrochemical properties exhibited by P(2EO-MO) chains are similar to those of PEO chains. This work opens the door to a new direction for creating new and improved polymer electrolytes either by combining existing polymers and salt or by synthesizing new polymers with the specific aim of including them in miscible polymer blend electrolytes.

Rapidly Reprocessable Cross-Linked Polyhydroxyurethanes Based on Disulfide Exchange.

Polymer networks that are cross-linked by dynamic covalent bonds often sacrifice the robust mechanical properties of traditional thermosets in exchange for rapid and efficient reprocessability. Polyurethanes are attractive materials for reprocessable cross-linked polymers because of their excellent mechanical properties, widespread use, and ease of synthesis, but their syntheses typically rely on harmful isocyanate precursors. Polyhydroxyurethanes (PHUs), derived from amines and cyclic carbonates, are promising alternatives to traditional polyurethanes. PHU networks are reprocessable via transcarbamoylation reactions even in the absence of external catalysts, but this process occurs over hours at temperatures above 150 °C. We have dramatically shortened the reprocessing times of PHU networks by incorporating dynamic disulfide bonds. Using cystamine as a comonomer gives materials with similar thermal stability and mechanical properties to other rigid cross-linked PHUs. Despite their excellent mechanical properties, these materials show rapid stress relaxation and have characteristic relaxation times as low as 30 s at 150 °C. This property enables reprocessing with quantitative recovery of cross-link density as measured by DMTA after only 30 min of elevated-temperature compression molding. Disulfide incorporation is a promising approach to obtain reprocessable, cross-linked PHU resins that are not derived from isocyanates.

Novel vitamin E analogue and 9-nitro-camptothecin administered as liposome aerosols decrease syngeneic mouse mammary tumor burden and inhibit metastasis.

PURPOSE: To test the anticancer properties of a nonhydrolyzable ether-linked acetic acid analogue of vitamin E, 2,5,7,8-tetramethyl-2R-(4R,8R, 12-trimethyltridecyl)chroman-6-yloxyacetic acid (alpha-TEA), and a derivative of camptothecin, 9-nitrocamptothecin (9-NC)singly and in combination against mouse mammary tumor cells (line 66 clone 4 stably transfected with green fluorescent protein; 66cl-4-GFP) cultured in vitro or transplanted subcutaneously into the inguinal region of female BALB/c mice to form established tumors. METHODS: Following in vitro treatment of 66cl-4-GFP cells with alpha-TEA and suboptimal concentrations of 9-NC, singly or in combination, apoptosis was measured by morphological evaluation of nuclei stained with 4',6-diamidino-2-phenylindole (DAPI), and DNA synthesis arrest was measured by tritiated thymidine uptake. For in vivo analyses alpha-TEA and 9-NC, both water-insoluble compounds, were formulated into liposomes using dil-auroylphosphatidylcholine and administered by aerosol to deliver doses calculated to be 36 and 0.4 microg/mouse per day, respectively, (singly or each separately for combined treatments) 7 days per week. RESULTS: Treatment of 66cl-4-GFP cells in culture for 3 days with a combination of alpha-TEA (10 microg/ml; singly produces 38% apoptosis), and suboptimal concentrations of 9-NC(15.6, 31.3, 62.5, or 125 ng/ml; singly produce 2-7% apoptosis), produced 47%, 58%, 64%, and 69% apoptosis. Likewise, combinations of alpha-TEA 9-NC inhibited DNA synthesis more than either agent administered singly. A significant reduction (P< 0.001)in growth of subcutaneous transplanted tumors was observed with liposome-formulated and aerosolized delivery of alpha-TEA + 9-NC to BALB/c mice. The incidence of macroscopic lung metastasis was 83% in control vs 8 % in alpha-TEA-, 9-NC-, or combination-treated mice. Fluorescence microscopic examination of lungs and axillary and brachial lymph nodes showed a statistically significant decrease in metastasis observed in alpha-TEA-,9-NC-, and combination- vs control-treated animals. Analyses of primary tumor tissue for proliferation and apoptosis showed treatment groups to have lower Ki-67 and higher terminal deoxynucleotidyl transferase-mediated nick end labeling, respectively. Treatments showed no measurable effects on two angiogenesis parameters,namely intratumoral blood volume as assessed by hemoglobin content and intratumoral blood vessel density as assessed with CD31 staining. CONCLUSIONS: Combination treatments enhanced antiproliferative and proapoptotic activities in cell culture, and when formulated in liposomes and delivered via aerosolization to treat an aggressive and metastatic syngeneic murine mammary tumor, the combination treatment showed a significant reduction in tumor volume in comparison to either treatment alone. Mechanistically, it appears that neither enhanced apoptosis, reduced cell proliferation,nor reduced blood vessel density can fully account for the enhanced effects of the combination treatment.

Direct access compared with referred physical therapy episodes of care: a systematic review.

BACKGROUND: Evidence suggests that physical therapy through direct access may help decrease costs and improve patient outcomes compared with physical therapy by physician referral. PURPOSE: The purpose of this study was to conduct a systematic review of the literature on patients with musculoskeletal injuries and compare health care costs and patient outcomes in episodes of physical therapy by direct access compared with referred physical therapy. DATA SOURCES: Ovid MEDLINE, CINAHL (EBSCO), Web of Science, and PEDro were searched using terms related to physical therapy and direct access. Included articles were hand searched for additional references. STUDY SELECTION: Included studies compared data from physical therapy by direct access with physical therapy by physician referral, studying cost, outcomes, or harm. The studies were appraised using the Centre for Evidence-Based Medicine (CEBM) levels of evidence criteria and assigned a methodological score. DATA EXTRACTION: Of the 1,501 articles that were screened, 8 articles at levels 3 to 4 on the CEBM scale were included. There were statistically significant and clinically meaningful findings across studies that satisfaction and outcomes were superior, and numbers of physical therapy visits, imaging ordered, medications prescribed, and additional non-physical therapy appointments were less in cohorts receiving physical therapy by direct access compared with referred episodes of care. There was no evidence for harm. DATA SYNTHESIS: There is evidence across level 3 and 4 studies (grade B to C CEBM level of recommendation) that physical therapy by direct access compared with referred episodes of care is associated with improved patient outcomes and decreased costs. LIMITATIONS: Primary limitations were lack of group randomization, potential for selection bias, and limited generalizability. CONCLUSIONS: Physical therapy by way of direct access may contain health care costs and promote high-quality health care. Third-party payers should consider paying for physical therapy by direct access to decrease health care costs and incentivize optimal patient outcomes.

Aerosol delivery of liposomal formulated paclitaxel and vitamin E analog reduces murine mammary tumor burden and metastases.

Paclitaxel is a chemotherapeutic agent used for the treatment of metastatic breast cancer. 2,5,7,8-Tetramethyl-2R-(4R, 8R-12-trimethyltridecyl) chroman-6-yloxyacetic acid (alpha-TEA) is an analog of vitamin E that inhibits primary tumor growth and the incidence of lymphatic and pulmonary metastases in preclinical animal models. Here, the efficacy of sequential treatment with paclitaxel and alpha-TEA was tested in the BALB/c syngeneic 66cl-4-GFP mammary cancer model. Both agents were formulated into liposomes and delivered by inhalation in an effort to increase anti-tumor efficacy and minimize paclitaxel toxicity. Combination treatment consisting of twelve days of every-other-day treatment with aerosolized paclitaxel (approximately 0.46 microg/mouse/treatment) followed by a daily regimen of aerosolized alpha-TEA (36 microg/mouse/treatment) significantly decreased primary tumor burden when compared to untreated or liposome control groups and was significantly better than individual treatments (P < 0.05). Importantly, combination treatment was significantly better at reducing lung and lymph node micrometastatic foci when compared to control and individual treatment groups (P < 0.05). Immunohistochemical analyses of tumor sections showed combination treatment when compared to liposome control or individual treatments to significantly decrease total number of cells staining positive for the endothelial cell marker CD31 or for the Ki67 marker of cellular proliferation and increase the number of apoptotic (TUNEL positive) tumor cells (P < 0.001). Studies addressing the toxicity of alpha-TEA demonstrated that alpha-TEA formulated in liposomes and delivered by aerosol (72 microg/mouse/day) or gavage (5 mg/mouse/day) for 25 days did not cause blood, liver, or kidney toxicity. In conclusion, sequential inhalation delivery of liposomal-formulated paclitaxel and alpha-TEA produces significantly better anti-tumor outcomes than single treatments.

Vitamin E analog alpha-TEA, methylseleninic acid, and trans-resveratrol in combination synergistically inhibit human breast cancer cell growth.

Alpha-tocopherol ether-linked acetic acid analog [2,5,7,8-tetramethyl-2R-(4R, 8R-12-trimethyltridecyl) chroman-6-yloxyacetic acid (alpha-TEA)] is a novel form of vitamin E effective at killing cancer cells but not normal cells. alpha -TEA alone and together with methylseleninic acid (MSA) and trans-resveratrol (t-RES) were investigated for ability to induce apoptosis, DNA synthesis arrest, and cellular differentiation and inhibit colony formation in human MDA-MB-435-F-L breast cancer cells in culture. The 3 agents alone were effective in inhibiting cell growth by each of the 4 different assays, and 3-way combination treatments synergistically inhibited cell proliferation in each assay in comparison to individual treatments. Furthermore, combinations of alpha -TEA, t-RES, and MSA significantly enhanced levels of apoptosis in human breast (MDA-MB-231, MCF7, and T47D) and prostate (LnCaP, PC-3, and DU-145) cancer cell lines as well as in immortalized but nontumorigenic MCF10A cells but not primary cultures of human mammary epithelial cells. Western immunoblotting confirmed the induction of apoptosis in that the 3 agents induced poly(adenosine diphosphate-ribose) polymerase cleavage, with earlier detection and more complete cleavage seen in the combination treatment. Mechanistic studies showed combination treatments to inhibit cell proliferation via downregulation of cyclin D1 and induce apoptosis via activation of caspases 8 and 9 and downregulation of prosurvival proteins FLIP and survivin. In summary, the combination of alpha-TEA, MSA, and t-RES is more effective than single treatments for inhibiting cell proliferation, inducing cellular differentiation, and inducing cell death by apoptosis in human cancer cells in culture.