Systematic mapping of the conformational landscape and dynamism of soluble fibrinogen.

BACKGROUND: Fibrinogen is a soluble, multisubunit, and multidomain dimeric protein, which, upon its proteolytic cleavage by thrombin, is converted to insoluble fibrin, initiating polymerization that substantially contributes to clot growth. Fibrinogen contains numerous, transiently accessible "cryptic" epitopes for hemostatic and immunologic proteins, suggesting that fibrinogen exhibits conformational flexibility, which may play functional roles in its temporal and spatial interactions. Hitherto, there have been limited integrative approaches characterizing the solution structure and internal flexibility of fibrinogen. METHODS: Here, utilizing a multipronged, biophysical approach involving 2 solution-based techniques, temperature-dependent hydrogen-deuterium exchange mass spectrometry and small angle X-ray scattering, corroborated by negative stain electron microscopy, we present a holistic, conformationally dynamic model of human fibrinogen in solution. RESULTS: Our data reveal 4 major and distinct conformations of fibrinogen accommodated by a high degree of internal protein flexibility along its central scaffold. We propose that the fibrinogen structure in the solution consists of a complex, conformational landscape with multiple local minima. This is further supported by the location of numerous point mutations that are linked to dysfibrinogenemia and posttranslational modifications, residing near the identified fibrinogen flexions. CONCLUSION: This work provides a molecular basis for the structural "dynamism" of fibrinogen that is expected to influence the broad swath of its functionally diverse macromolecular interactions and fine-tune the structural and mechanical properties of blood clots.

A Pilot Study of Nutritional Supplementation in Soft Tissue Sarcoma Patients.

Background: Wound healing is particularly important for sarcoma patients who undergo neoadjuvant radiation therapy. Previous studies have demonstrated wound complications in this population approaching 35%. With this high rate of wound healing issues, identifying treatment modalities to minimize these complications is of paramount importance. Methods: All patients with high grade bone and soft tissue sarcoma received 15 days of twice daily amino acid supplementation starting in the immediate post-operative period. We documented the healing status of the surgical wound, the primary outcome, at all follow up appointments until six months after surgery. Non-healing wounds were defined as any wound requiring 1) a return visit to the OR for debridement, 2) IV antibiotics (ABX), and 3) unhealed wounds at 6 months post-operatively.1 For each patient, we collected biometrics with lean body mass analysis at preoperative appointment, and two and six weeks postoperatively. The proportion with non-healing wounds was compared with a historical patient cohort using the chi-square test. In a subgroup of participants with body composition measurements, we also compared changes in mean fat mass, lean mass, and psoas index from pre-operative baseline to 6 months post-operative using generalized linear models. Results: A total of 33 consecutive patients were supplemented with a branched chain amino acid (BCAA) formulation. The historical cohort included 146 participants from the previous 7 years (2010-2017). 26% of patients in the historical cohort experienced wound complications compared to 30% in the supplemented group. (p=0.72) When focusing specifically on lower extremity sarcomas treated with neoadjuvant radiation therapy, 46% of patients in the supplemented group experienced wound healing complications compared to 39% in the non-supplemented group (p=0.68). BCAA supplementation was found to be protective with regards to decreasing muscle wasting with no difference in psoas index measurements throughout the study period compared to a 20% muscle loss in the historical cohort (p=0.02). Conclusion: In our limited sample size, there was no difference in wound healing complications between sarcoma patients who received postoperative BCAA supplementation compared to a historical cohort who were not supplemented. Patients who did not receive supplementation had a significant decline in post-operative psoas index following operative sarcoma removal. Level of Evidence: III.

Biological Characterization, Properties, and Clinical Use of a Novel Homeopathic Antiseptic Oral Recovery Kit: A Narrative Review.

Most available antiseptic solutions have strong antibacterial effects, but many also possess major cytotoxic effects on gingival fibroblasts, osteoblasts, osteoprogenitor cells, and/or epithelial cells. A novel VEGA Oral Care Recovery Kit (StellaLife) consisting of 16 active ingredients that are monographed in the Homeopathic Pharmacopeia of the United States (HPUS) has gained tremendous momentum as a replacement for more cytotoxic oral rinses such as chlorhexidine. While accumulating evidence has thus far supported its use, little of the gathered data have fully described the properties of the oral formulation. Therefore, the aim of the present review article was 3-fold. First, a biological characterization regarding the active ingredients found in StellaLife Recovery Kit including their biological properties was assessed in 4 predominant categories; 1) antimicrobial resistance, 2) accelerated wound healing, 3) pain management control, and 4) anti-cancer properties. The second aim of this review article was to assess both fundamental and clinical research to date comparing VEGA oral rinse (StellaLife) to the more commonly utilized CHX for differences regarding their effect on decreasing bacterial loads as well as cell viability, survival, proliferation, and expression of both regenerative cytokines and inflammatory markers. Lastly, clinical case examples are presented describing the use of StellaLife remedies in a variety of clinical situations. These include but are not limited to wisdom-tooth extraction, extraction site management, dental implants and ridge augmentation, soft-tissue grafting procedures, frenectomies, and also temporary relief of dry sockets, dry mouth, aphthous ulcers, mucositis, lichen planus, among others. In summary, findings from the present review article provide evidence from basic laboratory experiments that validate clinical studies supporting the use of the StellaLife oral rinse regarding its superior biocompatibility and wound healing properties when compared to common antiseptic solutions such as CHX.

Sensitizing brain metastases to stereotactic radiosurgery using hyperbaric oxygen: A proof-of-principle study.

PURPOSE: Increased oxygen levels may enhance the radiosensitivity of brain metastases treated with stereotactic radiosurgery (SRS). This project administered hyperbaric oxygen (HBO) prior to SRS to assess feasibility, safety, and response. METHODS: 38 patients were studied, 19 with 25 brain metastases treated with HBO prior to SRS, and 19 historical controls with 27 metastases, matched for histology, GPA, resection status, and lesion size. Outcomes included time from HBO to SRS, quality-of-life (QOL) measures, local control, distant (brain) metastases, radionecrosis, and overall survival. RESULTS: The average time from HBO chamber to SRS beam-on was 8.3 ± 1.7 minutes. Solicited adverse events (AEs) were comparable between HBO and control patients; no grade III or IV serious AEs were observed. Radionecrosis-free survival (RNFS), radionecrosis-free survival before whole-brain radiation therapy (WBRT) (RNBWFS), local recurrence-free survival before WBRT (LRBWFS), distant recurrence-free survival before WBRT (DRBWFS), and overall survival (OS) were not significantly different for HBO patients and controls on Kaplan-Meier analysis, though at 1-year estimated survival rates trended in favor of SRS + HBO: RNFS - 83% vs 60%; RNBWFS - 78% vs 60%; LRBWFS - 95% vs 78%; DRBWFS - 61% vs 57%; and OS - 73% vs 56%. Multivariate Cox models indicated no significant association between HBO treatment and hazards of RN, local or distant recurrence, or mortality; however, these did show statistically significant associations (p < 0.05) for: local recurrence with higher volume, radionecrosis with tumor resection, overall survival with resection, and overall survival with higher GPA. CONCLUSION: Addition of HBO to SRS for brain metastases is feasible without evident decrement in radiation necrosis and other clinical outcomes.

Do the National Institute for Occupational Safety and Health recommendations for working in the heat prevent excessive hyperthermia and body mass loss in unacclimatized males?

The National Institute for Occupational Safety and Health recommendations for work in the heat suggest workers consume 237 mL of water every 15-20 min and allow for continuous work at heavy intensities in hot environments up to 34 °C and 30% relative humidity. The goal was to determine whether the National Institute for Occupational Safety and Health recommendations prevented core temperature from exceeding 38.0 °C and greater than 2% body mass loss during heavy-intensity work in the heat. Eight males consumed 237 mL of water every 20 min during 2 hr of continuous heavy-intensity walking (6.4 kph, 1% grade) in a 34 °C/30% relative humidity environment, in accordance with the National Institute for Occupational Safety and Health recommendations. Projected core temperature and percent body mass loss were calculated for 4 and 8 hr of continuous work. Core temperature rose from baseline (36.8 ± 0.3 °C) to completion of 2 hr of work (38.1 ± 0.6 °C, p < 0.01), with two participants reaching the 38.0 °C threshold. Projected core temperatures remained elevated from baseline (p < 0.01), did not change from 2 to 4 hr (38.1 ± 0.7 °C, p > 0.99) and 4 to 8 hr (38.1 ± 0.8 °C, p > 0.99), respectively, and one participant exceeded 38.0 °C at 4 to 8 hr. There was no change in body mass loss over time (p > 0.99). During 2 hr of continuous heavy-intensity work in the heat, 75% of participants did not reach 38 °C core temperature and 88% did not reach 2% body mass loss when working to National Institute for Occupational Safety and Health recommendations.

Improving Allergy Documentation: A Retrospective Electronic Health Record System-Wide Patient Safety Initiative.

OBJECTIVES: Documentation of allergies in a coded, non-free-text format in the electronic health record (EHR) triggers clinical decision support to prevent adverse events. Health system-wide patient safety initiatives to improve EHR allergy documentation by specifically decreasing free-text allergy entries have not been reported. The goal of this initiative was to systematically reduce free-text allergen entries in the EHR allergy module. METHODS: We assessed free-text allergy entries in a commercial EHR used at a multihospital integrated health care system in the greater Boston area. Using both manual and automated methods, a multidisciplinary consensus group prioritized high-risk and frequently used free-text allergens for conversion to coded entries, added new allergen entries, and deleted duplicate allergen entries. Environmental allergies were moved to the patient problem list. RESULTS: We identified 242,330 free-text entries, which included a variety of environmental allergies (42%), food allergies (18%), contrast media allergies (13%), "no known allergy" (12%), drug allergies (2%), and "no contrast allergy" (2%). Most free-text entries were entered by medical assistants in ambulatory settings (34%) and registered nurses in perioperative settings (20%). We remediated a total of 52,206 free-text entries with automated methods and 79,578 free-text entries with manual methods. CONCLUSIONS: Through this multidisciplinary intervention, we identified and remediated 131,784 free-text entries in our EHR to improve clinical decision support and patient safety. Additional strategies are required to completely eliminate free-text allergy entry, and establish systematic, consistent, and safe guidelines for documenting allergies.

Safety and Tolerability of an Innovative Virtual Reality-Based Deep Breathing Exercise in Concussion Rehabilitation: A Pilot Study.

OBJECTIVE: To examine the safety and tolerability of a virtual reality-based deep breathing exercise for children and adolescents who are slow to recover from concussion. Methods: Fifteen participants (ages 11 to 22; mean = 16.9 years) were recruited from a specialty concussion clinic within a tertiary care medical center. Participants completed a 5-min paced deep breathing exercise administered via a virtual reality headset. Results: Nearly all participants (93.3%) reported the experience was either positive or extremely positive. No participants reported significant discomfort or discontinued the exercise. Three participants reported a mild increase in headache, dizziness, or nausea. Participants reported significant decreases in stress (r =.57), tension (r =.73), fatigue (r =.73), and confusion (r =.67), with large effect sizes, following the deep breathing exercise. Conclusion: A brief, virtual reality-based deep breathing exercise is worthy of additional study as a rehabilitation component for children and adolescents with prolonged concussion recoveries.

Progress or Pathology? Differential Diagnosis and Intervention Criteria for Meditation-Related Challenges: Perspectives From Buddhist Meditation Teachers and Practitioners.

Studies in the psychology and phenomenology of religious experience have long acknowledged similarities with various forms of psychopathology. Consequently, it has been important for religious practitioners and mental health professionals to establish criteria by which religious, spiritual, or mystical experiences can be differentiated from psychopathological experiences. Many previous attempts at differential diagnosis have been based on limited textual accounts of mystical experience or on outdated theoretical studies of mysticism. In contrast, this study presents qualitative data from contemporary Buddhist meditation practitioners and teachers to identify salient features that can be used to guide differential diagnosis. The use of certain existing criteria is complicated by Buddhist worldviews that some difficult or distressing experiences may be expected as a part of progress on the contemplative path. This paper argues that it is important to expand the framework for assessment in both scholarly and clinical contexts to include not only criteria for determining normative fit with religious experience or with psychopathology, but also for determining need for intervention, whether religious or clinical. Qualitative data from Buddhist communities shows that there is a wider range of experiences that are evaluated as potentially warranting intervention than has previously been discussed. Decision making around these experiences often takes into account contextual factors when determining appraisals or need for intervention. This is in line with person-centered approaches in mental health care that emphasize the importance of considering the interpersonal and cultural dynamics that inevitably constitute the context in which experiences are evaluated and rendered meaningful.

Inorganic nitrate and nitrite supplementation fails to improve skeletal muscle mitochondrial efficiency in mice and humans.

BACKGROUND: Inorganic nitrate, abundant in leafy green vegetables and beetroot, is thought to have protective health benefits. Adherence to a Mediterranean diet reduces the incidence and severity of coronary artery disease, whereas supplementation with nitrate can improve submaximal exercise performance. Once ingested, oral commensal bacteria may reduce nitrate to nitrite, which may subsequently be reduced to nitric oxide during conditions of hypoxia and in the presence of "nitrite reductases" such as heme- and molybdenum-containing enzymes. OBJECTIVE: We aimed to explore the putative effects of inorganic nitrate and nitrite on mitochondrial function in skeletal muscle. METHODS: Mice were subjected to a nitrate/nitrite-depleted diet for 2 wk, then supplemented with sodium nitrate, sodium nitrite, or sodium chloride (1 g/L) in drinking water ad libitum for 7 d before killing. Skeletal muscle mitochondrial function and expression of uncoupling protein (UCP) 3, ADP/ATP carrier protein (AAC) 1 and AAC2, and pyruvate dehydrogenase (PDH) were assessed by respirometry and Western blotting. Studies were also undertaken in human skeletal muscle biopsies from a cohort of coronary artery bypass graft patients treated with either sodium nitrite (30-min infusion of 10 µmol/min) or vehicle [0.9% (wt:vol) saline] 24 h before surgery. RESULTS: Neither sodium nitrate nor sodium nitrite supplementation altered mitochondrial coupling efficiency in murine skeletal muscle, and expression of UCP3, AAC1, or AAC2, and PDH phosphorylation status did not differ between the nitrite and saline groups. Similar results were observed in human samples. CONCLUSIONS: Sodium nitrite failed to improve mitochondrial metabolic efficiency, rendering this mechanism implausible for the purported exercise benefits of dietary nitrate supplementation. This trial was registered at clinicaltrials.gov as NCT04001283.

The ABCDEF Bundle for the Respiratory Therapist.

The clinical approach to the critically ill patient has changed dramatically over the last several decades from one of deep sedation to that of mobilizing patients on mechanical ventilation and limiting sedation. The ABCDEF bundle is a multidisciplinary, evidence-based approach to the holistic management of critically ill patients that aims to optimize patient recovery, minimize iatrogenesis, and engage and empower the patient and family during their hospitalization. To achieve this goal, the bundle includes assessments for pain, delirium, and readiness to stop sedation and to start spontaneous breathing trials. It also encourages early mobilization of the patient, avoidance of restraints, and engagement with the family in bedside rounds to improve communication. Performance of this bundle reduces mortality, ventilator days, intensive care readmissions, delirium, coma, restraint use, and discharge to facilities in a dose-dependent manner. The respiratory therapist, as a key member of the critical care team, is essential to the implementation, performance, and success of the ABCDEF bundle. This review aims to describe each component of the ABCDEF bundle, provide evidence for both the impact of individual interventions as well as the entire bundle, and detail the importance of this multidisciplinary approach to the care of the critically ill patient.

Pilot study of a lifestyle intervention for bipolar disorder: Nutrition exercise wellness treatment (NEW Tx).

BACKGROUND: Individuals with bipolar disorder (BD) are more likely than the general population to develop risk factors associated with cardiovascular disease, one of the leading causes of morbidity and mortality in this clinical population. To address this disproportionate medical burden, we developed Nutrition Exercise and Wellness Treatment (NEW Tx), a lifestyle intervention for individuals with BD. METHODS: In this study, participants were randomized to NEW Tx (n = 19) or a treatment as usual waitlist (n = 19). We examine the intervention's efficacy to improve the physical and psychological outcomes of individuals with BD. Assessors were blind to participant condition throughout study duration. RESULTS: The NEW Tx group reported increased weekly exercise duration and overall functioning, and decreased depression and illness severity over the study duration. However, only improvements in functioning were significantly greater in the NEW Tx group than in the control group. There were no group differences in weight loss or mood symptoms over the study duration. LIMITATIONS: Limitations to this study include lack of objective measurement of exercise and a small and relatively homogeneous sample. CONCLUSIONS: These data suggest that a manualized lifestyle intervention for BD may not be ideal to improve lifestyle changes in this clinical population. Further research is needed to pilot personalized approaches to creating a healthy lifestyle in BD.

Inorganic nitrate, hypoxia, and the regulation of cardiac mitochondrial respiration-probing the role of PPARα.

Dietary inorganic nitrate prevents aspects of cardiac mitochondrial dysfunction induced by hypoxia, although the mechanism is not completely understood. In both heart and skeletal muscle, nitrate increases fatty acid oxidation capacity, and in the latter case, this involves up-regulation of peroxisome proliferator-activated receptor (PPAR)α expression. Here, we investigated whether dietary nitrate modifies mitochondrial function in the hypoxic heart in a PPARα-dependent manner. Wild-type (WT) mice and mice without PPARα (Ppara-/-) were given water containing 0.7 mM NaCl (control) or 0.7 mM NaNO3 for 35 d. After 7 d, mice were exposed to normoxia or hypoxia (10% O2) for the remainder of the study. Mitochondrial respiratory function and metabolism were assessed in saponin-permeabilized cardiac muscle fibers. Environmental hypoxia suppressed mass-specific mitochondrial respiration and additionally lowered the proportion of respiration supported by fatty acid oxidation by 18% (P < 0.001). This switch away from fatty acid oxidation was reversed by nitrate treatment in hypoxic WT but not Ppara-/- mice, indicating a PPARα-dependent effect. Hypoxia increased hexokinase activity by 33% in all mice, whereas lactate dehydrogenase activity increased by 71% in hypoxic WT but not Ppara-/- mice. Our findings indicate that PPARα plays a key role in mediating cardiac metabolic remodeling in response to both hypoxia and dietary nitrate supplementation.-Horscroft, J. A., O'Brien, K. A., Clark, A. D., Lindsay, R. T., Steel, A. S., Procter, N. E. K., Devaux, J., Frenneaux, M., Harridge, S. D. R., Murray, A. J. Inorganic nitrate, hypoxia, and the regulation of cardiac mitochondrial respiration-probing the role of PPARα.

PLAG1 expression and target genes in the hypothalamo-pituitary system in male mice.

Knockout of pleomorphic adenoma gene 1 (PLAG1) in mice results in reduced fertility. To investigate whether PLAG1 is involved in reproductive control by the hypothalamo-pituitary system in males, we determined PLAG1 expression sites and compared gene expression between hypothalami and pituitary glands from Plag1 knockout and wildtype animals. Abundant expression of PLAG1 was detected throughout the pituitary gland, including gonadotropes and somatotropes. The hypothalamus also contained a large number of PLAG1-expressing cells. PLAG1 was expressed in some gonadotropin-releasing hormone neurons, but not in kisspeptin neurons. Gene ontology analysis indicated upregulation of cell proliferation in both structures, and of cholesterol biosynthesis in the hypothalamus, but functional confirmation is required. Expression levels of pituitary gonadotropins and gonadotropin-releasing hormone receptor, and of brain gonadotropin-releasing hormone and kisspeptin mRNA were unaffected in knockout mice. We conclude that PLAG1 deficiency does not have a major impact on the reproductive control by the hypothalamo-pituitary system.

Effect of probiotics on C-reactive protein levels in preterm infants: Secondary analysis of a randomized controlled trial.

BACKGROUND: Excessive inflammation is associated with adverse outcomes in preterm infants. C- reactive protein (CRP) is a marker of inflammation/infection. Probiotics have anti-inflammatory properties. Randomized controlled trials (RCTs) in preterm infants have not reported effect of probiotics on CRP. AIM: To evaluate effect of probiotics on CRP in preterm infants who had participated in a RCT of Bifidobacterium breve (B. breve) m-16v. METHODS: Data on all infants (GA <33 weeks, n = 159) enrolled in the RCT was analyzed. For study purpose, CRP <15 mg/L and ≤10 mg/L was considered normal for the first week, and thereafter respectively. Mixed logistic regression modelling was used to assess probiotic effect on CRP levels. RESULTS: There were 1579 CRP measurements (Probiotic: 851 vs. Placebo: 728). Baseline characteristics and number [Median (IQR)] of CRP estimations per infant [l0 (5, 20) vs. 10 (6, 17), p = 0.861] were comparable between probiotic vs. placebo group. There was no significant difference in the proportion of infants with high CRP over time (treatment by weekly time points interaction, p = 0.187), and across all time points between probiotic and placebo group (adjusted OR: 1.62, 95% CI: 0.91-2.88, p = 0.102)CONCLUSION:B. breve m-16v did not decrease CRP levels in preterm infants born <33 weeks.

Single-Shot Femoral Nerve Block Does Not Cause Long-Term Strength and Functional Deficits Following Anterior Cruciate Ligament Reconstruction.

PURPOSE: To determine if patients treated with a single-shot femoral nerve block have strength and functional deficits at 9-month follow-up. METHODS: Forty-three patients who underwent primary anterior cruciate ligament reconstructions were randomized to receive either a preoperative single-shot femoral nerve block or local infiltration anesthesia for primary pain control. All patients underwent a standardized comprehensive rehabilitation program postoperatively. Isokinetic strength and function was tested using a Biodex machine at 9 months or more postoperatively comparing the operative and nonoperative extremity. RESULTS: No significant difference in strength was found at an average of 10.6 months postoperatively (range, 9-15 months) between the femoral nerve block and control groups. In comparing strength deficits, we found no difference in slow isokinetic extension strength (22.4% vs 27.8%, P = .51), fast isokinetic extension strength (18.5% vs 12.5%, P = .41), slow isokinetic flexion strength (11.0% vs 15.1%, P = .55), and fast isokinetic flexion strength (8.2% vs 4.9%, P = .56) in the femoral nerve block versus control groups, respectively. In terms of functional outcomes, there also was no difference in deficits for single-leg hop distance (P = .12), timed single-leg hop (P = .74), and single-leg triple hop distance (P = .94). Maximal strength noted to be within 15% of the contralateral limb was achieved in 40% of patients and maximal function in 63% of patients at an average of 10.6 months postoperatively. A 13% complication rate was found in patients who received a femoral nerve block (1 with prolonged quadriceps inhibition and 2 with prolonged sensory disturbances). CONCLUSIONS: Our study found a 13% motor/sensory complication rate in patients who underwent femoral nerve block for pain control after anterior cruciate ligament reconstruction. Although these deficits may persist, they are not permanent and are not different when compared with controls at 9-month follow-up. However, maximal strength and function are not fully restored at normal return to play time and rehabilitation should continue long term to maximize recovery. LEVEL OF EVIDENCE: Level I, prospective randomized trial.

Brain network dynamics in the human articulatory loop.

OBJECTIVE: The articulatory loop is a fundamental component of language function, involved in the short-term buffer of auditory information followed by its vocal reproduction. We characterized the network dynamics of the human articulatory loop, using invasive recording and stimulation. METHODS: We measured high-gamma activity70-110 Hz recorded intracranially when patients with epilepsy either only listened to, or listened to and then reproduced two successive tones by humming. We also conducted network analyses, and analyzed behavioral responses to cortical stimulation. RESULTS: Presentation of the initial tone elicited high-gamma augmentation bilaterally in the superior-temporal gyrus (STG) within 40ms, and in the precentral and inferior-frontal gyri (PCG and IFG) within 160ms after sound onset. During presentation of the second tone, high-gamma augmentation was reduced in STG but enhanced in IFG. The task requiring tone reproduction further enhanced high-gamma augmentation in PCG during and after sound presentation. Event-related causality (ERC) analysis revealed dominant flows within STG immediately after sound onset, followed by reciprocal interactions involving PCG and IFG. Measurement of cortico-cortical evoked-potentials (CCEPs) confirmed connectivity between distant high-gamma sites in the articulatory loop. High-frequency stimulation of precentral high-gamma sites in either hemisphere induced speech arrest, inability to control vocalization, or forced vocalization. Vocalization of tones was accompanied by high-gamma augmentation over larger extents of PCG. CONCLUSIONS: Bilateral PCG rapidly and directly receives feed-forward signals from STG, and may promptly initiate motor planning including sub-vocal rehearsal for short-term buffering of auditory stimuli. Enhanced high-gamma augmentation in IFG during presentation of the second tone may reflect high-order processing of the tone sequence. SIGNIFICANCE: The articulatory loop employs sustained reciprocal propagation of neural activity across a network of cortical sites with strong neurophysiological connectivity.

Early Use of N-acetylcysteine With Nitrate Therapy in Patients Undergoing Primary Percutaneous Coronary Intervention for ST-Segment-Elevation Myocardial Infarction Reduces Myocardial Infarct Size (the NACIAM Trial [N-acetylcysteine in Acute Myocardial Infarction]).

BACKGROUND: Contemporary ST-segment-elevation myocardial infarction management involves primary percutaneous coronary intervention, with ongoing studies focusing on infarct size reduction using ancillary therapies. N-acetylcysteine (NAC) is an antioxidant with reactive oxygen species scavenging properties that also potentiates the effects of nitroglycerin and thus represents a potentially beneficial ancillary therapy in primary percutaneous coronary intervention. The NACIAM trial (N-acetylcysteine in Acute Myocardial Infarction) examined the effects of NAC on infarct size in patients with ST-segment-elevation myocardial infarction undergoing percutaneous coronary intervention. METHODS: This randomized, double-blind, placebo-controlled, multicenter study evaluated the effects of intravenous high-dose NAC (29 g over 2 days) with background low-dose nitroglycerin (7.2 mg over 2 days) on early cardiac magnetic resonance imaging-assessed infarct size. Secondary end points included cardiac magnetic resonance-determined myocardial salvage and creatine kinase kinetics. RESULTS: Of 112 randomized patients with ST-segment-elevation myocardial infarction, 75 (37 in NAC group, 38 in placebo group) underwent early cardiac magnetic resonance imaging. Median duration of ischemia pretreatment was 2.4 hours. With background nitroglycerin infusion administered to all patients, those randomized to NAC exhibited an absolute 5.5% reduction in cardiac magnetic resonance-assessed infarct size relative to placebo (median, 11.0%; [interquartile range 4.1, 16.3] versus 16.5%; [interquartile range 10.7, 24.2]; P=0.02). Myocardial salvage was approximately doubled in the NAC group (60%; interquartile range, 37-79) compared with placebo (27%; interquartile range, 14-42; P<0.01) and median creatine kinase areas under the curve were 22 000 and 38 000 IU·h in the NAC and placebo groups, respectively (P=0.08). CONCLUSIONS: High-dose intravenous NAC administered with low-dose intravenous nitroglycerin is associated with reduced infarct size in patients with ST-segment-elevation myocardial infarction undergoing percutaneous coronary intervention. A larger study is required to assess the impact of this therapy on clinical cardiac outcomes. CLINICAL TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry. URL: http://www.anzctr.org.au/. Unique identifier: 12610000280000.

The varieties of contemplative experience: A mixed-methods study of meditation-related challenges in Western Buddhists.

Buddhist-derived meditation practices are currently being employed as a popular form of health promotion. While meditation programs draw inspiration from Buddhist textual sources for the benefits of meditation, these sources also acknowledge a wide range of other effects beyond health-related outcomes. The Varieties of Contemplative Experience study investigates meditation-related experiences that are typically underreported, particularly experiences that are described as challenging, difficult, distressing, functionally impairing, and/or requiring additional support. A mixed-methods approach featured qualitative interviews with Western Buddhist meditation practitioners and experts in Theravada, Zen, and Tibetan traditions. Interview questions probed meditation experiences and influencing factors, including interpretations and management strategies. A follow-up survey provided quantitative assessments of causality, impairment and other demographic and practice-related variables. The content-driven thematic analysis of interviews yielded a taxonomy of 59 meditation-related experiences across 7 domains: cognitive, perceptual, affective, somatic, conative, sense of self, and social. Even in cases where the phenomenology was similar across participants, interpretations of and responses to the experiences differed considerably. The associated valence ranged from very positive to very negative, and the associated level of distress and functional impairment ranged from minimal and transient to severe and enduring. In order to determine what factors may influence the valence, impact, and response to any given experience, the study also identified 26 categories of influencing factors across 4 domains: practitioner-level factors, practice-level factors, relationships, and health behaviors. By identifying a broader range of experiences associated with meditation, along with the factors that contribute to the presence and management of experiences reported as challenging, difficult, distressing or functionally impairing, this study aims to increase our understanding of the effects of contemplative practices and to provide resources for mediators, clinicians, meditation researchers, and meditation teachers.

How vertical integration affects the quantity and cost of care for Medicare beneficiaries.

Health systems are employing physicians in growing numbers. The implications of this trend are poorly understood and controversial. We use rich data from the Centers for Medicare and Medicaid Services to examine the effects of a set of physician acquisitions by hospital systems on outpatient utilization and spending. We find that financial integration systematically produces economically large changes in the acquired physicians' behavior, but has less consistent effects at the acquiring system level.