Prevalence of poor cardiac anatomy in carcinoma of the breast treated with whole-breast radiotherapy: reconciling modern cardiac dosimetry with cardiac mortality data
PURPOSE: : The purpose of the study was to identify patient characteristics that predict for increased cardiac exposure through dosimetric analysis of the anatomy of a cohort of women treated with left-sided tangential breast radiation. Statistical analyses estimations for the appropriate sample sizes required for detection of significant differences in cardiac mortality at 15 years were conducted, assuming a threshold V25 for radiation-induced coronary artery disease (CAD) beyond which women are at risk for radiation-induced coronary artery disease.
METHODS AND MATERIALS: : Detailed heart dosimetry was recorded. Clinical factors (age, history of CAD, diabetes, receipt of cardiotoxic agents, weight/body mass index) and anatomic factors (heart volume, breast volume, cardiac contact distance) were recorded for each patient.
RESULTS: : The average heart V25 was 3.57%. The median percentage of the heart included in the tangential beam was 4.02%. There were no clinical or anatomic factors that predict suboptimal heart anatomy (ie, V25 of >/=6%) on multivariate analysis. The sample size calculations using thresholds for induction of CAD of V25 >/=1%, 6%, and 10% yielded sample sizes of 1314, 9504, and 61,342, respectively; considering node-positive breast cancer mortality and 15% loss to follow-up, these change to 2237, 16,166, and 104,334, respectively.
CONCLUSIONS: : Current studies with modern radiotherapy techniques would be underpowered to detect a difference in cardiac mortality where only some women are at risk. The heart, chest wall, and breast have a complex relationship to tangential breast radiation, and their interplay prevented this anatomic metric's success.
The National Cancer Institute (NCI) clinical cooperative groups have been instrumental over the past 50 years in developing clinical trials and evidence-based clinical trial processes for improvements in patient care. The cooperative groups are undergoing a transformation process to launch, conduct, and publish clinical trials more rapidly. Institutional participation in clinical trials can be made more efficient and include the expansion of relationships with international partners. This paper reviews the current processes that are in use in radiation therapy trials and the importance of maintaining effective credentialing strategies to assure the quality of the outcomes of clinical trials. The paper offers strategies to streamline and harmonize credentialing tools and processes moving forward as the NCI undergoes transformative change in the conduct of clinical trials.
Outcome of patients with localized orbital sarcoma who relapsed following treatment on Intergroup Rhabdomyosarcoma Study Group (IRSG) Protocols-III and -IV, 1984-1997: a report from the Children's Oncology Group
BACKGROUND: We wanted to ascertain patterns of recurrence, re-treatment, and outcome among 188 eligible patients treated for localized orbital sarcoma on IRSG Protocols III/IV, 1984-1997.
PROCEDURE: Retrospective chart review.
RESULTS: Twenty-four of 188 patients (12.8%) developed local (n = 22) or distant relapse (n = 2) at 0.057-7.05 years (median, 1.58) after enrollment. Ages at study entry were 0.14-17 years (median, 5 years). Initial tumor operations included biopsy (n = 20) or gross resection with microscopic residual (n = 4). Initial tumor diameters were 0.5-7 cm (median, 3). Pathologic subtypes were embryonal rhabdomyosarcoma (ERMS, n = 19), sarcoma not otherwise specified (n = 2), and alveolar RMS, botryoid ERMS, or undifferentiated sarcoma (n = 1 each). Initial treatment included vincristine/dactinomycin (n = 24) including an alkylator (n = 4) and radiotherapy (RT, n = 21). Twenty patients responded, 14 completely, 6 partially. After recurrence, patients underwent orbital exenteration (n = 10), enucleation (2), tumor excision (3), or biopsy (1); 7 had no operation, and 1 had no data. Post-relapse chemotherapy included combinations of etoposide (n = 14 patients), doxorubicin (14), ifosfamide (12), cyclophosphamide (7), and dacarbazine (n = 1). Six patients received RT, including four previously treated and two not irradiated initially. Two patients died; one at 1.79 years after contralateral brain metastasis followed by local recurrence, and another at 2.49 years after multiple local recurrences. Twenty-two patients (91.7%) survived sarcoma-free for 0.04-17 years (median, 6.9) after relapse, and 18 of 22 (82%) were alive >/=5 years after relapse.
CONCLUSION: Survival following recurrent localized orbital sarcoma appears likely after vigorous re-treatment given with curative intent.
Safety and efficacy of high-dose tamoxifen and sulindac for desmoid tumor in children: results of a Children's Oncology Group (COG) phase II study
BACKGROUND: Desmoid fibromatosis (desmoid tumor, DT) is a soft tissue neoplasm prone to recurrence despite complete surgical resection. Numerous small retrospective reports suggest that non-cytotoxic chemotherapy using tamoxifen and sulindac may be effective for DT. We evaluated the safety and efficacy of tamoxifen and sulindac in a prospective phase II study within the Children's Oncology Group.
PROCEDURES: Eligible patients were (PFS). Patients received tamoxifen and sulindac daily for 12 months or until disease progression or intolerable toxicity occurred. Response was assessed by magnetic resonance imaging.
RESULTS: Fifty-nine eligible patients were enrolled from 2004 to 2009; 78% were 10-18 years old. Twenty-two (38%) were previously untreated; 15 (41%) of the remaining 37 enrolling with recurrent DT had prior systemic chemotherapy and six (16%) had prior radiation. No life-threatening toxicity was reported. Twelve (40%) of 30 females developed ovarian cysts, which were asymptomatic in 11 cases. Ten patients completed therapy without disease progression or discontinuing treatment. Responses included four partial and one complete (5/59, 8%). The estimated 2-year PFS and survival rates were 36% (95% confidence interval: 0.23-0.48) and 96%, respectively. All three deaths were due to progressive DT.
CONCLUSIONS: Tamoxifen and sulindac caused few serious side effects in children with DT, although ovarian cysts were common. However, the combination showed relatively little activity as measured by response and PFS rates.
Semiquantitative mIBG scoring as a prognostic indicator in patients with stage 4 neuroblastoma: a report from the Children's oncology group
Radiolabeled metaiodobenzylguanidine (mIBG) is a highly sensitive and specific marker for detecting neuroblastoma. A semiquantitative mIBG score (Curie score [CS]) was assessed for utility as a prognostic indicator for a cohort of patients with high-risk metastatic disease.
METHODS: mIBG scans from 280 patients with mIBG-avid, stage 4 neuroblastoma enrolled on the Children's Oncology Group (COG) protocol A3973 were evaluated at diagnosis (n = 280), after induction chemotherapy (n = 237), and after an autologous stem cell transplantation (n = 178). Individual mIBG scans were evaluated at 10 different anatomic regions, with the scoring of each site (0-3) based on the extent of disease at that anatomic region.
RESULTS: There was no correlation between CS at diagnosis and subsequent treatment outcome. Patients with a CS > 2 after induction therapy had a significantly worse event-free survival (EFS) than those with scores 2 identified a cohort of patients at greater risk for an event, independent of other known neuroblastoma factors, including age, MYCN status, ploidy, mitosis-karyorrhexis index, and histologic grade. For MYCN-amplified tumors, the presence (CS > 0) versus absence (CS = 0) of residual mIBG avidity after induction was associated with a significantly worse outcome (3-y EFS: 11.8% +/- 7.8% vs. 49.6% +/- 7.7%, respectively; P = 0.003). After transplantation, patients with a CS > 0 had an EFS inferior to that of patients with a CS of 0 (3-y EFS: 28.9% +/- 6.8% vs. 49.3% +/- 4.9%, respectively [n = 133]; P = 0.009).
CONCLUSION: Curie scoring carries prognostic significance in the management of patients with high-risk neuroblastoma. In particular, patients with CSs > 2 after induction have extremely poor outcomes and should be considered for alternative therapeutic strategies.
Heart rate variability remains reduced and sympathetic tone elevated after temporal lobe epilepsy surgery
PURPOSE: There is evidence of autonomic dysregulation in temporal lobe epilepsy. The structures removed during temporal lobectomy are important centers of central cardiovascular control; therefore surgery may conceivably alter the cardiovascular autonomic function. The effects of temporal lobectomy on autonomic cardiac control are controversial. We investigated the effects of temporal lobectomy on heart rate variability (HRV) in the early and late postoperative periods.
METHODS: We used 1-h ECG recordings to assess heart rate variability by spectral analysis in 24 consecutive patients who underwent temporal lobectomy due to intractable temporal lobe epilepsy. ECG recordings were performed before and twice (early and late) after surgery. The results were compared with age and sex matched controls.
RESULTS: When compared with controls, all the time and frequency domain indices (SDRR, RMSSD, TP, LF and HF) were significantly lower in the patient group before surgery. Findings were similar in the early and late post-operative periods except that the LF/HF ratio increased in the patient group after the late post-operative period. Within the patient group, compared to pre-operative results, normalized HF was increased in the early post-operative period; however in the late post-operative period, LF/HF ratio was increased.
CONCLUSIONS: These findings show that in patients with intractable temporal lobe epilepsy, HRV is decreased globally in both sympathetic and parasympathetic domains. While the total HRV remains reduced throughout the postoperative periods, the LF/HF ratio, i.e., sympathovagal balance is altered, in favor of parasympathetic side early after surgery, but towards the sympathetic side after the first postoperative month. rights reserved.
Does quality of radiation therapy predict outcomes of multicenter cooperative group trials? A literature review
Central review of radiation therapy (RT) delivery within multicenter clinical trials was initiated in the early 1970s in the United States. Early quality assurance publications often focused on metrics related to process, logistics, and timing. Our objective was to review the available evidence supporting correlation of RT quality with clinical outcomes within cooperative group trials. A MEDLINE search was performed to identify multicenter studies that described central subjective assessment of RT protocol compliance (quality). Data abstracted included method of central review, definition of deviations, and clinical outcomes. Seventeen multicenter studies (1980-2012) were identified, plus one Patterns of Care Study. Disease sites were hematologic, head and neck, lung, breast, and pancreas. Between 0 and 97% of treatment plans received an overall grade of acceptable. In 7 trials, failure rates were significantly higher after inadequate versus adequate RT. Five of 9 and 2 of 5 trials reported significantly worse overall and progression-free survival after poor-quality RT, respectively. One reported a significant correlation, and 2 reported nonsignificant trends toward increased toxicity with noncompliant RT. Although more data are required, protocol-compliant RT may decrease failure rates and increase overall survival and likely contributes to the ability of collected data to answer the central trial question.
The recurrent nature of the 3 most common vestibulopathies suggests a recurrent cause. Histopathology in temporal bones from patients with these syndromes - vestibular neuronitis (VN, n = 7), Meniere's disease (MD, n = 8) and benign paroxysmal positional vertigo (BPPV, n = 5) - shows focal degeneration of vestibular nerve axons and degenerated nearby facial nerve meatal ganglion cells. Transmission electron microscopic confirmation of intracytoplasmic viral particles in surgically excised vestibular nerves from patients with VN and MD support a viral etiology in these vestibulopathies. Antiviral treatment of these syndromes in a series of 211 patients with a 3- to 8-year follow-up resulted in complete control of vertigo in VN (88%), MD (90%) and BPPV (60%).
OBJECT: The goal of this study was to evaluate outcomes in patients with >/= 10 CNS metastases treated with Gamma Knife stereotactic radiosurgery (GK-SRS).
METHODS: Patients with >/= 10 brain metastases treated using GK-SRS during the period between 2004 and 2010 were identified. Overall survival and local and regional control as well as necrosis rates were determined. The influence of age, sex, histological type, extracranial metastases, whole-brain radiation therapy, and number of brain metastases was analyzed using the Kaplan-Meier method. Univariate (log-rank) analyses were performed, with a p value of < 0.05 considered significant.
RESULTS: Fifty-three patients with >/= 10 brain metastases were treated between 2004 and 2010. All had a Karnofsky Performance Status score of >/= 70. Seventy-two percent had either non-small cell lung cancer (38%) or breast cancer (34%); melanoma, small cell lung cancer, renal cell carcinoma, and testicular, colon, and ovarian cancer contributed the remaining 28%. On average, 10.9 lesions were treated in a single session. Sixty-four percent of patients received prior whole-brain radiation therapy. The median survival was 6.5 months. One-year overall survival was 42% versus 14% when comparing breast cancer and other histological types, respectively (p = 0.074). Age, extracranial metastases, number of brain metastases, and previous CNS radiation therapy were not significant prognostic factors. Although the median time to local failure was not reached, the median time to regional failure was 3 months. Female sex was associated with longer time to regional failure (p = 0.004), as was breast cancer histological type (p = 0.089). No patient experienced symptomatic necrosis.
CONCLUSIONS: Patients with >/= 10 brain metastases who received prior CNS radiation can safely undergo repeat treatment with GK-SRS. With median survival exceeding 6 months, aggressive local treatment remains an option; however, rapid CNS failure is to be expected. Although numbers are limited, patients with breast cancer represent one group of individuals who would benefit most, with prolonged survival and extended time to CNS recurrence.
Discusses some of the challenges libraries are facing and how the Lamar Soutter Library at the University of Massachusetts Medical School is addressing them with an innovative library fellows program.
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease is a fatal neurodegenerative disease. ALS is typically adult onset and is characterized by rapidly progressive loss of both upper and lower motor neurons that leads to death usually within 3-5 years. About 90% of all the cases are sporadic with no family history while the remaining 10% are familial cases with mutations in several genes including SOD1, FUS/TLS, TDP43 and C9ORF72.
FUS/TLS (Fused in Sarcoma/Translocated in Liposarcoma or FUS) is an RNA/DNA binding protein that is involved in multiple cellular functions including DNA damage repair, transcription, mRNA splicing, RNA transport and stress response. More than 40 mutations have now been identified in FUS that account for about 5% of all the familial cases of ALS. However, the exact mechanism by which FUS causes ALS is unknown. While significant progress has been made in understanding the disease mechanism and identifying therapeutic strategies, several questions still remain largely unknown. The work presented here aims at understanding the normal functions of FUS as well as the pathogenic mechanisms by which it leads to disease.
Several studies showed the association of mutant-FUS with structures made up of RNA and proteins, called stress granules that form under various stress conditions. However, little is known about the role of endogenous FUS under stress conditions. I have shown that under hyperosmolar conditions, the predominantly nuclear FUS translocates into the cytoplasm and incorporates into stress granules. The response is specific to hyperosmolar stress because FUS remains nuclear under other stress conditions tested, such as oxidative stress, ER stress and heat shock. The response of FUS is rapid, and cells with reduced FUS levels are susceptible to the hyperosmolar stress, indicating a pro-survival role for FUS. In addition to investigating the functions of endogenous wild-type (WT) FUS, the work presented also focuses on identifying the pathogenic mechanism(s) of FUS variants. Using various biochemical techniques, I have shown that ALS-causing FUS variants are misfolded compared to the WT protein. Furthermore, in a squid axoplasm based vesicle motility assay, the FUS variants inhibit fast axonal transport (FAT) in a p38 MAPK dependent manner, indicating a role for the kinase in mutant-FUS mediated disease pathogenesis. Analysis of human ALS patient samples indicates higher levels of total and phospho p38, supporting the notion that aberrant regulation of p38 MAPK is involved in ALS.
The results presented in this dissertation 1) support a novel prosurvival role for FUS under hyperosmolar stress conditions and, 2) demonstrate that protein misfolding and aberrant kinase activation contribute to ALS pathogenesis by FUS variants.
An Integrated Structural Mechanism for Relief of Autoinhibition and Membrane Targeting in Cytohesin Family Guanine Nucleotide Exchange Factors: A Dissertation
Guanine nucleotide exchange factors (GEFs) regulate and organize diverse cellular processes through their role in converting GTPases from the inactive GDP bound state to the active GTP bound state. An increasing number of GEFs undergo autoregulatory mechanisms through complex intramolecular interactions. Relief of autoinhibition involves specific phosphorylation or binding to lipid and/or effector proteins at sites distal from the catalytic domain, and is often coupled to membrane recruitment. In Cytohesin Arf GEFs, the catalytic Sec7 domain is autoinhibited by a linker region and C-terminal helix flanking a Pleckstrin Homology (PH) domain. Upon binding of the PH domain to low abundance phosphoinositides, the GTPase Arf6-GTP can both relieve autoinhibition and recruit Cytohesins to the plasma membrane. This thesis focuses on determining the molecular mechanism underlying both these functions.
The structural mechanisms by which Arf6-GTP binding relieves autoinhibition were studied using biochemical and crystallographic studies. The crystal structure of the Grp1 PH domain in complex with Arf6 revealed that Arf6-GTP binding relieves autoinhibition through competitive sequestration of the inhibitory elements into grooves formed at the periphery of the interface. Importantly, the interaction orients all known membrane targeting components to a common surface. Detailed biochemical studies showed a common mode of binding among Cytohesin family members in which phosphoinositide head group binding primes the interaction with Arf6, and membrane recruitment of both stimulatory and substrate Arf enhances the effect.
To assess changes in the Sec7 domain conformation upon activation, Size Exclusion Chromatography in line with Small Angle X-Ray Scattering (SEC-SAXS) was performed. The unique nature of this data led to the development of a novel data analysis and processing strategy. A graphically based, python-extensible software package was created for data normalization, buffer correction, Guinier Analysis, and constant background subtraction. As an unbiased substitute for traditional buffer subtraction, a method to reconstruct the protein scattering through singular value decomposition (SVD) and linear combination of the basis vectors was developed. These methods produced exceptional data quality and allowed versatility for application to other data collection techniques or systems, especially those lacking confident buffer matching or low signal.
SEC-SAXS confirmed the overall structure of autoinhibited Grp1 in solution and showed only slight overall changes upon activation by deletion of the autoinhibitory Cterminal helix. Fusion of Arf6 with Grp1 produced a consistently elongated shape in the active state that was incompatible with the autoinhibited or theoretical active positions of the Sec7 domain. Monte Carlo and rigid body modeling using known structural domains revealed a requirement for Sec7-PH linker flexibility in addition to Sec7 domain mobility. These data support an integrated structural model whereby phosphoinositides and Arf-GTP support nucleotide exchange at membranes through allosteric activation, membrane recruitment, and large-scale rearrangement of the Sec7 domain. Overall, these findings offer insight into Cytohesin function that can be applied to assess relief of autoinhibition in the context of other GEFs and GTPases.
Identification of Molecular Determinants that Shift Co- and Post-Translational N-Glycosylation Kinetics in Type I Transmembrane Peptides: A Dissertation
Asparagine (N)-linked glycosylation occurs on 90% of membrane and secretory proteins and drives folding and trafficking along the secretory pathway. The N-glycan can be attached to an N-X-T/S-Y (X,Y ≠ P) consensus site by one of two oligosaccharyltransferase (OST) STT3 enzymatic isoforms either during protein translation (co-translational) or after protein translation has completed (post-translational). While co-translational N-glycosylation is both rapid and efficient, post-translational N-glycosylation occurs on a much slower time scale and, due to competition with protein degradation and forward trafficking, could be detrimental to the success of a peptide heavily reliant on post-translational N-glycosylation. In evidence, mutations in K+ channel subunits that shift N-glycosylation kinetics have been directly linked to cardiac arrhythmias. My thesis work focuses on identifying primary sequence factors that affect the rate of N-glycosylation.
To identify the molecular determinants that dictate whether a consensus site acquires its initial N-glycan during or after protein synthesis, I used short (~ 100-170 aa) type I transmembrane peptides from the KCNE family (E1-E5) of K+ channel regulatory subunits. The lifetime of these small membrane proteins in the ER translocon is short, which places a significant time constraint on the co-translational N-glycosylation machinery and increases the resolution between co- and post-translational events. Using rapid metabolic pulse-chase experiments described in Chapter II, I identified several molecular determinants among native consensus sites in the KCNE family that favor co-translational N-glycosylation: threonine containing-consensus sites (NXT), multiple N-terminal consensus sites, and long C-termini. The kinetics could also be shifted towards post-translational N-glycosylation by converting to a serine containing-consensus site (NXS), reducing the number of consensus sites in the peptide, and shortening the C-termini.
In Chapter III, I utilized an E2 scaffold peptide to examine the N-glycosylation kinetics of the middle X residue in an NXS consensus site. I found that large hydrophobic and negatively charged residues hinder co-translational N-glycosylation, while polar, small hydrophobic, and positively charged residues had the highest N-glycosylation efficiencies. Poorly N-glycosylated NXS consensus sites with large hydrophobic and negatively charged X residues had a significantly improved co-translational N-glycosylation efficiency upon conversion to NXT sites.
Also in Chapter III, I adapted a siRNA knockdown strategy to definitively identify the OST STT3 isoforms that perform co- and post-translational N-glycosylation for type I transmembrane substrates. I found that the STT3A isoform predominantly performs co-translational N-glycosylation while the STT3B isoform predominantly performs post-translational N-glycosylation, in agreement with the roles of these enzymatic subunits on topologically different substrates.
Taken together, these findings further the ability to predict the success of a consensus site by primary sequence alone and will be helpful for the identification and characterization of N-glycosylation deficiency diseases.
There is often a gap between what new library school graduates know and what is needed to navigate the first professional job. Additionally, the field of librarianship in general is growing and changing rapidly, requiring a diverse set of complex skills in new roles. It is essential to rethink how we train the next generation of librarians, while accepting and incorporating the unique insights new graduates may have. How can institutions help shape the next generation, while building skills that will be beneficial to all?
These challenges are being faced and addressed by an innovative library fellows program at the Lamar Soutter Library at the University of Massachusetts Medical School. This program is designed to foster the next generation of medical librarians by providing a 2-year experience for newly graduated library science students, emphasizing hands-on learning and research into topics of information management and the various complex roles within librarianship. An original curriculum has been developed incorporating training, professional development, mentorship, and research with the library as the learning laboratory. Curriculum components focus on librarianship foundations as well as rotations within core library functional areas.
Creating a culture of research within the library as a whole has also become a priority. Library fellows will conduct research designed to provide a self-directed course of study and investigation, ultimately with the goal of publishing the results. The research experience will expose the fellows to the research process and interpretation of results for decision-making in a library environment, as well as encouraging continued contribution to the field. This is facilitated by a research project database to which all staff can contribute and from which all can draw for ongoing academic discussion.
This presentation will provide a description and evaluation of the project to date, with successes, challenges, suggestions, and lessons learned discussed. It will look at the organizational changes that necessitated and facilitated the structural changes surrounding this program and the resulting effect on staff and operations. Administrators and creators of the program, as well as the first cohort of fellows, will present their perspectives.
Dramatic changes in how we structure libraries and librarianship are necessary to sustain and grow. These changes require rejecting old service models, rethinking our roles, redoing our professional identity and rejuvenating ourselves and our libraries. By changing the way we develop the knowledge and skills of new professionals, those who will be driving librarianship in the future, we strengthen all members of the profession and create a better, stronger foundation for librarianship.
Objectives: Traditional library work is spiraling downward. Health sciences librarians are taking on new roles such as embedded librarians or research data informationists. Simultaneously, institutionally mandated budget cuts force the question, "How do we maintain mission-critical work within our budget?" Survival means rejecting old service models, rethinking our roles, redoing our professional identity, and rejuvenating ourselves and our libraries.
Methods: The Library Fellows Program at the University of Massachusetts (UMass) Medical School is one response to the challenges we are facing. The fellows program, designed to foster the next generation of medical librarians, provides a two-year experience for newly graduated library science students, emphasizing hands-on learning and research into topics of information management and medical librarianship. This innovative curriculum incorporates training, professional development, mentorship, and research with the library as the learning laboratory. Curriculum components focus on medical librarianship foundations as well as rotations within core library functional areas. This paper serves as a project description and evaluation. It discusses organizational changes that necessitated and facilitated the structural changes surrounding this program and the resulting effect on staff and operations. The midpoint success of the program is determined and reported, with recommendations and future considerations.
Results/Conclusions: In early 2013, management at Lamar Soutter Library (LSL) planned organizational changes necessary to meet strategic initiatives and continue supporting the medical school's mission in the face of severe budget constraints. The final plan resulted in discontinuation of many traditional library activities, elimination of staff that supported those activities, and, ultimately, the development of the FELLOWS PROGRAM. In September 2013, three task forces were created to develop an implementation plan. A search committee was formed to begin the process of hiring three fellows. The Curriculum Task Force was charged with structuring the two-year fellowship program. The curriculum developed includes rotations through library departments, in-depth reference experience, expert searching training, structured projects, and performing research. The Reference Services Task Force was charged with developing a new reference model to replace the current triage and pager model. The Research Task Force was charged with laying the groundwork for creating a research environment in the library. With outside consultation, LSL developed a detailed evaluation plan. The program is in its eighth month. Modifications and refinements are being made as the first cohort experiences the program. The program has led to a redefinition of librarianship and a new professional identity based on a culture of achievement, research, and reflection.
Nurses are often the first members of the health care team with whom patients interact. The initial impression of the nurses’ receptiveness to the patients’ needs influences the patients’ views of their overall care. Researchers have suggested that understanding communication between individuals can provide the human link, or social element, to the successful implementation and use of electronic health records, including documentation (Lanham, Leykum, & McDaniel, 2012). Zadvinskis, Chipps, and Yen (2014) identified that the helpful features of bedside documentation systems were offset by the mismatch between the system and nurse’s workflow. The purpose of this micro-ethnography study was to explore the culture of nurse-patient interaction associated with electronic documentation at the bedside. Data were collected through passive participant observation, audio-taping of the nurse-patient interactions, and informal and semi-structured interviews with the nurses. A total of twenty-six observations were conducted on three nursing units at an urban healthcare facility in New England. These three units were occupied by similar patient populations and all patients required cardiac monitoring. Three themes consistently emerged from qualitative data analysis: the nurses paused during verbal communication, the nurses played a game of tag between the patient and the computer, and the nurses performed automatic or machine-like actions. The participants described these themes in the informal and semi-structured interviews. The nurses’ actions were observed during passive participant observation, and the audio-taped interactions supported these themes. Understanding the adaptation of caregiving necessitated by bedside electronic documentation will have a positive impact on developing systems that interface seamlessly with the nurses’ workflow and encourage patients’ active participation in their care.
Examining Change in Symptoms of Depression, Anxiety, and Stress in Adults after Treatment of Chronic Cough: A Dissertation
Background: Chronic cough is a common health problem with variable success rates to standardized treatment. Psychologic symptoms of depression, anxiety, and stress have been reported in association with chronic cough. The purpose of this study was to examine changes in the psychologic symptoms of depression, anxiety, and stress in adults with chronic cough 3 months after management using the ACCP cough treatment guidelines.
Methods: This study used a descriptive longitudinal observation design. The major tenets associated with the Theory of Unpleasant Symptoms were examined. Intervention fidelity to the study components was measured.
Results: A sample of 80 consecutive patients with chronic cough of greater than 8 weeks duration was recruited from one cough specialty clinic. Mean age of subjects was 58.54 years; 68.7% were female; 98.7% were white, and 97.5% were non-smokers. Mean cough duration was 85.99 months and mean cough severity was 6.11 (possible 0 –10; higher scores equal greater cough severity). Cough severity improved post treatment (n=65, M=2.32, (SE =.291), t (64) =7.98, p=.000); cough-specific quality-of-life also improved (n=65, M=9.17, (SE=1.30), t (64) =7.02, p=.000). Physiologic (urge-to-cough r=.360, ability to speak r=.469) and psychologic factors (depression r=.512, anxiety r=.507, stress r=.484) were significantly related to cough-specific quality-of-life and to cough severity (urge-to-cough r=.643, ability to speak r=.674 and depression r=.356, anxiety r=.419, stress r=.323) (all r, p=.01); social support and number of diagnoses were not related to either variable. Those experiencing greater financial strain had worse cough severity. Women, those experiencing financial strain, and those taking self-prescribed therapy had worse cough-specific quality-of-life. Intervention fidelity to the study plan was rated as high according to observation, participant receipt, and patient/physician concordance. Qualitative review identified potential areas of variability with intervention fidelity.
Conclusions: By measuring the factors related to the major tenets of the Theory of Unpleasant Symptoms, this theory has helped to explain why those with chronic cough may have symptoms of depression, anxiety, and stress and why these symptoms improve as cough severity and cough-specific quality-of-life improve. Moreover, by measuring intervention fidelity, it may be possible to determine why cough guidelines may not be yielding consistently favorable results.
Structural basis of the relaxed state of a Ca2+-regulated myosin filament and its evolutionary implications
Myosin filaments of muscle are regulated either by phosphorylation of their regulatory light chains or Ca(2+) binding to the essential light chains, contributing to on-off switching or modulation of contraction. Phosphorylation-regulated filaments in the relaxed state are characterized by an asymmetric interaction between the two myosin heads, inhibiting their actin binding or ATPase activity. Here, we have tested whether a similar interaction switches off activity in myosin filaments regulated by Ca(2+) binding. Cryo-electron microscopy and single-particle image reconstruction of Ca(2+)-regulated (scallop) filaments reveals a helical array of myosin head-pair motifs above the filament surface. Docking of atomic models of scallop myosin head domains into the motifs reveals that the heads interact in a similar way to those in phosphorylation-regulated filaments. The results imply that the two major evolutionary branches of myosin regulation--involving phosphorylation or Ca(2+) binding--share a common structural mechanism for switching off thick-filament activity in relaxed muscle. We suggest that the Ca(2+)-binding mechanism evolved from the more ancient phosphorylation-based system to enable rapid response of myosin-regulated muscles to activation. Although the motifs are similar in both systems, the scallop structure is more tilted and higher above the filament backbone, leading to different intermolecular interactions. The reconstruction reveals how the myosin tail emerges from the motif, connecting the heads to the filament backbone, and shows that the backbone is built from supramolecular assemblies of myosin tails. The reconstruction provides a native structural context for understanding past biochemical and biophysical studies of this model Ca(2+)-regulated myosin.
Myosin binding protein-C (MyBP-C) exists in three major isoforms: slow skeletal, fast skeletal, and cardiac. While cardiac MyBP-C (cMyBP-C) expression is restricted to the heart in the adult, it is transiently expressed in neonatal stages of some skeletal muscles. However, it is unclear whether this expression is necessary for the proper development and function of skeletal muscle. Our aim was to determine whether the absence of cMyBP-C alters the structure, function, or MyBP-C isoform expression in adult skeletal muscle using a cMyBP-C null mouse model (cMyBP-C((t/t))). Slow MyBP-C was expressed in both slow and fast skeletal muscles, whereas fast MyBP-C was mostly restricted to fast skeletal muscles. Expression of these isoforms was unaffected in skeletal muscle from cMyBP-C((t/t)) mice. Slow and fast skeletal muscles in cMyBP-C((t/t)) mice showed no histological or ultrastructural changes in comparison to the wild-type control. In addition, slow muscle twitch, tetanus tension, and susceptibility to injury were all similar to the wild-type controls. Interestingly, fMyBP-C expression was significantly increased in the cMyBP-C((t/t)) hearts undergoing severe dilated cardiomyopathy, though this does not seem to prevent dysfunction. Additionally, expression of both slow and fast isoforms was increased in myopathic skeletal muscles. Our data demonstrate that i) MyBP-C isoforms are differentially regulated in both cardiac and skeletal muscles, ii) cMyBP-C is dispensable for the development of skeletal muscle with no functional or structural consequences in the adult myocyte, and iii) skeletal isoforms can transcomplement in the heart in the absence of cMyBP-C.
Myosin filaments from many muscles are activated by phosphorylation of their regulatory light chains (RLCs). Structural analysis of relaxed tarantula thick filaments shows that the RLCs of the interacting free and blocked myosin heads are in different environments. This and other data suggested a phosphorylation mechanism in which Ser-35 of the free head is exposed and constitutively phosphorylated by protein kinase C, whereas the blocked head is hidden and unphosphorylated; on activation, myosin light chain kinase phosphorylates the monophosphorylated free head followed by the unphosphorylated blocked head, both at Ser-45. Our goal was to test this model of phosphorylation. Mass spectrometry of quickly frozen, intact muscles showed that only Ser-35 was phosphorylated in the relaxed state. The location of this constitutively phosphorylated Ser-35 was analyzed by immunofluorescence, using antibodies specific for unphosphorylated or phosphorylated Ser-35. In the relaxed state, myofibrils were labeled by anti-pSer-35 but not by anti-Ser-35, whereas in rigor, labeling was similar with both. This suggests that only pSer-35 is exposed in the relaxed state, while in rigor, Ser-35 is also exposed. In the interacting-head motif of relaxed filaments, only the free head RLCs are exposed, suggesting that the constitutive pSer-35 is on the free heads, consistent with the proposed mechanism.