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We present an algorithm and implementation for the parallel computation of exact exchange in Quantum ESPRESSO (QE) that exhibits greatly improved strong scaling. QE is an open-source software package for electronic structure calculations using plane wave density functional theory, and supports the use of local, semi-local, and hybrid DFT functionals. Wider application of hybrid functionals is desirable for the improved simulation of electronic band energy alignments and thermodynamic properties, but the computational complexity of evaluating the exact exchange potential limits the practical application of hybrid functionals to large systems and requires efficient implementations. We demonstrate that existing implementations of hybrid DFT that utilize a single data structure for both the local and exact exchange regions of the code are significantly limited in the degree of parallelization achievable. We present a band-pair parallelization approach, in which the calculation of exact exchange is parallelized and evaluated independently from the parallelization of the remainder of the calculation, with the wavefunction data being efficiently transformed on-the-fly into a form that is optimal for each part of the calculation. For a 64 water molecule supercell, our new algorithm reduces the overall time to solution by nearly an order of magnitude.

Background: Seroprevalence studies, to estimate the proportion of people that has been infected by SARS-CoV-2 are importance in African countries, where incidence is among the lowest in the world. Objective: This study aimed at evaluating the exposure to SARS-CoV-2 within a university setting of Cameroon. Methods: A cross-sectional study performed in December 2020 - December 2021, among students and staffs of the Evangelical University of Cameroon. COVID-19 antigen rapid detection test (RDT) was performed using Standard Q Biosensor, and one year after SARS-CoV-2 antibody-test was performed within the same population using RDT and chemiluminescence immunoassay (CLIA). Results: 106 participants were enrolled (80% students), female sex was the most represented. Positivity to SARS-CoV-2 was 0.0% based on antigen RDTs. The seroprevalence of SARSCoV- 2 antibodies was estimated at 73.6% (95% CI. 64.5-81.0) for IgG and 1.9% (95% CI. 0.2-6.8) for IgM/IgG with RDTs, and 91.9% (95% CI. 84.7-96.4) for anti-nucleocapsid with CLIA. 95.3% (101) reported having developed at least one of the known COVID-19 symptoms (cough and headache being the most common). 90.3% (28) of people who experienced at least one of these symptoms developed IgG antibodies. 40.6% (43) of participants took natural herbs, whereas 55.7% (59) took conventional drugs. The most used herb was Zingiber officinale, while the most used drugs were antibiotics. Conclusion: In this Cameroonian University community, SARS-CoV-2 seroprevalence is high, with a greater detection using advanced serological assays. This indicates a wide viral exposure, and the need to adequate control measures especially for those experiencing any related COVID-19 symptoms.

The American Association for Respiratory Care has established a task force to identify potential new roles and responsibilities of respiratory therapists (RTs) in 2015 and beyond. The first task force conference confirmed that the healthcare system in the United States is on the verge of dramatic change, driven by the need to decrease costs and improve quality. Use of evidence-based protocols that follow a nationally accepted standard of practice, and application of biomedical innovation continue to be important competency areas for RTs. The goal of the second task force conference was to identify specific competencies needed to assure safe and effective execution of RT roles and responsibilities in the future. The education needed by the workforce to assume the new responsibilities emerging as the healthcare system changes starts with a close look at the competencies that will be needed by graduate RTs upon entry into practice. Future specialty practice areas for experienced RTs are identified without defining specific competencies. We present the findings of the task force on the competencies needed by graduate RTs upon entry into practice in 2015. [ABSTRACT FROM AUTHOR]

There are numerous resistant microorganisms but meticillin-resistant Staphylococcus aureus (MRSA) is probably the most notorious. MRSA is a resistant variation of the common bacterium, Staphylococcus aureus, that has developed the ability to survive treatment with a number of beta-lactam antibiotics, including meticillin. The focus of this article is a narrative literature review concerning the challenge that MRSA presents to nurses and other healthcare workers. A historical overview of antimicrobial resistance and the origins of MRSA are given, together with the factors involved in the persistence of antimicrobial resistance. The relevant microbiology, pathogenesis and epidemiology of MRSA will be discussed to provide a detailed rationale for the contemporary management of this persistent, resistant organism. [ABSTRACT FROM AUTHOR]

The respiratory care profession is over 60 years old. Throughout its short history, change and innovation have been the terms that best describe the development of the profession. The respiratory therapist (RT) of today barely resembles the clinicians of 60 years ago, and the future role of the RT is clearly open to debate. Medicine is continually changing, with new approaches to disease management emerging almost daily. Third-party payers are challenging payment for iatrogenic injury, manpower issues are affecting all disciplines in medicine, and the nonphysician and physician work force is aging. These factors make us question what the respiratory care profession will look like in the year 2015. To address this issue the American Association for Respiratory Care established a task force to envision the RT of the future. The goal is to identify potential new roles and responsibilities of RTs in 2015 and beyond, and to suggest the elements of education, training, and competency-documentation needed to assure safe and effective execution of those roles and responsibilities. We present the initial findings of that task force. [ABSTRACT FROM AUTHOR]

BACKGROUND: Hyperventilation during cardiopulmonary resuscitation (CPR) is harmful. METHODS: We tested the hypotheses that, during CPR, 2 breaths/min would result in higher cerebral perfusion pressure and brain-tissue oxygen tension than 10 breaths/min, and an impedance threshold device (known to increase circulation) would further enhance cerebral perfusion and brain-tissue oxygen tension, especially with 2 breaths/min. RESULTS: Female pigs (30.4 +/- 1.3 kg) anesthetized with propofol were subjected to 6 min of untreated ventricular fibrillation, followed by 5 min of CPR (100 compressions/min, compression depth of 25% of the anterior-posterior chest diameter), and ventilated with either 10 breaths/min or 2 breaths/min, while receiving 100% oxygen and a tidal volume of 12 mL/kg. Brain-tissue oxygen tension was measured with a probe in the parietal lobe. The impedance threshold device was then used during an 5 additional min of CPR. During CPR the mean +/- SD calculated coronary and cerebral perfusion pressures with 10 breaths/min versus 2 breaths/min, respectively, were 17.6 +/- 9.3 mm Hg versus 14.3 +/- 6.5 mm Hg (p = 0.20) and 16.0 +/- 9.5 mm Hg versus 9.3 +/- 12.5 mm Hg (p = 0.25). Carotid artery blood flow, which was prospectively designated as the primary end point, was 65.0 +/- 49.6 mL/min in the 10-breaths/min group, versus 34.0 +/- 17.1 mL/min in the 2-breaths/min group (p = 0.037). Brain-tissue oxygen tension was 3.0 +/- 3.3 mm Hg in the 10-breaths/min group, versus 0.5 +/- 0.5 mm Hg in the 2-breaths/min group (p = 0.036). After 5 min of CPR there were no significant differences in arterial pH, P(O(2)), or P(CO(2)) between the groups. During CPR with the impedance threshold device, the mean carotid blood flow and brain-tissue oxygen tension in the 10-breaths/min group and the 2-breaths/min group, respectively, were 102.5 +/- 67.9 mm Hg versus 38.8 +/- 23.7 mm Hg (p = 0.006) and 4.5 +/- 6.0 mm Hg versus 0.7 +/- 0.7 mm Hg (p = 0.032). CONCLUSIONS: Contrary to our initial hypothesis, during the first 5 min of CPR, 2 breaths/min resulted in significantly lower carotid blood flow and brain-tissue oxygen tension than did 10 breaths/min. Subsequent addition of an impedance threshold device significantly enhanced carotid flow and brain-tissue oxygen tension, especially in the 10-breaths/min group. [ABSTRACT FROM AUTHOR]

18 October 2007 marks an important anniversary in chiropractic history. In the 1950s, chiropractic visionary and pioneer Dr. Lorraine M. Golden enlisted the support of leaders in many fields as well as chiropractic patients and families of children with handicaps, to build and operate a multidisciplinary facility based on chiropractic's philosophy, science and art. Her dream was to provide chiropractic care in an integrated healthcare setting to thousands of physically and men-tally challenged children. Now celebrating fifty years of service to children and their families, Kentuckiana Children's Center in Louisville, Kentucky, continues to provide chiropractic care to a special pediatric population. [ABSTRACT FROM AUTHOR]

Abstract Echinococcus transmission is known to be affected by various environmental factors, which may be modified by human influence or natural events including global warming. Considerable population growth in the last fifty years in Ningxia Hui Autonomous Region (NHAR), the People’s Republic of China (PRC), has led to dramatic increases in deforestation and modified agricultural practices. In turn, this has resulted in many changes in the habitats for the definitive and intermediate hosts of both Echinococcus granulosus and E. multilocularis, which have increased the risks for transmission of both parasites, affecting echinococcosis prevalence and human disease. Ecological environmental changes due to anthropogenic activities and natural events drive Echinococcus transmission and NHAR provides a notable example illustrating how human activity can impact on a parasitic infection of major public health significance. It is very important to continually monitor these environmental (including climatic) factors that drive the distribution of Echinococcus spp. and their impact on transmission to humans because such information is necessary to formulate reliable future public health policy for echinococcosis control programs and to prevent disease spread.

Contending with discrimination can yield a cascade of negative psychological and physiological outcomes which adversely affect health. How individuals manage their emotions in response to discrimination can influence the extent of these negative health outcomes. Research finds, however, that Black and Latine individuals are more likely to use expressive suppression (vs. cognitive reappraisal) in response to discrimination, which is associated with adverse mental health outcomes. In the present research, we explored whether self-control (the ability to manage impulses and regulate thoughts, emotions, and behavior to achieve long-term goals) and impression management emotion-regulation goals (regulating emotions to shape others' perceptions of one's personality and skills) could help explain the differential use of suppression and reappraisal in response to discrimination. Across two cross-sectional studies, we found that Black and Latine participants' everyday discrimination experiences were related to lower self-control and increased impression management emotion-regulation goals. Reduced self-control was, in turn, linked to less use of reappraisal, while impression management emotion-regulation goals were associated with both greater reappraisal and suppression use in response to discrimination. Reappraisal was also related to participants' self-reported depressive symptoms. These findings contribute to our understanding of the factors that are associated with emotion regulation in response to discrimination., (© 2024. The Author(s).)

A portable and performant graphics processing unit (GPU)-accelerated library for electron repulsion integral (ERI) evaluation, named LibERI, has been developed and implemented via directive-based (e.g., OpenMP and OpenACC) and standard language parallelism (e.g., Fortran DO CONCURRENT). Offloaded ERIs consist of integrals over low and high contraction s, p, and d functions using the rotated-axis and Rys quadrature methods. GPU codes are factorized based on previous developments [Pham et al., J. Chem. Theory Comput. 19(8), 2213-2221 (2023)] with two layers of integral screening and quartet presorting. In this work, the density screening is moved to the GPU to enhance the computational efficacy for large molecular systems. The L-shells in the Pople basis set are also separated into pure S and P shells to increase the ERI homogeneity and reduce atomic operations and the memory footprint. LibERI is compatible with any quantum chemistry drivers supporting the MolSSI Driver Interface. Benchmark calculations of LibERI interfaced with the GAMESS software package were carried out on various GPU architectures and molecular systems. The results show that the LibERI performance is comparable to other state-of-the-art GPU-accelerated codes (e.g., TeraChem and GMSHPC) and, in some cases, outperforms conventionally developed ERI CUDA kernels (e.g., QUICK) while fully maintaining portability., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

The MolSSI Driver Interface (MDI) Project is an effort to simplify and standardize the process of enabling tight interoperability between independently developed code bases and is supported by numerous software packages across the domain of chemical physics. It enables a wide variety of use cases, including quantum mechanics/molecular mechanics, advanced sampling, path integral molecular dynamics, machine learning, ab initio molecular dynamics, etc. We describe two major developments within the MDI Project that provide novel solutions to key interoperability challenges. The first of these is the development of the MDI Plugin System, which allows MDI-supporting libraries to be used as highly modular plugins, with MDI enforcing a standardized application programming interface across plugins. Codes can use these plugins without linking against them during their build process, and end-users can select which plugin(s) they wish to use at runtime. The MDI Plugin System features a sophisticated callback system that allows codes to interact with plugins on a highly granular level and represents a significant advancement toward increased modularity among scientific codes. The second major development is MDI Mechanic, an ecosystem management tool that utilizes Docker containerization to simplify the process of developing, validating, maintaining, and deploying MDI-supporting codes. Additionally, MDI Mechanic provides a framework for launching MDI simulations in which each interoperating code is executed within a separate computational environment. This eliminates the need to compile multiple production codes within a single computational environment, reducing opportunities for dependency conflicts and lowering the barrier to entry for users of MDI-enabled codes., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Introduction: Liquid biopsy is recommended to diagnose molecular resistance to targeted therapy in patients with lung cancer. Nevertheless, not all jurisdictions provide funding and patient access. We report patients' perceived value of liquid biopsy in targeted therapy resistance., Methods: Canadian patients participating in a national EGFR T790M liquid biopsy validation study completed structured interviews measuring perceived value and willingness-to-pay for plasma circulating tumor DNA testing as an alternative to tumor biopsy using open-ended and iterative bidding approaches., Results: A total of 60 patients with advanced lung cancer participated with a median age of 64 years (range: 31-87 y); 69% were Asian and 45% female. All had received prior EGFR tyrosine kinase inhibitor; 17% also received chemotherapy. All patients preferred to have plasma testing over repeat tumor biopsy. In the context of the Canadian publicly funded system, patients estimated that a median of 300 (interquartile range: 150-800) Canadian dollars was a reasonable price to pay for liquid biopsy. Patients were personally willing to pay a median 100 (interquartile range: 33-350) Canadian dollars., Conclusions: In a system that covers the cost of standard diagnostic tests, patients with lung cancer indicated high willingness-to-pay out-of-pocket for liquid biopsy in the setting of acquired targeted therapy resistance. Patients have high perceived value of plasma genotyping and prefer it to repeat tumor biopsy., (© 2024 by the International Association for the Study of Lung Cancer.)

Objective: The authors sought to identify factors that affect hospital staff's decision to pursue criminal charges against patients who assault staff on inpatient psychiatric units., Methods: Data on assaults occurring on inpatient psychiatric units in one hospital system were collected over 32 months, from November 1, 2016, to July 1, 2019. The events were grouped by whether staff pursued criminal charges after the incident. Descriptive statistics and regression models were used to describe the data and identify predictive variables., Results: Data were reviewed from 9,654 admissions, of which 124 patient encounters involved assaults on staff. Overall, 27 (22%) of 124 assaults on staff resulted in staff pursuing criminal charges. Regression models indicated that criminal history (odds ratio [OR]=2.18, 95% CI=1.26-3.78, p=0.006), age (OR=0.92, 95% CI=0.91-0.94, p<0.001), and diagnosis of chronic mental illness with psychotic symptoms (OR=7.23, 95% CI=1.49-35.04, p=0.01) predicted patient assaults resulting in contact with law enforcement. Several variables were not statistically significantly associated with filing of criminal charges, including race, gender, degree of injury from the assault, number of instances of restraint, and number of as-needed medications., Conclusions: This is the largest quantitative study to examine the demographic and clinical factors that may play a role in whether staff pursue criminal charges against patients on inpatient psychiatric units. The results suggest that certain patients are more likely to be reported to law enforcement. Institutions should monitor factors that increase the likelihood of assaults on staff resulting in criminal charges and create policies that mitigate discrepancies in criminal justice involvement.

Community efforts in the computational molecular sciences (CMS) are evolving toward modular, open, and interoperable interfaces that work with existing community codes to provide more functionality and composability than could be achieved with a single program. The Quantum Chemistry Common Driver and Databases (QCDB) project provides such capability through an application programming interface (API) that facilitates interoperability across multiple quantum chemistry software packages. In tandem with the Molecular Sciences Software Institute and their Quantum Chemistry Archive ecosystem, the unique functionalities of several CMS programs are integrated, including CFOUR, GAMESS, NWChem, OpenMM, Psi4, Qcore, TeraChem, and Turbomole, to provide common computational functions, i.e., energy, gradient, and Hessian computations as well as molecular properties such as atomic charges and vibrational frequency analysis. Both standard users and power users benefit from adopting these APIs as they lower the language barrier of input styles and enable a standard layout of variables and data. These designs allow end-to-end interoperable programming of complex computations and provide best practices options by default.

Purpose: Plasma detection of EGFR T790M mutations is an emerging alternative to tumor rebiopsy in acquired epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance. Validation of analytical sensitivity and clinical utility is required before routine diagnostic use in clinical laboratories., Patients and Methods: Sixty-three patients with advanced EGFR -mutant lung cancer at 7 Canadian centers, who were being screened for the ASTRIS trial (ClinicalTrials.gov identifier: NCT02474355), participated in this companion study. Plasma T790M mutation was detected using droplet digital polymerase chain reaction, Cobas (Roche Diagnostics, Indianapolis, IN), or next-generation sequencing in 4 laboratories. T790M concordance was assessed between plasma and tumor samples., Results: Assessment of T790M in tumor biopsy tissue was successful in 81% of patients; 49% had confirmed T790M results (tumor or plasma) for ASTRIS. Plasma testing in this companion study yielded T790M results in 97% of patients; 62% had T790M-positive results, 36% had negative results, and 2% had indeterminate results. Of 38 patients with negative or indeterminate biopsy results, 55% had positive plasma T790M results, increasing the proportion with T790M-positive results to 73%. Sensitivity of plasma T790M testing was 75%. Overall concordance between tissue and plasma was 64%, and concordance among laboratories was 90.3%. Response to osimertinib and duration of therapy were similar irrespective of testing method (overall response rate, 62.5% for tissue, 66.7% for plasma, and 70.6% for both)., Conclusion: This multicenter validation study demonstrates that plasma EGFR T790M testing can identify significantly more patients than biopsy alone who may benefit from targeted therapy.

Background: The national supply of intravenous pain medications has been restricted since 2018 due to shortages. In late 2017, the ongoing shortages combined with the increased demand for alternative formulations resulted in interruptions in the supply of medications. The cascading effect of interruptions in supply caused hospitals to implement restrictive measures to extend the availability of these medications. This study aims to evaluate differences in pain control in postoperative cardiac patients due to intravenous opioid shortage at a standalone pediatric hospital., Method: A retrospective chart review of postoperative patients in the cardiac intensive care unit at Children's National Hospital was conducted from January to September 2017 and 2018. The objective of this study is to determine if a difference in postoperative pain scores in the period before and during the national intravenous opioid shortage exists, analyzed by differences in Face, Legs, Activity, Cry, Consolability (FLACC) scores., Results: No differences were found in mean FLACC scores for the 140 patients who were evaluated. Patients in 2017 reported faster decline of pain symptoms compared with those in 2018. No differences in baseline characteristics or secondary outcomes were noted., Conclusion: Pain management was better controlled immediately postoperatively in 2018 compared with 2017, but the pain was better controlled for the duration of the postoperative period in 2017., (© 2020 Wiley Periodicals, Inc.)

Background: Recent studies have demonstrated improved outcomes with real-time patient-reported outcome questionnaires (PRO questionnaires) using questions adapted for patient use from the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE). Outside of the clinical trial setting, limited information exists on factors affecting the completion of PRO questionnaires in routine practice. The primary aim of this prospective cross-sectional study was to evaluate patient willingness to complete PRO questionnaires on a regular basis and to better understand responder biases to improve patient feedback., Materials and Methods: Patients performing PRO-CTCAE toxicity and symptom PRO questionnaires in oncology clinics at Princess Margaret Cancer Centre from 2013 to 2016 were assessed for their willingness to complete PRO questionnaires using a nine-item, tablet-based acceptability survey. Patient-reported characteristics (i.e., age, sex, language, marital status, education, occupation, etc.), cancer type, treatment modalities, and health metrics (i.e., Eastern Cooperative Oncology Group) were also collected. Characteristics were evaluated by logistic regression (odds ratios [OR]) using the primary outcome with prespecified levels of significance for univariate ( p ≤ .10), and additional multivariate ( p ≤ .05) testing., Results: A total of 1,792 patients (median age 60 years; range 18-97) with various cancer diagnoses were assessed. A greater proportion of female (56%) and white (74%) respondents with an annual household income of <$100,000 (69%) participated. More than half (58%) of respondents were willing to complete PRO questionnaires at every clinic visit, and a high proportion (77%) found utility in reporting physical and emotional feelings to clinicians using PRO questionnaires. In general, patients did not find that PRO questionnaires made clinic visits more difficult (93%). In uni- and multivariable testing, patients were more willing to complete sleep- and fatigue-related PRO questionnaires relative to chemotoxicity-based PRO questionnaires (OR 1.52; p = .012). Patients aged 40-65 versus 18-40 years were also more likely to report high PRO questionnaire acceptability (OR 1.49; p = .025). Additional patient characteristics such as white ethnicity (OR 1.76), Canada as country of birth (OR 1.66), and English language (OR 2.15) relative to other had higher acceptability on uni- ( p < .001) and multivariable ( p < .001) analyses. Patients reporting treatment intent as palliative (OR 0.69; p = .0013) or hematological (OR 0.73; p = .027) were less likely to report high PRO questionnaire acceptability on univariable analysis; however, only palliative patients (OR 0.72) maintained this effect on multivariable testing ( p = .012). Patients reporting higher health utility scores (per change in .05) also had significantly increased PRO questionnaire acceptability in uni- (OR 1.06; p < .001) and multivariable (OR 1.05; p = .008) analyses. No significant differences in PRO questionnaire acceptability were seen between cancer types, education level, household income, employment status, or treatment modality., Conclusion: Routine assessment using PRO questionnaires is associated with moderate acceptability by patients with cancer. Specific patient characteristics are associated with higher completion willingness. Additional research is necessary to identify factors associated with low acceptability of PRO questionnaires and to develop site-, ethnicity-, and treatment-specific instruments to assess the value of PRO questionnaires for symptom monitoring in clinical practice., Implications for Practice: This study will help to identify the clinical, demographic, and survey characteristics associated with willingness to complete patient-reported outcome questionnaires regularly in the cancer outpatient setting., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© 2019 The Authors. The Oncologist published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Introduction: HER2 mutations occur in 1-3% of lung adenocarcinomas. With increasing use of next-generation sequencing at diagnosis, more patients with HER2-mutant tumours present for treatment. Few data are available to describe the clinical course and outcomes of these patients when treated with afatinib, a pan-HER inhibitor., Methods: We identified patients with metastatic or recurrent HER2-mutant lung adenocarcinomas treated with afatinib among seven institutions across Europe, Australia, and North America between 2009 and 2017. We determined the partial response rate to afatinib, types of HER2 mutations, duration of response, time on treatment, and survival., Results: We collected information on 27 patients with stage IV or recurrent HER2-mutant lung adenocarcinomas treated with afatinib. Of 23 patients evaluable for response, three partial responses were noted (13%, 95% confidence interval [CI] 4-33%). In addition, 57% of patients (13/23) had stable disease, and 30% (7/23) had progressive disease. We documented partial responses in patients with HER2 exon 20 insertions, including two with YVMA insertion and one with VAG insertion. Two patients with partial responses were previously treated with trastuzumab and pertuzumab. Median duration of response to afatinib was 6 months (range 5-10); median time on treatment was 3 months (range 1-30) and median overall survival from the date of diagnosis of metastatic or recurrent disease was 23 months (95% CI 18-53 months)., Conclusions: Afatinib is modestly active in patients with HER2-mutant lung adenocarcinomas, including responses after progression on prior HER2-targeted therapies. However, investigations into the biology of HER2-mutant lung adenocarcinomas and development of better HER2-directed therapies are warranted., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Rechargeable batteries that utilize divalent Mg ions as the charge carrier species can in principle achieve substantially greater volumetric energy densities than conventional Li-ion batteries. One significant impediment to the development of commercially viable Mg-ion batteries is the slow rate of Mg ion diffusion through otherwise promising cathode materials. Accurate prediction of the activation energies associated with this diffusion process using density functional theory (DFT) is especially challenging due to self-interaction errors intrinsic to DFT that lead to over-delocalization of the d-electrons. One effective but highly computationally demanding approach to reducing self-interaction errors is the use of hybrid functionals, which incorporate a fraction of exact Hartree-Fock exchange. In this work, we assess the effects of exact exchange on computed activation energies for ion diffusion in one potential cathode material, α-MoO3. In contrast to previous studies that primarily utilize non-hybrid functionals, we perform nudged elastic band calculations in which the nuclear coordinates are fully converged using both hybrid functionals and k-point sampling. It is found that while non-hybrid functionals indicate the existence of thermodynamically accessible channels for bulk Mg ion diffusion in all three dimensions, hybrid functionals predict that some of these channels are largely inaccessible under typical charge/discharge conditions. Furthermore, it is demonstrated that certain commonly used approximations for incorporating the effects of Hartree-Fock exchange are inadequate for this system, including DFT+U calculations and the use of single-point hybrid calculations using atomic positions obtained using non-hybrid functionals.

Tumours with sensitizing mutations in the EGFR gene constitute a distinct molecular subgroup of non-small-cell lung cancers (nsclcs) that benefit from precision medicine. First- and second-generation epidermal growth factor receptor (egfr) tyrosine kinase inhibitors (tkis) are recommended as upfront therapy for EGFR -mutated advanced nsclc and, compared with chemotherapy, have resulted in superior progression-free survival, improved tumour response rates, and improved quality of life. However, resistance inevitably develops, and the third-generation tki osimertinib has been approved to target the gatekeeper EGFR mutation T790M, which is responsible for resistance in 60% of cases. Multiple drivers of tki resistance have now been identified, and many new drugs are in development. With respect to this rapidly evolving field, our review highlights the current status of treatment options for patients with EGFR -mutated advanced nsclc, focusing especially on identified causes of resistance, challenges, and clinical trials aiming to improve outcomes in this patient population.

Background: A number of randomized controlled trials (RCTs) have reported improvement in breast cancer outcomes from extending treatment with aromatase inhibitors (AIs) beyond the initial five years after diagnosis. However, the toxicity profile of extended AIs is uncertain., Methods: We identified RCTs that compared extended AIs to placebo or no treatment using MEDLINE and a review of abstracts from key conferences between 2013 and 2016. Odds ratios (ORs), 95% confidence intervals (CIs), absolute risks, and the number needed to harm (NNH) were computed for prespecified safety and tolerability outcomes including cardiovascular events, bone fractures, second cancers (excluding new breast cancer), treatment discontinuation for adverse events, and death without recurrence. All statistical tests were two-sided., Results: Seven trials comprising 16 349 patients met the inclusion criteria. Longer treatment with AIs was associated with increased odds of cardiovascular events (OR = 1.18, 95% CI = 1.00 to 1.40, P = .05, NNH = 122), bone fractures (OR = 1.34, 95% CI = 1.16 to 1.55, P < .001, NNH = 72), and treatment discontinuation for adverse events (OR = 1.45, 95% CI = 1.25 to 1.68, P < .001, NNH = 21). Longer treatment with AIs did not influence the odds of either second malignancy (OR = 0.93, 95% CI = 0.73 to 1.18, P = .56) or deaths without breast cancer recurrence (OR = 1.11, 95% CI = 0.90 to 1.36, P = .34)., Conclusions: Extended treatment with AIs is associated with an increased risk of cardiovascular events and bone fractures. There is no statistically significant increase in deaths without breast cancer recurrence among patients receiving longer treatment with AIs. These data should be taken into account when considering extended adjuvant AIs., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

This corrects the article DOI: 10.1038/bjc.2017.220.

Interactions between immune and malignant cells have been known to have clinical relevance for decades. The potential for immune control is now being therapeutically enhanced with checkpoint inhibitors and other novel agents to improve outcomes in cancer. The importance of the immune infiltrate as a prognostic marker is increasingly relevant. In this minireview, we present an overview of the immune infiltrate and its spatial organisation, and summarise the prognostic value of immune cells in different cancer types. International collaborative efforts are standardising histopathologic reporting of the immune infiltrate, to allow application of these parameters in the clinical and research settings. In general terms, a 'pro-inflammatory' tumour microenvironment and infiltrating CD8-expressing T lymphocytes are associated with improved clinical outcomes in a broad range of tumour types. The inhibitory function of other immune cells, for example, myeloid-derived suppressor cells and regulatory T cells, appear to have a major role in disrupting the capacity for the immune control of cancers.

Sensitizing mutations in the epidermal growth factor receptor ( EGFR ) predict response to EGFR tyrosine kinase inhibitors (TKIs) and both first- and second-generation TKIs are available as first-line treatment options in patients with advanced EGFR -mutant non-small cell lung cancer. Eventual resistance develops with multiple mechanisms identifiable both upon repeat biopsy and in plasma circulating tumor DNA. The T790M gatekeeper mutation is responsible for almost 60% of cases. A number of third-generation TKIs are in clinical development, and osimertinib has been approved by the US Food and Drug Administration for the treatment of patients with EGFR T790M mutant lung cancer after failure of initial EGFR kinase therapy. Resistance mechanisms are being identified to these novel agents, and the treatment landscape of EGFR -mutant lung cancer continues to evolve. The sequence of EGFR TKIs may change in the future and combination therapies targeting resistance appear highly promising.

Background: New anti-cancer drugs utilize diverse mechanisms of action. Here we evaluate their differential efficacy, safety, tolerability and price., Methods: Drugs approved for solid tumor treatment between 2000 and 2015 were identified and analyzed in subgroups: agents targeting oncogenes (group 1), anti-angiogenics (group 2), immunotherapy (group 3), and chemotherapy (group 4). Hazard ratios (HRs) were extracted from the registration trials and pooled in a meta-analysis. Odds ratios for toxic death, treatment discontinuation and grade 3-4 toxicity were compared to control groups. The Micromedex Red Book was used to calculate the monthly price., Results: Analysis included 74 studies comprising 48,527 patients. Progression-free survival (PFS) was improved to a greater degree with groups 1 and 2 than with groups 3 and 4, (pooled HR: 0.54, 0.56, 0.63, and 0.76 for groups 1-4 respectively, p for difference <0.001). Compared to PFS, there was a lower magnitude of improvement overall survival in all groups and the degree of benefit was less for group 4 than for other groups (pooled HR: 0.77, 0.78, 0.68, and 0.83 for groups 1-4 respectively, p for difference=0.007). Compared to control groups in individual trials, immunotherapy was associated with better safety and tolerability than other groups. Drug prices have increased over time with no significant difference between groups. There was no meaningful correlation between pricing and efficacy., Conclusions: Compared to control groups, immunotherapeutics and drugs targeting oncogenes or angiogenesis improve efficacy to a greater degree than chemotherapy. Immunotherapy appears to have better safety and tolerability profile compared to other cancer therapies. Market price of drugs is not related to efficacy., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objectives: The role of anti-angiogenic tyrosine kinase inhibitors (AATKI) for patients with non-small-cell lung cancers (NSCLC) is uncertain. We conducted a comprehensive meta-analysis to assess the overall utility of adding AATKI to chemotherapy., Materials and Methods: We included 15 randomized controlled trials (RCTs) of AATKI plus chemotherapy versus chemotherapy involving 7997 patients with advanced NSCLC. Meta-analysis was performed to obtain pooled hazard ratios (HR) for OS and PFS, and pooled odds ratios (OR) for objective response rate (ORR) and grade 3 or greater toxicity. Pre-specified subgroup analyses were performed according to line of chemotherapy, chemotherapeutic regimen and histology., Results: The addition of AATKI to chemotherapy significantly increased progression-free survival (PFS) (HR 0.83, 95% CI 0.79, 0.87; P<0.00001) and ORR [OR 1.63, 95% CI 1.45, 1.84; P<0.00001], but not overall survival (OS) (HR 0.96, 95% CI 0.91, 1.01; P=0.14). OS benefit was seen in the subset of patients with adenocarcinomas (HR 0.86; 95% CI 0.79, 0.95; P=0.002), especially in the second line setting (HR 0.85; 95% CI 0.76, 0.96; P=0.008). However, both grade ≥3 toxicity (HR 2.08, 95% CI 1.59, 2.73; P<0.00001) and treatment-related deaths (OR 2.37, 95% CI 1.58, 3.56; P<0.0001) were significantly higher with the addition of AATKI., Conclusion: The addition of AATKI to chemotherapy in patients with advanced NSCLC significantly increased PFS and ORR but not OS, and did so at the expense of increased toxicity and treatment-related deaths. Preclinical and translational research in predictive biomarkers are essential for the clinical development of this class of drugs., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Localized malignant pleural mesothelioma (LMM) is a rare subset of malignant pleural mesothelioma. Its epidemiology, biology, natural history and optimal treatment are poorly understood. We report a case of LMM treated aggressively with complete surgical resection and adjuvant radiotherapy, but subsequently complicated by local chest wall recurrence and solitary metastasis to the kidney. This case is examined in the context of a small number of cases of LMM in the literature to emphasize the existence of this rare disease entity, their unusual biological behaviour and the need for further tumour molecular and genomic research.

We analyze the sources of error in quantum embedding calculations in which an active subsystem is treated using wavefunction methods, and the remainder using density functional theory. We show that the embedding potential felt by the electrons in the active subsystem makes only a small contribution to the error of the method, whereas the error in the nonadditive exchange-correlation energy dominates. We test an MP2 correction for this term and demonstrate that the corrected embedding scheme accurately reproduces wavefunction calculations for a series of chemical reactions. Our projector-based embedding method uses localized occupied orbitals to partition the system; as with other local correlation methods, abrupt changes in the character of the localized orbitals along a reaction coordinate can lead to discontinuities in the embedded energy, but we show that these discontinuities are small and can be systematically reduced by increasing the size of the active region. Convergence of reaction energies with respect to the size of the active subsystem is shown to be rapid for all cases where the density functional treatment is able to capture the polarization of the environment, even in conjugated systems, and even when the partition cuts across a double bond.

Objective: Autosomal recessive hypercholesterolemia is a rare inherited disorder, characterized by extremely high total and low-density lipoprotein cholesterol levels, that has been previously linked to mutations in LDLRAP1. We identified a family with autosomal recessive hypercholesterolemia not explained by mutations in LDLRAP1 or other genes known to cause monogenic hypercholesterolemia. The aim of this study was to identify the molecular pathogenesis of autosomal recessive hypercholesterolemia in this family., Approach and Results: We used exome sequencing to assess all protein-coding regions of the genome in 3 family members and identified a homozygous exon 8 splice junction mutation (c.894G>A, also known as E8SJM) in LIPA that segregated with the diagnosis of hypercholesterolemia. Because homozygosity for mutations in LIPA is known to cause cholesterol ester storage disease, we performed directed follow-up phenotyping by noninvasively measuring hepatic cholesterol content. We observed abnormal hepatic accumulation of cholesterol in the homozygote individuals, supporting the diagnosis of cholesterol ester storage disease. Given previous suggestions of cardiovascular disease risk in heterozygous LIPA mutation carriers, we genotyped E8SJM in >27 000 individuals and found no association with plasma lipid levels or risk of myocardial infarction, confirming a true recessive mode of inheritance., Conclusions: By integrating observations from Mendelian and population genetics along with directed clinical phenotyping, we diagnosed clinically unapparent cholesterol ester storage disease in the affected individuals from this kindred and addressed an outstanding question about risk of cardiovascular disease in LIPA E8SJM heterozygous carriers.

Density functional theory (DFT) provides a formally exact framework for performing embedded subsystem electronic structure calculations, including DFT-in-DFT and wavefunction theory-in-DFT descriptions. In the interest of efficiency, it is desirable to truncate the atomic orbital basis set in which the subsystem calculation is performed, thus avoiding high-order scaling with respect to the size of the MO virtual space. In this study, we extend a recently introduced projection-based embedding method [F. R. Manby, M. Stella, J. D. Goodpaster, and T. F. Miller III, J. Chem. Theory Comput. 8, 2564 (2012)] to allow for the systematic and accurate truncation of the embedded subsystem basis set. The approach is applied to both covalently and non-covalently bound test cases, including water clusters and polypeptide chains, and it is demonstrated that errors associated with basis set truncation are controllable to well within chemical accuracy. Furthermore, we show that this approach allows for switching between accurate projection-based embedding and DFT embedding with approximate kinetic energy (KE) functionals; in this sense, the approach provides a means of systematically improving upon the use of approximate KE functionals in DFT embedding.

Density functional theory (DFT) embedding provides a formally exact framework for interfacing correlated wave-function theory (WFT) methods with lower-level descriptions of electronic structure. Here, we report techniques to improve the accuracy and stability of WFT-in-DFT embedding calculations. In particular, we develop spin-dependent embedding potentials in both restricted and unrestricted orbital formulations to enable WFT-in-DFT embedding for open-shell systems, and develop an orbital-occupation-freezing technique to improve the convergence of optimized effective potential calculations that arise in the evaluation of the embedding potential. The new techniques are demonstrated in applications to the van-der-Waals-bound ethylene-propylene dimer and to the hexa-aquairon(II) transition-metal cation. Calculation of the dissociation curve for the ethylene-propylene dimer reveals that WFT-in-DFT embedding reproduces full CCSD(T) energies to within 0.1 kcal/mol at all distances, eliminating errors in the dispersion interactions due to conventional exchange-correlation (XC) functionals while simultaneously avoiding errors due to subsystem partitioning across covalent bonds. Application of WFT-in-DFT embedding to the calculation of the low-spin/high-spin splitting energy in the hexaaquairon(II) cation reveals that the majority of the dependence on the DFT XC functional can be eliminated by treating only the single transition-metal atom at the WFT level; furthermore, these calculations demonstrate the substantial effects of open-shell contributions to the embedding potential, and they suggest that restricted open-shell WFT-in-DFT embedding provides better accuracy than unrestricted open-shell WFT-in-DFT embedding due to the removal of spin contamination.

Objective: Information and opinions were sought on the need for graduating and practicing respiratory therapists to obtain 66 competencies necessary for practice in 2015 and beyond, the required length of respiratory care programs, the educational needs of practicing therapists, current and future workforce positions, and the appropriate credential needed by graduating therapists., Methods: Survey responses from respiratory therapy department directors or managers are the basis of this report. After pilot testing and refining the questions, a self-administered, Internet based, American Association for Respiratory Care (AARC) endorsed survey was used to gather information from 2,368 individuals designated as respiratory therapy department directors or managers in the AARC membership list as of May 2010., Results: A total of 663 valid survey responses (28.0%) were received. On average, the vacancy rate of surveyed hospitals was only 0.81 full-time equivalents (FTEs). Responses by directors on 66 competencies described in the second 2015 conference as needed by graduate and practicing respiratory therapists indicated 90% agreement on 37, between 50% and 90% agreement on 25, and < 50% agreement on 4 competencies. There was no consensus among directors on the academic preparation of new graduates, with 245 (36.8%) indicating a preference for a baccalaureate or master's degree, 243 (36.7%) indicating a preference for an associate degree, and 176 (26.5%) indicating no preference. There were 270 (41.8%) respondents who indicated that a baccalaureate or master's degree in respiratory therapy should be required to qualify for a license to deliver respiratory care. The survey indicated that 523 (81.2%) of directors are in favor of the RRT credential being required to practice in 2015 and beyond., Conclusions: There was good agreement that graduate and practicing therapists should obtain the vast majority of the 66 competencies surveyed and that the entry level credential should be the RRT. Similar numbers of managers favored an entry level baccalaureate degree as favored an associate degree.

Background: A sexual dimorphism exists in the incidence and prevalence of coronary artery disease--men are more commonly affected than are age-matched women. We explored the role of the Y chromosome in coronary artery disease in the context of this sexual inequity., Methods: We genotyped 11 markers of the male-specific region of the Y chromosome in 3233 biologically unrelated British men from three cohorts: the British Heart Foundation Family Heart Study (BHF-FHS), West of Scotland Coronary Prevention Study (WOSCOPS), and Cardiogenics Study. On the basis of this information, each Y chromosome was tracked back into one of 13 ancient lineages defined as haplogroups. We then examined associations between common Y chromosome haplogroups and the risk of coronary artery disease in cross-sectional BHF-FHS and prospective WOSCOPS. Finally, we undertook functional analysis of Y chromosome effects on monocyte and macrophage transcriptome in British men from the Cardiogenics Study., Findings: Of nine haplogroups identified, two (R1b1b2 and I) accounted for roughly 90% of the Y chromosome variants among British men. Carriers of haplogroup I had about a 50% higher age-adjusted risk of coronary artery disease than did men with other Y chromosome lineages in BHF-FHS (odds ratio 1·75, 95% CI 1·20-2·54, p=0·004), WOSCOPS (1·45, 1·08-1·95, p=0·012), and joint analysis of both populations (1·56, 1·24-1·97, p=0·0002). The association between haplogroup I and increased risk of coronary artery disease was independent of traditional cardiovascular and socioeconomic risk factors. Analysis of macrophage transcriptome in the Cardiogenics Study revealed that 19 molecular pathways showing strong differential expression between men with haplogroup I and other lineages of the Y chromosome were interconnected by common genes related to inflammation and immunity, and that some of them have a strong relevance to atherosclerosis., Interpretation: The human Y chromosome is associated with risk of coronary artery disease in men of European ancestry, possibly through interactions of immunity and inflammation., Funding: British Heart Foundation; UK National Institute for Health Research; LEW Carty Charitable Fund; National Health and Medical Research Council of Australia; European Union 6th Framework Programme; Wellcome Trust., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Variants in the gene encoding the γ-subunit of the epithelial sodium channel (SCNN1G) are associated with both Mendelian and quantitative effects on blood pressure. Here, in 4 cohorts of 1611 white European families composed of a total of 8199 individuals, we undertook staged testing of candidate single-nucleotide polymorphisms for SCNN1G (supplemented with imputation based on data from the 1000 Genomes Project) followed by a meta-analysis in all of the families of the strongest candidate. We also examined relationships between the genotypes and relevant intermediate renal phenotypes, as well as expression of SCNN1G in human kidneys. We found that an intronic single-nucleotide polymorphism of SCNN1G (rs13331086) was significantly associated with age-, sex-, and body mass index-adjusted blood pressure in each of the 4 populations (P<0.05). In an inverse variance-weighted meta-analysis of this single-nucleotide polymorphism in all 4 of the populations, each additional minor allele copy was associated with a 1-mm Hg increase in systolic blood pressure and 0.52-mm Hg increase in diastolic blood pressure (SE=0.33, P=0.002 for systolic blood pressure; SE=0.21, P=0.011 for diastolic blood pressure). The same allele was also associated with higher 12-hour overnight urinary potassium excretion (P=0.04), consistent with increased epithelial sodium channel activity. Renal samples from hypertensive subjects showed a nonsignificant (P=0.07) 1.7-fold higher expression of SCNN1G compared with normotensive controls. These data provide genetic and phenotypic evidence in support of a role for a common genetic variant of SCNN1G in blood pressure determination.

Objective: As background for the American Association for Respiratory Care (AARC) third 2015 and Beyond conference, we sought information and opinions on the ability of the current respiratory therapy education infrastructure to make changes that would assure competent respiratory therapists in the envisioned healthcare future., Methods: After pilot testing and refining the questions, we invited the directors of 435 respiratory therapy programs (based in 411 colleges) that were fully accredited or in the process of being accredited by the Commission on Accreditation for Respiratory Care as of May, 2010, to participate in the survey., Results: Three-hundred forty-eight program directors (80%) provided valid survey responses. Three of the 5 competencies related to evidence-based medicine and respiratory care protocols were taught less often in the associate-degree programs than in the baccalaureate-degree programs. Eighty percent of the baccalaureate-degree programs, compared to 42% of the associate-degree programs, instruct students how to critique published research (P < .001). Only 34% of the associate-degree programs teach students the general meaning of statistical tests, compared to 78% of the baccalaureate-degree programs (P < .001). Ninety-four percent of the baccalaureate-degree programs, versus 81% of the associate-degree programs, teach the students to apply evidence-based medicine to clinical practice (P = .01). Teaching students how to describe healthcare and financial reimbursement systems and the need to reduce the cost of delivering respiratory care (a leadership competency identified by the second 2015 and Beyond conference) was significantly more common in the baccalaureate-degree programs (72%) than in the associate-degree programs (56%) (P = .03). Other competencies showed trends toward differences, and the baccalaureate-degree programs reported higher percentages of success than the associate-degree programs., Conclusions: There are important differences between the baccalaureate-degree and associate-degree programs.

The American Association for Respiratory Care established a task force in late 2007 to identify likely new roles and responsibilities of respiratory therapists (RTs) in the year 2015 and beyond. A series of 3 conferences was held between 2008 and 2010. The first task force conference affirmed that the healthcare system is in the process of dramatic change, driven by the need to improve health while decreasing costs and improving quality. This will be facilitated by application of evidence-based care, prevention and management of disease, and closely integrated interdisciplinary care teams. The second task force conference identified specific competencies needed to assure safe and effective execution of RT roles and responsibilities in the future. The third task force conference was charged with creating plans to change the professional education process so that RTs are able to achieve the needed skills, attitudes, and competencies identified in the previous conferences. Transition plans were developed by participants after review and discussion of the outcomes of the first two conferences and 1,011 survey responses from RT department managers and RT education program directors. This is a report of the recommendations of the third task force conference held July 12-14, 2010, on Marco Island, Florida. The participants, who represented groups concerned with RT education, licensure, and practice, proposed, discussed, and accepted that to be successful in the future a baccalaureate degree must be the minimum entry level for respiratory care practice. Also accepted was the recommendation that the Certified Respiratory Therapist examination be retired, and instead, passing of the Registered Respiratory Therapist examination will be required for beginning clinical practice. A date of 2020 for achieving these changes was proposed, debated, and accepted. Recommendations were approved requesting resources be provided to help RT education programs, existing RT workforce, and state societies work through the issues raised by these changes.

Embedded density functional theory (e-DFT) is used to describe the electronic structure of strongly interacting molecular subsystems. We present a general implementation of the Exact Embedding (EE) method [J. Chem. Phys. 133, 084103 (2010)] to calculate the large contributions of the nonadditive kinetic potential (NAKP) in such applications. Potential energy curves are computed for the dissociation of Li(+)-Be, CH(3)-CF(3), and hydrogen-bonded water clusters, and e-DFT results obtained using the EE method are compared with those obtained using approximate kinetic energy functionals. In all cases, the EE method preserves excellent agreement with reference Kohn-Sham calculations, whereas the approximate functionals lead to qualitative failures in the calculated energies and equilibrium structures. We also demonstrate an accurate pairwise approximation to the NAKP that allows for efficient parallelization of the EE method in large systems; benchmark calculations on molecular crystals reveal ideal, size-independent scaling of wall-clock time with increasing system size.

We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 × 10⁻⁸ and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.

Objective: To describe a practical method for family practitioners to stage chronic obstructive pulmonary disease (COPD) by the use of office spirometry., Methods: This is a review of the lessons learned from evaluations of the use of office spirometry in the primary care setting to identify best practices using the most recent published evaluations of office spirometry and the analysis of preliminary data from a recent spirometry mass screening project. A mass screening study by the American Association for Respiratory Care and the COPD Foundation was used to identify the most effective way for general practitioners to implement office spirometry in order to stage COPD., Results: A simple three-step method is described to identify people with a high pre-test probability in an attempt to detect moderate to severe COPD: COPD questionnaire, measurement of peak expiratory flow, and office spirometry. Clinical practice guidelines exist for office spirometry basics for safety, use of electronic peak flow devices, and portable spirometers., Conclusion: Spirometry can be undertaken in primary care offices with acceptable levels of technical expertise. Using office spirometry, primary care physicians can diagnose the presence and severity of COPD. Spirometry can guide therapies for COPD and predict outcomes when used in general practice.