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Digital health tools are positive for delivering evidence-based care. However, few studies have applied rigorous frameworks to understand their use in community settings. This study aimed to identify implementation determinants of the Automated Heart-Health Assessment (AH-HA) tool within outpatient oncology settings as part of a hybrid effectiveness-implementation trial. A mixed-methods approach informed by the Consolidated Framework for Implementation Research (CFIR) examined barriers and facilitators to AH-HA implementation in four NCI Community Oncology Research Program (NCORP) practices participating in the WF-1804CD AH-HA trial. Provider surveys were analyzed using descriptive statistics. Interviews with providers (n = 15) were coded using deductive (CFIR) and inductive codes by trained analysts. The CFIR rating tool was used to rate each quote for (i) valence, defined as a positive (+) or negative (-) influence, and (ii) strength, defined as a neutral (0), weak (1), or strong (2) influence on implementation. All providers considered discussing cardiovascular health with patients as important (61.5%, n = 8/13) or somewhat important (38.5%, n = 5/13). The tool was well-received by providers and was feasible to use in routine care among cancer survivors. Providers felt the tool was acceptable and usable, had a relative advantage over routine care, and had the potential to generate benefits for patients. Common reasons clinicians reported not using AH-HA were (i) insufficient time and (ii) the tool interfering with workflow. Systematically identifying implementation determinants from this study will guide the broader dissemination of the AH-HA tool across clinical settings and inform implementation strategies for future scale-up hybrid trials., (© Society of Behavioral Medicine 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

It is essential to provide the community with evidenced-based care to optimize healthcare outcomes; more specifically, women in underserved communities with limited access to healthcare services. The purpose of this research was to determine the effectiveness of a single virtual movement-based pelvic health education session on women's pelvic health knowledge, adherence to performing pelvic exercises and confidence in performing the exercises. Forty-two female participants were recruited in Western Arkansas. Participants completed an online pre-session (pre) questionnaire and then received a single virtual education session led by a healthcare provider trained in pelvic health. A post-session (post-1) questionnaire was completed by each participant as well as a 1-month follow-up (post-2) questionnaire. Thirty-five women completed all three questionnaires and pelvic health knowledge, adherence to pelvic floor exercises and confidence in performing pelvic floor exercises were assessed. After the participants completed the post-2 questionnaire, they were invited for a semi-structured interview and 13 women participated. Results of this study suggest pelvic health knowledge increased after a single session of movement-based education, and this was retained 1 month later. Adherence and confidence to perform the exercises did not change; however, learning about pelvic health in a virtual movement-based method was a positive experience and initiated an eagerness to learn more about pelvic health. Pelvic health education can be implemented in a virtual approach to engage women in underserved communities to learn more about pelvic health through a positive experience for an educational baseline to gain healthcare autonomy., (© The Author(s) 2024. Published by Oxford University Press.)

Etherified Carboxymethylcellulose Matrix (eCMC) is a revolutionary application of carboxymethylcellulose (CMC) in wound care, known for its potential in hemostasis and tissue regeneration. This study aims to investigate the mechanism of eCMC in tissue healing by establishing a rat burn model and administering eCMC as a treatment. The objective is to analyze cytokines and inflammatory mediators using a Cytokine Array and histochemical staining to understand the effects of eCMC on tissue regeneration. A rat burn model was created, and eCMC was applied as a treatment. Tissue samples were collected at multiple time points to assess the expression of cytokines and inflammatory mediators using a Cytokine Array. In addition, histochemical staining was performed to evaluate tissue regeneration factors. eCMC induced the expression of endogenous cytokines, particularly vascular epithelial growth factor and platelet-derived growth factor, while inhibiting inflammatory cytokines such as CINC-1, CINC-2, and MMP-8. This dual action facilitated wound healing and mitigated the risk of infection. eCMC demonstrates promising potential for enhancing skin regeneration. Further research is warranted to delve into the precise mechanism of eCMC's cytokine regulation. In vitro and in vivo studies should be conducted to comprehensively investigate the therapeutic capabilities of eCMC in wound healing., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Burn Association.)

Context: Conventional therapy for hypoparathyroidism aims to alleviate symptoms of hypocalcemia but does not address insufficient parathyroid hormone (PTH) levels., Objective: Assess the long-term efficacy and safety of TransCon PTH (palopegteriparatide) for hypoparathyroidism., Design: Phase 3 trial with a 26-week double-blind, placebo-controlled period followed by a 156-week open-label extension (OLE)., Setting: 21 sites across North America and Europe., Participants: 82 adults with hypoparathyroidism were randomized and received study drug and 78 completed week 52., Intervention(s): All OLE participants received TransCon PTH administered once daily., Main Outcome Measure(s): Multi-component efficacy endpoint: proportion of participants at week 52 who achieved normal serum calcium (8.3-10.6 mg/dL) and independence from conventional therapy (≤600 mg/day of elemental calcium and no active vitamin D). Other efficacy endpoints included patient-reported outcomes (PROs) and bone mineral density (BMD). Safety was assessed by 24-hour urine calcium and treatment-emergent adverse events (TEAEs)., Results: At week 52, 81% (63/78) met the multi-component efficacy endpoint, 95% (74/78) achieved independence from conventional therapy, and none required active vitamin D. PROs showed sustained improvements in quality of life, physical functioning, and well-being. Mean BMD Z-scores decreased toward age- and sex-matched norms from baseline to week 52. Mean (SD) 24-hour urine calcium excretion decreased from 376 (168) mg/day at baseline to 195 (114) mg/day at week 52. Most TEAEs were mild or moderate and none led to trial discontinuation during the OLE., Conclusions: At week 52 of the PaTHway trial, TransCon PTH showed sustained efficacy, safety, and tolerability in adults with hypoparathyroidism., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Janus kinase (JAK) inhibitors tofacitinib and upadacitinib are effective therapies for inflammatory bowel disease and rheumatologic disorders but currently possess a warning for increased venous thromboembolism (VTE) risk. Some patients with a history of VTE may benefit from a JAK inhibitor, but the risk of recurrent VTE with JAK inhibitor use is unclear. Our goal was to observe rates of new VTE events after starting JAK inhibitor therapy in patients with a prior VTE, and observe whether concurrent anticoagulation (AC) reduces this risk., Methods: We conducted a review of adults prescribed tofacitinib or upadacitinib between January 1, 2000, and June 30, 2023, with a prior history of VTE. Patient charts were reviewed for demographic data, disease type, and VTE date(s), and to verify duration of JAK inhibitor use along with any concurrent AC. VTEs following JAK inhibitor initiation were identified by International Classification of Diseases-Tenth Revision code and verified by physician documentation and imaging., Results: We identified 79 patients with a documented VTE history before initiating JAK inhibitors, 47 of whom began a JAK inhibitor with concurrent AC. Of these, 15 patients discontinued AC while receiving JAK inhibitors. In total, 5 new VTE events were observed during 55.42 patient-years of JAK inhibitor treatment without concurrent AC (9.0 events per 100 patient-years), while no new VTE events occurred during 65.2 patient-years of JAK inhibitor treatment with concurrent AC, demonstrating a lower risk of recurrent VTE (P = .020)., Conclusions: These results suggest that for patients with a prior VTE history there is a high risk for recurrent VTE while receiving JAK inhibitors. Concurrent use of AC with JAK inhibitors appears to be protective against recurrent VTEs in this population., (© The Author(s) 2024. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

A significant component of care for infants with bronchopulmonary dysplasia (BPD) is providing an optimal environment for supporting neurodevelopment and growth. Interventions that support the behavioral and physiologic stability of this population may play an important role in improving overall outcomes. Contingent singing is a music intervention that allows the caregiver to tailor certain musical elements, such as rhythm and tempo, to match behavioral and physiologic cues and support the infant in achieving optimal stabilization. A randomized crossover design was used to study the effect of contingent singing on the behavioral state and physiologic measures compared to standard care practices in the neonatal intensive care unit (NICU). Data were collected on a sample of 37 infants diagnosed with BPD. There were no significant differences in the physiologic measures or behavioral states of infants in the contingent singing sessions compared to control sessions. Parents and staff reported favorable views of music therapy in the NICU, and there were no adverse responses from infants during contingent singing. Further research is needed to determine the effectiveness of this intervention on the physiologic stability of infants with BPD., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Music Therapy Association. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Conventional therapy for hypoparathyroidism consisting of active vitamin D and calcium aims to alleviate hypocalcemia but fails to restore normal parathyroid hormone (PTH) physiology. PTH replacement therapy is the ideal physiologic treatment for hypoparathyroidism. The double-blind, placebo-controlled, 26-week, phase 3 PaTHway trial assessed the efficacy and safety of PTH replacement therapy for hypoparathyroidism individuals with the investigational drug TransCon PTH (palopegteriparatide). Participants (n = 84) were randomized 3:1 to once-daily TransCon PTH (initially 18 μg/d) or placebo, both co-administered with conventional therapy. The study drug and conventional therapy were titrated according to a dosing algorithm guided by serum calcium. The composite primary efficacy endpoint was the proportion of participants at week 26 who achieved normal albumin-adjusted serum calcium levels (8.3-10.6 mg/dL), independence from conventional therapy (requiring no active vitamin D and ≤600 mg/d of calcium), and no increase in study drug over 4 weeks before week 26. Other outcomes of interest included health-related quality of life measured by the 36-Item Short Form Survey (SF-36), hypoparathyroidism-related symptoms, functioning, and well-being measured by the Hypoparathyroidism Patient Experience Scale (HPES), and urinary calcium excretion. At week 26, 79% (48/61) of participants treated with TransCon PTH versus 5% (1/21) wiplacebo met the composite primary efficacy endpoint (p < 0.0001). TransCon PTH treatment demonstrated a significant improvement in all key secondary endpoint HPES domain scores (all p < 0.01) and the SF-36 Physical Functioning subscale score (p = 0.0347) compared with placebo. Additionally, 93% (57/61) of participants treated with TransCon PTH achieved independence from conventional therapy. TransCon PTH treatment normalized mean 24-hour urine calcium. Overall, 82% (50/61) treated with TransCon PTH and 100% (21/21) wiplacebo experienced adverse events; most were mild (46%) or moderate (46%). No study drug-related withdrawals occurred. In conclusion, TransCon PTH maintained normocalcemia while permitting independence from conventional therapy and was well-tolerated in individuals with hypoparathyroidism. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

We report on probable factory-based contamination of portable water heaters with waterborne pathogens and 2 bloodstream infections potentially attributable to off-label use of these water heaters to warm extracorporeal membrane oxygenation circuits. Great caution is warranted when using water-based devices to care for critically ill patients., Competing Interests: Potential conflicts of interest. M. B., C. R., and M. K. have received grant funding from the Centers for Disease Control and Prevention within the past 3 years for research on severe acute respiratory syndrome coronavirus 2 prevention and transmission and currently receive grant funding for research on unrelated topics. C. R. and M. K. also have grant funding from AHRQ. M. K. receives funding from the Massachusetts Department of Public Health to support public health surveillance. M. K. has received royalties from UpToDate, Inc., for chapters on preventing nosocomial pneumonia and other unrelated topics. C. R. has received royalties from UpToDate, Inc., for chapters related to procalcitonin use. M. H. H. and M. R. S. are employees of Day Zero Diagnostics. A. S. received consulting fees from Inspira Technologies. R. S. reports consulting fees from BD. C. R. reports consulting fees from Pfizer and Cytovale. M. B. reports holding a leadership or fiduciary role on the SHEA Guidelines Committee. All other authors report no potential conflicts., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: Many therapies are used to treat COVID-19, the disease caused by the virus SARS-CoV-2, including convalescent plasma. The clinical utility of using 2 units of convalescent plasma for COVID-19 hospitalized patients is not fully understood., Objective: Many therapies are used to treat COVID-19, the disease caused by the virus SARS-CoV-2, including convalescent plasma. The clinical utility of using 2 units of convalescent plasma for COVID-19 hospitalized patients is not fully understood. Our study aims to determine the safety and efficacy of treating hospitalized COVID-19 patients with 2 units of COVID-19 convalescent plasma (CCP)., Method: This was a retrospective study of Arkansas patients treated with CCP using the (US) Food and Drug Administration (FDA) emergency Investigational New Drug (eIND) mechanism from April 9, 2020, through August 9, 2020. It was a multicenter, statewide study in a low-resource setting, which are areas that lack funding for health care cost coverage on various levels including individual, family, or social. Adult patients (n = 165, volunteer sample) in Arkansas who were hospitalized with severe or life-threatening acute COVID-19 disease as defined by the FDA criteria were transfused with 2 units of CCP (250 mL/unit) using the FDA eIND mechanism. The primary outcome was 7- and 30-day mortality after the second unit of CCP., Results: Unadjusted mortality was 12.1% at 7 days and 23.0% at 30 days. The unadjusted mortality was reduced to 7.7% if the first CCP unit was transfused on the date of diagnosis, 8.7% if transfused within 3 days of diagnosis, and 32.0% if transfused at or after 4 or more days of diagnosis. The risk of death was higher in patients that received low, negative, or missing titer CCP units in comparison to those that received higher titer units., Conclusion: The provision of 2 units of CCP was associated with a reduction in mortality in patients treated with high titer units within 3 days of COVID-19 diagnosis. Given the results, CCP is a viable, low-cost therapy in resource-constrained states and countries., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Burkholderia cepacia complex is a group of potential nosocomial pathogens often linked to contaminated water. We report on a cluster of 8 B. cepacia complex infections in cardiothoracic intensive care unit patients, which were attributed to contaminated extracorporeal membrane oxygenation (ECMO) water heaters., Methods: In December 2020, we identified an increase in B. cepacia complex infections in the cardiothoracic intensive care unit at Brigham and Women's Hospital. We sought commonalities, sequenced isolates, obtained environmental specimens, and enacted mitigation measures., Results: Whole-genome sequencing of 13 B. cepacia complex clinical specimens between November 2020 and February 2021 identified 6 clonally related isolates, speciated as Burkholderia contaminans. All 6 occurred in patients on ECMO. Microbiology review identified 2 additional B. contaminans cases from June 2020 that may have also been cluster related, including 1 in a patient receiving ECMO. All 8 definite or probable cluster cases required treatment; 3 patients died, and 3 experienced recurrent infections. After ECMO was identified as the major commonality, all 9 of the hospital's ECMO water heaters were cultured, and B. contaminans grew in all cultures. Cultures from air sampled adjacent to the water heaters were negative. Water heater touch screens were culture positive for B. contaminans, and the sink drain in the ECMO heater reprocessing room also grew clonal B. contaminans. Observations of reprocessing revealed opportunities for cross-contamination between devices through splashing from the contaminated sink. The cluster was aborted by removing all water heaters from clinical service., Conclusions: We identified a cluster of 8 B. cepacia complex infections associated with contaminated ECMO water heaters. This cluster underscores the potential risks associated with water-based ECMO heaters and, more broadly, water-based care for vulnerable patients., Competing Interests: Potential conflicts of interest. C. R. and M. K. report grants or contracts outside the scope of this work from the Centers for Disease Control and Prevention and the Agency for Healthcare Quality and Research and royalties from UpToDate. M. A. B. reports a leadership or fiduciary role on the Guidelines Committee of the Society for Healthcare Epidemiology of America. M. S. and M. Huntley report stock or stock options and other financial or nonfinancial interests in their employer, Day Zero Diagnostics. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Purpose: The objectives of the ongoing, Phase 3, open-label extension trial enliGHten are to assess the long-term safety and efficacy of weekly administered long-acting growth hormone lonapegsomatropin in children with growth hormone deficiency., Methods: Eligible subjects completing a prior Phase 3 lonapegsomatropin parent trial (heiGHt or fliGHt) were invited to participate. All subjects were treated with lonapegsomatropin. Subjects in the United States switched to the TransCon hGH Auto-Injector when available. Endpoints were long-term safety, annualized height velocity, pharmacodynamics [insulin-like growth factor-1 SD score (SDS) values], and patient- and caregiver-reported assessments of convenience and tolerability., Results: Lonapegsomatropin treatment during enliGHten was associated with continued improvements in height SDS through week 104 in treatment-naïve subjects from the heiGHt trial (-2.89 to -1.37 for the lonapegsomatropin group; -3.0 to -1.52 for the daily somatropin group). Height SDS also continued to improve among switch subjects from the fliGHt trial (-1.42 at fliGHt baseline to -0.69 at week 78). After 104 weeks, the average bone age/chronological age ratio for each treatment group was 0.8 (0.1), showing only minimal advancement of bone age relative to chronological age with continued lonapegsomatropin treatment among heiGHt subjects. Fewer local tolerability reactions were reported with the TransCon hGH Auto-Injector compared with syringe/needle., Conclusions: Treatment with lonapegsomatropin continued to be safe and well-tolerated, with no new safety signals identified. Children treated with once-weekly lonapegsomatropin showed continued improvement of height SDS through the second year of therapy without excess advancement of bone age., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Non-powder firearms, such as BB guns, are considered safer than traditional firearms and are often marketed toward younger demographics as children's toys. Recent advances in compressed-gas technology have drastically increased the firing power of these types of firearms, which has caused them to be more dangerous and capable of causing severe injury. We report the case of an 11-year-old male admitted for nasal injury caused by a BB gun pellet. The projectile had an unpredictable course: it pierced the skin of his left nasal sidewall, traversed through the soft tissues of the nose to the right nasal cavity violating the posterior septum, and lodged in the right posterior ethmoids adjacent to the posterior attachment of the middle turbinate. The metallic foreign object was successfully retrieved from the right nasal cavity via an endoscopic approach after minimal endoscopic dissection, guided by the preoperative radiologic imaging., (Published by Oxford University Press and JSCR Publishing Ltd. © The Author(s) 2022.)

Purpose: To determine a patient's clinical course based on the use of an activated partial thromboplastin time (aPTT) or heparin anti-Xa assay when transitioning from rivaroxaban or apixaban to an unfractionated heparin infusion., Methods: A retrospective chart review was conducted to investigate how unfractionated heparin infusions were managed at a tertiary care hospital in the setting of recent apixaban or rivaroxaban administration. Patients were separated into 2 cohorts based on the chosen heparin infusion monitoring assay: heparin anti-Xa or aPTT. The primary composite outcome was total number of bleeding and thrombotic events; the secondary composite outcome was average incidence of heparin infusion holds and rate changes per patient., Results: Data were collected from 76 patients (heparin anti-Xa = 69, aPTT = 7). Due to the limited number of patients within the aPTT cohort, this data was excluded from the analysis, and heparin anti-Xa descriptive statistics were reported without statistical comparisons. In the heparin anti-Xa group, a total of 10 bleeds and 1 thrombus were discovered. Additionally, the average number of infusion holds and rate changes was 0.841 and 2.65 times per patient, respectively, for those patients monitored via heparin anti-Xa assay., Conclusion: In the presence of a recently administered oral anti-Xa anticoagulant, more down-titrations occurred in the initial 6 hours of the heparin infusion when measuring anti-Xa activity, and most up-titrations occurred after 36 hours. Baseline heparin anti-Xa activity may be a useful tool to identify patients with residual plasma concentrations of apixaban and rivaroxaban to help better individualize heparin therapy., (© American Society of Health-System Pharmacists 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Chronic kidney disease (CKD) incidence is increasing and associated mortality and morbidity are high. Educating patients is effective in delaying progression and establishing optimal renal replacement therapy (RRT). Tele-education/telemedicine (TM) can be an effective tool to provide such education, but there are no available data quantifying its effectiveness. We attempted to establish such evidence correlating the effect of education in patient choices and with the start of actual RRT. We present results from a 3-year pilot study evaluating the effectiveness of comprehensive predialysis education (CPE) through TM for CKD patients compared with a standard care group [face to face (FTF)]. The patient's ability to choose RRT was the primary endpoint., Methods: This was a randomized controlled study providing CPE over three classes at nine sites (one FTF and eight TM). Three assessment tools were utilized to compare groups: CKD knowledge, literacy and quality of life., Results: A total of 47.1% of FTF and 52.2% of TM patients reported not having enough information to choose a modality. This decreased by the third visit (FTF 7.4%, TM 13.2%). Home modality choices more than doubled in both groups (FTF 25.8-67.7%, TM 22.2-50.1%). In patients that completed one visit and needed to start RRT, 47% started on a home modality or received a pre-emptive transplant (home hemodialysis 6%, peritoneal dialysis 38%, transplant 3%)., Conclusions: Results show almost 90% (TM 87%, FTF 95%) of the attendees could choose a modality after education. Home modality choices doubled. Patients were able to make an informed choice regardless of the modality of education., (© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA.)

Earth's largest aquifer ecosystem resides in igneous oceanic crust, where chemosynthesis and water-rock reactions provide the carbon and energy that support an active deep biosphere. The Calvin Cycle is the predominant carbon fixation pathway in cool, oxic, crust; however, the energy and carbon metabolisms in the deep thermal basaltic aquifer are poorly understood. Anaerobic carbon fixation pathways such as the Wood-Ljungdahl pathway, which uses hydrogen (H 2 ) and CO 2 , may be common in thermal aquifers since water-rock reactions can produce H 2 in hydrothermal environments and bicarbonate is abundant in seawater. To test this, we reconstructed the metabolisms of eleven bacterial and archaeal metagenome-assembled genomes from an olivine biofilm obtained from a Juan de Fuca Ridge basaltic aquifer. We found that the dominant carbon fixation pathway was the Wood-Ljungdahl pathway, which was present in seven of the eight bacterial genomes. Anaerobic respiration appears to be driven by sulfate reduction, and one bacterial genome contained a complete nitrogen fixation pathway. This study reveals the potential pathways for carbon and energy flux in the deep anoxic thermal aquifer ecosystem, and suggests that ancient H 2 -based chemolithoautotrophy, which once dominated Earth's early biosphere, may thus remain one of the dominant metabolisms in the suboceanic aquifer today.

Recurrent events often serve as the outcome in epidemiologic studies. In some observational studies, the goal is to estimate the effect of a new or "experimental" (i.e., less established) treatment of interest on the recurrent event rate. The incentive for accepting the new treatment may be that it is more available than the standard treatment. Given that the patient can choose between the experimental treatment and conventional therapy, it is of clinical importance to compare the treatment of interest versus the setting where the experimental treatment did not exist, in which case patients could only receive no treatment or the standard treatment. Many methods exist for the analysis of recurrent events and for the evaluation of treatment effects. However, methodology for the intersection of these two areas is sparse. Moreover, care must be taken in setting up the comparison groups in our setting; use of existing methods featuring time-dependent treatment indicators will generally lead to a biased treatment effect since the comparison group construction will not properly account for the timing of treatment initiation. We propose a sequential stratification method featuring time-dependent prognostic score matching to estimate the effect of a time-dependent treatment on the recurrent event rate. The performance of the method in moderate-sized samples is assessed through simulation. The proposed methods are applied to a prospective clinical study in order to evaluate the effect of living donor liver transplantation on hospitalization rates; in this setting, conventional therapy involves remaining on the wait list or receiving a deceased donor transplant., (© 2015, The International Biometric Society.)

Background: Enterococci are an important cause of healthcare-associated infections. We retrospectively analyzed risk factors and outcome of vancomycin-resistant enterococci (VRE) and vancomycin-sensitive enterococci (VSE) infections., Methods: Seven hundred fifty-two patients who received hematopoietic stem cell transplants from 2004 through 2008 at the University of Minnesota were included., Results: Ninety-three patients had enterococcal bloodstream infection (BSI) during the first year after transplant. Vancomycin resistance was observed in 66% and 31% of isolates in adults and children, respectively. Cumulative incidence of VRE and VSE bacteremia was 6.6% (95% confidence interval [CI], 4.8%-8.4%) and 5.7% (95% CI, 4.0%-7.4%), respectively. Colonization with VRE before or after transplant was a risk factor for VRE bacteremia (odds ratio [OR], 3.3 [95% CI, 1.3-8.3] and 7.0 [95% CI, 4.0-14.8], respectively). Delay in engraftment increased the incidence of VRE bacteremia from 4.5% (95% CI, 2.9-6.6) if engrafted before day 21 and to 15% (95% CI, 3.2%-38%) if engrafted between days 36 and 42. In adults, mortality 30 days after infection was 38% for both VRE (95% CI, 25%-54%) and VSE cases (95% CI, 21%-62%). The hazard ratio for all-cause mortality up to 1 year after transplant was 4.2 (95% CI, 3.1-6.9) and 2.7 (95% CI, 1.4-5.1) for patients with VRE and VSE BSIs, respectively, compared to patients without enterococcal BSI. In pediatric patients, mortality 30 days after VRE and VSE bacteremia was 20% (95% CI, 5.4%-59%) and 4.5% (95% CI, .6%-28%), respectively., Conclusion: High rates of vancomycin resistance and association of enterococcal infections with significant mortality warrant further efforts to optimize prevention and management of these infections.

Patients with dysphagia require long-term nutritional support. This can be delivered by the enteral route via a percutaneous endoscopic gastrostomy (PEG) tube. Enteral nutrition (EN) bypasses the body's innate defences that prevent the microbial colonization of the proximal gut, which predisposes to microbial overgrowth. A continuous culture model simulating the upper gastrointestinal tract microbiota of EN patients was used to investigate the effects of a synbiotic (Lactobacillus acidophilus DUN-311, Bifidobacterium bifidum BB-02, Bifidobacterium lactis BL-01, Synergy 1) on microbial community structure and metabolism. A PEG tube was inserted into the fermenters to study biofilm formation. The synbiotic delivered in sterile semi-skimmed milk (SSSM) was introduced either 48 h prior to or after PEG tube insertion. The synbiotic reduced biofilm formation on PEG tube surfaces, with suppression of Escherichia coli and Klebsiella pneumoniae when it was added subsequent to PEG insertion. When synbiotic feeding was commenced prior to PEG insertion, colonization by Staphylococcus aureus, Candida albicans and Candida famata was also inhibited. Lactate production increased in response the synbiotic or control (SSSM). These results indicate that the use of a synbiotic has the potential to reduce pathogen colonization on PEG tube surfaces in vivo, thereby reducing the incidence of biofilm-related infectious complications., (© 2011 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.)

CP-724,714, a potent and selective orally active HER2 tyrosine kinase inhibitor, was discontinued from clinical development due to unexpected hepatotoxicity in cancer patients. Based on the clinical manifestation of the toxicity, CP-724,714 likely exerted its hepatotoxicity via both hepatocellular injury and hepatobiliary cholestatic mechanisms. The direct cytotoxic effect, hepatobiliary disposition of CP-724,714, and its inhibition of active canalicular transport of bile constituents were evaluated in established human hepatocyte models and in vitro transporter systems. CP-724,714 exhibited direct cytotoxicity using human hepatocyte imaging assay technology with mitochondria identified as a candidate organelle for its off-target toxicity. Additionally, CP-724,714 was rapidly taken up into human hepatocytes, partially via an active transport process, with an uptake clearance approximately fourfold higher than efflux clearance. The major human hepatic uptake transporter, OATP1B1, and efflux transporters, multidrug resistance protein 1 (MDR1) and breast cancer resistance protein, were involved in hepatobiliary clearance of CP-724,714. Furthermore, CP-724,714 displayed a concentration-dependent inhibition of cholyl-lysyl fluorescein and taurocholate (TC) efflux into canaliculi in cryopreserved and fresh cultured human hepatocytes, respectively. Likewise, CP-724,714 inhibited TC transport in membrane vesicles expressing human bile salt export pump with an IC(50) of 16 microM. Finally, CP-724,714 inhibited the major efflux transporter in bile canaliculi, MDR1, with an IC(50) of approximately 28 microM. These results suggest that inhibition of hepatic efflux transporters contributed to hepatic accumulation of drug and bile constituents leading to hepatocellular injury and hepatobiliary cholestasis. This study provides likely explanations for clinically observed adverse liver effects of CP-724,714.

Aims: This study investigates the effects of N-(n-dodecyl)diethanolamine (DDA) on enzymes and growing cells of Escherichia coli NCIMB 8277., Methods and Results: Enzyme activities in the presence of DDA were determined by measuring substrate-dependent oxygen consumption by whole cells, or of NADH formation or oxidation by cell extracts. Lysis of growing cells was followed by measuring changes in turbidity and cell count. DDA promptly arrested oxygen uptake on pyruvate and acetate, due to cofactor loss rather than to enzyme denaturation, since cell-free glyceraldehyde-3-phosphate and NADH dehydrogenases remained active. Formate and succinate oxidation by membrane-bound enzyme systems independent of cofactors was likewise unaffected. DDA lysed growing cells at rates related to drug concentration, pH, and the previous growth rate., Conclusions: Loss of cellular enzyme activity following addition of DDA is due to cofactor leakage and not to enzyme denaturation. Whereas nongrowing cells remain intact in the presence of DDA, actively-growing organisms undergo lysis, consistent with autolysin action., Significance and Impact of the Study: Cell lysis, not normally observed with membrane-active antimicrobials, also occurs with cetrimide, and may be dependent on the alkyl chain length in these compounds. The action on growing cells parallels that of penicillin and daptomycin, which bears a decanoyl residue that penetrates the cell membrane, causing leakage and membrane depolarization.

Background: From 2003 through 2007, Vibrio cholerae serogroup O75 strains possessing the cholera toxin gene were isolated from 6 patients with severe diarrhea, including 3 in Georgia, 2 in Alabama, and 1 in South Carolina. These reports represent the first identification of V. cholerae O75 as a cause of illness in the United States. V. cholerae O75 was isolated from a water sample collected from a pond in Louisiana in 2004. Subsequently, 3 V. cholerae isolates from Louisiana (2 from patients with diarrhea in 2000 and 1 from a water sample collected in 1978) that had been previously reported as serogroup O141 were also discovered to be serogroup O75., Results: All 8 patients who were infected with V. cholerae O75 were adults who became ill after consuming seafood; 2 had eaten raw oysters traced back to the Gulf Coast of the United States. All 10 isolates possessed the cholera toxin gene and were susceptible to 10 antimicrobials. One clinical isolate and 1 environmental (water) isolate had the same pulsed-field gel electrophoresis pattern; 4 clinical isolates shared a common pulsed-field gel electrophoresis pattern., Conclusions: The occurrence of these cases over many years and the concurrent identification of V. cholerae O75 in water from a Gulf Coast state suggest that these strains may survive for long periods in this environment. The patients' exposure histories suggest that infection can be acquired from consumption of raw oysters from the Gulf Coast. Clinicians and public health authorities should be vigilant for the occurrence of new toxigenic serogroups of V. cholerae that are capable of causing severe diarrhea.

Drug-induced liver injury (DILI) is the most common adverse event causing drug nonapprovals and drug withdrawals. Using drugs as test agents and measuring a panel of cellular phenotypes that are directly linked to key mechanisms of hepatotoxicity, we have developed an in vitro testing strategy that is predictive of many clinical outcomes of DILI. Mitochondrial damage, oxidative stress, and intracellular glutathione, all measured by high content cellular imaging in primary human hepatocyte cultures, are the three most important features contributing to the hepatotoxicity prediction. When applied to over 300 drugs and chemicals including many that caused rare and idiosyncratic liver toxicity in humans, our testing strategy has a true-positive rate of 50-60% and an exceptionally low false-positive rate of 0-5%. These in vitro predictions can augment the performance of the combined traditional preclinical animal tests by identifying idiosyncratic human hepatotoxicants such as nimesulide, telithromycin, nefazodone, troglitazone, tetracycline, sulindac, zileuton, labetalol, diclofenac, chlorzoxazone, dantrolene, and many others. Our findings provide insight to key DILI mechanisms, and suggest a new approach in hepatotoxicity testing of pharmaceuticals.

Background and Purpose: The International Classification of Functioning, Disability and Health (ICF) has been proposed as a possible framework for organizing physical therapist practice. The purpose of this case report is to describe an evaluative and diagnostic process that is based on the ICF framework for a patient with a patellar dislocation., Case Description: The patient was a 23-year-old woman who sustained a right knee and patellofemoral joint injury, resulting in a sprain of the medial collateral ligament and a suspected sprain of the medial patellofemoral ligament. Evaluation at 4 weeks demonstrated a primary impairment of patellar instability associated with the primary activity limitation of limited walking distances. A plan of care to address impairments, activity limitations, and participation restrictions was developed, with modifications made on the basis of the patient's health condition and personal and environmental factors., Outcomes: The patient attained all of her goals for therapy and was able to return to her normal activities and recreational pursuits without a recurrence of a patellar dislocation. Lower-Extremity Function Scale scores increased from 30 out of 80 to 76 out of 80 during the course of treatment., Discussion: The ICF model has been proposed as a framework for developing diagnostic classifications for rehabilitation professionals. The ICF model also should be assessed with regard to whether it provides a useful process for clinical decision making. The ICF model directs practitioners to address patients' problems at the level of the whole person, with modifications made on the basis of health conditions and personal and environmental factors.

Mitochondrial toxicity is increasingly implicated in a host of drug-induced organ toxicities, including hepatotoxicity. Nefazodone was withdrawn from the U.S. market in 2004 due to hepatotoxicity. Accordingly, we evaluated nefazodone, another triazolopyridine trazodone, plus the azaspirodecanedione buspirone, for cytotoxicity and effects on mitochondrial function. In accord with its clinical disposition, nefazodone was the most toxic compound of the three, trazodone had relatively modest effects, whereas buspirone showed the least toxicity. Nefazodone profoundly inhibited mitochondrial respiration in isolated rat liver mitochondria and in intact HepG2 cells where this was accompanied by simultaneous acceleration of glycolysis. Using immunocaptured oxidative phosphorylation (OXPHOS) complexes, we identified Complex 1, and to a lesser amount Complex IV, as the targets of nefazodone toxicity. No inhibition was found for trazodone, and buspirone showed 3.4-fold less inhibition of OXPHOS Complex 1 than nefazodone. In human hepatocytes that express cytochrome P450, isoform 3A4, after 24 h exposure, nefazodone and trazodone collapsed mitochondrial membrane potential, and imposed oxidative stress, as detected via glutathione depletion, leading to cell death. Our results suggest that the mitochondrial impairment imposed by nefazodone is profound and likely contributes to its hepatotoxicity, especially in patients cotreated with other drugs with mitochondrial liabilities.

In step and shoot spot-scanning, a small-diameter proton beam is magnetically swept and varied in energy in order to cover the tumour. Initial estimates of the beam size indicate that additional collimating hardware will be needed for lower energy proton beams in order to achieve a clinically acceptable lateral dose falloff at the edge of the proton beam. In this report, we present dosimetric data from Monte Carlo simulations with a model of a simple multileaf collimator which indicate that such a device may be used to improve the lateral dose falloff. The dosimetric quantities relevant to the clinical usefulness of the device are studied, including lateral penumbra, leaf transmission and scalloping effect. Multileaf collimation is compared with a differential spot-weighting technique of sharpening the lateral dose falloff.

The Bevatron of the Lawrence Berkeley National Laboratory operated with no permanent shielding-roof from 1954 to 1962. Neutron fluences measured at the laboratory perimeter reached a maximum in 1959, and were reported as an annual dose equivalent of 8.1 mSv (54% of the then operative radiation limit). The addition of temporary local shielding and improved operational techniques subsequently led to a steady decline in dose equivalent at the laboratory perimeter. A permanent concrete shielding-roof was constructed in 1962. In those early years of operation the reported dose equivalent, H, was derived from a measured total neutron fluence, phi, and an estimated spectrum-weighted fluence to dose equivalent conversion coefficient, (g), where H= (g) phi. The uncertainty in H was almost entirely due to the uncertainty in (g). While the measurements of phi were accurate the estimates of (g) were quite crude and depended upon measurements of average neutron energy, on assumptions about the shape of the neutron energy spectrum, and primitive values of fluence to dose equivalent conversion coefficients for monoenergetic neutrons. These early reported dose equivalents were known to be overestimated. This paper has reappraised the dose equivalents in the light of better information now available. Environmental neutron spectra have been calculated which more accurately correspond to the operational conditions of the Bevatron in the 1950s and early 1960s. than did those spectra available at that time. A new fluence to dose equivalent conversion function based on the latest data and for isotropic irradiation geometry was developed. From these two parameters better estimates of the coefficient (g) were determined and compared with the earlier values. From this reappraisal it is shown that the early reported dose equivalents were conservative by a factor of at least five.

A novel insertion sequence (IS), IS1471, has been identified which is inserted into IS element IS1071 possessed by plasmid pIJB1 in Burkholderia cepacia strain 2a. Nucleotide sequencing has revealed that IS1471 is 1112 bp in length and is flanked by 22/21-bp imperfect inverted repeats with a 3-bp duplication of the target sequence IS1471 contains a single open reading frame encoding a putative polypeptide of 345 amino acids with molecular mass of 39406 Da. Searches of DNA and protein sequence databases did not result in the detection of any homologous IS elements, suggesting that IS1471 is novel and may not belong to any known IS groups.

Psychotropic drug prescribing in 1280 medical inpatients between 1973-75 was compared with that in 1200 similar patients during 1982-83. Three benzodiazepines accounted for 64% of prescriptions in 1973-75 and nine benzodiazepines for 82% of prescriptions in 1982-83. Over the decade, use of psychotropic drugs fell from 56% to 38% (P less than 0.001), primarily due to a reduction in patients treated only in hospital (34% vs 16%, P less than 0.001). Before admission, the proportions of patients receiving these drugs were similar (17% vs 18%). During admission, concomitant administration of similar drugs declined from 22% of patients in 1973-75 to 11% in 1982-83 (P less than 0.001), while concurrent prescribing before admission increased from 13 to 19%. The marked fall in psychotropic drug use and in inappropriate concomitant therapy indicates an encouraging trend towards more rational drug use at least in hospital. This was achieved without fiscal control and further rationalization of prescribing habits may be achieved by self-audit within the profession without legislative action.